lignans and magnolol

Magnolol and honokiol are natural lignans with good physiological effects. As the main active substances derived from Magnolia officinalis, their pharmacological activities have attracted extensive attention. It is reported that both of them can cross the blood-brain barrier (BBB) and exert neuroprotective effects through a variety of mechanisms. This suggests that these two ingredients can be used as effective therapeutic compounds to treat a wide range of neurological diseases. This article provides a review of the mechanisms involved in the therapeutic effects of magnolol and honokiol in combating diseases, such as cerebral ischemia, neuroinflammation, Alzheimer's disease, and brain tumors, as well as psychiatric disorders, such as anxiety and depression. Although magnolol and honokiol have the pharmacological effects described above, their clinical potential remains untapped. More research is needed to improve the bioavailability of magnolol and honokiol and perform experiments to examine the therapeutic potential of magnolol and honokiol.

Topics: Biphenyl Compounds; Humans; Lignans; Signal Transduction

Magnolol and Honokiol are the primary active components that have been identified and extracted from Magnolia officinalis, and several investigations have demonstrated that they have significant pharmacological effects. Despite their therapeutic benefits for a wide range of illnesses, research on and the implementation of these compounds have been hindered by their poor water solubility and low bioavailability. Researchers are continually using chemical methods to alter their structures to make them more effective in treating and preventing diseases. Researchers are also continuously developing derivative drugs with high efficacy and few adverse effects. This article summarizes and analyzes derivatives with significant biological activities reported in recent research obtained by structural modification. The modification sites have mainly focused on the phenolic hydroxy groups, benzene rings, and diene bonds. Changes to the allyl bisphenol structure will result in unexpected benefits, including high activity, low toxicity, and good bioavailability. Furthermore, alongside earlier experimental research in our laboratory, the structure-activity relationships of magnolol and honokiol were preliminarily summarized, providing experimental evidence for improving their development and utilization.

Topics: Biphenyl Compounds; Lignans; Magnolia; Structure-Activity Relationship

Black and Hispanic cancer patients have a higher incidence of cancer mortality. Many factors (e.g., socioeconomic differences, insufficient access to healthcare) contribute to racial disparity. Emerging research implicates biological disparity in cancer outcomes. Studies show distinct differences in the tumor immune microenvironment (TIME) in Black cancer patients. Studies also have linked altered mitochondrial metabolism to changes in immune cell activation in TIME. Recent publications revealed a novel immunomodulatory role for triphenylphosphonium-based mitochondrial-targeted drugs (MTDs). These are synthetically modified, naturally occurring molecules (e.g., honokiol, magnolol, metformin) or FDA-approved small molecule drugs (e.g., atovaquone, hydroxyurea). Modifications involve conjugating the parent molecule via an alkyl linker chain to a triphenylphosphonium moiety. These modified molecules (e.g., Mito-honokiol, Mito-magnolol, Mito-metformin, Mito-atovaquone, Mito-hydroxyurea) accumulate in tumor cell mitochondria more effectively than in normal cells and inhibit mitochondrial respiration, induce reactive oxygen species, activate AMPK and redox transcription factors, and inhibit cancer cell proliferation. Besides these intrinsic effects of MTDs in redox signaling and proliferation in tumors, MTDs induced extrinsic effects in the TIME of mouse xenografts. MTD treatment inhibited tumor-suppressive immune cells, myeloid-derived suppressor cells, and regulatory T cells, and activated T cells and antitumor immune effects. One key biological disparity in Black cancer patients was related to altered mitochondrial oxidative metabolism; MTDs targeting vulnerabilities in tumor cells and the TIME may help us understand this biological disparity. Clinical trials should include an appropriate number of Black and Hispanic cancer patients and should validate the intratumoral, antihypoxic effects of MTDs with imaging.

Topics: Atovaquone; Biphenyl Compounds; Black People; Health Status Disparities; Hispanic or Latino; Humans; Immune Checkpoint Inhibitors; Lignans; Mitochondria; Neoplasms; Oxidative Phosphorylation; Tumor Microenvironment

Topics: Antineoplastic Agents; Apoptosis; Biological Products; Biphenyl Compounds; Lignans; NF-kappa B; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; TOR Serine-Threonine Kinases

Plant lignans constitute an important group of polyphenols, which have been demonstrated to significantly induce cancer cell death and suppress cancer cell proliferation with minimal toxicity against non-transformed cells. Numerous epidemiological studies have shown that the intake of lignans is associated with lower risk of several cancers. These natural compounds have the potential to inhibit carcinogenesis, tumor growth, and metastasis by targeting various signaling molecules and pathways. Growing evidence indicates that honokiol and magnolol as natural lignans possess potent anticancer activities against various types of human cancer. The aim of present review is to provide the reader with the newest findings in understanding the cellular and molecular mechanisms mediating anticancer effects of honokiol and magnolol. This review comprehensively elucidates the effects of honokiol and magnolol on the molecular targets and signal transduction pathways implicated in cancer cell proliferation and metastasis. The findings of current review indicate that honokiol and magnolol can be considered as promising carcinopreventive and anticancer agents.

Topics: Antineoplastic Agents; Biphenyl Compounds; Humans; Lignans

Diabetes mellitus is a chronic metabolic disease characterized by disturbances in carbohydrate, protein, and lipid metabolism, often accompanied by oxidative stress. Diabetes treatment is a complicated process in which, in addition to the standard pharmacological action, it is necessary to append a comprehensive approach. Introducing the aspect of non-pharmacological treatment of diabetes allows one to alleviate its many adverse complications. Therefore, it seems important to look for substances that, when included in the daily diet, can improve diabetic parameters. Magnolol, a polyphenolic compound found in magnolia bark, is known for its health-promoting activities and multidirectional beneficial effects on the body. Accordingly, the goal of this review is to systematize the available scientific literature on its beneficial effects on type 2 diabetes and its complications. Taking the above into consideration, the article collects data on the favorable effects of magnolol on parameters related to glycemia, lipid metabolism, or oxidative stress in the course of diabetes. After careful analysis of many scientific articles, it can be concluded that this lignan is a promising agent supporting the conventional therapies with antidiabetic drugs in order to manage diabetes and diabetes-related diseases.

Topics: Animals; Biphenyl Compounds; Blood Glucose; Diabetes Complications; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Eye Diseases; Homeostasis; Humans; Hypoglycemic Agents; Inflammation; Lignans; Lipid Metabolism; Magnolia; Mice; Oxidative Stress; Plant Bark; Polyphenols; Treatment Outcome

Periodontal disease and diabetes mellitus are two pathologies that are extremely widespread worldwide and share the feature of chronic inflammation. Carvacrol is a phenolic monoterpenoid, produced by a variety of herbs, the most well-known of which is

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Biphenyl Compounds; Cymenes; Diabetes Mellitus; Humans; Lignans; Magnolia; Origanum; Periodontitis

Honokiol and its isomer magnolol are poly-phenolic compounds isolated from the Magnolia officinalis that exert cardiovascular modulating effects via a variety of mechanisms. They are used as blood-quickening and stasis-dispelling agents in Traditional Chinese Medicine and confirmed to have therapeutic potential in atherosclerosis, thrombosis, hypertension, and cardiac hypertrophy. This comprehensive review summarizes the current data regarding the cardioprotective mechanisms of those compounds and identifies areas for further research.

Topics: Biphenyl Compounds; Humans; Lignans; Magnolia; Medicine, Chinese Traditional

Topics: Anti-Inflammatory Agents; Antineoplastic Agents; Antioxidants; Biphenyl Compounds; Cardiovascular Agents; Drugs, Chinese Herbal; Humans; Lignans; Magnolia; MAP Kinase Signaling System; Medicine, Chinese Traditional; Neuroprotective Agents; NF-E2-Related Factor 2; NF-kappa B; Phosphatidylinositol 3-Kinases; Signal Transduction

Topics: Animals; Biphenyl Compounds; Drug Interactions; Humans; Lignans; Magnolia; Mutagenicity Tests; Plant Extracts; Tissue Distribution

The past few decades have witnessed widespread research to challenge carcinogenesis; however, it remains one of the most important health concerns with the worst prognosis and diagnosis. Increasing lines of evidence clearly show that the rate of cancer incidence will increase in future and will create global havoc, designating it as an epidemic. Conventional chemotherapeutics and treatment with synthetic disciplines are often associated with adverse side effects and development of chemoresistance. Thus, discovering novel economic and patient friendly drugs that are safe and efficacious is warranted. Several natural compounds have proved their potential against this dreadful disease so far. Magnolol is a hydroxylated biphenyl isolated from the root and stem bark of Magnolia tree. Magnolol can efficiently prevent or inhibit the growth of various cancers originating from different organs such as brain, breast, cervical, colon, liver, lung, prostate, skin, etc. Considering these perspectives, the current review primarily focuses on the fascinating role of magnolol against various types of cancers, and the source and chemistry of magnolol and the molecular mechanism underlying the targets of magnolol are discussed. This review proposes magnolol as a suitable candidate that can be appropriately designed and established into a potent anti-cancer drug.

Topics: Animals; Antineoplastic Agents, Phytogenic; Biphenyl Compounds; Humans; Lignans; Magnolia; Neoplasms

Magnolia bark contains magnolol, metabolized to tetrahydromagnolol and honokiol, with both GABA-ergic/cannabimimetic activities, hence of possible attraction to vulnerable individuals/recreational misusers.. A literature review, assessment of related anecdotal online Magnolia misuse's reports and an overview of Magnolia products' online acquisition possibilities has been here described.. No peer-reviewed papers about Magnolia abuse/misuse/dependence/addiction were identified. Conversely, from a range of websites emerged potentially 3 groups of Magnolia misusers: (a) subjects with a psychiatric history already treated with benzodiazepines, being attracted to Magnolia bark as a "natural sedative"; (b) polydrug misusers, ingesting Magnolia with a range of other herbs/plants, attracted by the GABA-ergic/cannabimimetic activities; (c) subjects naive to the misusing drugs' scenario, perceiving Magnolia as a natural dietary supplement/weight-control compound.. To the best of our knowledge, this is the first paper commenting on the possible Magnolia derivatives' potential of misuse. Magnolia's recent increase in popularity, mainly as a sedative, may be arguably due to its peculiar pharmacological properties/acceptable affordability levels/virtually worldwide favorable legal status and customers' attraction to a product being perceived as "natural" and hence somehow "safe." Future/potent/synthetic magnolol and honokiol structural analogues could however contribute to increasing the number of synthetic GABA-ergic/cannabimimetic misusing compounds.

Topics: Biphenyl Compounds; Humans; Lignans; Magnolia; Plant Bark; Plant Extracts; Substance-Related Disorders

This study evaluated the antioxidative effects of magnolol based on the mouse model induced by Enterotoxigenic Escherichia coli (E. coli, ETEC). All experimental mice were equally treated with ETEC suspensions (3.45×109 CFU/ml) after oral administration of magnolol for 7 days at the dose of 0, 100, 300 and 500 mg/kg Body Weight (BW), respectively. The oxidative metabolites and antioxidases for each sample (organism of mouse) were determined: Malondialdehyde (MDA), Nitric Oxide (NO), Glutathione (GSH), Myeloperoxidase (MPO), Catalase (CAT), Superoxide Dismutase (SOD), and Glutathione Peroxidase (GPx). In addition, we also determined the corresponding mRNA expressions of CAT, SOD and GPx as well as the Total Antioxidant Capacity (T-AOC). The experiment was completed with a theoretical study that predicts a series of 79 ChEMBL activities of magnolol with 47 proteins in 18 organisms using a Quantitative Structure- Activity Relationship (QSAR) classifier based on the Moving Averages (MAs) of Rcpi descriptors in three types of experimental conditions (biological activity with specific units, protein target and organisms). Six Machine Learning methods from Weka software were tested and the best QSAR classification model was provided by Random Forest with True Positive Rate (TPR) of 0.701 and Area under Receiver Operating Characteristic (AUROC) of 0.790 (test subset, 10-fold crossvalidation). The model is predicting if the new ChEMBL activities are greater or lower than the average values for the magnolol targets in different organisms.

Topics: Animals; Biphenyl Compounds; Enteritis; Enterotoxigenic Escherichia coli; Escherichia coli Infections; Lignans; Machine Learning; Mice; Oxidative Stress

Honokiol and magnolol (an isomer of honokiol) are small-molecule polyphenols isolated from the barks of Magnolia officinalis, which have been widely used in traditional Chinese and Japanese medicines. In the last decade, a variety of biological properties of honokiol and magnolol (e.g., anti-oxidativity, antitumor activity, anti-depressant activity, anti-inflammatory activity, neuroprotective activity, anti-diabetic activity, antiviral activity, and antimicrobial activity) have been reported. Meanwhile, certain mechanisms of action of some biological activities were also investigated. Moreover, many analogs of honokiol and magnolol were prepared by structural modification or total synthesis, and some exhibited very potent pharmacological activities with improved water solubility. Therefore, the present review will provide a systematic coverage on recent developments of honokiol and magnolol derivatives in regard to semisynthesis, total synthesis, and structure-activity relationships from 2000 up to now.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Biphenyl Compounds; Cell Line; Humans; Isomerism; Lignans; Magnolia; Plant Bark; Structure-Activity Relationship

Developed regions, including Japan, have become "aged societies," and the number of adults with senile dementias, such as Alzheimer's disease (AD), Parkinson's disease, and Huntington's disease, has also increased in such regions. Neurotrophins (NTs) may play a role in the treatment of AD because endogenous neurotrophic factors (NFs) prevent neuronal death. However, peptidyl compounds have been unable to cross the blood-brain barrier in clinical studies. Thus, small molecules, which can mimic the functions of NFs, might be promising alternatives for the treatment of neurodegenerative diseases. Natural products, such as or nutraceuticals or those used in traditional medicine, can potentially be used to develop new therapeutic agents against neurodegenerative diseases. In this review, we introduced the neurotrophic activities of polyphenols honokiol and magnolol, which are the main constituents of Magnolia obovata Thunb, and methanol extracts from Zingiber purpureum (BANGLE), which may have potential therapeutic applications in various neurodegenerative disorders.

Topics: Alzheimer Disease; Animals; Biphenyl Compounds; Cells, Cultured; Dietary Supplements; Hippocampus; Humans; Lignans; Magnolia; Mice; Molecular Weight; Nerve Growth Factors; Neurodegenerative Diseases; Neurogenesis; Phytotherapy; Polyphenols; Rats; Structure-Activity Relationship; Zingiberales

Magnolol is one of main active constituents from Magnolia officinalis, a widely used traditional Chinese medicine. Previous studies have proved its multiple pharmacological effects, such as anti-oxidation, anti-microbial and anti-tumor. In recent years, more and more studies have focused on magnolol both at home and abroad. This essay summarizes the advance in the latest studies on the pharmacological effects of magnolol, and briefs main problems in current studies and future development orientation.

Topics: Animals; Biphenyl Compounds; Drugs, Chinese Herbal; Humans; Lignans; Magnolia

Chinese herbs have been and still are widely used as important remedies in Oriental medicine. Over the recent years, a variety of biologically active constituents have been isolated from these sources and confirmed to have multifunctional activity in experimental studies. Honokiol is a small-molecule polyphenol isolated from the genus Magnolia. It is accompanied by other related polyphenols, including magnolol, with which it shares certain biological properties. Recently, honokiol and magnolol have been found to have anti-oxidative, anti-inflammatory, anti-tumor, and anti-microbial properties in preclinical models, without appreciable toxicity. These findings have increased interest in bringing honokiol and magnolol to the clinic as novel therapeutic agents in dermatology. In this review, the findings concerning the major mechanisms of action of honokiol and magnolol are described. Knowledge of the multiple activities of honokiol and magnolol can assist with the development of honokiol and magnolol derivatives and the design of clinical trials that will maximize the potential benefit of honokiol and magnolol in the patient setting for dermatologic disorders.

Topics: Antioxidants; Biphenyl Compounds; Dermatologic Agents; Drugs, Chinese Herbal; Humans; Lignans; Skin Diseases

Some of the active phytochemicals in herbal medicine are finding therapeutic use. For example, patients with heart disease are reported to benefit from treatment with herbal medicine with fewer side effects. Previous studies showed the inhibitory effects of tetramethylpyrazine, an active component of medicinal herb, on phosphodiesterase that is associated with heart disease and the cardio-protective effects of other herbal medicine that was used to protect ischemia-reperfusion injury of rat hearts. Individual herbal medicines show antipyretic, analgesic and anti-inflammatory and anti-cancer effects. In addition to sharing many therapeutic activities, the active components of herbal medicine are also used in nutrient supplement for cardiovascular disease. Numerous in vitro studies of herbal medicine on different cell lines and in vivo study of herbal medicine have been reported. However, the mechanism of actions remains unclear. The present review aims to give an overview of the recent development of herbal medicine in treatment of cardiovascular disease, and covers the possible mechanism of action of some of active principles. The study will provide insights into drug action and demonstrate the therapeutic benefits of herbal medicine for the treatment of cardiovascular disease.

Topics: Alkaloids; Astragalus propinquus; Biphenyl Compounds; Cardiovascular Agents; Drugs, Chinese Herbal; Flavonoids; Glycyrrhizic Acid; Herbal Medicine; Humans; Lignans; Phenanthrenes; Pyrazines

This review deals with the advances in the study of chemical constituents and analytical methods of the medicinal plant Houpo.

Topics: Alkaloids; Biphenyl Compounds; Chromatography; Drugs, Chinese Herbal; Lignans; Oils, Volatile

Magnolol is a multifunctional plant polyphenol. To evaluate the effects of magnolol on laying hens in the late laying period, 360 (50-week-old) laying hens were randomly assigned to 4 dietary treatments: a non-supplemented control diet (C), and control diets supplemented with 100, 200, and 300 mg/kg of magnolol (M100, M200, and M300), respectively. Each treatment had 6 replicates with 15 hens per replicate. Results showed that dietary supplementation of 200 and 300 mg/kg of magnolol increased the laying rate and the M200 group had a lower feed conversion ratio (P < 0.05). Magnolol supplementation (200 and 300 mg/kg) could linearly increase albumen height and Haugh unit of fresh eggs in the late phase of the laying cycle (P < 0.01). And magnolol linearly alleviated the decline of the albumen height and Haugh unit of eggs stored for 14 d (P < 0.01). The total superoxide dismutase activity in the ovaries of M100 group was greater than that in the other treatments (P < 0.05). As dietary magnolol levels increased, villus height of jejunum and ileum linearly increased (P < 0.01). M200 and M300 groups had higher expression level of occludin in the ileum compared with group C (P < 0.01). The level of nitric oxide production and inducible nitric oxide synthase expression in the ileum of M200 group were lower than that in the C group (P < 0.05). In conclusion, dietary supplementation of 200 and 300 mg/kg magnolol can improve hen performance, albumen quality of fresh and storage eggs, and hepatic lipid metabolism in the late laying cycle. Also, magnolol has a good effect on increasing villi and improving the intestinal mucosal mechanical barrier function.

Topics: Animal Feed; Animals; Antioxidants; Biphenyl Compounds; Chickens; Diet; Dietary Supplements; Eggs; Female; Intestines; Lignans; Lipid Metabolism; Liver; Oviposition; Ovum

Antibiotic is one of the most important discoveries in human and animal medicine. However, the inefficient use of antibiotics has caused widespread and persistent contamination of ecosystems, setting off microbial resistance storms. Magnolol is a botanical antibiotic, but poor physicochemical properties result in low bioavailability. Increasing solubility of magnolol can help to reduce the doses of medications to patients, minimize bothersome side effects. In this work, three novel multicomponent crystalline solids were synthesized from magnolol and isomeric coformers by mechanochemistry. It was found that the multicomponent crystalline solids achieved the customizable release profile of magnolol by manipulating the substituent positions of the isomers and complexation. Antibacterial activity test showed that bioactivity on two bacteria was considerably improved by designed MGN multicomponent crystals. In addition, the coformers controlled the dissolution behavior and further stabilized the improvement according to the variable statistical analysis. In conclusion, the properties of antibiotic multicomponent solids can be manipulated through the coformers. This provides an effective strategy for managing the release of drugs to meet individual biological differences and diverse therapeutic needs.

Topics: Animals; Biphenyl Compounds; Ecosystem; Humans; Lignans; Solubility

Glioma is difficult-to-treat because of its infiltrative nature and the presence of the blood-brain barrier. Temozolomide is the only FDA-approved drug for its management. Therefore, finding a novel chemotherapeutic agent for glioma is of utmost importance. Magnolol, a neolignan, has been known for its apoptotic role in glioma. In this work, we have explored a novel anti-glioma mechanism of Magnolol associated with its role in autophagy modulation. We found increased expression levels of Beclin-1, Atg5-Atg12, and LC3-II and lower p62 expression in Magnolol-treated glioma cells. PI3K/AKT/mTOR pathway proteins were also downregulated in Magnolol-treated glioma cells. Next, we treated the glioma cells with Insulin, a stimulator of PI3K/AKT/mTOR signaling, to confirm that Magnolol induced autophagy by inhibiting this pathway. Insulin reversed the effect on Magnolol-mediated autophagy induction. We also established the same in in vivo glioma model where Magnolol showed an anti-glioma effect by inducing autophagy. To confirm the cytotoxic effect of Magnolol-induced autophagy, we used Chloroquine, a late-stage autophagy inhibitor. Chloroquine efficiently reversed the anti-glioma effects of Magnolol both in vitro and in vivo. Our study revealed the cytotoxic effect of Magnolol-induced autophagy in glioma, which was not previously reported. Additionally, Magnolol showed no toxicity in non-cancerous cell lines as well as rat organs. Thus, we concluded that Magnolol is an excellent candidate for developing new therapeutic strategies for glioma management.

Topics: Animals; Antineoplastic Agents; Apoptosis; Autophagy; Cell Line, Tumor; Chloroquine; Glioma; Insulins; Lignans; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats; TOR Serine-Threonine Kinases

The understanding of the use of Magnolia officinalis L. (Magnoliaceae) as a possible dietary supplement for supporting the treatment of airway pathologies might be of clinical interest. Two commercially available bark extracts (M. officinalis extract [MOE]) were characterized by quantitation in honokiol and magnolol content by means of high-performance liquid chromatography with UV detection. MOE effects, as well as those of the reference compounds per se, on some targets connected to airway pathologies (antibacterial- and lung and trachea relaxing- activities) were investigated. Results showed that MOE possessed interesting antibacterial activity against Staphylococcus aureus, Pseudomonas aeruginosa, and Streptococcus pneumoniae. This was accompanied by a spasmolytic and antispasmodic activity, possibly owing to its ability to concurrently modulate different targets such as H

Topics: Biphenyl Compounds; Humans; Lignans; Magnolia; Medicine, Chinese Traditional; Plant Bark; Plant Extracts; Respiratory Tract Diseases

Obesity is a complex disease defined as an excessive amount of body fat. It is considered a risk factor for several pathologies; therefore, there is an increasing interest in its treatment. Pancreatic lipase (PL) plays a key role in fat digestion, and its inhibition is a preliminary step in the search for anti-obesity agents. For this reason, many natural compounds and their derivatives are studied as new PL inhibitors. This study reports the synthesis of a library of new compounds inspired by two natural neolignans, honokiol (1) and magnolol (2) and bearing amino or nitro groups linked to a biphenyl core. The synthesis of unsymmetrically substituted biphenyls was achieved through an optimisation of the Suzuki-Miyaura cross-coupling reaction followed by the insertion of allyl chains, thus furnishing the O- and/or N-allyl derivatives, and finally, a sigmatropic rearrangement yielding in some cases, the C-allyl analogues. Magnolol, honokiol and the twenty-one synthesised biphenyls were evaluated for their in vitro inhibitory activity toward PL. Three compounds (15b, 16 and 17b) were more effective inhibitors than the natural neolignans (magnolol IC

Topics: Biphenyl Compounds; Lignans

The development of environmentally friendly, green, and nontoxic adhesives with excellent dry and wet adhesion properties is of great attraction. In nature, barnacles and mussels exhibit strong adhesion by secreting a hydroxyl-rich dopa. Inspired by their adhesion mechanism, a simple biobased MAG-PETMP (MP) adhesive was prepared from magnolol (MAG) and pentaerythritol tetra (3-mercaptopropionate) (PETMP) by a thiol-ene click chemistry reaction. MP as an adhesive exhibits high bond strength with other substrates due to hydrogen bonds formed by the abundant hydroxyl groups at the interface and shows an inherent thermosetting network structure. Since MP has a thermosetting network, it exhibits excellent thermal stability, solvent resistance, and high mechanical strength, which make the adhesive stable in a humid environment. The cross-linking degree of MP can be easily controlled by adjusting the molar ratio of MAG and PETMP. Among the synthesized samples, the elongation at break of the MP 1 formulation is 174.27%, which makes it promising for use as a flexible adhesive. Moreover, the inherent antibacterial properties of MAG enable MP to exhibit antimicrobial properties and antibacterial adhesion to some extent. This work provides a simple biomimetic strategy that could enable the application of MAG for adhesives.

Topics: Adhesives; Anti-Bacterial Agents; Biphenyl Compounds; Lignans

The weight coefficients of appearance traits, extract yield of standard decoction, and total content of honokiol and magnolol were determined by analytic hierarchy process(AHP), criteria importance though intercrieria correlation(CRITIC), and AHP-CRITIC weighting method, and the comprehensive scores were calculated. The effects of ginger juice dosage, moistening time, proces-sing temperature, and processing time on the quality of Magnoliae Officinalis Cortex(MOC) were investigated, and Box-Behnken design was employed to optimize the process parameters. To reveal the processing mechanism, MOC, ginger juice-processed Magnoliae Officinalis Cortex(GMOC), and water-processed Magnoliae Officinalis Cortex(WMOC) were compared. The results showed that the weight coefficients of the appearance traits, extract yield of standard decoction, and total content of honokiol and magnolol determined by AHP-CRITIC weighting method were 0.134, 0.287, and 0.579, respectively. The optimal processing parameters of GMOC were ginger juice dosage of 8%, moistening time of 120 min, and processing at 100 ℃ for 7 min. The content of syringoside and magnolflorine in MOC decreased after processing, and the content of honokiol and magnolol followed the trend of GMOC>MOC>WMOC, which suggested that the change in clinical efficacy of MOC after processing was associated with the changes of chemical composition. The optimized processing technology is stable and feasible and provides references for the modern production and processing of MOC.

Topics: Biphenyl Compounds; Drugs, Chinese Herbal; Lignans; Magnolia; Zingiber officinale

Salicylic acid has been used as an anti-acne agent with its comedolytic property and antimicrobial activity. However, there is a limit to use for leave-on cosmetics because of the transient skin irritation and low efficacy at neutral pH condition. We prepared a salicylic acid-based ionic pair with. After verifying the structure of IP-BHA, we confirmed anti-acne activities including the regulation of exfoliation, lipogenesis, bacterial growth, and inflammation with IP-BHA and/or magnolol.. The antibacterial activity of IP-BHA and magnolol was evaluated by determining the minimum antibacterial inhibitory concentration. Magnolol showed strong activity against Cutibacterium acnes, which was better than a medical antibiotic acne drug, clindamycin. The combined application with IP-BHA was more effective in antibacterial activity by 2.5 times. It was confirmed that testosterone-induced lipogenesis was significantly inhibited by treatment with IP-BHA and magnolol, while single treatment had no significant inhibitory effect. Interestingly, MMP-1 and VEGF were induced by C. acnes lysate in human keratinocytes. We found that these inflammatory molecules were completely inhibited by combined application of IP-BHA and magnolol. Through ex vivo test, the dose-dependent exfoliation effect of IP-BHA was confirmed at pH 5.5, and the synergic exfoliation effect was shown in the combined application of IP-BHA and magnolol. When topically applied, the emulsion containing IP-BHA and magnolol relieved the sodium dodecyl sulfate-induced erythema and improved inflamed acne with papule and pustule.. Our data demonstrate that the ionic paired salicylic acid with

Topics: Acne Vulgaris; Anti-Bacterial Agents; Carnitine; Humans; Inflammation; Lignans; Lipogenesis; Salicylic Acid

Bladder cancer (BC) is a challenging disease to manage. Researchers have been investigating the potential of magnolol, a compound derived from Magnolia officinalis, as an anti-cancer agent. However, the exact regulatory mechanism of magnolol and its impact on the NF-κB signaling pathway in BC remain unclear.. To comprehensively evaluate its therapeutic potential, the researchers conducted a series of experiments using BC cell lines (TSGH8301, T24, and MB49) and in vivo animal models.. The results of the study demonstrated that magnolol exhibits cytotoxic effects on BC cells by activating both the extrinsic and intrinsic apoptosis signaling pathways. Additionally, the expression of anti-apoptotic genes was downregulated by magnolol treatment. The researchers also uncovered the regulatory role of PKCδ/ERK and miR-124-3p in the NF-κB pathway, which may be influenced by magnolol. Treatment with magnolol led to the inactivation of PKCδ/ERK and an increase in miR-124-3p expression, effectively inhibiting NF-κB-mediated progression of BC. Importantly, the administration of magnolol did not result in significant toxicity in normal tissues, highlighting its potential as a safe adjunctive therapy with minimal adverse effects.. These findings position magnolol as a promising therapeutic agent for the treatment of BC. By activating apoptosis signaling pathways and inhibiting NF-κB pathway through the upregulation of miR-124-3p and downregulation of PKCδ/ERK activation, magnolol holds promise for suppressing tumor progression and improving patient outcomes in BC. Further research and clinical trials are warranted to explore the full potential of magnolol in the future.

Topics: Animals; Apoptosis; Biphenyl Compounds; Cell Line, Tumor; Cell Proliferation; Lignans; MicroRNAs; NF-kappa B; Urinary Bladder Neoplasms

Topics: Biphenyl Compounds; Cell Membrane; Chromatography; Lignans; Vascular Endothelial Growth Factor A

Alzheimer's disease (AD) is a common neurodegenerative disease characterized by neuronal degeneration and hyperphosphorylated Tau. Magnolol is an active component isolated from Magnolia officinalis with potential neuroprotection activity. However, the function and mechanism of magnolol in AD progression is largely uncertain. In present study, the biomarkers related to AD and magnolol were predicted by bioinformatics analyses. The key biomarker levels were predicted by GSE5281 and GSE36980 using AlzData. Cell viability was detected by CCK-8 assay. mRNA and protein levels were examined by qRT-PCR and western blotting assays. Cell apoptosis was investigated by caspase-3 activity and flow cytometry analyses. The cAMP/PKA/CREB signaling was evaluated by ELISA and western blotting analyses. The results showed that CHRM1 was a key biomarker for magnolol against AD progression. Magnolol attenuated Aβ-induced viability inhibition, Tau hyperphosphorylation and apoptosis in SH-SY5Y cells by upregulating CHRM1. In addition, the cAMP signaling might be a potential pathway of CHRM1 in AD. Magnolol contributed to activation of the cAMP/PKA/CREB pathway through enhancing CHRM1 level. Inactivation of the cAMP/PKA/CREB signaling reversed the suppressive effect of magnolol on Tau hyperphosphorylation and apoptosis in Aβ-treated SH-SY5Y cells. As a conclusion, magnolol mitigated Aβ-induced Tau hyperphosphorylation and neuron apoptosis by upregulating CHRM1 and activating the cAMP/PKA/CREB pathway.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Apoptosis; Biphenyl Compounds; Humans; Lignans; Neurodegenerative Diseases; Neurons; Receptor, Muscarinic M1

In this study, we aimed to investigate the effect of Magnolol on Alzheimer's disease (AD). After the model of streptozotocin-induced AD mice with brain insulin resistance was established, the mice were treated with Magnolol or miR-200c antagomiR. The abilities of ambulations, rearings, discrimination, spatial learning, and memory were evaluated by open-field test (OFT), novel object recognition (NOR), and morris water maze (MWM) tests. The levels of malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), C-reactive protein (CRP), and miR-200c in the mice hippocampus were evaluated by enzyme-linked immunosorbent assay, Western blot, or Quantitative real-time Polymerase Chain Reaction. In AD mice model, streptozotocin induced the locomotor impairment and cognitive deficit, up-regulated levels of MDA, TNF-α, IL-6, and CRP, while down-regulated levels of GSH, SOD, and miR-200c. Magnolol increased the rearings numbers and discrimination index of AD mice in OFT and NOR tests. Magnolol increased the number of entries in the target quadrant and time spent in the target quadrant and decreased the escape latency of AD mice in the MWM test. Magnolol also down-regulated the levels of MDA, TNF-α, IL-6, and CRP, and up-regulated the levels of GSH, SOD, and miR-200c in the hippocampus tissues of AD mice. However, miR-200c antagomiR did the opposite and further offset the effects of the Magnolol on AD mice. Magnolol attenuated the locomotor impairment, cognitive deficit, and neuroinflammatory in AD mice with brain insulin resistance via up-regulating miR-200c.

Topics: Alzheimer Disease; Animals; Antagomirs; Biphenyl Compounds; Brain; Disease Models, Animal; Insulin Resistance; Lignans; Locomotion; Male; Malondialdehyde; Mice; Morris Water Maze Test; Spatial Learning; Streptozocin

Alternaria porri (Ellis) Clf. causes purple blotch disease on Allium plants which results in the reduction of crop yields and quality. In this study, to efficiently find natural antifungal compounds against A. porri, we optimized the culture condition for the spore production of A. porri and the disease development condition for an in vivo antifungal assay. From tested plant materials, the methanol extracts derived from ten plant species belonging to the families Cupressaceae, Fabaceae, Dipterocarpaceae, Apocynaceae, Lauraceae, and Melastomataceae were selected as potent antifungal agents against A. porri. In particular, the methanol extract of Caryodaphnopsis baviensis (Lec.) A.-Shaw completely inhibited the growth of A. porri at a concentration of 111 μg/ml. Based on chromatographic and spectroscopic analyses, a neolignan compound magnolol was identified as the antifungal compound of the C. baviensis methanol extract. Magnolol showed a significant inhibitory activity against the spore germination and mycelial growth of A. porri with IC50 values of 4.5 and 5.4 μg/ml, respectively. Furthermore, when magnolol was sprayed onto onion plants at a concentration of 500 μg/ml, it showed more than an 80% disease control efficacy for the purple blotch diseases. In terms of the antifungal mechanism of magnolol, we explored the in vitro inhibitory activity on individual oxidative phosphorylation complexes I-V, and the results showed that magnolol acts as multiple inhibitors of complexes I-V. Taken together, our results provide new insight into the potential of magnolol as an active ingredient with antifungal inhibitory action to control purple blotch on onions.

Topics: Alternaria; Antifungal Agents; Biphenyl Compounds; Lauraceae; Lignans; Methanol; Mycelium; Onions; Plant Diseases; Plant Extracts

Intractable skin defects, which involve excessive inflammation and bacterial infections, caused by burns, trauma, and diabetes are a major challenge for clinicians. Compared with traditional skin transplantation, tissue-engineered skin has the advantages of a wide range of sources, prominent biological activity, and no damage to the donor area during the operation. Therefore, an effective wound-healing mat with antibacterial, anti-inflammatory, and microvascularization bioactivities is urgent to be developed. In this study, we have synthesized a poly(ester-urethane)urea/silk fibroin/magnolol nanofibrous composite mat (PSM) through electrospinning and post-hydrogen bond cross-linking. The results show that the hybrid magnolol has no adverse effect on the microstructure, porosity, wettability, and mechanical properties of PSM. Antibacterial experiments and cytocompatibility in vitro have proved that the addition of magnolol significantly improves the antibacterial ability and promotes cell adhesion and proliferation of PSM. In addition, the wound model of rat back and H&E staining, Masson trichrome staining, and CD31 and CD68 immunofluorescence staining were performed for evaluating the therapeutic efficiency of PSM. All the results show that the better wound treatment effect of magnolol hybrid nanofibrous mats in infectious skin tissue defected repair indicates their great potential for wound healing clinically.

Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Biphenyl Compounds; Lignans; Nanofibers; Rats; Wound Healing

The potential of combination therapy using nanoparticle delivery systems in improving triple-negative breast cancer treatment efficacy remains to be explored. Here, we report a novel nanoparticle system using a cholesterol biguanide conjugate hydrochloride (CBH) as both a drug and carrier to load magnolol (MAG). Poly(ethylene glycol)-poly(lactic-co-glycolic acid) (mPEG-PLGA) and aminoethyl anisamide-poly(ethylene glycol)-poly(lactic-co-glycolic acid) (AEAA-PEG-PLGA) were added to form nanoparticles. Nanoparticles accumulated most in tumor tissues when the weight ratio of AEAA-PEG-PLGA to mPEG-PLGA was 4:1. MAG and CBH exerted a synergistic inhibitory effect on 4 T1 cells. An in vitro study showed that nanoparticles displayed the highest tumor cell uptake rate, highest apoptosis rate, and strongest inhibitory effect on tumor cell migration and monoclonal formation. CBH might promote nanoparticle uptake by cells and lysosomal escape. After intravenous administration to mice with 4 T1 breast tumors in situ, the nanoparticles inhibited tumor growth without obvious toxicity. Western blot results showed that nanoparticles altered the levels of p53, p-AKT, and p-AMPK in the tumor tissue. Moreover, cell apoptosis was found in the same area of H&E-stained and TUNEL-stained tumors treated with the nanoparticles. Collectively, this nanoparticle system provides a novel combination drug delivery strategy for treating triple-negative breast cancer.

Topics: Animals; Biguanides; Biphenyl Compounds; Cell Line, Tumor; Drug Carriers; Humans; Lignans; Mice; Nanoparticles; Polyethylene Glycols; Triple Negative Breast Neoplasms

Flos Magnoliae (the dried flower buds of Magnolia biondii Pamp, FM) is a known herbal traditional medicine used for the symptomatic relief of nasal congestion and rhinorrhea caused by rhinitis and sinusitis. Magnolol, a neolignan from the magnolia family, is a secondary metabolite known to have anti-allergic and anti-inflammatory effects. However, the underlying mechanisms and therapeutic effect of magnolol in the treatment of allergic rhinitis (AR) remain elusive.. Anoctamin 1 (ANO1), a calcium-activated anion channel, mediates mucus and electrolyte secretion in nasal airway epithelial cells, whereas calcium release-activated calcium channel protein 1 (ORAI1) participates in the activation of T-lymphocytes and mast cells. The aim of our study is to understand the mechanisms of action of magnolol against AR, i.e., whether it acts through the modulation of ANO1 and ORAI1 channels that are expressed in nasal epithelial cells and T-lymphocytes, respectively.. Whole-cell patch clamp was used to record the activity of ORAI1 and ANO1 ion channels in ORAI1 or ANO1 overexpressed HEK293T cells, while the Ussing chamber apparatus was used to measure electrolyte transport via the epithelium, in Calu-3 cells cultured in an air-liquid interface. Additionally, calcium imaging of Jurkat T-lymphocytes was used to assess changes in the intracellular calcium concentration. Magnolol toxicity was assessed using the CCK-8 assay, and its effect on T-lymphocyte proliferation was measured by labeling human primary T-lymphocytes with carboxyfluorescein succinimidyl ester. Finally, OVA-induced Balb/c mice were employed to evaluate the effect of magnolol on nasal symptoms, as well as cytokine and eosinophil infiltration in AR.. Magnolol inhibits ORAI1 and ANO1 channels in a concentration-dependent manner. Magnolol (30 μM) inhibits anti-CD3 induced cellular proliferation and production of IL-2 via ORAI1 channels in T-lymphocytes. Further, ATP-induced electrolyte transport mediated by ANO1 channels is significantly inhibited by magnolol in IL-4 sensitized Calu-3 cells. Notably, 300 μM magnolol significantly attenuates cytokine and eosinophil infiltration, thus alleviating AR symptoms in mice OVA-induced AR.. Magnolol may be a promising therapeutic agent for the treatment and prevention of AR.

Topics: Animals; Anoctamin-1; Anti-Allergic Agents; Biphenyl Compounds; Cell Line, Tumor; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Flowers; HEK293 Cells; Humans; Lignans; Magnolia; Mice; Mice, Inbred BALB C; Neoplasm Proteins; ORAI1 Protein; Ovalbumin; Patch-Clamp Techniques; Rhinitis, Allergic

Magnolia officinalis Cortex (M. officinalis) is a classical traditional Chinese medicine (TCM) widely used to treat digestive system diseases. It effectively regulates gastrointestinal motility to improve abdominal pain, abdominal distension and other symptoms. Magnolol (MAG) and honokiol (HON) are the main pharmacodynamic components responsible for the gastrointestinal activity of M. officinalis.. The transient receptor potential (TRP) family is highly expressed in the gastrointestinal tract and participates in the regulation of gastrointestinal motility, visceral hypersensitivity, visceral secretion and other physiological activities. In this study, the calcium-lowering mechanisms of MAG and HON contributing to the smooth muscle relaxation associated with TRP are discussed.. The relaxation smooth muscle effects of MAG and HON were tested by the isolated intestine tone tests. A synthetic MAG probe (MAG-P) was used to target fishing for their possible target. The distribution of MAG on the smooth muscle was identified by a molecular tracer based on chemical biology. Ca. After confirming the smooth muscle relaxation in the small intestine induced by MAG and HON, the relaxation effect was identified mainly due to the downregulation of intracellular calcium by controlling external calcium influx. Although MAG and HON inhibited both TRPV4 and TRPC4 channels to reduce calcium levels, the inhibitory effect on TRPC4 channels is an important mechanism of their smooth muscle relaxation effect, since TRPC4 is widely expressed in the small intestinal smooth muscle cells.. The inhibition of MAG and HON on TRPC4 channels contributes to the relaxation of intestinal smooth muscle.

Topics: Animals; Biphenyl Compounds; Calcium Signaling; HEK293 Cells; Humans; Intestines; Lignans; Male; Medicine, Chinese Traditional; Muscle Contraction; Muscle, Smooth; Myocytes, Smooth Muscle; Rats; Rats, Sprague-Dawley; TRPC Cation Channels; TRPV Cation Channels

Topics: Animal Feed; Animals; Antioxidants; Biphenyl Compounds; Chickens; Diet; Dietary Supplements; Gastrointestinal Microbiome; Glutamate-Cysteine Ligase; Glutathione; Lignans; Male; Meat; Oxidative Stress; Superoxide Dismutase

This article aimed to design a new type of supersaturated solid dispersion (NS-SD) loaded with Magnolol (Mag) to raise the oral bioavailability in rats. In the light of the solubility parameters, phase solubility experiments, inhibition precipitation experiment, and in vitro release experiment, Plasdone-630 (PS-630) was selected as the optimum carrier. In addition, Mag-NS-SD was prepared by adding Monoglyceride (MG) and Lecithin High Potency (LHP) into the Mag-S-SD (Mag:PS-630 = 1:3), so as to reduce the dosage of carrier and improve the release rate. Using central composite design of response surface method, the prescription was further optimized. As the optimized condition was Mag:PS-630: MG: LHP = 1:3:0.8:0.266, the drug release rate was the fastest. Besides, after 45 min, the release rate was nearly 100%. The constructed Mag-S-SD and Mag-NS-SD were characterized by powder X-ray diffraction and infrared absorption spectrum. The XRD patterns of Mag-S-SD and Mag-NS-SD indicated that all APIs were amorphous. The IR spectra of Mag-S-SD and Mag-NS-SD demonstrated the existence of hydrogen bonding in the systems. Furthermore, in vivo pharmacokinetic study in rats revealed that compared with Mag and Mag-S-SD, Mag-NS-SD significantly increased the bioavailability (the relative bioavailability was 213.69% and 142.37%, separately). In this study, Mag-NS-SD was successfully prepared, which could improve the oral bioavailability and may increase the clinical application.

Topics: Animals; Biological Availability; Biphenyl Compounds; Lignans; Rats; Solubility

Multiple sclerosis (MS) is an immune-mediated chronic inflammatory demyelinating disease of the central nervous system (CNS). The aim of the current study was to investigate the effects of magnolol in an experimental autoimmune encephalomyelitis (EAE) model of MS in female mice. Magnolol (0.1, 1, and 10 mg/kg) was administered once daily for 21 days after immunization of mice. Magnolol post-immunization treatment significantly reversed clinical scoring, EAE-associated pain parameters, and motor dysfunction in a dose-dependent manner. Magnolol treatment significantly inhibited oxidative stress by reducing malondialdehyde (MDA), nitric oxide (NO) production, and myeloperoxidase (MPO) activity while enhancing the level of antioxidants such as reduced glutathione (GSH), glutathione-S-transferase (GST), catalase, and superoxide dismutase (SOD) in the brain and spinal cord. It reduced cytokine levels in the brain and spinal cord. It suppressed CD8

Topics: Animals; Antioxidants; Apoptosis; Biphenyl Compounds; Brain Injuries; Caspase 3; CD8-Positive T-Lymphocytes; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Female; Lignans; Mice; Molecular Docking Simulation; Multiple Sclerosis; NF-E2-Related Factor 2; Oxidative Stress

Magnolol is a component of the bark of Magnolia officinalis, which is a traditional herbal remedy used in China. In this study, we investigated whether magnolol can reduce myocardial injury induced by renal ischemia and reperfusion (I/R).. Renal I/R was elicited by a 60-minute occlusion of the bilateral renal arteries and a 24-hour reperfusion in Sprague-Dawley rats. Magnolol was administered intravenously 10 minutes before renal I/R to evaluate its effects on myocardial injury induced by renal I/R.. Renal I/R significantly increased the serum levels of creatine phosphokinase (CPK), lactate dehydrogenase (LDH), and cardiac troponin I and caused myocardial damage. The terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive nuclei and caspase-3 activation was significantly increased in the myocardium, indicating increase of apoptosis. Echocardiography revealed left ventricular dysfunction, as evidenced by reduction of left ventricular ejection fraction and left ventricular fractional shortening. Furthermore, serum levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6 were significantly elevated, while the IL-10 level was suppressed. However, intravenously, pretreatment with magnolol at doses of 0.003 and 0.006 mg/kg 10 minutes before renal I/R significantly prevented the increases of CPK, LDH, and cardiac troponin I levels, as well as the histological damage and the apoptosis in the myocardium. Echocardiography showed significant improvement of left ventricular function. Furthermore, the increases in TNF-α, IL-1β, and IL-6 and the decrease in IL-10 were significantly limited, while Bcl-2 was increased and Bax was decreased in the myocardium. Phosphorylation of Akt and extracellular signal-regulated kinases 1 and 2 was increased, while phosphorylation of p38 and c-Jun N-terminal kinase was reduced.. Magnolol reduces myocardial injury induced by renal I/R. The underlying mechanisms for this effect might be related to modulation of the production of pro- and anti-inflammatory cytokines and the limiting of apoptosis.

Topics: Animals; Apoptosis; Biphenyl Compounds; Interleukin-10; Interleukin-6; Ischemia; Lignans; Myocardial Reperfusion Injury; Myocardium; Rats; Rats, Sprague-Dawley; Reperfusion; Reperfusion Injury; Stroke Volume; Troponin I; Tumor Necrosis Factor-alpha; Ventricular Function, Left

Topics: Animals; Biphenyl Compounds; Cell Proliferation; Cells, Cultured; Hypertension, Pulmonary; Hypoxia; Lignans; Myocytes, Smooth Muscle; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Vascular Remodeling

Bacterial infection and oxidative stress seriously delay wound healing. Here, magnolol-grafted-chitosan hydrochloride (CSCl-MAG) was synthesized and crosslinked with genipin to form hydrogel (CSMH). By embedding magnolol-loaded chitosan nanocapsules (MCNGs) into CSMH, we designed a novel nanocapsule- embedded hydrogel dressing (MCNG-H) with sustained antibacterial and antioxidant properties. The swelling, rheology, cytotoxicity, antibacterial and antioxidant properties of MCNG-H were studied. MCNG-H exhibited good swelling properties and biocompatibility. The antibacterial and antioxidant assays in vitro demonstrated the corporative effect of CSM-H and MCNGs in inhibiting bacteria and eliminating reactive oxygen species (ROS). Moreover, MCNG-H revealed the pH-responsive release profiles of loaded MAG, and ensured sustained release of MAG with the dual protective effects of MCNG and CSMH, which helped to maintain long-term antibacterial and antioxidant activities. Finally, MCNG-H significantly accelerated wound healing in a splinted excisional dermal wound model, promising a competitive dressing for the treatment of infected wounds.

Topics: Anti-Bacterial Agents; Antioxidants; Biphenyl Compounds; Chitosan; Hydrogels; Hydrogen-Ion Concentration; Lignans; Nanocapsules; Wound Healing

Topics: Animals; Bass; Biphenyl Compounds; Female; Fish Diseases; Lignans; Rhabdoviridae

Non-small-cell lung cancer (NSCLC) is the most common type of lung cancer worldwide, and treatment outcomes are still poor. Magnolol, a hydroxylated biphenyl isolated from Magnolia officinalis, was found to be effective against hepatocellular carcinoma via inactivating nuclear-factor-kappa B (NF-B) signaling. However, whether magnolol targets not only NF-B but also other factors in NSCLC and may contribute to the suppression of tumor progression is unclear.. Cell viability, flow cytometry, and western blotting assays were used to identify the mechanism of magnolol action in human lung adenocarcinoma cell lines A549 and CL1-5-F4.. Our results indicated that magnolol induced cytotoxicity through extrinsic/intrinsic apoptosis signaling and suppressed phosphorylation of signal transducer and activator of transcription 3 (STAT3)/NF-B and expression of their downstream proteins.. Magnolol not only induced extrinsic and intrinsic apoptosis signaling but also inactivated STAT3/NF-B and attenuated their signaling of epithelial-mesenchymal transition and metastasis-related protein expression in NSCLC.

Topics: Apoptosis; Biphenyl Compounds; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Humans; Lignans; Lung Neoplasms; NF-kappa B; STAT3 Transcription Factor

The stem bark of Magnolia officinalis is a traditional Chinese medicine for the treatment of abdominal distention and functional dyspepsia. The pharmacokinetics of three glycosides (magnoloside A, magnoloside B, and syringin) and two lignans (honokiol and magnolol) in both normal and functional dyspepsia rats were firstly investigated by ultra-performance liquid chromatography-triple quadrupole mass spectrometry method and the influences of the coexisting compounds on the pharmacokinetic parameters of honokiol and magnolol were also studied. It was found that all of the five target compounds were quickly absorbed and eliminated in both normal and functional dyspepsia rats, while, their residence time was significantly decreased in pathological states except magnoloside A. The coexisting compounds in the stem bark of M. officinalis significantly reduced absorption and increased elimination of honokiol in vivo. It's worth noticing that the volume of distribution of lignan was quite lower than that of a glycoside. Moreover, the metabolic profiling of magnoloside A, honokiol, and magnolol in vivo was analyzed by ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry method, from which three prototypes were identified and 35 metabolites were putatively characterized, and 18 unknown metabolites were reasonably characterized for the first time. The results indicated that sulfation and glucuronidation were the main metabolic pathways of honokiol and magnolol.

Topics: Animals; Biphenyl Compounds; Chromatography, High Pressure Liquid; Chromatography, Liquid; Dyspepsia; Glycosides; Lignans; Magnolia; Plant Bark; Rats; Tandem Mass Spectrometry

Magnolol, a lignin compound extracted from

Topics: Antifungal Agents; beta-Glucans; Biphenyl Compounds; Candida albicans; Fungal Proteins; Lignans; Mitogen-Activated Protein Kinase 3; Signal Transduction; Virulence Factors

Osteosarcoma is an aggressive primary malignant bone tumor that occurs in childhood. Although the diagnostic and treatment options have been improved, osteosarcoma confers poor prognosis. Magnolol, an active component of Magnoliae officinalis cortex, has been widely applied in herb medicine and has been shown to have multiple pharmacological activities. However, whether magnolol possesses anti-osteosarcoma capacity remains unknown.. We examined magnolol is cytotoxicity, and whether it regulates apoptosis and oncogene expression using MTT, flow cytometry and Western blotting assays in osteosarcoma cells.. Magnolol exerted toxicity towards U-2 OS cells by inducing intrinsic/extrinsic apoptosis pathways. Additionally, treatment of U-2 OS cells with magnolol inhibited MAPK1 mitogen-activated protein kinase 1 (ERK)/Nuclear factor kappa B (NF-B) signaling involved in tumor progression and reduced the expression of anti-apoptotic and metastasis-associated genes.. Magnolol may induce apoptosis and inactivate ERK/NF-B signal transduction in osteosarcoma cells.

Topics: Apoptosis; Biphenyl Compounds; Bone Neoplasms; Cell Line, Tumor; Extracellular Signal-Regulated MAP Kinases; Humans; Lignans; NF-kappa B; Osteosarcoma; Signal Transduction

Diabetic peripheral neuropathy (DPN) is a common complication of diabetes lacking efficient treatment. Magnolol (MG), a peroxisome proliferator-activated receptor γ (PPARγ) agonist, is a natural product derived from Magnolia officinalis and widely used to treat a variety of diseases as a traditional Chinese medicine and Japanese Kampo medicine.. Here, we aimed to investigate the potential of MG in ameliorating DPN-like pathology in mice and decipher the mechanism of MG in treating DPN.. MG promoted DRG neuronal neurite outgrowth and effectively ameliorated neurological dysfunctions in both T1DM and T2DM diabetic mice, including improvement of paw withdrawal threshold, thermal response latency and MNCV. Additionally, MG promoted neurite outgrowth of DRG neurons, protected sciatic nerve myelin sheath structure, and ameliorated foot skin intraepidermal nerve fiber (IENF) density in DPN mice by targeting PPARγ. Mechanism research results indicated that MG improved mitochondrial dysfunction involving PPARγ/MKP-7/JNK/SIRT1/LKB1/AMPK/PGC-1α pathway in DRG neurons, repressed inflammation via PPARγ/NF-κB signaling and inhibited apoptosis through regulation of PPARγ-mediated Bcl-2 family proteins in DRG neurons and sciatic nerves.. Our work has detailed the mechanism underlying the amelioration of PPARγ agonist on DPN-like pathology in mice with MG as a probe, and highlighted the potential of MG in the treatment of DPN.

Topics: AMP-Activated Protein Kinases; Animals; Biological Products; Biphenyl Compounds; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Hypoglycemic Agents; Lignans; Male; Mice; NF-kappa B; PPAR gamma; Proto-Oncogene Proteins c-bcl-2; Sciatic Nerve; Sirtuin 1

Cancer stem cells (CSCs) have been known to be implicated in tumorigenesis, metastasis, and drug resistance in oral squamous cell carcinomas (OSCC). In this study, we aimed to investigate whether magnolol, a polyphenolic component derived from Magnolia officinalis, exhibited the anti-CSCs properties.. The cytotoxicity of magnolol was tested using normal gingival epithelioid SG cells and sphere-forming OSCC-CSCs isolated from SAS, OECM1, and GNM cells. Secondary sphere-forming ability, the proportion of ALDH1 positive cells, Transwell migration, and invasion capacities were examined as well. The chemosensitive effects of magnolol were investigated using MTT, secondary sphere-forming, and invasion assays.. Magnolol exerted a higher cytotoxicity of OSCC-CSCs and cancer stemness features, including self-renewal ability, the expression CSC marker, migration, and invasion capacities were all downregulated in magnolol-treated OSCC-CSCs. Moreover, administration of magnolol potentiated the effect of cisplatin, including a decrease in cell viability, self-renewal, and invasion activities. In addition, we observed that the secretion of IL-6 and phosphorylation of Stat3 were decreased in OSCC-CSCs treated with magnolol.. Our data suggest that magnolol is able to target CSCs and suppress the cancer stemness properties, at least in part, via IL-6/Stat3 signaling. Besides, a dietary supplement of magnolol may function as an adjunct to cisplatin treatment.

Topics: Biphenyl Compounds; Cell Line, Tumor; Humans; Interleukin-6; Lignans; Squamous Cell Carcinoma of Head and Neck; STAT3 Transcription Factor

The placenta is the organ that determines the growth of the fetus and the outcome of pregnancy. Magnolol is a multifunctional polyphenol with antioxidant, anti-inflammatory, anticancer and neuroprotective functions. However, there is less knowledge of the effects or complications in the placenta and the mechanism underlying the effect of magnolol when used during pregnancy. The aim of this study was to explore the effects of maternal magnolol supplementation on pregnancy outcomes and placental alterations in a pregnant mouse model. A total of 128 pregnant mice were randomly divided into 4 groups supplemented with 0, 40, 80 and 160 μM magnolol from gestational day 0 (GD0) to delivery. Our results revealed that the number of large-for-gestation-age fetuses on GD13 and the weaning weight of offspring were increased in the magnolol treatment groups. Moreover, maternal magnolol supplementation increased superoxide dismutase (SOD), decreased malondialdehyde (MDA) in maternal serum, and promoted the expression of heme oxygenase-1 (HO-1) in the placenta. Furthermore, magnolol significantly increased the area of the junctional zone and decidua in the placentas and increased the expression of interferon-γ (INF-γ), tumor necrosis factor-α (TNF-α), chemokine (CC Motif) Ligand 3 (CCL3), chemokine (CXC motif) ligand 10 (CXCL10), insulin-like growth factor-1 (IGF-1) and T-box transcription factor 21 (T-bet) in the placenta during GD13 in pregnant mice, while suppressor of cytokine signaling 1 (SOCS1) was reduced. Moreover, the ratio of blood space in the labyrinth area, hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) were all increased in the magnolol treatment groups on GD13. Taken together, these results indicate that magnolol can improve the growth of offspring, which might be due to the alteration of placental morphology and the promotion of placental angiogenesis during mid-gestation.

Topics: Animals; Biphenyl Compounds; Cytokines; Dietary Supplements; Drug Evaluation, Preclinical; Female; Fetal Development; Gene Expression Regulation; Lignans; Magnolia; Mice; Neovascularization, Physiologic; Phytotherapy; Placenta; Plant Extracts; Pregnancy

Topics: Animals; ATP Binding Cassette Transporter, Subfamily G, Member 2; Biphenyl Compounds; Cell Survival; Dogs; Drug Resistance, Multiple; Drug Resistance, Neoplasm; ErbB Receptors; Lignans; Madin Darby Canine Kidney Cells; Magnolia; Neoplasm Proteins; Phosphatidylinositol 3-Kinases; Phosphorylation; Plant Extracts; Polyphenols; Signal Transduction

Magnolol is a bioactive polyphenolic compound commonly found in Magnolia officinalis. The aim of this study is to clarify the contribution of the magnolol additive on the growth performance of Linwu ducklings aging from 7 to 28 d, comparing to the effects of antibiotic additive (colistin sulphate). A total of 325, 7-d-old ducklings were assigned to 5 groups. Each group had 5 cages with 13 ducklings in each cage. The ducklings in different groups were fed with diets supplemented with 0, 100, 200 and 300 mg/kg magnolol additive (MA) (Control, MA100, MA200 and MA300) and 30 mg/kg colistin sulphate (CS30) for 3 weeks, respectively. Parameters regarding to the growth performance, intestinal mucosal morphology, serum biochemical indices, antioxidant and peroxide biomarkers and the expression levels of antioxidant-related genes were evaluated by one way ANOVA analysis. The results showed that 30 mg/kg colistin sulphate, 200 and 300 mg/kg magnolol additive improved the average final weight (P = 0.045), average daily body weight gain (P = 0.038) and feed/gain ratios (P = 0.001) compared to the control group. 200 and 300 mg/kg magnolol additive significantly increased the villus height/crypt depth ratio of ileum, compared to the control and CS30 groups (P = 0.001). Increased serum level of glucose (P = 0.011) and total protein (P = 0.006) were found in MA200 or MA300 group. In addition, comparing to the control and CS30 groups, MA200 or MA300 significantly increased the levels of superoxide dismutase (P = 0.038), glutathione peroxidase (P = 0.048) and reduced glutathione (P = 0.039) in serum. Moreover, the serum and hepatic levels of 8-hydroxy-2'-deoxyguanosine (P = 0.043 and 0.007, respectively) were lower in all MA groups compared to those of the control and CS30 group. The hepatic mRNA expression levels of superoxide dismutase-1, catalase and nuclear factor erythroid-2-related factor 2/erythroid-derived CNC-homology factor were also increased significantly in MA200 and MA300 groups (P < 0.05). Taken together, these data demonstrated that MA was an effective feed additive enhancing the growth performance of Linwu ducklings at 7 to 28 d by improving the antioxidant and intestinal mucosal status. It suggested that MA could be a potential ingredient to replace the colistin sulphate in diets.

Topics: Animals; Antioxidants; Biomarkers; Biphenyl Compounds; Diet; Ducks; Female; Gene Expression Regulation; Intestinal Mucosa; Lignans; Liver; Nutrients; Peroxides; RNA, Messenger

Honokiol and magnolol are natural components isolated from Magnolia bark that is used in traditional Chinese and Japanese herbal medicine. These two isomers are used as a component of dietary supplements and cosmetic products. In this study, we investigated the antimicrobial effect of honokiol and magnolol on pathogens causing oral diseases, their mechanism of action in biofilm formation and drug resistance of oral pathogens, and inflammatory regulation in mammalian cells.. We determined the minimum inhibitory concentration and minimum bactericidal concentration of honokiol and magnolol, and their stability at different temperatures and pH. We also evaluated their effect on biofilm formation, antibiotic-resistance gene expression in MRSA, and pro-inflammatory gene expression in mammalian cells.. Honokiol showed better antimicrobial activity than magnolol. Both honokiol and magnolol showed stable bacterial inhibitory activity over a wide range of temperature and pH, reduced biofilm formation, and antibiotic resistance in oral pathogens. The biofilm formation- and antibiotic resistance-related gene expression was consistent with the respective phenotypes. Furthermore, these two isomers repressed the expression of pro-inflammatory genes in RAW264.7 cells.. Our study provides evidence of the potential application of honokiol and magnolol in dental medicine to cure or prevent oral diseases.

Topics: Animals; Anti-Bacterial Agents; Biphenyl Compounds; Humans; Inflammation; Lignans; Macrophages

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Autophagy; Biphenyl Compounds; Carcinoma, Non-Small-Cell Lung; Cell Cycle Checkpoints; Cell Line, Tumor; Drug Screening Assays, Antitumor; Female; Humans; Lignans; Lung Neoplasms; Magnolia; Mice, Inbred BALB C; Plant Extracts; Solubility; Structure-Activity Relationship

Wheat is one of three major food crops in China. Alternaria species can cause spoilage of wheat with consequent mycotoxin accumulation. Alternariol (AOH), alternariol monomethyl ether (AME), and tenuazonic acid (TeA) are the most common and frequently studied mycotoxins. There are limited regulations placed on Alternaria mycotoxin concentrations worldwide due to the lack of toxicity data available. More data on the levels of mycotoxin contamination are also needed. It is also important to reduce the risks of Alternaria mycotoxins.. One hundred and thirty-two wheat samples were collected from Hebei Province, China, and analyzed for AOH, AME, and TeA. Tenuazonic acid was found to be the predominant Alternaria mycotoxin, especially in flour samples. Studying Alternaria species that cause black-point disease of wheat indicated that Alternaria alternata and Alternaria tenuissima were the dominant species. Most of the Alternaria strains studied produced more than one mycotoxin and TeA was produced at the highest concentration, which may have resulted in the high level of TeA contamination in the wheat samples. Furthermore, magnolol displayed obvious antifungal and antimycotoxigenic activity against Alternaria. This is the first report on the antimycotoxigenic activity of magnolol against Alternaria species.. The Alternaria mycotoxin contamination levels in wheat and wheat products from Hebei Province, China, were correlated with the toxigenic capacity of the Alternaria strains colonizing the wheat. Considering its safety, magnolol could be developed as a natural fungicide in wheat, or as a natural alternative food preservative based on its strong antifungal and antimycotoxigenic activity against Alternaria strains. © 2020 Society of Chemical Industry.

Topics: Alternaria; Biphenyl Compounds; China; Flour; Food Contamination; Fungicides, Industrial; Lactones; Lignans; Plant Diseases; Tenuazonic Acid; Triticum

Multiple myeloma (MM) is incurable cancer in the blood system. Magnolol is an effective component against various cancers. This study tried to investigate the effect and mechanism of magnolol on MM via regulating miR-129. Human normal plasma cells (nPCs) and MM cells U266 and LP1 were used in this study, accompanied by treatment of magnolol. The miR-129 inhibitor was transfected into U266 and LP1 cells during experiments. Cell viability was detected by Cell Counting Kit-8 assay. Cell migration and invasion were tested by wound healing assay and Transwell assay. And Annexin-V-FITC/PI assay was utilized to assess cell apoptosis. miR-129, miR-1271-5p, miR-342-3p, and miR-124-3p expressions were detected by quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and western blot was adopted to evaluate Cyclin D1, matrix metalloprotein (MMP)-7, MMP-9, phosphorylation (p)-IκBα, p-p65, and p65 protein levels. In U266 and LP1 cells, with magnolol concentration increasing, cell viability, migration, and invasion rates, Cyclin D1, MMP-7, and MMP-9 expressions decreased, while cell apoptosis rose. And magnolol increased the miR-129 expression in MM cells. Besides, miR-129 inhibitor antagonized the above-mentioned effect of magnolol and partly offset the magnolol-induced decrease of p-IκBα and p-p65 expression, as well as the ratio of p-p65 to p65 in U266 and LP1 cells. Magnolol suppressed cell migration and invasion and induced cell apoptosis via inhibiting NF-κB pathway activation, by upregulating miR-129 in MM.

Topics: Apoptosis; Biphenyl Compounds; Cell Line, Tumor; Cell Movement; Cell Proliferation; Humans; Lignans; MicroRNAs; Multiple Myeloma; NF-kappa B; Signal Transduction

A novel surface plasmon resonance-based P-gp ligand screening system (SPR-PLSS) combined with lentiviral particle (LVP) stabilization strategy was constructed to screen out potential P-gp inhibitors from natural products. Firstly, we constructed LVPs with high and low expression levels of P-gp. The LVPs can ensure the natural conformation of P-gp based on the principle that LVPs germinated from packaging cells will contain cell membrane fragments and P-gp they carry. Then the LVPs with high P-gp expression for active channel and LVPs with low P-gp expression for reference channel were immobilized on CM5 chip respectively. The affinity detection was thus carried out with the signal reduction on the two channels. The P-gp inhibitors, Valspodar (Val) and cyclosporin (CsA), as positive compounds, were detected to characterize the chip's activity, and the K

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Products; Biosensing Techniques; Biphenyl Compounds; Cell Line, Tumor; Cell Survival; Chemistry, Pharmaceutical; Cyclosporine; Cyclosporins; Dogs; Drug Evaluation, Preclinical; HEK293 Cells; Humans; In Vitro Techniques; Kinetics; Lentivirus; Ligands; Lignans; Madin Darby Canine Kidney Cells; MCF-7 Cells; Membrane Proteins; Resveratrol; Surface Plasmon Resonance

Periodontal disease and diabetes mellitus (DM) are both chronic inflammatory and highly prevalent diseases. A large amount of evidence suggested that the accumulation of oxidative stress plays a significant role in the deterioration of both diseases. Magnolol has been known to possess anti-inflammatory and anti-oxidant activities in various tissues, but its effects on gingival cells under diabetic conditions have not been fully understood.. We assessed the generation of reactive oxygen species (ROS), Transwell migration, and wound healing ability in response to the advanced glycation end products (AGEs) stimulation with or without Magnolol treatment. Subsequently, we examined the expression of Nrf2 and HO-1 to ascertain whether Magnolol was able to activate the anti-oxidant signaling. We also measured the secretion of IL-6 and IL-8, and conducted a knockdown experiment to elucidate the effect of Mrf2 on their secretion.. The AGEs-induced ROS was dose-dependently downregulated following the Magnolol treatment. Likewise, the reduced Transwell migration and wound healing ability were improved by various concentrations of Magnolol. Results from qRT-PCR indicated that the suppression of Nrf2 and HO-1 following AGEs stimulation was reversed by Magnolol. Also, the AGEs-elicited production of IL-6 and IL-8 was inhibited by Magnolol. Moreover, our results demonstrated that this anti-inflammatory effect was mediated by the upregulation of Nrf2.. These findings showed that excessive AGEs in the gingiva may lead to the accumulation of ROS and pro-inflammatory cytokines. Supplement of Magnolol may be beneficial to improve the impaired wound healing and inflammation by upregulation of Nrf2 signaling for DM patients with periodontal disease.

Topics: Biphenyl Compounds; Diabetes Mellitus; Glycation End Products, Advanced; Humans; Inflammation; Lignans; Oxidative Stress; Periodontitis; Reactive Oxygen Species

Chaiqin chengqi decoction (CQCQD) and its derivatives have been widely used in China for the early management of patients with acute pancreatitis (AP). Numerous studies demonstrate the anti-inflammatory and anti-oxidative effects of CQCQD and derivatives, but whether these effects can be attributed to suppressing neurogenic inflammation, has never been studied.. To investigate the effects of CQCQD on substance P (SP)-neurokinin 1 receptor (NK1R) based neurogenic inflammation in an experimental AP model.. For AP patients on admission, pain score was accessed by visual analog scale (VAS); the levels of serum SP and expressions of pancreatic SP and NK1R were also determined. For in vivo study, mice received 7 intraperitoneal injections of cerulein (50 μg/kg) at hourly intervals to induce AP, whilst controls received normal saline injections. In the treatment groups, CQCQD (10 g/kg, 200 μl) was intragastrically given at the third, fifth, and seventh of the cerulein injection or the NK1R antagonist CP96345 (5 mg/kg) was intraperitoneally injected 30 min before the first cerulein administration. The von Frey test was performed to evaluate pain behavior. Animals were sacrificed at 12 h from the first cerulein/saline injection for severity assessment. Pharmacology network analysis was used to identify active ingredients of CQCQD for AP and pain. In vitro, freshly isolated pancreatic acinar cells were pre-treated with CQCQD (5 mg/ml), CP96345 (1 μM), or selected active compounds of CQCQD (12.5, 25, and 50 μM) for 30 min, followed by SP incubation for another 30 min.. The VAS score as well as the levels of serum SP and expressions of pancreatic SP-NK1R were up-regulated in moderately severe and severe patients compared with those with mild disease. CQCQD, but not CP96345, consistently and significantly ameliorated pain, pancreatic necrosis, and systemic inflammation in cerulein-induced AP as well as inhibited NK1R internalization of pancreatic acinar cells. These effects of CQCQD were associated with reduction of pancreatic SP-NK1R and neuron activity in pancreas, dorsal root ganglia, and spinal cord. Baicalin, emodin, and magnolol, the top 3 active components of CQCQD identified via pharmacology network analysis, suppressed NK1R internalization and NF-κB signal pathway activation in isolated pancreatic acinar cells.. CQCQD ameliorated cerulein-induced AP and its associated pain via inhibiting neuron activation-mediated pancreatic acinar cell SP-NK1R signaling pathways and its active compounds baicalin, emodin, and magnolol contributed to this effect.

Topics: Acinar Cells; Analgesics; Animals; Anti-Inflammatory Agents; Biphenyl Compounds; Ceruletide; Drugs, Chinese Herbal; Emodin; Flavonoids; Ganglia, Spinal; Humans; Lignans; Male; Mice, Inbred C57BL; Neurons; Pain; Pancreas; Pancreatitis; Receptors, Neurokinin-1; Signal Transduction; Spinal Cord; Substance P

Traditional Chinese medicine (TCM) preparations are very complex mixtures, and the content of bioactive components is usually very low. Therefore, before final analysis, the preparation of an appropriate sample is necessary. Sample preparation is the most time-consuming and error-prone part of the analytical procedure, and the choice of purification technology greatly influences the reliability of the final analysis.. In the present study, we evaluated the feasibility of hollow fiber centrifugal ultrafiltrate (HFCF-UF) as a purification technology for the analysis of bioactive components in TCM preparations. The HFCF-UF technology was applied to analyze honokiol and magnolol in TCM preparations containing Cortex Magnoliae Officinalis (Hou Po in Chinese Pinyin). A mini centrifugal device based on hollow fiber was employed to remove the macromolecule components. A single step of simple centrifugation was required before the filtrate could be directly injected into an existing high performance liquid chromatography (HPLC) system without any further clean-up step or use of special columns. This greatly simplified the pretreatment steps, and improved the accuracy of analytic methods. The separation was achieved on a Diamonsil C18 column (i.d. 5 µm, 150 mm × 4.6 mm) with V (methanol):V (acetonitrile):V (0.5% acetic acid solution) =44:22:34 as the mobile phase at a flow rate of 1.0 mL/min.. It had good linear relationship between the peak areas of honokiol and magnolol and their concentrations at 6.40-205 and 3.15-101 µg/mL (r=0.9999), respectively. The method recovery was over 92.6% with a relative standard deviation (RSD) of less than 3.0%. The average recovery of honokiol was 97.7% with an RSD of 3.0%, and that of magnolol was 96.8% with RSD of 2.8%.. The application of HFCF-UF in TCM preparations could assist in making the quality control of TCM simple, rapid, and accurate. The HFCF-UF purification procedure can be used as an alternative means for analyzing bioactive components in TCM preparations.

Topics: Biphenyl Compounds; Humans; Lignans; Medicine, Chinese Traditional; Reproducibility of Results; Technology

Inhibiting myocardial fibrosis can help prevent cardiovascular diseases, including heart failure. Magnolol (Mag), a natural component of Magnoliae officinalis, has been reported to inhibit fibrosis. However, the mechanism of Mag activity and its effects on myocardial fibrosis remain unclear. Here, we investigated the involvement of ALDH2, an endogenous protective agent against myocardial fibrosis, in the Mag-mediated inhibition of cardiac fibroblast proliferation and collagen synthesis. We found that Mag significantly inhibited cardiac fibroblast proliferation and collagen synthesis, based on the results of MTT, EdU and western blot assays. Moreover, molecular docking, molecular dynamics simulation and surface plasmon resonance (SPR) assays showed that Mag could bind directly and stably to ALDH2. Further analysis of the mechanism of these effects indicated that treatment with Mag dose-dependently enhanced ALDH2 activity without altering protein expression. Mag could enhance the activity of recombinant human ALDH2 proteins with a half-maximal effective concentration of 5.79 × 10

Topics: Aldehyde Dehydrogenase, Mitochondrial; Biphenyl Compounds; Cell Proliferation; Collagen; Dose-Response Relationship, Drug; Fibroblasts; Humans; Lignans; Magnolia; Molecular Structure; Myocytes, Cardiac; Structure-Activity Relationship

Although magnolol (Mag), an anti-inflammatory natural compound, has been demonstrated to play protective effects on ulcerative colitis (UC), its application as an alternative therapeutic reagent for UC treatment is still greatly impeded due to its poor stability in the gastrointestinal tract and insufficient accumulation in the inflamed colon lesion. Nano-/microsized drug delivery systems can potentially overcome some challenges regarding the oral administration of phytochemicals, which still confront premature early drug release, degradation of NPs, or the sustained drug release of MPs. In this study, we primarily loaded Mag into the core-shell zein-based nanoparticles with chondroitin sulfate coating (Mag@CS-Zein NPs) with an average size of 142.27 ± 5.11 nm, showing significant macrophage-targeting and enhanced colon epithelial cellular uptake capacity. Then, we embedded Mag@CS-Zein NPs into hydrogel microspheres via an electrospraying technology. The Mag@CS-Zein NPsinMPs presented a uniform-sized sphere with an average size of 164.36 ± 6.29 μm and sustained drug-release profiles. Compared to CS-Zein NPs, the developed CS-Zein NPsinMPs exhibited prolonged colon retention on the inflammatory surface, as seen from

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Biphenyl Compounds; Cell Line, Tumor; Chondroitin Sulfates; Colitis, Ulcerative; Colon; Dextran Sulfate; Drug Carriers; Drug Liberation; Humans; Hydrogels; Lignans; Male; Mice, Inbred ICR; Microspheres; Nanoparticles; Occludin; Zein; Zonula Occludens-1 Protein

Magnolol (MAG), a biphenolic neolignan, has various biological activities including antitumor effects. In this study, 15 MAG derivatives were semi-synthesized and evaluated for their in vitro anticancer activities. From these derivatives, compound

Topics: Antineoplastic Agents; Biphenyl Compounds; Cell Line, Tumor; Cell Movement; Cell Proliferation; Drug Screening Assays, Antitumor; Female; Humans; Lignans; Neoplasm Invasiveness; Triple Negative Breast Neoplasms

The aims of this study were to develop the magnolol-chitosan films and study the positive effect of the combination of magnolol and chitosan. The addition of magnolol made the magnolol-chitosan films exhibit higher density (1.06-1.87 g/cm

Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Biphenyl Compounds; Chitosan; Food Packaging; Food Preservation; Lignans; Pork Meat; Pseudomonas aeruginosa; Pseudomonas Infections; Swine

In this study, twenty novel cinnamic acid magnolol derivatives were synthesized, and screened for their anti-hyperglycemic potential. All synthesized compounds exhibited good to moderate α-glucosidase and α-amylase inhibitory activities with IC

Topics: alpha-Amylases; alpha-Glucosidases; Biphenyl Compounds; Cinnamates; Dose-Response Relationship, Drug; Glycoside Hydrolase Inhibitors; Humans; Lignans; Molecular Docking Simulation; Molecular Structure; Structure-Activity Relationship

Topics: Biphenyl Compounds; Cell Membrane; Lignans; Plant Diseases; Rhizoctonia

Although hepatitis B and/or hepatitis C virus were recognized as major risk factor for the development of hepatocellular carcinoma (HCC), certain occupational, environmental, and lifestyle factors also play key roles in HCC tumorigenesis. Moreover, in molecular signaling route, extracellular signal-regulated kinase (ERK)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling was found to be overexpressed and linked to poor prognosis in HCC. Thus, to identify possible nature compound that can suppress ERK/NF-κB may be benefit to HCC patient. Magnolol, a natural compound derived from herbal plant Magnolia officinalis, has been recognized as a liver protection and antitumor reagent. However, whether magnolol-inhibited HCC progression correlates with disruption of ERK/NF-κB signaling is remained unclear. In this studies, we performed SK-Hep1/luc2 HCC bearing animal model to investigate the anticancer efficacy and mechanism of magnolol on tumor progression. Tumor size and tumor growth rate were dramatically suppressed after treatment of magnolol. In addition, expression of phospho-ERK (p-ERK), NF-κB p65 (Ser536), and tumor progression-associated proteins, such as matrix metallopeptidase 9 (MMP-9), vascular endothelial growth factor (VEGF), X-linked inhibitor of apoptosis protein (XIAP), and CyclinD1 were all significantly decreased by magnolol. Most important, major extrinsic and intrinsic apoptosis signaling factors, including active caspase-8 and caspase-9 were both enhanced by magnolol. This study indicated that apoptosis induction through extrinsic/intrinsic pathways and blockage of ERK/NF-κB activation were associated with magnolol-inhibited tumor progression in HCC in vivo.

Topics: Animals; Apoptosis; Biphenyl Compounds; Carcinoma, Hepatocellular; Cell Line, Tumor; Disease Progression; Extracellular Signal-Regulated MAP Kinases; Humans; Lignans; Liver Neoplasms, Experimental; Medicine, Chinese Traditional; NF-kappa B; Signal Transduction; Transcription Factor RelA

Topics: AMP-Activated Protein Kinases; Biomarkers; Biphenyl Compounds; Chondrocytes; Gene Expression Regulation; Humans; Interleukin-1beta; Lignans; Membrane Potential, Mitochondrial; Mitochondria; NF-kappa B; Oxidative Stress; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Reactive Oxygen Species; Signal Transduction; Sirtuin 1

This study aims to investigate whether magnolol (MG), a natural neolignane compound, can prevent AD induced by beta-amyloid (Aβ) and the possible mechanisms involved. MG dose-dependently reduces Aβ deposition, toxicity and memory impairment caused by Aβ in transgenic C. elegans. More importantly, these effects are reversed by GW9662, a selective peroxisome proliferator-activated receptor-γ (PPAR-γ) antagonist. MG is more effective in enhancing PPAR-γ luciferase levels than honokiol (HK). Meanwhile, MG has the potential to bind with the ligand binding domain of PPAR-γ (PPAR-γ-LBD). As expected, MG inhibited the luciferase activity of NF-κB and its target genes of inflammatory cytokines, and this effect was blocked by GW9662. The luciferase activity of Nrf2-ARE expression can be activated by MG and decreased Aβ-induced reactive oxygen species (ROS). The target gene LXR of PPAR-γ is activated by MG, which upregulates ApoE and promotes microglia phagocytosis and the degradation of Aβ, and these effects were also reversed by GW9662. In summary, MG can attenuate Aβ-induced AD and the underlying mechanism is the reduction of inflammation and promotion of phagocytosis and degradation of Aβ, which is dependent on PPAR-γ.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Animals, Genetically Modified; Apolipoproteins E; Biphenyl Compounds; Caenorhabditis elegans; Disease Models, Animal; Dose-Response Relationship, Drug; Humans; Inflammation; Lignans; Microglia; NF-kappa B; Phagocytosis; PPAR gamma

With the aim to discover interesting lead compounds that could be further developed into compounds active against pharmacoresistant epilepsies, we first collected 14 medicinal plants used in traditional Chinese medicine (TCM) against epilepsy. Of the six extracts that tested positive in a pentylenetetrazole (PTZ) behavioral zebrafish model, only the ethanol and acetone extracts from

Topics: Animals; Anticonvulsants; Biphenyl Compounds; Epilepsy; Lignans; Magnolia; Medicine, Chinese Traditional; Mice; Plant Extracts; Zebrafish

Topics: Biphenyl Compounds; Cell Differentiation; Humans; Lignans; Skin

Magnolia extract (ME) is known to inhibit cancer growth and metastasis in several cell types in vitro and in animal models. However, there is no detailed study on the preventive efficacy of ME for oral cancer, and the key components in ME and their exact mechanisms of action are not clear. The overall goal of this study is to characterize ME preclinically as a potent oral cancer chemopreventive agent and to determine the key components and their molecular mechanism(s) that underlie its chemopreventive efficacy.. The antitumor efficacy of ME in oral cancer was investigated in a 4-nitroquinoline-1-oxide (4NQO)-induced mouse model and in two oral cancer orthotopic models. The effects of ME on mitochondrial electron transport chain activity and ROS production in mouse oral tumors was also investigated.. ME did not cause detectable side effects indicating that it is a promising and safe chemopreventive agent for oral cancer. Three major key active compounds in ME (honokiol, magnolol and 4-O-methylhonokiol) contribute to its chemopreventive effects. ME inhibits mitochondrial respiration at complex I of the electron transport chain, oxidizes peroxiredoxins, activates AMPK, and inhibits STAT3 phosphorylation, resulting in inhibition of the growth and proliferation of oral cancer cells.. Our data using highly relevant preclinical oral cancer models, which share histopathological features seen in human oral carcinogenesis, suggest a novel signaling and regulatory role for mitochondria-generated superoxide and hydrogen peroxide in suppressing oral cancer cell proliferation, progression, and metastasis. Video abstract.

Topics: Animals; Antineoplastic Agents, Phytogenic; Biphenyl Compounds; Cell Line, Tumor; Drug Evaluation, Preclinical; Female; Humans; Lignans; Magnolia; Mice; Mice, Nude; Mitochondria; Mouth Neoplasms; Plant Extracts; Reactive Oxygen Species

Topics: Animals; Apoptosis; Biphenyl Compounds; Cell Line, Tumor; Cell Proliferation; Cell Survival; Colorectal Neoplasms; Disease Progression; Humans; Lignans; Male; Mice, Inbred BALB C; Mitochondria; Neoplasm Invasiveness; NF-kappa B; Phosphorylation; Protein Kinase C-delta; Protein Kinase Inhibitors; Receptors, Death Domain; Signal Transduction

Intestinal obstruction (IO) is a kind of acute abdomen with high morbidity and mortality. Patients suffer from poor quality of life and tremendous financial pressure. Da-Cheng-Qi decoction (DCQD), a classical purgation prescription, has clinically been proven to be an effective treatment for IO.. Network pharmacology integrated with bioactive equivalence assessment was used to discover the quality marker (Q-marker) of DCQD against IO.. As there is hardly any targets recorded in database, thus the collection of IO targets was conducted by searching those of alternative diseases which have similar pathological symptoms with IO. In order to improve the reliability of the obtained targets, IO metabolomics data was introduced. Active compounds combination (ACC) was focused as potential Q-markers via component-target network analysis and function query from the identified components corresponding to the common targets. Bioequivalence between ACC and DCQD was assessed from the aspects of intestine motility (somatostatin secretion), inflammation (IL-6 secretion) and injury (wound healing assay) in vitro and was further validated in ileus rat model. PPI network analysis of core targets followed by gene pedigree classification and experimental validation confirmed the potential intervention pathway.. A combination of 11 ingredients, including emodin, physcion, aloe-emodin, rhein, chrysophanol, gallic acid, magnolol, honokiol, naringenin, tangeretin, and nobiletin was finally confirmed bioequivalence with DQCD to some extent and could serve as Q-markers for DCQD to attenuate IO. PI3K/AKT was verified as a possible affected pathway that DCQD exerted the effectiveness against IO.. For the disease with few recorded targets, searching those of alternative diseases which have similar pathological symptoms could be a feasible and effective approach. The proposed network pharmacology integrated bioactive equivalence evaluation paradigm is efficient to discover Q-marker of herbal formulae.

Topics: Algorithms; Animals; Anthraquinones; Biomarkers, Pharmacological; Biphenyl Compounds; Data Mining; Drugs, Chinese Herbal; Flavanones; HT29 Cells; Humans; Intestinal Obstruction; Lignans; Male; Phosphatidylinositol 3-Kinases; Rats, Sprague-Dawley; Reproducibility of Results; Therapeutic Equivalency

Advances in cancer nanotechnology aim at improving specificity and effectiveness for tumor treatment. Amalgamation of different treatment modalities is expected to provide better cancer combating. Herein, We developed a long circulating nanocarrier comprising trastuzumab (TZB) surface modified polylactic-co-glycolic acid (PLGA) nanoparticles (NPs) co-encapsulating magnolol (Mag) and gold nanoparticles (GNPs). A modified single step nanoprecipitation method was adopted ensuring particle coating with D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) while co-encapsulating GNPs. TZB was then anchored on NPs surface using a carbodiimide chemistry. The cytotoxicity of the developed system was evaluated with and without photothermal irradiation. NPs cellular uptake was then followed using confocal microscopical imaging. A hybrid matrix composed of PLGA/TPGS and surface decorated with TZB with a conjugation efficiency of ˃65%, was confirmed via FTIR,

Topics: Adenocarcinoma; Antineoplastic Agents, Phytogenic; Biphenyl Compounds; Breast Neoplasms; Cell Line, Tumor; Drug Carriers; Drug Compounding; Drug Liberation; Female; Gold; Humans; Lignans; Metal Nanoparticles; Microscopy, Confocal; Oxazines; Particle Size; Photothermal Therapy; Polylactic Acid-Polyglycolic Acid Copolymer; Proton Magnetic Resonance Spectroscopy; Spectroscopy, Fourier Transform Infrared; Surface Properties; Trastuzumab; Vitamin E

Cancer cachexia is a complex and multifactorial syndrome that influences about 50-80% of cancer patients and may lead to 20% of cancer deaths and muscle atrophy is the key characteristic of the syndrome. Recent researches have shown that myostatin is a negative regulator in the growth and differentiation of skeletal muscle. Herein, C2C12 cancer cachexia model was established with C26 conditioned culture medium (CCM), then treated with magnolol to evaluate the pharmacological activity of magnolol in myotube atrophy. Our results demonstrated that magnolol inhibited the activity of myostatin promotor and the myostatin signaling pathway. In C2C12 cancer cachexia model, magnolol decreased myostatin expression, inhibited the phosphorylation of SMAD2/3 activated by C26 conditioned culture medium (CCM), and elevated the phosphorylation of FOXO3a lowered by CCM. Myosin heavy chain (MyHC), myogenin (MyoG), and myogenic differentiation (MyoD), as three common myotube markers in C2C12 myotube, were decreased by CCM, which could be effectively reversed by magnolol via activation of AKT/mTOR-regulated protein synthesis and inhibition of ubiquitin-mediated proteolysis. This study reveals that magnolol inhibits myotube atrophy induced by CCM by increasing protein synthesis and decreasing ubiquitin-mediated proteolysis, so that magnolol is a promising leading compound in treating muscle atrophy induced by cancer cachexia.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Biological Products; Biphenyl Compounds; Cachexia; Cell Line, Tumor; Humans; Lignans; Mice; Muscle Fibers, Skeletal; Muscular Atrophy; Myostatin; Neoplasms; Transfection

Magnolol, known to have extensive biological activities, is the major bioactive ingredient isolated from the root and stem bark of

Topics: Administration, Oral; Animals; Biological Availability; Biphenyl Compounds; Caco-2 Cells; Drug Delivery Systems; Humans; Lignans; Micelles; Microscopy, Electron, Transmission; Nanoparticles; Poloxamer; Polyethylene Glycols; Polyvinyls; Rats; Surface-Active Agents; Suspensions

Two isomeric biphenyl neolignans, magnolol and honokiol, are considered as constituents responsible for the healing effect of magnolia bark, a traditional Oriental medicine. To survey the increasing number of dietary supplements that contain magnolia bark or its extract, an affordable quantitative thin-layer chromatography (TLC) - densitometry method was developed. The methanol extracts were analyzed on the silica gel plates after manual sample application using n-hexane - ethyl acetate - ethanol (16:3:1, v/v/v) as a mobile phase. For quantitation, the chromatograms were scanned in the absorbance mode at the wavelength λ = 290 nm. The limits of detection and quantitation were 90 and 280 ng/zone for magnolol and 70 and 200 ng/zone for honokiol, respectively. None of the two targeted neolignans were detected in two of the six analyzed supplements. In the other four samples, the measured amounts were between 0.95-114.69 mg g

Topics: Biphenyl Compounds; Chromatography, Thin Layer; Densitometry; Dietary Supplements; Lignans; Limit of Detection; Magnolia; Medicine, East Asian Traditional; Plant Bark

In the present study, a novel strategy based on unidirectional freezing and atom transfer radical polymerization combined with activator regenerated by electron transfer (ARGET-ATRP) was applied to synthesizing orderly macroporous monolithic column with restricted-access (RA) property in a 1000μL pipette tip. The RA column was composed of hydrophobic inner column (poly(styrene-co-ethylene glycol dimethacrylate) and hydrophilic outer layer (poly-hydroxyethyl methacrylate chain) which was grafted on the hydrophobic surface by means of the second ARGET-ATRP reaction. The as-prepared RA monolithic tip was connected to a 2mL syringe for directly extracting magnolol and honokiol from rat plasma just by manually pushing operation. The surface morphology and chemical composition of the column were characterized by scanning electronic microscope, infrared spectroscopy and X-ray photoelectron spectroscopy respectively. The determined results of evaluation experiments based on the optimized solid phase extraction conditions showed that the RA column possessed good protein exclusion power, extraction recovery and reusability. The constructed RA-SPE-HPLC/UV method for simultaneously analyzing magnolol and honokiol in rat plasma was validated with quality control (QC) samples at four concentration levels. Good precision (RSDs, 3.39~11.16%) and acceptable accuracy (relative recoveries, 89.52%~108.42%) were obtained for intra- and inter-day assays. The determined results of real rat plasma as well as the standard-addition samples demonstrated the developed method with good accuracy and precision. It can be extrapolated from the experimental results that this simple and cost-efficient RA-SPE method is also suitable for directly extracting other hydrophobic constituents in biological body fluid for therapeutic drug monitoring or pharmacokinetic study.

Topics: Animals; Biphenyl Compounds; Chromatography, High Pressure Liquid; Freezing; Hydrophobic and Hydrophilic Interactions; Lignans; Methacrylates; Polyethylene Glycols; Quality Control; Rats; Reproducibility of Results; Solid Phase Extraction

Magnolol, a natural bioactive neolignan, was found in the bark of a traditional Chinese medicine Magnoliae officinalis ("Hou Po" in Chinese). In this study, thrity-two magnolol-based Mannich base derivatives 3a-p and 4a-p were synthesized, and evaluated for their anti-proliferative activities against a panel of human tumor cell lines (T47D, MCF-7, Hela and A549). Among all derivatives, compound 3p displayed the most potent antiproliferative activity against T47D, MCF-7 and Hela cell lines with IC

Topics: Antineoplastic Agents; Autophagy; Biphenyl Compounds; Cell Line, Tumor; Chemistry Techniques, Synthetic; Humans; Lignans; Mannich Bases; Structure-Activity Relationship

Melanoma is an aggressive form of skin cancer for which there are no effective drugs for prolonged treatment. The existing kinase inhibitor antiglycolytic drugs (B-Raf serine/threonine kinase or BRAF inhibitors) are effective for a short time followed by a rapid onset of drug resistance.. Here, we show that a mitochondria-targeted analog of magnolol, Mito-magnolol (Mito-MGN), inhibits oxidative phosphorylation (OXPHOS) and proliferation of melanoma cells more potently than untargeted magnolol. Mito-MGN also inhibited tumor growth in murine melanoma xenografts. Mito-MGN decreased mitochondrial membrane potential and modulated energetic and mitophagy signaling proteins.. Results indicate that Mito-MGN is significantly more potent than the FDA-approved OXPHOS inhibitor in inhibiting proliferation of melanoma cells.. These findings have implications in the treatment of melanomas with enhanced OXPHOS status due to metabolic reprogramming or drug resistance.

Topics: Animals; Autophagy; Biphenyl Compounds; Cell Line, Tumor; Cytoprotection; Humans; Lignans; Melanoma; Mice; Mice, Nude; Mitophagy; Nitric Oxide Synthase; Oxidative Phosphorylation

Magnolol is a biologically active compound, isolated from the Chinese herb

Topics: A549 Cells; Apoptosis; Biphenyl Compounds; CASP8 and FADD-Like Apoptosis Regulating Protein; Cell Line, Tumor; Cell Proliferation; Down-Regulation; HeLa Cells; Humans; Lignans; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasms; Proteasome Endopeptidase Complex; Receptors, TNF-Related Apoptosis-Inducing Ligand; TNF-Related Apoptosis-Inducing Ligand; Up-Regulation

Topics: Alternaria; Biphenyl Compounds; Fungal Proteins; Fungicides, Industrial; Gene Expression Regulation, Fungal; Gene Regulatory Networks; Lactones; Lignans; Mycotoxins; Transcriptome

In the present work, the anti-inflammatory and antiasthmatic potential of biseugenol, isolated as the main component from

Topics: Animals; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Biological Availability; Biphenyl Compounds; Computer Simulation; Disease Models, Animal; Granulocytes; Inflammation; Lignans; Linear Models; Male; Mice, Inbred BALB C; Phenyl Ethers; Respiratory Function Tests; Respiratory Hypersensitivity

Honokiol and magnolol were considered as markers for the analysis of Cortex Magnoliae Officinalis, its related Chinese Patent Medicines and their metabolites. However, the determination of these two analytes in a water-soluble sample is difficult and therefore requires a more efficient method.. To develop a sensitive method for the determination of honokiol and magnolol in a water-soluble sample for better quality control of Cortex Magnoliae Officinalis and its related Chinese Patent Medicines.. In this work, a combination of dispersive micro-solid-phase extraction (DMSPE) and high-performance liquid chromatography (HPLC) has been developed for simultaneous preconcentration and determination of honokiol and magnolol in complex bio-samples. Several experimental factors affecting the extraction efficiency were optimized by single factor test.. Under the optimized extraction conditions, the proposed method exhibited good linearity of not less than 0.9998, satisfactory precision with relative standard deviation of less than 1.3%, and acceptable mean recoveries of 97.3% and 101.5% for honokiol and magnolol, respectively. Furthermore, the method exhibits extremely high sensitivity with detection limits of 0.0097 and 0.0231 ng/mL, which is even more sensitive than those methods developed by MS.. The method established in this study is fast, economic, accurate, easy to operate, and importantly well suited to the extraction and analysis of honokiol and magnolol in a real complex sample matrix.

Topics: Biphenyl Compounds; Chromatography, High Pressure Liquid; Lignans; Magnolia; Solid Phase Extraction

Herein, we sought to evaluate the contribution of the 1,3,5-triazine ring through the metformin cyclization unit to the biological activity of magnolol and honokiol-conjugates. One of the phenolic OH groups of magnolol or honokiol was replaced by a 1,3,5-triazine ring to further explore their synthesis and medicinal versatility. In this study, a robust procedure of three steps was adopted for the synthesis of magnolol and honokiol derivatives by alkylation of potassium carbonate with a 1,3,5-triazine ring. To our knowledge, this is the first report to connect one of the phenolic OH positions of magnolol or honokiol to a 1,3,5-triazine ring cyclized by metformin. The structural characterization of three new compounds was carried out via spectroscopic techniques, i.e.,

Topics: Animals; Antineoplastic Agents; Biphenyl Compounds; Cell Line, Tumor; Cell Survival; Chemistry Techniques, Synthetic; Cyclization; Cytokines; Gene Expression Regulation; Humans; Lignans; Macrophages; Metformin; Mice; Molecular Structure; RAW 264.7 Cells; Structure-Activity Relationship; Triazines

The antifungal activity of magnolol and honokiol, two naturally occurring hydroxylated biphenyls, and of their synthetic derivatives was evaluated on a collection of representative isolates of Fusarium oxysporum, F. solani and F. verticillioides of clinical and ecological concern. The tested compounds were proposed as a 'natural' alternative to conventional fungicides, even though a larger range of concentrations (5-400 μg/ml) was applied. The activity of magnolol and honokiol was compared with that of terbinafine (0.1-10 μg/ml), and fluconazole (1-50 μg/ml), two fungicides widely used in treating fungal infections on humans. Magnolol showed similar fungicidal activity compared to fluconazole, whereas honokiol was more effective in inhibiting mycelium growth compared to this fungicide on all tested clinical Fusarium spp. isolates. Compared to terbinafine, honokiol showed similar antifungal activity when tested on clinical F. solani isolates, whereas magnolol was less effective at all selected concentrations (5-400 μg/ml). The different position of the phenol-OH group, as well as its protection, explain different in vitro activities between magnolol, honokiol, and their derivatives. Furthermore, magnolol showed mycelium dry weight reduction at a concentration of 0.5 mM when tested on a set of agricultural isolates of Fusaria, leading to complete inhibition of some of them. Magnolol and honokiol are proposed as efficient and safe candidates for treating clinically relevant Fusaria.

Topics: Antifungal Agents; Biphenyl Compounds; Fusariosis; Fusarium; Humans; Lignans; Microbial Sensitivity Tests; Plant Diseases

Magnoliae Cortex contains a range of bioactive components including terpenes (e.g. α-, β- and γ-eudesmol), phenylpropanoids (e.g. honokiol and magnolol) and alkaloids (e.g. magnocurarine). We recently reported that pretreatment of PC12 cells with Magnoliae Cortex extract significantly suppresses cytotoxicity induced by H

Topics: Animals; Biphenyl Compounds; Catalase; Cell Death; Cell Survival; Hydrogen Peroxide; Lignans; NAD(P)H Dehydrogenase (Quinone); Oxidopamine; PC12 Cells; Protective Agents; Rats

Magnolol, a neolignan natural product with antioxidant properties, contains inherent, orthogonal, phenolic, and alkenyl reactive groups that were used in both direct thermoset synthesis, as well as the stepwise synthesis of a small library of monomers, followed by transformation into thermoset materials. Each monomer from the small library was prepared via a single step functionalization reaction of the phenolic groups of magnolol. Thermoset materials were realized through solvent-free, thiol-ene reactions, and the resulting cross-linked materials were each comprised of thioether and ester linkages, with one retaining the hydrophilic phenols from magnolol, another having the phenols protected as an acetonide, and two others incorporating the phenols into additional cross-linking sites via hydrolytically labile carbonates or stable ether linkages. With this diversity of chemical compositions and structures, the thermosets displayed a range of thermomechanical properties including glass transition temperatures, T

Topics: 3-Mercaptopropionic Acid; Animals; Antioxidants; Biodegradable Plastics; Biphenyl Compounds; Cattle; Cells, Cultured; Endothelial Cells; Lignans; Phenols; Propylene Glycols; Stimuli Responsive Polymers; Stress, Mechanical; Temperature

Magnolol and honokiol are the main active components of Magnolia officinalis Rehd. et Wils. The study of their interactions with liver microsomes is very important for the clinical safety of M. officinalis Rehd. et Wils.. The main metabolites of magnolol and honokiol in rat liver microsomes were investigated using ultrahigh-performance liquid chromatography/mass spectrometry and their possible structures were identified. In addition, cytochrome P450 (CYP450) isoenzymes of the major rat metabolites of magnolol and honokiol were identified using a specific inhibitor.. This study suggests that the CYP2E1 subtype is responsible for the oxidation of magnolol and honokiol terminal double bonds to epoxy metabolites. CYP3A4 appears to be the major subtype responsible for further hydrolytic metabolism, while CYP1A2 may promote decarboxylation of the metabolites. CYP2A6 may be the main subtype responsible for the hydrogenation of magnolol (p < 0.05).. This study demonstrated that different CYP450 enzyme isoforms showed different activities in the in vitro metabolism of magnolol and honokiol in rat liver microsomes. It has certain practical applications in that we should pay attention to drug-drug interactions in clinical medications and also to drug-enzyme interactions.

Topics: Animals; Biphenyl Compounds; Chromatography, High Pressure Liquid; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Inactivation, Metabolic; Inhibitory Concentration 50; Lignans; Male; Mass Spectrometry; Microsomes, Liver; Rats, Sprague-Dawley; Substrate Specificity

Magnolol is a natural extract and the main bioactive component from Chinese medicine-Magnolia. We speculate that it's functional action might be associated with the anti-inflammatory effects of magnolol. Herein, the main purpose was to elucidate the phagocytic immune function and anti-inflammatory activities associated. The toxicity of magnolol on U937 and LO-2 cells was assayed by MTT, flow cytometry and laser scanning confocal microscope was utilized to detect the phagocytosis effect on U937 cells, C57BL/6 mice and the follow-up hematoxylin-eosin staining methods were used to evaluate its bioactivity in vivo. The results showed that magnolol had dose dependent effects on enhancement of phagocytosis ability and significantly inhibited the NO production at the concentration range from10 to 40 μM. Furthermore, Magnolol significantly reduced the gene expression and protein release of IL-1β and TNF-α. However, the p-ERK1/2 in MAPK signaling pathway was not significantly affected by magnolol, whereas p-JNK and p-P38 were down-regulated. Magnolol also inhibited the expression of p-IκBα and p-P65 of NF-κB signaling pathways. The loss of body weight and the shorter length of colon were significantly improved in DSS-treated colitis C57BL/6 mice after the administration of magnolol. The cytokines of pro-inflammatory factors TNF-α, IL-6 and IL-1β attenuated significantly in a concentration dependent manner. The histopathological manifestations of 5-20 mg/kg after the treatment magnolol were markedly improved in the DSS-treated mice. These findings showed that magnolol exerted an anti-inflammatory effect through immunoregulatory phagocytosis, MAPK and NF-κB signaling pathways. Our results provide experimental evidence and theory basis for research on anti-inflammatory effects for magnolol as a potentially anti-inflammatory drug candidate.

Topics: Animals; Biphenyl Compounds; Cytokines; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; Female; Humans; Inflammation; Lignans; MAP Kinase Signaling System; Mice; NF-kappa B; Phagocytosis; U937 Cells

Magnolol (Mag), an effective natural compound isolated from the stem bark of Magnolia officinalis, was found to have the potential for antitumor activity by inducing apoptosis in tumor cells. However, the effect of Mag on renal carcinoma cells and its molecular mechanism are unexplored. Our study provided evidence that Mag induced apoptosis in 786-O and OS-RC-2 cell lines via the mitochondrial pathway and cell cycle arrest. In this work, we found that Mag induced morphological changes and inhibited the proliferation of 786-O and OS-RC-2 cells in a dose- and time-dependent manner but exerted no notable inhibitory effects on normal human renal proximal tubular (HK-2) cells. Treatment with Mag suppressed the migration and invasion ability of renal carcinoma cells. Moreover, Mag caused the openness of mPTP, the accumulation of intracellular ROS and decreased △Ψm, leading to mitochondrial dysfunction. However, pretreatment with the antioxidant N-acetyl cysteine (NAC) reversed the apoptosis induced by Mag and decreased the generation of ROS. In addition, the increased proportion of the G1/G0 phase indicated that Mag caused cell cycle arrest. Further analyses suggested that magnolol-induced apoptosis was related to the abnormal expression of p53, Bax, Bcl-2, cytochrome c and caspase activation. Together, the results above revealed that Mag had antitumor effects in renal carcinoma cells via ROS production as well as cell cycle arrest and the apoptotic mitochondrial pathway was suppressed in part by NAC.

Topics: Apoptosis; Apoptosis Regulatory Proteins; Biphenyl Compounds; Cell Cycle; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Movement; Cell Proliferation; Humans; Inhibitory Concentration 50; Kidney Neoplasms; Lignans; Membrane Potential, Mitochondrial; Mitochondria; Neoplasm Metastasis; Reactive Oxygen Species

Intracerebral haemorrhage (ICH) induces inflammation, which can cause severe secondary injury. Recent evidence has suggested that magnolol (MG) has a protective effect against ischaemic stroke through the inhibition of inflammation. However, the anti-inflammatory effect of MG in intracerebral haemorrhage (ICH) remains unclear. Here, we report that the protective effect of MG in a rat model of ICH can be achieved by anti-inflammatory processes. We found that MG administration significantly reduced the brain water content, restored the blood-brain barrier (BBB) and subsequently attenuated neurological deficits via decreasing the activation of glial cells, decreasing the infiltration of neutrophils and reducing the production of pro-inflammation factors (IL-1β, TNF-α and MMP-9) in a rat model of ICH. These results suggest that MG reduced inflammatory injury and improved neurological outcomes in ICH model.

Topics: Animals; Anti-Inflammatory Agents; Astrocytes; Biphenyl Compounds; Blood-Brain Barrier; Brain; Brain Edema; Brain Ischemia; Cerebral Hemorrhage; Cytokines; Disease Models, Animal; Inflammation; Lignans; Male; Neuroglia; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Stroke

Most BRAF-mutant melanoma patients experience a fulminate relapse after several months of treatment with BRAF/MEK inhibitors. To improve therapeutic efficacy, natural plant-derived compounds might be considered as potent additives. Here, we show that magnolol, a constituent of Magnolia officinalis, induced G1 arrest, apoptosis and cell death in BRAF- and NRAS-mutant melanoma cells at low concentration, with no effect in BRAF- and NRAS wild-type melanoma cells and human keratinocytes. This was confirmed in a 3D spheroid model. The apoptosis-inducing effect of magnolol was completely rescued by activating Akt suggesting a mechanism relying primarily on Akt signaling. Magnolol significantly downregulated the PI3K/Akt pathway which led to a global decrease of the active histone mark H3K4me3. Alongside, the repressive histone mark H3K9me3 was increased as a response to DNA damage. Magnolol-induced alterations of histone modifications are reversible upon activation of the Akt pathway. Magnolol-induced a synergistic effect in combination with either BRAF/MEK inhibitors dabrafenib/trametinib or docetaxel at a lower concentration than usually applied in melanoma patients. Combination of magnolol with targeted therapy or chemotherapy also led to analogous effects on histone marks, which was rescued by Akt pathway activation. Our study revealed a novel epigenetic mechanism of magnolol-induced cell death in melanoma. Magnolol might therefore be a clinically useful addition to BRAF/MEK inhibitors with enhanced efficacy delaying or preventing disease recurrence.

Topics: Apoptosis; Biphenyl Compounds; Cell Death; Cell Line, Tumor; Epigenesis, Genetic; G1 Phase Cell Cycle Checkpoints; Gene Expression Regulation, Neoplastic; GTP Phosphohydrolases; Humans; Lignans; Melanoma; Membrane Proteins; Models, Biological; Mutation; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-akt; Signal Transduction

Magnolol is a compound that is extracted from magnolia, is used in Chinese medicine and is a type of lignan. Magnolol has various anti-inflammation, anti-proliferation and pro-autophagy effects. Ossified tendinopathy affects many athletes and people with repetitive tendon injuries. Ossified tendinopathy is a tremendous economic burden, and no effective and safe drugs are available to prevent the pathogenesis of ectopic ossification. In this study, we aimed to study how magnolol affects ossified tendinopathy by evaluating its effects on osteogenic differentiation of tendon-derived stem cells (TDSCs). Our data suggested that magnolol attenuated ectopic ossification in the Achilles tendon caused by Achilles tenotomy. Magnolol inhibited PGE2-induced ALP activity and prevented calcium deposits in TDSCs in vitro. Magnolol also exerted inhibitory effects on expression of osteogenic factors, such as Runx2, OCN, and BMP2 in vivo. Further investigation revealed the underlying mechanism by which magnolol prevents PGE2-induced ectopic ossification. Specifically, magnolol inhibits PGE2-induced PI3K/AKT/β-catenin pathway activation in TDSCs. Our findings demonstrated that magnolol inhibited ossified tendinopathy through preventing osteogenic differentiation of TDSCs via downregulation PGE2-induced PI3K/AKT/β-catenin pathways.

Topics: Achilles Tendon; Animals; Anti-Inflammatory Agents; beta Catenin; Biphenyl Compounds; Cell Differentiation; Cells, Cultured; Dinoprostone; Humans; Lignans; Male; Medicine, Chinese Traditional; Osteogenesis; Phosphatidylinositol 3-Kinases; Rats; Rats, Sprague-Dawley; Signal Transduction; Tendinopathy; Tenotomy

Magnolol is the active component of the traditional Chinese medicine Magnolia officinalis, and has antioxidant, anti‑inflammatory and anticancer activities, as well as an effect on bone metabolism in vitro. In the present study, it is reported that magnolol suppresses osteoclastogenesis in vivo and in vitro. Magnolol prevented ovariectomy‑induced bone loss and osteoclastogenesis in vivo, and decreased the serum levels of C‑terminal telopeptide of type 1 collagen, interleukin‑6, tumor necrosis factor (TNF)‑α and tartrate‑resistant acid phosphatase 5B. In vitro, magnolol inhibited the osteoclastogenesis induced by the receptor activator for nuclear factor‑κB ligand, and impaired the osteoclast function in bone marrow monocytes and RAW264.7 cells in a dose‑dependent manner. Furthermore, magnolol suppressed the expression levels of the osteoclastogenesis markers cathepsin K, calcitonin receptor, matrix metalloproteinase 9, TNF receptor‑associated factor 6 and tartrate‑resistant acid phosphatase by inhibiting the nuclear factor‑κB and mitogen‑activated protein kinase pathways. Therefore, magnolol is a promising agent for the treatment of osteoporosis and associated disorders.

Topics: Actins; Animals; Biomarkers; Biphenyl Compounds; Bone Resorption; Lignans; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; NF-kappa B; Osteoclasts; Osteogenesis; Ovariectomy; Phosphorylation; RAW 264.7 Cells

Oxaliplatin (OXL) is the first line treatment therapy for gastrointestinal (GI) cancers and often combines with other chemotherapy. However, few reports have studied on its GI toxicity. Magnolol (MG), one of the mainly active constituents in Magnolia, has been reported to treat digestive diseases. Therefore, the purpose of this study is to evaluate the intestinal protective effect of MG in OXL treatment group. OXL administration mice showed body weight loss, diarrhea, and intestinal damage characterized by the shortening of villi and destruction of intestinal crypts, as well as the colon length change. MG significantly reduced body weight loss, alleviated diarrhea, reversed histopathological changes, and prevented colon length reduction. Oxidative stress and inflammation were activated after OXL, and these responses were repressed by MG through increasing the activities of superoxide dismutase, glutathione peroxidase, and glutathione, decreasing level of nuclear factor of kappa b and downregulating the following pro-inflammatory cytokines. Although the expression of tight junction protein occludin and numbers of proliferative crypt cells were reduced on ileum and colon after OXL, MG administration promoted these expressions. The fecal gut microbiota composition disturbed by OXL was significantly reversed by MG. Thus, MG could prevent the development and progression of mucositis induced by oxaliplatin through multipathway.

Topics: Animals; Antineoplastic Agents; Biphenyl Compounds; Flowers; Intestinal Mucosa; Lignans; Male; Mice; Oxaliplatin

We investigated the protective effect of a natural polyphenol, magnolol, on Saccharomyces cerevisiae cells under oxidative stress, and during aging. Our results showed the sensitivity of S. cerevisiae antioxidant gene deficient mutants (sod1∆, sod2∆, cta1∆, ctt1∆, gtt2∆ and tsa1∆) against hydrogen peroxide (H2O2) and menadione stress was rescued by magnolol as demonstrated in spot and colony forming unit counts. Yeast cells pretreated with magnolol showed decreased intracellular oxidation, lipid peroxidation and an increased level of reduced glutathione. Further, SOD1, CTA1 and GTT2 gene expression was examined by reverse transcription-polymerase chain reaction, and was found that magnolol significantly attenuated the upregulation of SOD1 and CTA1 genes under oxidative stress. Finally, longevity of the wild type and sod1 mutant cells were extended by magnolol, and also enhance stress resistance against oxidant stress during chronological aging.

Topics: Antioxidants; Biphenyl Compounds; Catalase; Colony Count, Microbial; Gene Expression; Glucose Transporter Type 2; Glutathione; Lignans; Lipid Peroxidation; Microbial Viability; Oxidation-Reduction; Oxidative Stress; Reactive Oxygen Species; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Superoxide Dismutase-1

An effective strategy based on high-speed counter-current chromatography (HSCCC) knockout combination with HPLC-DAD-QTOF-MS/MS analysis were developed to identify minor lignans, alkaloids, and phenylpropanoid glycosides in M. officinalis. Petroleum ether/ethyl acetate/methanol/water (8:4:7:5, v/v/v/v) as solvent system was firstly selected to separate the crude extract of M. officinalis. Two major lignans, honokiol and magnolol were knocked out, and minor components were enriched. Then, five standards (honokiol, magnolol, magnocurarine, magnoflorine and acteoside) were used as examples to discuss their fragmentation patterns for structural identification. By comprehensive screening, sixteen lignans, nine alkaloids, six phenylpropanoid glycosides were unambiguously or tentatively identified by comparing their retention time, UV spectra, accurate mass and fragmentation patterns with standards or reported components. Eight of them, as far as was known, were discovered from M. officinalis for the first time. The proposed method might provide a model for the effective identification of minor components from complex herbs. Additionally, this study laid a foundation for the study of quality control, and clinical applications of M. officinalis.

Topics: Alkaloids; Aporphines; Biphenyl Compounds; Chromatography, High Pressure Liquid; Glucosides; Glycosides; Isoquinolines; Lignans; Magnolia; Methanol; Phenols; Propanols; Tandem Mass Spectrometry

A highly selective and efficient LC-MS/MS method was developed to determine the plasma concentration of magnolol, hesperidin, neohesperidin and geniposide following oral administration of Zhi-Zi-Hou-Po decoction in normal and depressed rats. Plasma samples were pretreated by protein precipitation with methanol. Chromatographic separation was performed on an XTerra

Topics: Administration, Oral; Animals; Biphenyl Compounds; Corticosterone; Depression; Disease Models, Animal; Drugs, Chinese Herbal; Hesperidin; Iridoids; Lignans; Limit of Detection; Linear Models; Male; Rats; Rats, Sprague-Dawley; Reproducibility of Results

A fluorometric imaging plate reader (FLIPR) assay utilizing Chinese hamster ovary (CHO) cells stably transfected with GABA

Topics: Alkaloids; Animals; Benzodioxoles; Biological Assay; Biphenyl Compounds; CHO Cells; Chromatography, High Pressure Liquid; Cricetulus; Fluorometry; Indenes; Lignans; Magnolia; Oocytes; Piper nigrum; Piperidines; Plant Extracts; Polyunsaturated Alkamides; Receptors, GABA-A; Sesquiterpenes; Valerian; Xenopus laevis

Osteosarcoma is a highly invasive primary malignancy of bone. Magnolol is biologically active, which shows antitumor effects in a variety of cancer cell lines. However, it has not been elucidated magnolol's effects on human osteosarcoma cells (HOC). This study aimed to determine antitumor activity of magnolol and illustrate the molecular mechanism in HOC. Magnolol showed significant inhibition effect of growth on MG-63 and 143B cells and induced apoptosis and cell cycle arrest at G0/G1. In osteosarcoma cells, magnolol upregulated expressions of proapoptosis proteins and suppressed expressions of antiapoptosis proteins. Additionally, under the pretreatment of pifithrin-a (PFT-a, a p53 inhibitor), the magnolol-induced apoptosis was significantly reversed. The results above indicated that magnolol induces apoptosis in osteosarcoma cells may via G0/G1 phase arrest and p53-mediated mitochondrial pathway.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; bcl-2-Associated X Protein; Biphenyl Compounds; Cell Line, Tumor; Cyclin D1; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinase Inhibitor p27; G1 Phase Cell Cycle Checkpoints; Gene Expression Regulation, Neoplastic; Humans; Lignans; Membrane Potential, Mitochondrial; Mitochondria; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Osteoblasts; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species; Resting Phase, Cell Cycle; Signal Transduction; Tumor Suppressor Protein p53

Magnolol, the most abundant bioactive constituent of the Chinese herb Magnolia officinalis, has been found with multiple biological activities, including anti-oxidative, anti-inflammatory and enzyme-regulatory activities. In this study, the inhibitory effects and inhibition mechanism of magnolol on human carboxylesterases (hCEs), the key enzymes responsible for the hydrolytic metabolism of a variety of endogenous esters as well as ester-bearing drugs, have been well-investigated. The results demonstrate that magnolol strongly inhibits hCE1-mediated hydrolysis of various substrates, whereas the inhibition of hCE2 by magnolol is substrate-dependent, ranging from strong to moderate. Inhibition of intracellular hCE1 and hCE2 by magnolol was also investigated in living HepG2 cells, and the results showed that magnolol could strongly inhibit intracellular hCE1, while the inhibition of intracellular hCE2 was weak. Inhibition kinetic analyses and docking simulations revealed that magnolol inhibited both hCE1 and hCE2 in a mixed manner, which could be partially attributed to its binding at two distinct ligand-binding sites in each carboxylesterase, including the catalytic cavity and the regulatory domain. In addition, the potential risk of the metabolic interactions of magnolol via hCE1 inhibition was predicted on the basis of a series of available pharmacokinetic data and the inhibition constants. All these findings are very helpful in deciphering the metabolic interactions between magnolol and hCEs, and also very useful for avoiding deleterious interactions via inhibition of hCEs.

Topics: Binding Sites; Biocatalysis; Biphenyl Compounds; Carboxylic Ester Hydrolases; Catalytic Domain; Drugs, Chinese Herbal; Hep G2 Cells; Humans; Hydrolysis; Kinetics; Lignans; Molecular Docking Simulation

In this study, two phenol compounds, magnolol and honokiol, were extracted from

Topics: Alternaria; Antifungal Agents; Biphenyl Compounds; Lignans; Magnolia; Nicotiana; Plant Diseases

Cyclodextrin (CD) inclusions are generally used to increase the solubility of poorly soluble drugs. In this study, magnolol (MAG) was used as a model drug for exploring the effects of CD on the degradation of pharmaceutical drugs by intestinal microflora. MAG/β-cyclodextrin (β-CD) and MAG/hydroxypropyl-β-CD (HP-β-CD) inclusion complexes were successfully prepared by the saturated aqueous solution and freeze-drying methods, respectively. Structural characterisation along with analyses of solubility, residual water content and drug content of the inclusion complexes was performed. The intestinal microflora of male rats was used to study MAG degradation in vitro. At three concentrations, the degradation of both the inclusion complexes was slower than that of the MAG monomer, MAG and CD mixtures and the MAG-poloxamer 188 micelle. There were no statistically significant differences in the degradation of the MAG/β-CD and MAG/HP-β-CD inclusion complexes. A simulation first-order equation of the degradation parameters revealed that the degradation of the inclusion complexes was slower and pronounced, judging by slope. The experimental findings were verified by molecular docking for predicting the stable molecular structure of the inclusion complexes. In conclusion, the inclusion complexes partially protected MAG from degradation by the intestinal bacteria.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Animals; Bacteria; beta-Cyclodextrins; Biphenyl Compounds; Freeze Drying; Intestines; Lignans; Male; Molecular Docking Simulation; Molecular Structure; Rats; Rats, Sprague-Dawley; Solubility

Glucuronidation of SN-38 serves as an important metabolic pathway in determining the toxic effects of irinotecan. The role of UDP-glucuronosyltransferases (UGT) 1A9 in SN-38 glucuronidation pathway is very confusing. This study re-investigates the pathway through testing effects of bovine serum albumin (BSA) and the selective inhibitor on SN-38 glucuronidation in pooled human liver microsomes (HLM) and recombinant UGT1A1/UGT1A9. For UGT1A1, SN-38 glucuronidation was little affected by BSA. Whether in the presence of BSA or not, the reactions both obey Michaelis-Menten kinetics with closed Vmax/Km values. For UGT1A9 and HLM, BSA can significantly accelerate SN-38 glucuronidation activities and similar effects are further observed on kinetic patterns. In the absence of BSA, reactions by HLM and UGT1A9 both display substrate inhibition kinetics. When BSA is included in the incubations, the reactions exhibit Michaelis-Menten kinetics. To get the true contribution of UGT1A9 in SN-38 glucuronidation, a relative activity factor (RAF) approach was additionally used. It is suggested that UGT1A9 and 1A1 contribute equally to SN-38 glucuronidation in HLM. Furthermore, in the presence of BSA, magnolol, a selective UGT1A9 inhibitor, displays moderate inhibition against HLM. Results together conclude that UGT1A9 serves as an additional important contributor to hepatic SN-38 glucuronidation.

Topics: Antineoplastic Agents, Phytogenic; Biphenyl Compounds; Camptothecin; Enzyme Inhibitors; Glucuronides; Glucuronosyltransferase; Humans; Irinotecan; Lignans; Metabolic Networks and Pathways; Microsomes, Liver; Recombinant Proteins; Serum Albumin, Bovine; UDP-Glucuronosyltransferase 1A9

Many natural products from medicinal plants are small molecular weight compounds with enormous structural diversity and show various biological activities. Magnolol is a biphenol compound rich in the stem bark of Magnolia officinalis Rehd et Wils., and is able to suppress viral replication in GCRV-infected grass carp (Ctenopharyngodon idella) kidney (CIK) cells in the previous study. In this study, in vivo studies demonstrated that magnolol was efficient to restrain the replication of GCRV and repair the low level of superoxide dismutase and total antioxidant capacity in serum at the non-toxic concentration in vivo. Furthermore, magnolol inhibited CIK cell apoptosis induced by GCRV and kept the normal cellular morphological structure, reflecting in the protection of CIK cells from cell swelling, the formation of apoptotic bodies, the disappearance of cellular morphology and nuclear fragmentation. Reverse transcript quantitative polymerase chain reaction (RT-qPCR) showed that magnolol facilitated the expression of apoptosis-inhibiting gene bcl-2, while suppressed the expression of apoptosis-promoting gene bax in GCRV-infected cells. Besides, RT-qPCR and enzyme activity assays proved that magnolol suppressed the expression of caspase 3, caspase 8 and caspase 9. Moreover, interactions between magnolol and proteins were predicted by using the STITCH program, which revealed that ten proteins including caspase 3, were involved in the apoptosis pathway, p53 signaling pathway, mitogen-activated protein kinase (MAPK) signaling pathway and toll-like receptor signaling pathway. Further assays were performed to test the effect of magnolol on apoptosis pathway, which showed that magnolol dramatically inhibited the activity of caspase 3 rather than those of caspase 8 and caspase 9. Collectively, the present study revealed that magnolol heightened the resistance of grass carp against GCRV infection and refrained GCRV-induced apoptosis, which may be attributed to the direct interaction of magnolol with caspase 3. The present results make a contribution to understanding the mechanisms by which small-molecule drugs possess antiviral activities, and lay a foundation for the development of broad-spectrum antiviral compounds in aquaculture industry.

Topics: Animals; Antiviral Agents; Apoptosis; Biphenyl Compounds; Carps; Cell Line; Cytopathogenic Effect, Viral; Fish Diseases; Immunity, Innate; Lignans; Reoviridae; Reoviridae Infections

The present study aimed to investigate the protective effects of magnolol on acute 2,4,6-trinitrobenzene sulfonic acid (TNBS)‑induced colitis, and its underlying mechanisms. Experimental colitis was induced by intracolonic administration of TNBS/ethanol into rats. The model rats were randomly assigned into groups: TNBS, magnolol (high, medium and low doses), and salazosulfapyridine (positive control). All intervention regimens were administered by oral gavage, once a day for 7 consecutive days, 24 h after colitis induction. Histological and biochemical changes in colonic inflammation were evaluated by hematoxylin and eosin and immunohistochemistry, respectively. Rats treated with all doses of magnolol exhibited decreased colonic myeloperoxidase activity (P<0.05 vs. TNBS), reduced serum levels of proinflammatory cytokines [including interleukin (IL)‑6 and IL‑17], and downregulated Toll‑like receptor-4 (TLR‑4) mRNA expression. Histological analysis revealed that medium and high doses of magnolol conferred an anti‑inflammatory effect, which was indicated by a decrease in disease activity index, an increase in thymus index, and downregulation of nuclear factor (NF)‑κB p65 mRNA and TLR‑4 protein expression. However, only high‑dose magnolol significantly ameliorated the elevated colon weight/length ratio. The results of the present study indicate that magnolol exerts protective effects against acute TNBS‑induced colitis in rats, and the TLR‑4/NF‑κB signaling pathway‑mediated inhibitory effect on inflammatory cascades may contribute to the protective activity of magnolol.

Topics: Acute Disease; Animals; Biphenyl Compounds; Colitis; Cyclooxygenase 2; Down-Regulation; Enzyme-Linked Immunosorbent Assay; Interleukin-17; Interleukin-6; Lignans; Male; Nitric Oxide Synthase Type II; Peroxidase; Protective Agents; Rats; Rats, Wistar; Spleen; Thymus Gland; Toll-Like Receptor 4; Transcription Factor RelA; Trinitrobenzenesulfonic Acid

In the present study, the neuroprotective potential of magnolol against ischemia-reperfusion brain injury was examined via in vivo and in vitro experiments. Magnolol exhibited strong radical scavenging and antioxidant activity, and significantly inhibited the production of interleukin‑6, tumor necrosis factor‑a and nitrite/nitrate (NOX) in lipopolysaccharide-stimulated BV2 and RAW 264.7 cells when applied at concentrations of 10 and 50 µM, respectively. Magnolol (100 µM) also significantly attenuated oxygen‑glucose deprivation‑induced damage in neonatal rat hippocampal slice cultures, when administered up to 4 h following the insult. In a rat model of stable ischemia, compared with a vehicle‑treated ischemic control, pretreatment with magnolol (0.01‑1 mg/kg, intravenously) significantly reduced brain infarction following ischemic stroke, and post‑treatment with magnolol (1 mg/kg) remained effective and significantly reduced infarction when administered 2 h following the onset of ischemia. Additionally, magnolol (0.3 and 1 mg/kg) significantly reduced the accumulation of superoxide anions at the border zones of infarction and reduced oxidative damage in the ischemic brain. This was assessed by measuring the levels of NOX, malondialdehyde and myeloperoxidase, the ratio of glutathione/oxidized glutathione and the immunoreactions of 8‑hydroxy‑2'‑deoxyguanosine and 4‑hydroxynonenal. Thus, magnolol was revealed to protect against ischemia‑reperfusion brain damage. This may be partly attributed to its antioxidant, radical scavenging and anti‑inflammatory effects.

Topics: Animals; Antioxidants; Biphenyl Compounds; Brain; Brain Ischemia; Cell Line; Glucose; Lignans; Male; Mice; Neuroprotective Agents; Oxidative Stress; Oxygen; Rats, Sprague-Dawley; RAW 264.7 Cells; Reperfusion Injury

Magnolol, the main and active ingredient of the Magnolia officinalis, has been widely used in traditional prescription to the human disorders. Magnolol has been proved to have several pharmacological properties including anti-bacterial, anti-oxidant and anti-inflammatory activities. However, the effects of magnolol on ulcerative colitis (UC) have not been reported. The aim of this study was to investigate the protective effects and mechanisms of magnolol on dextran sulphate sodium (DSS)-induced colitis in mice. The results showed that magnolol significantly alleviated DSS-induced body weight loss, disease activities index (DAI), colon length shortening and colonic pathological damage. In addition, magnolol restrained the expression of TNF-α, IL-1β and IL-12 via the regulation of nuclear factor-κB (NF-κB) and Peroxisome proliferator-activated receptor-γ (PPAR-γ) pathways. Magnolol also enhanced the expression of ZO-1 and occludin in DSS-induced mice colonic tissues. These results showed that magnolol played protective effects on DSS-induced colitis and may be an alternative therapeutic reagent for colitis treatment.

Topics: Animals; Biphenyl Compounds; Cecum; Colitis, Ulcerative; Colon; Cytokines; Dextran Sulfate; Gastrointestinal Agents; Inflammation; Inflammation Mediators; Intestinal Mucosa; Lignans; Male; Mice; Mice, Inbred C57BL; Occludin; PPAR gamma; Weight Loss

The hepatocellular carcinoma is one of the most common malignant tumour with high level of mortality rate due to its rapid progression and high resistance to conventional chemotherapies. Thus, the search for novel therapeutic leads is of global interest. Herein, a small set of derivatives of magnolol 1 and honokiol 2, the main components of Magnolia grandiflora and Magnolia obovata, were evaluated in in vitro assay using tumoral hepatocytes. The pro-drug approach was applied as versatile strategy to the improve bioactivity of the compounds by careful transformation of the hydroxyl groups of magnolol 1 and honokiol 2 in suitable ester derivatives. Compounds 10 and 11 resulted to be more potent than the parental honokiol 2 at concentration down to 1 μM with complete viability of treated fibroblast cells up to concentrations of 80 μM. The combination of a butyrate ester and a bare phenol-OH group in the honokiol structure seemed to play a significant role in the antiproliferative activity identifying an interesting pharmacological clue against hepatocellular carcinoma.

Topics: Biphenyl Compounds; Carbon-13 Magnetic Resonance Spectroscopy; Carcinoma, Hepatocellular; Cell Line; Cell Line, Tumor; Drug Screening Assays, Antitumor; Humans; Lignans; Liver Neoplasms; Proton Magnetic Resonance Spectroscopy

Hyperlipidemia is a risk factor of arteriosclerosis, stroke, and other coronary heart disease, which has been shown to correlate with single nucleotide polymorphisms of genes essential for lipid metabolism, such as lipoprotein lipase (LPL) and apolipoprotein A5 (APOA5). In this study, the effect of magnolol, the main active component extracted from Magnolia officinalis, on LPL activity was investigated. A dose-dependent up-regulation of LPL activity, possibly through increasing LPL mRNA transcription, was observed in mouse 3T3-L1 pre-adipocytes cultured in the presence of magnolol for 6 days. Subsequently, a transgenic knock-in mice carrying APOA5 c.553G>T variant was established and then fed with corn oil with or without magnolol for four days. The baseline plasma triglyceride levels in transgenic knock-in mice were higher than those in wild-type mice, with the highest increase occurred in homozygous transgenic mice (106 mg/dL vs 51 mg/dL, p<0.01). After the induction of hyperglyceridemia along with the administration of magnolol, the plasma triglyceride level in heterozygous transgenic mice was significantly reduced by half. In summary, magnolol could effectively lower the plasma triglyceride levels in APOA5 c.553G>T variant carrier mice and facilitate the triglyceride metabolism in postprandial hypertriglyceridemia.

Topics: 3T3-L1 Cells; Animals; Apolipoprotein A-V; Biphenyl Compounds; Gene Knock-In Techniques; Heterozygote; Humans; Hypertriglyceridemia; Lignans; Lipoprotein Lipase; Magnolia; Mice; Mice, Transgenic; Triglycerides; Up-Regulation

We aimed to prepare novel magnolol-loaded mixed micelles (MAG-M) by pluronic F127 and L61 to overcome the challenges of magnolol's poor solubility and then further improve its oral bioavailability.. Magnolol-loaded mixed micelles containing pluronic F127 and L61 were prepared by an organic solvent evaporation method. Physicochemical, transport experiment across Caco-2 cell monolayers and pharmacokinetic studies were performed to characterize MAG-M and to determine the final improvement of the oral bioavailability.. The MAG-M solution was transparent and colourless with average size, polydispersity index and zeta potential of 228.0 ± 2.1 nm, 0.298 ± 0.012 and -0.89 ± 0.02 mV. The micelle solution has a higher EE% and DL% of 81.57 ± 1.49% and 27.58 ± 0.53%, respectively. TEM result showed that the morphology of MAG-M was homogeneous and spherical shape. The dilution stability of MAG-M was no significant change in particle size and entrapment efficiency. MAG was demonstrated a sustained-release behaviour after encapsulated in micelles. MAG permeability across a Caco-2 cell monolayer was enhanced, and the pharmacokinetics study of MAG-M showed a 2.83-fold increase in relative oral bioavailability compared with raw MAG.. The mixed micelles containing pluronic F127 and L61 as drug delivery system provided a well strategy for resolving the poor solubility and bioavailability problems of MAG.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Biphenyl Compounds; Caco-2 Cells; Drug Delivery Systems; Humans; Lignans; Male; Micelles; Poloxamer; Rats; Rats, Sprague-Dawley

A novel method based on amino acid ionic liquids (AAILs) as an additive synchronous fluorescence spectrometry is proposed for simultaneous determination of magnolol (MN) and honokiol (HN) in traditional Chinese medicine Houpu. The overlapping fluorescence spectrum of MN and HN could be completely separated in the AAILs medium. Experiment parameters (the type and concentration of AAILs, pH values and temperature) were discussed. The detection limits of MN and HN reached 1.46ng/mL, 0.92ng/mL and the recovery rates ranged from 98.6%-100.7%, 99.7%-100.6%, respectively. This methods was successfully employed for simultaneously determination of MN and HN in real samples. No significant differences could be found in the results of this method and the pharmacopoeia of People's Republic of China 2015 (Ch.P.2015). The experiment mechanisms were discussed by the Gaussian simulation and fluorescence quantum yield.

Topics: Amino Acids; Biphenyl Compounds; Hydrogen-Ion Concentration; Imidazoles; Ionic Liquids; Lignans; Limit of Detection; Linear Models; Models, Molecular; Reproducibility of Results; Spectrometry, Fluorescence; Temperature

Topics: AMP-Activated Protein Kinases; Animals; Anti-Inflammatory Agents; Biphenyl Compounds; Fatty Liver; Hep G2 Cells; Humans; Hyperlipidemias; Lignans; Lipid Metabolism; Male; Mice, Inbred C57BL; Mitogen-Activated Protein Kinases; NF-kappa B; Oleic Acid; PPAR alpha

Magnolol, a polyphenol compound from herbal medicines, was shown to alter physiology in various cell models. However, the effect of magnolol on Ca. Cytosolic Ca. Together, in OC2 cells, magnolol induced [Ca

Topics: Biphenyl Compounds; Calcium; Calcium Signaling; Cell Line, Tumor; Cell Survival; Cytosol; Endoplasmic Reticulum; Fura-2; Homeostasis; Humans; Lignans; Manganese; Mouth Neoplasms; Protein Kinase C; Tetrazolium Salts; Type C Phospholipases

The aim of this study was to explore the browning and antioxidative effects of magnolol in 3T3-L1 adipocytes, as recruitment of beige-like adipocytes (browning) by natural compounds is being considered as a promising strategy to fight against obesity.. Magnolol-induced browning effect was evaluated by determining the expression levels of specific marker genes and proteins using real-time polymerase chain reaction and immunoblotting, respectively. Induction of thermogenesis and suppression of oxidative stress in 3T3-L1 adipocytes were further validated by immunofluorescence.. Magnolol significantly enhanced expression of a core set of brown fat-specific marker genes (Ucp1, Cd137, Prdm16, Cidea, and Tbx1) and proteins (UCP1, PRDM16, and PGC-1α). Increased expression of UCP1 and other brown fat-specific markers contributed to the browning of 3T3-L1 adipocytes possibly via activation of the AMPK, PPARγ, and protein kinase A (PKA) pathways. In addition, magnolol up-regulated key fatty acid oxidation and lipolytic markers (CPT1, ACSL1, SIRT1, and PLIN) and down-regulated lipogenic markers (FAS and SREBP1). Magnolol also reduced the production and release of reactive oxygen species.. The current data suggest possible roles for magnolol in browning of white adipocytes, augmentation of lipolysis, and thermogenesis, as well as repression of oxidative stress and lipogenesis. Thus, magnolol may be explored as a potentially promising therapeutic agent for the prevention of obesity and other metabolic disorders.

Topics: 3T3-L1 Cells; Adipocytes; Adipose Tissue, Brown; Animals; Antioxidants; Apoptosis Regulatory Proteins; Biphenyl Compounds; Cell Culture Techniques; DNA-Binding Proteins; Lignans; Lipogenesis; Lipolysis; Mice; Oxidative Stress; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; T-Box Domain Proteins; Thermogenesis; Transcription Factors; Tumor Necrosis Factor Receptor Superfamily, Member 9; Uncoupling Protein 1

Evidence showed that the stress hormone corticosterone (CORT) injection resulted in dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis implicated in major depressive disorder. Magnolol, main constituent identified in the barks of Magnolia officinalis, exerted antidepressant effects in a rat model of depression induced by chronic unpredictable mild stress in previous studies. However, its antidepressant-like effects and mechanisms have never been studied in depression model induced by CORT administration in rodents. This study aimed to investigate the antidepressant-like effects and possible mechanisms of magnolol in CORT-treated mice by utilizing a combination of behavioral and biochemical analysis. The depressive model was developed by subcutaneous injection of CORT for 21 days at a dose of 20 mg/kg. CORT administration formed depressive-like behaviors in mice, as indicated by increased immobility time in the forced swim test (FST) and tail suspension test (TST), as well as decreased sucrose intake in sucrose preference test (SPT). Moreover, we also found that CORT levels in serum were significantly increased, along with the decrease of brain-derived neurotrophic factor (BDNF) mRNA, BDNF protein, 5-hydroxytryptamine (5-HT) and norepinephrine (NE) levels in the hippocampus. Treatment with magnolol alleviated depressive-like behaviors, reduced the levels of CORT, and improved the levels of BDNF protein, 5-HT, and NE compared with those in CORT-treated mice. These findings indicated that magnolol possessed antidepressant effects in mice exposed to CORT, which might be partially related to modulate HPA axis, up-regulate BDNF expression and increase neurotransmitters levels in the hippocampus.

Topics: Animals; Antidepressive Agents; Behavior, Animal; Biphenyl Compounds; Brain-Derived Neurotrophic Factor; Corticosterone; Depression; Disease Models, Animal; Food Preferences; Gene Expression Regulation; Hippocampus; Hypothalamus; Injections; Lignans; Male; Mice; Mice, Inbred ICR; Norepinephrine; Pituitary-Adrenal System; RNA, Messenger; Serotonin; Sucrose

Our previous studies have shown that Magnolol (Mag) improves the symptoms and decreases the levels of cytokines during infection induced by Streptococcus suis (S. suis) in mice. Although some reports show that Mag inhibits lipopolysaccharide-induced inflammatory responses via downregulating mitogen-activated protein kinases (MAPK) and nuclear factor-κB (NF-κB) signaling pathways, the molecular mechanisms underlying Mag-mediated inhibition of S. suis-induced inflammatory responses are poorly understood. Here, RAW264.7 cells were stimulated with S. suis in the presence or absence of Mag. Cell viability and bactericidal effects were examined, and the concentrations of tumor necrosis factor-a (TNF-α), IL-1β (interleukin-1β), IL-6 (interleukin-6), and IL-8 (interleukin- 8) were determined by ELISA. The change in ROS (reactive oxygen species) was determined by fluorescence microscopy and ELISA. The levels of Toll-like receptor 2 (TLR2) and MAPK family proteins and NF-κB signaling were determined by Western blot analysis. S. suis induced massive RAW264.7 cell death, a decline in bactericidal activity, the release of inflammatory cytokines, increased oxidative stress, and activation of TLR2/MAPK/NF-κB signaling pathways. Mag treatment significantly suppressed macrophage cell death and caused a decline in bactericidal activity. Furthermore, Mag decreased inflammatory cytokines production and ROS generation. It also prevented p38, extracellular regulated protein kinases (ERK), c-Jun N-terminal kinase (JNK), inhibitor of NF-κB (IκB), and NF-κB phosphorylation induced by S. suis in a dose-dependent manner. Our results indicate that Mag exerts anti-inflammatory and cell-protective effects and mediates the activation of MAPK and NF-κB signaling by downregulating the expression of TLR2 upregulated by S. suis.

Topics: Animals; Anti-Bacterial Agents; Biphenyl Compounds; Gene Expression Regulation; Lignans; Mice; Mitogen-Activated Protein Kinase Kinases; Molecular Structure; NF-kappa B; RAW 264.7 Cells; Reactive Oxygen Species; Streptococcal Infections; Streptococcus suis; Toll-Like Receptor 2

Magnolol, the main constituent of Magnolia officinalis, has been shown to produce antidepressant-like effect in rodents. Growing evidence shows that neuroinflammation, oxidative stress and neuroendocrine contribute to the pathogenesis of major depression. Here, the aim of this present study was to determine whether magnolol affected these systems in mice exposed to chronic mild stress (CMS). The ameliorative effect of magnolol on depressive-like symptoms was investigated through behavioral tests, including the classical sucrose preference and forced swimming tests. The behavioral evaluation showed that magnolol reversed the depressive-like deficits both in sucrose preference test and forced swimming test. The elevation of prefrontal cortex pro-inflammatory cytokines such as interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) was decreased by magnolol. Consistently, the microglia activation by CMS was also alleviated by magnolol. In addition, the hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis induced by CMS was attenuated by magnolol. Moreover, the increased lipid peroxidation such as malonaldehyde (MDA) and decreased antioxidant defense enzymes including superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) induced by CMS were also reversed by magnolol. These findings suggest that administration of magnolol could alleviate depressive-like behaviors in CMS mice that are mediated by suppressing neuroinflammation and oxidative stress in the prefrontal cortex.

Topics: Adrenocorticotropic Hormone; Animals; Anti-Inflammatory Agents; Antidepressive Agents; Behavior, Animal; Biphenyl Compounds; Corticosterone; Cytokines; Depression; Glutathione Peroxidase; Lignans; Male; Malondialdehyde; Mice; Oxidative Stress; Prefrontal Cortex; Stress, Psychological; Superoxide Dismutase

BACKGROUND The cortex of Magnolia officinalis has long been used as an element of traditional Chinese medicine for the treatment of anxiety, chronic bronchitis, and gastrointestinal dysfunction. This study aimed to elucidate the underlying mechanism of its functional ingredients (magnolol and honokiol) in modifying the secretion and absorption homeostasis and protecting mucosal integrity in an Enterotoxigenic Escherichia coli (ETEC)-induced diarrhea mouse model. MATERIAL AND METHODS This study established a diarrhea mouse model infected by ETEC at a dosage of 0.02 ml/g live body weight (BW) in vivo. Magnolol or honokiol was followed by an intraperitoneal administration at dosages of 100, 300, and 500 mg/kg BW according to a 3×3 factorial arrangement. The useful biomarkers for evaluating the integrity of intestinal tract and histologic injury were analyzed and morphological development (including villus height, crypt depth, and ratio of villus height to crypt depth) and the expressions of inflammatory cytokines were determined by real-time PCR. RESULTS The results showed that magnolol and honokiol (500 mg/kg BW) reduced the concentrations of NO, DAO, and DLA, and iNOS activity, and the mRNA expressions of the interferon gamma (IFN-γ) and interleukin 10 (IL-10), and inhibited intestinal epithelial cell apoptosis. Magnolol and honokiol (300 mg/kg BW) elongated the villus height and crypt depth and decreased the number of goblet cells and the ratio of villus height to crypt depth. CONCLUSIONS The current results indicate that magnolol and honokiol enhance the intestinal anti-inflammatory capacities, elongate the villus height and crypt depth, and reduce goblet cell numbers to inhibit the intestinal epithelium apoptosis and effectively protect the intestinal mucosa. These results show that magnolol and honokiol protect the intestinal mucosal integrity and regulate gastrointestinal dysfunction.

Topics: Administration, Oral; Animals; Apoptosis; Biphenyl Compounds; Cytokines; Enterotoxigenic Escherichia coli; Homeostasis; Inflammation Mediators; Intestinal Absorption; Intestinal Mucosa; Lignans; Mice; Nitric Oxide Synthase

Interference rejection in amperometric biosensors can be more effective introducing some modifiers during electro-deposition of permselective film. Addition of β-cyclodextrin (βCD), a cyclic oligosaccharide composed of seven glucose units, to the ortho-phenylendiamine (oPD) monomer were already demonstrated to provide an enhancement in ascorbic acid (AA) rejection. Here we evaluated the improvement in permselectivity of poly-eugenol and poly-magnolol films electro-polymerized in presence of different amounts of βCD or eugenol-βCD inclusion complex for amperometric biosensor application. Starting from Pt-Ir wire as transducer several microsensors were covered with polymeric films doped with βCD-based modifiers through constant potential amperometry. Characterization of modified polymers was achieved by scanning electron microscopy and permselectivity analysis. Poly-magnolol film in combination with βCD showed a worsening in permselectivity compared to poly-magnolol alone. In contrast, the introduction of βCD-based modifier enhanced the interference rejection toward the archetypal interferent AA, while slightly affecting permeability toward H

Topics: Ascorbic Acid; beta-Cyclodextrins; Biosensing Techniques; Biphenyl Compounds; Electrochemical Techniques; Eugenol; Glutamic Acid; Lignans; Polymers

Glioblastoma is a primary malignant brain tumor with a poor prognosis. An effective treatment for glioblastoma is needed. Magnolol is a natural compound from Magnolia officinalis suggested to have antiproliferative activity. The aim of this research was to investigate the anticancer effects of magnolol in glioma, with an emphasis on migration and the underlying mechanism. Magnolol decreased the expression of focal adhesion-related proteins and inhibited LN229 and U87MG glioma cell migration. The levels of phosphorylated myosin light chain (p-MLC), phosphorylated myosin light chain kinase and myosin phosphatase target subunit 1 were reduced in response to magnolol treatment. In addition, immunostaining and membrane fractionation showed that the distribution of N-cadherin at the glioma cell membrane was decreased by magnolol. In an orthotropic xenograft animal model, magnolol treatment not only inhibited tumor progression but also reduced p-MLC and N-cadherin protein expression. In conclusion, magnolol reduces cell migration, potentially through regulating focal adhesions and N-cadherin in glioma cells. Magnolol is a potential candidate for glioma treatment.

Topics: Animals; Antineoplastic Agents, Phytogenic; Biphenyl Compounds; Brain Neoplasms; Cadherins; Cell Line, Tumor; Cell Movement; Cell Survival; Glioblastoma; Humans; Lignans; Mice; Mice, Inbred BALB C; Myosin-Light-Chain Kinase; Neoplasm Transplantation; Phosphorylation; Wound Healing

Honokiol (2-(4-hydroxy-3-prop-2-enyl-phenyl)-4-prop-2-enyl-phenol) and magnolol (4-Allyl-2-(5-allyl-2-hydroxy-phenyl)phenol) are the major active polyphenol constituents of

Topics: Administration, Intravenous; Animals; Biphenyl Compounds; Chromatography, High Pressure Liquid; Cytochrome P-450 CYP1A1; Cytochrome P-450 Enzyme System; Diclofenac; Drug Interactions; Gene Expression Regulation; Lignans; Liver; Microsomes, Liver; Molecular Structure; Phenacetin; Rats; Rats, Sprague-Dawley

The natural product magnolol (1) and a selection of its bioinspired derivatives 2-5, were investigated by Inverse Virtual Screening in order to identify putative biological targets from a panel of 308 proteins involved in cancer processes. By this in silico analysis we selected tankyrase-2 (TNKS2), casein kinase 2 (CK2) and bromodomain 9 (Brd9) as potential targets for experimental evaluations. The Surface Plasmon Resonance assay revealed that 3-5 present a good affinity for tankyrase-2, and, in particular, 3 showed an antiproliferative activity on A549 cells higher than the well-known tankyrase-2 inhibitor XAV939 used as reference compound.

Topics: Algorithms; Antineoplastic Agents; Biphenyl Compounds; Cell Proliferation; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Screening Assays, Antitumor; Humans; Lignans; Molecular Structure; Recombinant Proteins; Structure-Activity Relationship; Surface Plasmon Resonance; Tankyrases; Thermodynamics; Tumor Cells, Cultured

Magnolol, a compound from the traditional Korean herb

Topics: Animals; Biphenyl Compounds; Bone Marrow Cells; Cell Differentiation; Coculture Techniques; Cyclooxygenase 2; Dinoprostone; Interleukin-1; Lignans; Magnolia; Male; Mice; Mice, Inbred ICR; Osteoblasts; Osteoclasts; RANK Ligand

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Biphenyl Compounds; Carcinoma, Non-Small-Cell Lung; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Female; Human Umbilical Vein Endothelial Cells; Humans; Lignans; Lung Neoplasms; Magnolia; Mice, Inbred BALB C; Mice, Nude; Xenograft Model Antitumor Assays

Topics: Animals; Antidepressive Agents; Biphenyl Compounds; Brain; Depression; Female; HEK293 Cells; Hindlimb Suspension; Humans; Lignans; Male; Mice; Rats, Sprague-Dawley; Receptor, Melatonin, MT1; Receptor, Melatonin, MT2

Honokiol and magnolol, which are lignans isolated from Magnolia quinquepeta, have some pharmacological effects. However, the anti-inflammatory effects of honokiol and magnolol on periodontal disease are still uncertain. The aim of this study was to examine the effect of honokiol and magnolol on CXC chemokine receptor 3 (CXCR3) ligands, which are related with Th1 cell migration, production in interleukin (IL)-27-stimulated human oral epithelial cells (TR146 cells). Honokiol and magnolol inhibited CXC chemokine ligand (CXCL)10 and CXCL11 production in IL-27-stimulated TR146 cells in a dose-dependent manner. Moreover, we revealed that honokiol and magnolol could suppress signal transducer and activator of transcription (STAT)3 and protein kinase B (Akt) phosphorylation in IL-27-stimulated TR146 cells though STAT1 phosphorylation was not suppressed by honokiol and magnolol treatment. Furthermore, STAT3 and Akt inhibitors could suppress CXCR3 ligand production in TR146 cells. In summary, honokiol and magnolol could reduce CXCR3 ligand production in oral epithelial cell by inhibiting STAT3 and Akt activation.

Topics: Anti-Inflammatory Agents; Biphenyl Compounds; Chemokine CXCL10; Chemokine CXCL11; Epithelial Cells; Humans; Interleukin-27; Ligands; Lignans; Mouth; Periodontal Diseases; Proto-Oncogene Proteins c-akt; Receptors, CXCR3; STAT3 Transcription Factor

The aim of this study was to prepare two novel magnolol (MO)-loaded binary mixed micelles (MO-M) using biocompatible copolymers of Soluplus (SOL) and Solutol

Topics: Administration, Oral; Animals; Biological Availability; Biphenyl Compounds; Caco-2 Cells; Drug Carriers; Drug Liberation; Humans; Lignans; Male; Micelles; Permeability; Polymers; Rats; Rats, Sprague-Dawley; Solubility; Solvents; Surface-Active Agents

Partial agonists of the transcription factor PPARγ (peroxisome proliferator-activated receptor γ) have shown potential for the treatment of metabolic and inflammatory conditions and novel activators serve as valuable tool and lead compounds. Based on the natural product magnolol (I) and recent structural information of the ligand-target interaction we have previously developed magnolol dimer (II) which has been shown to have enhanced affinity towards PPARγ and improved selectivity over RXRα (retinoid X receptor α), PPARγ's heterodimerization partner. In this contribution we report the synthesis and evaluation of three fragments of the dimeric lead compound by structural simplifications. Sesqui magnolol A and B (III and IV) were found to exhibit comparable activities to magnolol dimer (II) and selectivity over RXRα persisted. Computational studies suggest a common pharmacophore of the distinctive biphenyl motifs. Truncated magnolol dimer (V) on the other hand does not share this feature and was found to act as an antagonist.

Topics: Biphenyl Compounds; Crystallography, X-Ray; Dimerization; Drug Discovery; HEK293 Cells; Humans; Ligands; Lignans; Molecular Docking Simulation; PPAR gamma; Protein Binding; Retinoid X Receptor alpha

In traditional Asian medicinal systems, preparations of the root and stem bark of

Topics: Adrenergic Neurons; Anti-Anxiety Agents; Benzhydryl Compounds; Biphenyl Compounds; Central Nervous System; HEK293 Cells; Humans; Lignans; Magnolia; Norepinephrine; Norepinephrine Plasma Membrane Transport Proteins; Plant Bark; Plant Extracts; Receptors, GABA-A

Topics: Biphenyl Compounds; Cells, Cultured; Endothelial Cells; Intercellular Adhesion Molecule-1; Lignans; Nanoparticles; Nanotechnology; NF-kappa B; Solubility; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1

2-O-methylmagnolol (MM1), a derivative of magnolol bearing one methoxy moiety, has been shown to display improved anti-tumor activity against skin cancers. In this study, we examined the anti-tumor effects of magnolol and MM1 on oral squamous cell carcinoma (OSCC).. Trypane blue staining and clonogenic assays were performed to determine the cytotoxic effects of magnolol and MM1 in OSCC cells. Migration and matrigel invasion assays were carried out to examine the metastasis effects of magnolol and MM1 in OSCC cells. IL6-stimulation, Western blot, and immunohistochemistry were used to investigate the IL-6/STAT3 signaling and apoptosis. A bioluminescent mouse model of orthotopically implanted SAS cells was used to determine the anti-tumor activity of MM1 in vivo.. MM1 displays greater activity than magnolol on affecting the cytotoxicity, migration, and invasion of OSCC cells cultured in vitro. The improved anti-tumor activity of MM1 was shown to associate with its greater activity to inhibit STAT3 signaling and to induce apoptosis in the OSCC. In addition, we presented evidence that MM1 is effective in inhibiting the growth of orthotopic implanted OSCC cells in vivo.. Our data indicate that MM1 displays greater anti-tumor activity than magnolol in OSCC and is an attractive agent to be further explored for its potential clinical application.

Topics: Animals; Apoptosis; Biphenyl Compounds; Cadherins; Carcinoma, Squamous Cell; Caspase 3; Cell Line, Tumor; Cell Movement; Cell Proliferation; Humans; Interleukin-6; Lignans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Mouth Neoplasms; Signal Transduction; STAT3 Transcription Factor; Transplantation, Heterologous; Vimentin

This paper builds on the fact that high aspect ratio rectilinear tubing columns of the same length and outside dimensions can double column efficiency. It demonstrates that further improvements in efficiency can be made by using rectilinear tubing columns with half the wall thickness thus replacing heavy PTFE with light solvent systems and producing lighter higher capacity columns. Increases in sample loading/throughput of up to 55x are demonstrated by comparing the separation of Honokiol and Magnolol using a Hexane: Ethyl Acetate: Methanol: Water (5:2:5:2) phase system with the new thin wall rectilinear column (56 mL, 30 mL/min, 2.1 g/h in 6.5 min.) with the original optimization performed using a conventional DE-Mini column (18 mL, 0.8 mm bore circular PTFE tubing, 2.5 mL/min, 0.038 g/h in 45 min.). Honokiol is currently going through first phase clinical trials as an anti-lung cancer therapy where preparative countercurrent chromatography was used for its manufacture. To be competitive in the future it is important for the technology to become more efficient. This is the first big step in that direction.

Topics: Biphenyl Compounds; Chemistry, Pharmaceutical; Countercurrent Distribution; Hexanes; Lignans; Methanol; Solvents; Water

Magnolol, a neolignan compound isolated from traditional Chinese medicine Magnolia officinalis, has a potentially therapeutic influence on ischemic stroke. Previous studies have demonstrated that cerebral ischemia-reperfusion (I-R) and blood-brain barrier (BBB) are involved in the pathogeneses of stroke. Therefore, in vivo and in vitro studies were designed to investigate the effects of magnolol on I-R-induced neural injury and BBB dysfunction. In cerebral I-R model of mice, cerebral infarct volumes, brain water content, and the exudation of Evans blue were significantly reduced by intravenous injection with magnolol at the doses of 1.4, 7.0, and 35.0 μg/kg. When primary cultured microglial cells were treated with 1 μg/ml lipopolysaccharide (LPS) plus increasing concentrations of magnolol, ranging from 0.01 to 10 μmol/L, magnolol could statistically inhibit LPS-induced NO release, TNF-α secretion, and expression of p65 subunit of NF-κB in the nucleus of microglial cells. In the media of brain microvascular endothelial cells (BMECs), oxygen and glucose deprivation-reperfusion (OGD-R) could remarkably lead to the elevation of TNF-α and IL-1β levels, while magnolol evidently reversed these effects. In BBB model in vitro, magnolol dose- and time-dependently declined BBB hyperpermeability induced by oxygen and glucose deprivation (OGD), OGD-R, and ephrin-A1 treatment. More importantly, magnolol could obviously inhibit phosphorylation of EphA2 (p-EphA2) not only in ephrin-A1-treated BMECs but also in cerebral I-R model of mice. In contrast to p-EphA2, magnolol significantly increased ZO-1 and occludin levels in BMECs subjected to OGD. Taken together, magnolol can protect neural damage from cerebral ischemia- and OGD-reperfusion, which may be associated with suppressing cerebral inflammation and improving BBB function.

Topics: Animals; Biphenyl Compounds; Blood-Brain Barrier; Brain Ischemia; Dose-Response Relationship, Drug; Interleukin-1beta; Lignans; Mice; Microglia; Nitric Oxide; Phosphorylation; Rats; Rats, Sprague-Dawley; Receptor, EphA2; Reperfusion Injury; Tumor Necrosis Factor-alpha

Silent information regulator 1 (SIRT1), a histone deacetylase, plays a protective role in ischemic brain injury. Previous studies have shown that magnolol has a beneficial effect on ischemic stroke; however, the role of SIRT1 in the protective effect of magnolol against cerebral ischemia has not been investigated.. We used a middle cerebral artery occlusion model of stroke in rats. Before stroke induction, the rats received intraperitoneal injections of magnolol with or without the SIRT1 inhibitor, EX527. Brain water content, neurological score, and infarct volume were measured. Moreover, the levels of the proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were measured. Western blot analysis was performed to detect Ac-FOXO1, SIRT1, bax, and Bcl-2 expression.. Magnolol exerted a beneficial effect on cerebral ischemia, as indicated by reduced brain edema, decreased infarct volume, and improved neurological score. Magnolol had an anti-inflammatory effect mediated by a decrease in the expression of IL-1β and TNF-α in the brain tissue. Additionally, magnolol down-regulated bax and Ac-FOXO1 expression and up-regulated Bcl-2 and SIRT1 expression. This effect of magnolol was abolished by EX527 treatment.. In conclusion, our data clearly indicate that magnolol modulates brain injury caused by ischemic stroke by inhibiting inflammatory cytokines and apoptosis through SIRT1 activation.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Biphenyl Compounds; Gene Expression Regulation; Hypoxia, Brain; Inflammation; Lignans; Nerve Tissue Proteins; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; Sirtuin 1; Stroke

Chemical modification of magnolol, an uncommon dimeric neolignan contained in Magnolia genus trees, provides a unique array of polyphenols having interesting biological activity potentially related to radical scavenging. The chain-breaking antioxidant activity of four new hydroxylated and methoxylated magnolol derivatives was explored by experimental and computational methods. The measurement of the rate constant of the reaction with ROO˙ radicals (k

Topics: Antioxidants; Biphenyl Compounds; Hydrogen Bonding; Hydroxylation; Lignans; Molecular Structure; Peroxides; Quantum Theory

Topics: Animals; Biphenyl Compounds; Colitis; Dextran Sulfate; Indoleacetic Acids; Indoles; Interleukin-1beta; Interleukin-6; Kynurenic Acid; Lignans; Male; Mice; Mice, Inbred C57BL; Polyphenols; Tumor Necrosis Factor-alpha

The tubulin/microtubule system, which is an integral component of the cytoskeleton, plays an essential role in mitosis. Targeting mitotic progression by disturbing microtubule dynamics is a rational strategy for cancer treatment.. Microtubule polymerization assay was performed to examine the effect of Magnolol (a novel natural phenolic compound isolated from Magnolia obovata) on cellular microtubule polymerization in human non-small cell lung cancer (NSCLC) cells. Cell cycle analysis, mitotic index assay, cell proliferation assay, colony formation assay, western blotting analysis of cell cycle regulators, Annexin V-FITC/PI staining, and live/dead viability staining were carried out to investigate the Magnolol's inhibitory effect on proliferation and viability of NSCLS cells in vitro. Xenograft model of human A549 NSCLC tumor was used to determine the Magnolol's efficacy in vivo.. Magnolol treatment effectively inhibited cell proliferation and colony formation of NSCLC cells. Further study proved that Magnolol induced the mitotic phase arrest and inhibited G2/M progression in a dose-dependent manner, which were mechanistically associated with expression alteration of a series of cell cycle regulators. Furthermore, Magnolol treatment disrupted the cellular microtubule organization via inhibiting the polymerization of microtubule. We also found treatment with NSCLC cells with Magnolol resulted in apoptosis activation through a p53-independent pathway, and autophgy induction via down-regulation of the Akt/mTOR pathway. Finally, Magnolol treatment significantly suppressed the NSCLC tumor growth in mouse xenograft model in vivo.. These findings identify Magnolol as a promising candidate with anti-microtubule polymerization activity for NSCLC treatment.

Topics: A549 Cells; Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Biphenyl Compounds; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; G2 Phase Cell Cycle Checkpoints; Humans; Lignans; Lung Neoplasms; M Phase Cell Cycle Checkpoints; Magnolia; Male; Mice, Nude; Microtubules; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases; Transplantation, Heterologous; Tumor Suppressor Protein p53

Magnolol has shown the potential anticancer properties against a variety of cancers. However, the role of magnolol in cholangiocarcinoma (CCA) cells is unknown. In this study, we assessed the effect of magnolol on the CCA cells.. CCA cells were treated with magnolol in the absence or presence of TNFα, the activator for NF-κB. After co-incubation with magnolol, cell proliferation and growth were examined by MTT, colony formation and xenograft tumors; cell cycle was analyzed by flow cytometry; cell migration and invasion were detected by wound healing and transwell assays; the expression of PCNA, Ki67, CyclinD1, MMP-2, MMP-7 and MMP-9 and NF-κB pathway were evaluated by using Western blot.. Magnolol inhibited the abilities of CCA cell growth, migration and invasion accompanying with a decreased expression of PCNA, Ki67, MMP-2, MMP-7 and MMP-9 (all P<0.05).. with magnolol induced cell cycle arrest in G1 phase with a downregulation of cell cycle protein CyclinD1 (all P<0.05). In addition, magnolol suppressed the expression of p-IκBα and p-P65 and the effect of magnolol on CCA cells could be inhibited by TNFα.. Magnolol could inhibit the growth, migration and invasion of CCA cells through regulation of NF-κB pathway, and these data indicate that magnolol is a potential candidate for treating of CCA.

Topics: Animals; Antineoplastic Agents; Biphenyl Compounds; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cholangiocarcinoma; Humans; Lignans; Mice, Inbred BALB C; Mice, Nude; Neoplasm Invasiveness; NF-kappa B; Signal Transduction; Tumor Stem Cell Assay; Xenograft Model Antitumor Assays

Lupus nephritis (LN) is a common complication of systemic lupus erythematosus. The present study aimed to elucidate the protective effect of magnolol (MG) on the progression of LN, via inhibition of key signaling pathways. The results of the present study demonstrated that administration of MG caused inhibition of the activation of NACHT, LRR and PYD domains‑containing protein 3 and interleukin‑1β production. Histopathological analysis confirmed that the vehicle‑treated group exhibited characteristic glomerular disease, which was observed to be suppressed following the administration of MG; a marked decrease in glomerular and vascular lesions was observed compared with the vehicle control. This decrease was further demonstrated through analysis of kidney sections. The expression level of cell surface glycoprotein F4/80 was demonstrated to be markedly decreased in the MG‑treated mice compared with the vehicle control group. The MG‑treated mice exhibited a marked decrease in serum and renal tumor necrosis factor‑α expression levels.

Topics: Animals; Anti-Arrhythmia Agents; Antibodies, Antinuclear; Biopsy; Biphenyl Compounds; Cytokines; Disease Models, Animal; Female; Histocytochemistry; Inflammasomes; Inflammation Mediators; Lignans; Lupus Nephritis; Macrophages; Mice; Mice, Inbred MRL lpr; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Signal Transduction

Chronic hyperglycemia aggravates insulin resistance, in part due to increased formation of advanced glycation end-products (AGEs). Methylglyoxal (MG), a major precursor of AGEs, accumulates abnormally in various tissues and organs and participates in oxidative damage. We investigated the insulinotropic benefits of magnolol, a hydroxylated biphenyl compound isolated from Magnolia officinalis, in pancreatic β-cells exposed to MG in vitro. When exposed to cytotoxic levels of MG for 48 h, RIN-m5F β-cells exhibited a significant loss of viability and impaired insulin secretion, whereas pretreatment with magnolol protected against MG-induced cell death and decreased insulin secretion. Moreover, magnolol increased the expression of genes involved in β-cell survival and function, including Ins2 and PDX1. Furthermore, magnolol increased the levels of AMPK phosphorylation, SIRT1, and PGC1α in RIN-5F β-cells. In addition, magnolol increased the activity of glyoxalase I and decreased the levels of MG-modified protein adducts, which suggests that magnolol protects against MG-induced protein glycation. Taken together, the results indicate the potential application of magnolol as an intervention against MG-induced hyperglycemia.

Topics: Animals; Biphenyl Compounds; Cell Death; Cell Line; Cell Survival; Cytoprotection; Insulin; Insulin-Secreting Cells; Lignans; Magnolia; Protective Agents; Pyruvaldehyde; Rats

Magnolol, a constituent of the bark of Magnolia officinalis, has been reported to decrease myocardial stunning and infarct size. In this study, we investigated whether magnolol can reduce renal ischemia and reperfusion (I/R) injury. Renal I/R, induced by a 60-min occlusion of bilateral renal arteries and a 24-h reperfusion, significantly increased blood urea nitrogen (BUN) and creatinine levels, and caused histological damage to the kidneys of rats. Apoptosis, as evaluated by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining and caspase-3 activation, was significantly increased in the kidneys. Furthermore, serum levels of tumor necrosis factor-[Formula: see text] (TNF-[Formula: see text]), interleukin-1β (IL-1β), and interleukin-6 (IL-6) were significantly elevated, while the interleukin-10 (IL-10) level was suppressed. However, intravenous pretreatment with magnolol at doses of 0.003[Formula: see text]mg/kg and 0.006[Formula: see text]mg/kg 10[Formula: see text]min before renal I/R significantly limited the increases of BUN, creatinine, the histological damage, and apoptosis in the kidneys. The increases in TNF-[Formula: see text], IL-1β, and IL-6, and the decrease in IL-10 were also significantly inhibited. Additionally, magnolol increased Bcl-2 and decreased Bax in the kidneys. Phosphorylation of the prosurvival kinases, including Akt and extracellular signal-regulated kinases 1 and 2 (ERK1/2), was elevated, while phosphorylation of the pro-apoptotic mitogen-activated protein kinases, including p38 and c-Jun N-terminal kinase (JNK), was suppressed. In conclusion, magnolol reduces renal I/R injury. The underlying mechanisms for this effect might be related to the prevention of apoptosis, possibly via the inhibition of both extrinsic and intrinsic apoptotic pathways, including the reduction of TNF-[Formula: see text] production and the modulation of pro- and anti-apoptotic signaling elements.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Biphenyl Compounds; Blood Urea Nitrogen; Creatinine; Dose-Response Relationship, Drug; Infusions, Intravenous; Interleukin-10; Interleukin-1beta; Interleukin-6; Ischemia; JNK Mitogen-Activated Protein Kinases; Kidney; Lignans; Male; Mitogen-Activated Protein Kinase 3; Phosphorylation; Phytotherapy; Proto-Oncogene Proteins c-bcl-2; Rats, Sprague-Dawley; Reperfusion Injury; Signal Transduction; Tumor Necrosis Factor-alpha

The novel target products were synthesized in the formation of a triazine ring from berberine, magnolol, and metformin catalyzed by sodium methylate. The structures of products

Topics: Anti-Inflammatory Agents; Berberine; Biphenyl Compounds; Cyclization; Humans; Inflammation; Insulin Resistance; Lignans; Metformin; Molecular Structure; Sodium; Structure-Activity Relationship; Triazines

The nuclear receptors peroxisome proliferator-activated receptor γ (PPARγ) and its hetero-dimerization partner retinoid X receptor α (RXRα) are considered as drug targets in the treatment of diseases like the metabolic syndrome and diabetes mellitus type 2. Effort has been made to develop new agonists for PPARγ to obtain ligands with more favorable properties than currently used drugs. Magnolol was previously described as dual agonist of PPARγ and RXRα. Here we show the structure-based rational design of a linked magnolol dimer within the ligand binding domain of PPARγ and its synthesis. Furthermore, we evaluated its binding properties and functionality as a PPARγ agonist in vitro with the purified PPARγ ligand binding domain (LBD) and in a cell-based nuclear receptor transactivation model in HEK293 cells. We determined the synthesized magnolol dimer to bind with much higher affinity to the purified PPARγ ligand binding domain than magnolol (K

Topics: Biphenyl Compounds; Dimerization; Drug Design; HEK293 Cells; Humans; Ligands; Lignans; Pioglitazone; PPAR gamma; Protein Domains; Retinoid X Receptor alpha; Structure-Activity Relationship

The incidence of oral candidosis has increased in recent years due to the escalation in HIV-infection, cancer treatments, organ transplantation, and diabetes. In addition, corticosteroid use, dentures, and broad-spectrum antibiotic use have also contributed to the problem. Treatment of oral candidosis has continued to be problematic because of the potential toxicity of antifungals in clinical use, and, above all, development of drug resistance among patients. In this study, the antifungal effect of magnolol was investigated against 64 strains of Candida spp. (four standard and 60 oral isolates) through minimum inhibitory concentration (MIC) and growth curve assays. Insight into the mechanisms of the antifungal action has been gained through ultrastructural studies using confocal scanning laser microscopy (CSLM), scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Molecular docking was done for predicting the interactions of magnolol with ergosterol at supramolecular level. The toxicity of magnolol on human erythrocytes was measured by in vitro hemolytic assay. MIC values of magnolol ranged from 16-64 μg/ml, respectively. All tested isolates showed a marked sensitivity towards magnolol in growth curve assays. Biofilm results suggested that magnolol showed strong anti-biofilm activity. The results obtained for four different Candida spp. demonstrated that MBIC values of magnolol showed the average biofilm inhibition by 69.5%, respectively. CLSM experiments showed that cells exposed to magnolol (MIC) exhibited cell membrane disruption. SEM analysis of magnolol treated cells resulted in deformed cells. TEM micrographs showed rupturing of the cell wall and plasma membrane, releasing the intracellular content, and swelling of the cell wall. Hemolytic activity of magnolol is 11.9% at its highest MIC compared to an activity level of 25.4% shown by amphotericin B (Amp B) at 1 μg/ml. Lipinski's parameters calculated for magnolol suggested its good oral bioavailability. Docking studies indicated that magnolol might be interacting with ergosterol in the fungal cell membranes. Together, the present study provides enough evidence for further work on magnolol so that better strategies could be employed to treat oral candidosis.

Topics: Amphotericin B; Antifungal Agents; Biofilms; Biphenyl Compounds; Candida; Candidiasis, Oral; Cell Membrane; Ergosterol; Erythrocytes; Humans; Lignans; Microbial Sensitivity Tests; Microscopy; Molecular Docking Simulation

Aeromonas hydrophila is a common zoonotic pathogen which can cause several infections both in human and animals, particular aquatic animals. Antibiotics have been widely used in the treatment of A. hydrophila infections, however, the development of resistance has limited the treatment for these infections. There is an urgent need for novel agents and strategies against these infections. Aerolysin, a pore-forming toxin secreted by most pathogenic A. hydrophila, is known to contribute to the pathogenesis of A. hydrophila infections. Therefore, aerolysin has been identified as a potential target for drug discovery. In this paper, we found that magnolol, a natural compound without anti -A. hydrophila activity, could significantly inhibit the hemolytic activity of A. hydrophila culture supernatants by inhibiting the transcription of the aerolysin encoding gene aerA at low concentrations. Furthermore, the survival assay showed that magnolol could significantly reduce the mortality induced by A. hydrophila infection in channel catfish (Ictalurus punctatus). Taken together, these findings provide a potent agent against A. hydrophila infections.

Topics: Aeromonas hydrophila; Animals; Bacterial Toxins; Biphenyl Compounds; Fish Diseases; Gram-Negative Bacterial Infections; Hemolysis; Ictaluridae; Lignans; Microbial Sensitivity Tests; Pore Forming Cytotoxic Proteins; Virulence Factors

Due to gravity the venous vasculature in the lower extremities is exposed to elevated pressure levels which may be amplified by obesity or pregnancy. As a consequence, venules dilate and may be slowly transformed into varicose or spider veins. In fact, chronically elevated venous pressure was sufficient to cause the corkscrew-like enlargement of superficial veins in mice. We hypothesized that biomechanical activation of endothelial cells contributes to this process and investigated the inhibitory capacity of Magnolol in this context - a natural compound that features multiple properties counteracting cellular stress. While Magnolol did not influence endothelial capillary sprout formation, it interfered with proliferation, ERK1/2 activity, gelatinase activity as well as baseline production of reactive oxygen species in these cells or murine veins. The anti-oxidative and anti-proliferative capacity of Magnolol was mediated through stimulation of heme oxygenase-1 expression. Finally, local transdermal application of Magnolol attenuated pressure-mediated development of varicose/spider veins in mice and was accompanied by the absence of proliferating and MMP-2 positive endothelial cells. Collectively, our data identified Magnolol as a potent inhibitor of biomechanically evoked endothelial cell activity during pressure-mediated venous remodeling processes which contribute to the development of varicose and spider veins.

Topics: Animals; Antioxidants; Biphenyl Compounds; Cell Proliferation; Cells, Cultured; Endothelial Cells; Human Umbilical Vein Endothelial Cells; Humans; Lignans; Male; MAP Kinase Signaling System; Matrix Metalloproteinase 2; Mice; Reactive Oxygen Species; Signal Transduction; Vascular Remodeling; Veins; Venous Pressure

The expression of the adhesion molecule vascular cell adhesion molecule-1 (VCAM-1) on endothelial cells enables the attachment of leukocytes to the endothelium, which may lead to inflammation and the development of atherosclerosis. Magnolol is a major bioactive compound derived from the plant species Magnolia officinalis. In this study, we synthesized a novel nanoparticle formulation of magnolol to improve its water solubility and physicochemical properties, evaluated its effects on TNF-α-induced VCAM-1 expression in endothelial cells, and determined the signal transduction pathways involved. Our findings demonstrated that the magnolol nanoparticle system showed great improvements in physicochemical properties and water solubility owing to a reduction in particle size, transformation from a crystalline to amorphous structure, and the formation of hydrogen bonds with the nanoparticle carriers. In terms of its biological actions, magnolol nanoparticles attenuated TNF-α-induced VCAM-1 protein expression, promoter activity, and mRNA expression in endothelial cells in vitro. This was found to be mediated by the ERK, AKT, and NF-κB signaling pathways. In addition, magnolol nanoparticles inhibited TNF-α-induced leukocyte adhesion to endothelial cells, and suppressed TNF-α-induced VCAM-1 expression in the aortic endothelium of mice. In summary, since magnolol nanoparticles inhibit endothelial VCAM-1 expression and leukocyte adhesion to endothelial cells, this novel drug formulation may be a potentially useful therapeutic formulation to prevent the development of atherosclerosis and inflammatory diseases.

Topics: Animals; Biphenyl Compounds; Body Water; Cells, Cultured; Down-Regulation; Drug Compounding; Endothelial Cells; Humans; Lignans; Mice; Mice, Inbred C57BL; Nanoparticles; Particle Size; Solubility; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1

Topics: Acetylcholine; Acetylcholinesterase; Alcohol Oxidoreductases; Ascorbic Acid; Biosensing Techniques; Biphenyl Compounds; Electrochemical Techniques; Eugenol; Lignans; Microscopy, Electron, Scanning; Phenols; Phenylenediamines; Polymerization; Polymers; Reproducibility of Results

Topics: Animals; Biphenyl Compounds; Cell Differentiation; Cells, Cultured; Concanavalin A; Hepatic Stellate Cells; Humans; Lignans; Liver Cirrhosis, Experimental; Mice; Mice, Inbred BALB C; Signal Transduction; Smad3 Protein; Smad4 Protein; Th17 Cells

Medicinal plants have been widely used for a long history. Exploration of pharmacologically active compounds from medicinal plants present a broad prevalent of application. By examining viral mRNA expression in GCRV-infected Ctenopharyngodon idella kidney (CIK) cells treated with thirty kinds of plant extracts, we identified Magnolia officinalis Rehd et Wils. was able to preferably suppress viral replication. Further studies demonstrated that the main ingredients of magnolia bark, namely, magnolol and honokiol presented protective pharmacological function when treated GCRV-infected CIK cells with a concentration of 2.00 μg/ml and 1.25 μg/ml, respectively. Furthermore, reverse transcript quantitative polymerase chain reaction (RT-qPCR) and western blot showed that both magnolol and honokiol were efficient to restrain the replication of GCRV in CIK cells at non-toxic concentration (2.51 ± 0.51 μg/ml for magnolol, and 3.18 ± 0.61 μg/ml for honokiol). Moreover, it was found that magnolol and honokiol promoted the expression of immune-related genes. Magnolol obviously significantly increased the expression of interferon (IFN) regulatory factor (IRF)7 rather than that of IRF3 in the GCRV-infected cells, leading to the activation of type I IFN (IFN-I). Simultaneously, magnolol drastically facilitated the expression of interleukin (IL)-1β, but failed to induce the molecules in nuclear factor (NF)-κB pathways. Differently, honokiol strikingly motivated not only the expression of IL-1β, but also those of tumor necrosis factor α (TNFα) and NF-κB. Interestingly, though honokiol motivated the expression of IFN-β promoter stimulator 1 (IPS-1), IRF3 and IRF7, it failed to up-regulate the expression of IFN-I, indicating that honokiol enhanced the host innate antiviral response to GCRV infection via NF-κB pathways. Collectively, the present study revealed that magnolol and honokiol facilitated the expression of innate immune-related genes to strengthen the innate immune signaling responses to resist GCRV infection, which contributed to understanding the mechanisms by which small-molecule drugs possessed antiviral activities. In addition, these results lay a foundation for the development of broad-spectrum antiviral compounds in aquaculture industry.

Topics: Animals; Biphenyl Compounds; Carps; Cell Line; Colorimetry; Cytopathogenic Effect, Viral; Fish Diseases; Immunity, Innate; Lignans; Magnolia; Reoviridae; Reoviridae Infections; Tetrazolium Salts; Thiazoles

18F-9-Fluoropropyl-(+)-dihydrotetrabenazine [18F-FP-(+)-DTBZ] positron emission tomography (PET) has been shown to detect dopaminergic neuron loss associated with Parkinson's disease (PD) in human and neurotoxin-induced animal models. A polyphenol compound, magnolol, was recently proposed as having a potentially restorative effect in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)- or 6-hydroxydopamine-treated animal models. In this study, 18F-FP-(+)-DTBZ PET was used to determine the therapeutic efficacy of magnolol in an MPTP-PD mouse model that was prepared by giving an intraperitoneally (i.p.) daily dose of 25 mg/kg MPTP to male C57BL/6 mice for 5 consecutive days. Twenty-minute static 18F-FP-(+)-DTBZ PET scans were performed before MPTP treatment and 5 days after the termination of MPTP treatment to set up the baseline control. Half of the MPTP-treated mice then received a daily dose of magnolol (10 mg/kg dissolved in corn oil, i.p.) for 6 days. 18F-FP-(+)-DTBZ PET imaging was performed the day after the final treatment. All 18F-FP-(+)-DTBZ PET images were analysed and the specific uptake ratio (SUr) was calculated. Ex vivo autoradiography (ARG) and corresponding immunohistochemistry (IHC) studies were conducted to confirm the distribution of dopaminergic terminals in the striatum. The striatal SUr ratios of 18F-FP-(+)-DTBZ PET images for the Sham, the MPTP, and the MPTP + Magnolol-treated groups were 1.25 ± 0.05, 0.75 ± 0.06, and 1.00 ± 0.11, respectively (n = 4 for each group). The ex vivo 18F-FP-(+)-DTBZ ARG and IHC results correlated favourably with the PET imaging results. 18F-FP-(+)-DTBZ PET imaging suggested that magnolol post-treatment may reverse the neuronal damage in the MPTP-lesioned PD mice. In vivo imaging of the striatal vesicular monoamine transporter type 2 (VMAT2) distribution using 18F-FP-(+)-DTBZ animal PET is a useful method to evaluate the efficacy of therapeutic drugs i.e., magnolol, for the management of PD.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Biphenyl Compounds; Corpus Striatum; Disease Models, Animal; Fluorine Radioisotopes; Humans; Lignans; Mice; Neurons; Parkinson Disease; Parkinson Disease, Secondary; Positron-Emission Tomography; Tetrabenazine; Vesicular Monoamine Transport Proteins

To explore the pharmacokinetics and pharmacodynamics of Da-Cheng-Qi decoction (DCQD) in the liver of rats with severe acute pancreatitis (SAP) based on an herbal recipe tissue pharmacology hypothesis.. Healthy male Sprague-Dawley rats were randomly divided into a sham operation group (SOG); a model group (MG); and low-, median- and high-dose treatment groups (LDG, MDG, and HDG, respectively). Different dosages (6, 12 and 24 g/kg for the LDG, MDG, and HDG, respectively) of DCQD were administered to the rats with SAP. The tissue concentrations of aloe-emodin, rhein, emodin, chrysophanol, honokiol, rheo chrysophanol, magnolol, hesperidin, naringenin and naringin in the liver of the treated rats were detected by high-performance liquid chromatography tandem mass spectrometry. Alanine transaminase (ALT) and aspartate transaminase (AST) in serum, inflammatory mediators in the liver and pathological scores were evaluated.. The major components of DCQD were detected in the liver, and their concentrations increased dose-dependently. The high dose of DCQD showed a maximal effect in ameliorating the pathological damages, decreasing the pro-inflammatory mediators tumor necrosis factor-α and interleukin (IL)-6 and increasing anti-inflammatory mediators IL-4 and IL-10 in the liver. The pathological scores in the pancreas for the MG were significantly higher than those for the SOG (. DCQD could alleviate liver damage by altering the inflammatory response in rats with SAP based on the liver distribution of its components.

Topics: Acute Disease; Alanine Transaminase; Animals; Anthraquinones; Aspartate Aminotransferases; Biphenyl Compounds; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Emodin; Flavanones; Hesperidin; Inflammation; Lignans; Liver; Male; Pancreatitis; Rats; Rats, Sprague-Dawley; Tandem Mass Spectrometry

In this study, solid dispersion system of magnolol in croscarmellose sodium was prepared by using the solvent evaporation method, in order to increase the drug dissolution. And its dissolution behavior, stability and physical characteristics were studied. The solid dispersion was prepared with magnolol and croscarmellose sodium, with the proportion of 1∶5, the in vitro dissolution of magnolol solid dispersion was up to 80.66% at 120 min, which was 6.9 times of magnolol. The results of DSC (differential scanning calorimetry), IR (infra-red) spectrum and SEM (scanning electron microscopy) showed that magnolol existed in solid dispersion in an amorphous form. After an accelerated stability test for six months, the drug dissolution and content in magnolol solid dispersion showed no significant change. So the solid dispersion prepared with croscarmellose sodium as the carrier can remarkably improve the stability and dissolution of magnolol.

Topics: Biphenyl Compounds; Calorimetry, Differential Scanning; Chemistry, Pharmaceutical; Drug Compounding; Drugs, Chinese Herbal; Lignans; Microscopy, Electron, Scanning; Solubility

To conduct multiple-reaction monitoring(MRM) quantitative analysis with high-performance liquid chromatography coupled with mass spectrometry method, establish the quantification method of magnolol and honokiol in blood sample under negative ion mode with ibuprofen as internal standard, investigate the pharmacokinetic process of lignans constituents after oral administration of Weichang'an pill(WCA) at different doses, and provide theoretical basis to further reveal the material basis of WCA's anti-diarrhea effect. In the plasma samples, the linear relationship was good over the concentration range of 5.25 to 1 344.00 μg•L ⁻¹ for magnolol and 10.08 to 2 580.00 μg•L ⁻¹ for honokiol. The results of precision, stability, and extraction recovery tests showed that the determination method of plasma concentration for such compositions was stable and reliable. Dose-dependence was shown for magnolol and honokiol in the plasma concentration-time profile. The results indicated that the time to reach the maximum plasma concentration(Tmax) for lignanoids was 0.55-1.42 h, when the maximum plasma concentration(Cmax) could reach 996.36-2 330.96,189.87-1 469.43 μg•L ⁻¹ respectively for magnolol and honokiol. The lignanoids could be absorbed rapidly in the blood after oral administration of WAC pills, providing experimental basis to prove rapid and long-acting anti-diarrhea effect of WAC pills after oral administration.

Topics: Animals; Biphenyl Compounds; Drugs, Chinese Herbal; Lignans

In this study, magnolol phospholipid complex (MPC) was prepared and solidified with polyvingypyrrolidone (PVPP). The influence of PVPP on MPC's flowability, dissolution and oral bioavailability was investigated. The results of phase characterization using differential scanning calorimetry (DSC), infrared spectroscopy (IR), and scanning electron microscopy (SEM) showed that magnolol existed in solidified powder and MPC in an amorphous state. In flowability and dissolution experiments, solidified powder showed significant superiority. At the same time, it showed a higher oral bioavailability compared with MPC, with AUC0-∞ of 73.47 μg•h•mL⁻¹ vs. 63.48 μg•h•mL⁻¹. This process for solidifying powder with PVPP is simple and convenient.

Topics: Biological Availability; Biphenyl Compounds; Calorimetry, Differential Scanning; Lignans; Microscopy, Electron, Scanning; Phospholipids; Povidone; Solubility; Spectroscopy, Fourier Transform Infrared

Magnolol (MAG; 5,5'-diallyl-2,2'-biphenyldiol) is a major bioactive component of Magnolia officinalis. We investigated the metabolic interactions of MAG with hepatic cytochrome P450 monooxygenase (CYP) through in vitro microsomal metabolism study using human (HLM) and rat liver microsomes (RLM). CYP2C and 3A subfamilies were significantly involved in the metabolism of MAG, while CYP1A subfamily was not in HLM and RLM. The relative contribution of phase I enzymes including CYP to the metabolism of MAG was comparable to that of uridine diphosphate glucuronosyltransferase (UGT) in RLM. Moreover, MAG potently inhibited the metabolic activity of CYP1A (IC50 of 1.62 μM) and 2C (IC50 of 5.56 μM), while weakly CYP3A (IC50 of 35.0 μM) in HLM and RLM. By the construction of Dixon plot, the inhibition type of MAG on CYP activity in RLM was determined as follows: uncompetitive inhibitor for CYP1A (Ki of 1.09-12.0 μM); competitive inhibitor for CYP2C (Ki of 10.0-15.2 μM) and 3A (Ki of 93.7-183 μM). Based on the comparison of the current IC50 and Ki values with a previously reported liver concentration (about 13 μM) of MAG after its seven times oral administration at a dose of 50 mg/kg in rats, it is suggested that MAG could show significant inhibition of CYP1A and 2C, but not CYP3A, in the in vivo rat system. These results could lead to further studies in clinically significant metabolism-mediated MAG-drug interactions.

Topics: Administration, Oral; Animals; Biphenyl Compounds; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Dose-Response Relationship, Drug; Drug Interactions; Humans; Inhibitory Concentration 50; Lignans; Magnolia; Male; Microsomes, Liver; Rats; Rats, Sprague-Dawley

Zhi-Zi-Hou-Po decoction (ZZHPD) is one of the famous antidepressant Chinese formulas and is composed of Magnolia officinalis cortex (HP), Gardenia jasminoides Ellis (ZZ) and Citrus aurantium L. (ZS). Magnolol (MN) and honokiol (HN) from HP are the major active ingredients responsible for the therapeutic effects of ZZHPD. The aim of this study is to compare the pharmacokinetics and rat brain distribution of MN and HN after oral administration of HP extract and its compatibility with other herbal medicines in ZZHPD by HPLC-FLD. Compared with the HP group, Tmax (time to reach peak drug concentration in plasma) and AUC(0-τ) significantly increased in the ZZHPD and HP-ZZ groups. There was little change in the HP-ZS group in comparison with the HP group, which indicated that ZZ promotes absorption extent and defers the absorption rate of MN. The different compatibility of ZZHPD had a different degree of impact on the concentration of MN and HN in brain. The concentration of MN significantly increased in the HP-ZZ group while it decreased in the HP-ZS group compared with the HP group, which explained the concentration of compounds being slightly greater in the ZZHPD group than in the HP group. HP mixed with other medicines resulted in a decrease in HN concentration in the brain, particularly HP compatible with ZS. The results could be helpful for revealing the compatibility mechanism and providing clinical medication guidance for ZZHPD.

Topics: Administration, Oral; Animals; Biphenyl Compounds; Brain Chemistry; Chromatography, High Pressure Liquid; Drug Interactions; Drugs, Chinese Herbal; Iridoids; Lignans; Magnolia; Male; Plant Extracts; Rats; Tissue Distribution

In the present study, we investigated the effects of Magnolol on the retinal neovascularization (RNV) and local glial cells in an oxygen-induced retinopathy (OIR) model and explored their molecular mechanisms.. Neonatal C57BL/6J mice were subjected to 75% O2 ± 5% from postnatal day (P) 7 to P12 and subsequently returned to room air. Mice were injected with 25 mg/kg Magnolol intraperitoneally once a day from P12 to P17, then retinas were harvested and flat-mounted to assess the retinal vessels, astrocytes and microglia. To clarify the molecular mechanisms of Magnolol, we observed the level of inflammatory cytokines such as interleukin (IL)-1β, IL-6, monocyte chemoattractant protein-1, tumor necrosis factor-α, and analyzed the hypoxia-inducible factor (HIF)-1α/vascular endothelial growth factor (VEGF) pathway in OIR mice.. Intraperitoneal administration of Magnolol resulted in significant reduction of RNV without retinal toxicity or perturbation of developmental retinal angiogenesis. In addition, Magnolol preserved the astrocyte morphology and diminished the activation of microglia. Moreover, Magnolol down regulated the expression of inflammatory cytokines and inactivated the HIF-1α/VEGF pathway.. These results indicated that Magnolol might have potential for the treatment of pathological retinal angiogenesis and glial dysfunctions via anti-inflammation and inhibition of HIF-1α/VEGF pathway.

Topics: Angiogenesis Inhibitors; Animals; Animals, Newborn; Anti-Inflammatory Agents, Non-Steroidal; Astrocytes; Biphenyl Compounds; Cytokines; Injections, Intraperitoneal; Lignans; Mice; Mice, Inbred C57BL; Microglia; Oxygen; Retinal Diseases; Retinal Neovascularization; Retinal Vessels

Dental caries affects people of all ages and is a worldwide health concern. Streptococcus mutans is a major cariogenic bacterium because of its ability to form biofilm and induce an acidic environment. In this study, the antibacterial activities of magnolol and honokiol, the main constituents of the bark of magnolia plants, toward planktonic cell and biofilm of S. mutans were examined and compared with those of chlorhexidine. The minimal inhibitory concentrations of magnolol, honokiol and chlorhexidine for S. mutans were 10, 10 and 0.25 µg/mL, respectively. In addition, each agent showed bactericidal activity against S. mutans planktonic cells and inhibited biofilm formation in a dose- and time-dependent manner. Magnolol (50 µg/mL) had greater bactericidal activity against S. mutans biofilm than honokiol (50 µg/mL) and chlorhexidine (500 µg/mL) at 5 min after exposure, while all showed scant activity against biofilm at 30 s. Furthermore; chlorhexidine (0.5-500 µg/mL) exhibited high cellular toxicity for the gingival epithelial cell line Ca9-22 at 1 hr, whereas magnolol (50 µg/mL) and honokiol (50 µg/mL) did not. Thus; it was found that magnolol has antimicrobial activities against planktonic and biofilm cells of S. mutans. Magnolol may be a candidate for prevention and management of dental caries.

Topics: Anti-Bacterial Agents; Biofilms; Biphenyl Compounds; Cell Line; Dose-Response Relationship, Drug; Gingiva; Humans; Lignans; Magnolia; Microbial Sensitivity Tests; Microscopy, Fluorescence; Plant Bark; Plant Extracts; Streptococcus mutans

Aristolochic acids (AA) are nephrotoxic agents found in Aristolochia species whose consumption leads to the onset of a progressive tubulointerstitial fibrosis. This AA-nephropathy was first reported during the Belgian outbreak of the 1990's in which more than a hundred patients consumed slimming pills containing an Aristolochia species and Magnolia officinalis. The patients developed an end-stage kidney disease requiring dialysis or transplantation. Magnolol and honokiol are bioactive compounds from M. officinalis known for their potent antioxidant activity. As they can alleviate oxidative stress, we investigated their respective effects on AA-mediated tubulotoxicity using HK-2 cells. Magnolol and honokiol were able to reduce the oxidative stress associated with AA-treatment. Cytotoxicity alleviation was further investigated and overall cell viability measurements unexpectedly revealed that both compounds worsened the survival of AA-treated cells. Flow cytometry analyses of annexin V/PI stained cells indicated that the lignans efficiently prevented AA-induced apoptosis; but favored necrosis. Microscopy observations highlighted extensive vacuolization; other types of cell death, including autophagy, paraptosis or accelerated senescence were excluded. Ki-67 index and cell cycle analysis indicated that both magnolol and honokiol inhibited proliferation by blocking the cell cycle at the G1 phase; they also prevented the AA-induced G2/M arrest.

Topics: Aristolochic Acids; Biphenyl Compounds; Cell Cycle; Cell Line; Free Radical Scavengers; Humans; Kidney Tubules; Lignans; Molecular Structure; Oxidative Stress; Picrates

The high-performance liquid chromatography fingerprint method is a simple and reliable technique to evaluate the quality of leaves of Magnolia officinalis Rehd.et Wils. var. biloba Rehd.et Wils. We used the following bioactive phenolic constituents as reference compounds: rutin, afzelin, hyperoside, isoquercitrin, quercetin-3-O-α-l-rhamnoside, honokiol and magnolol. The conditions of an Agilent 1200 HPLC were: YMC-Pack-ODS-AQ column (250 × 4.6 mm id S-5 μm, 12 nm), mobile phase acetonitrile and 0.2% phosphoric acid in a gradient elute mode, flow rate 1.0 mL/min, detection wavelength 280 nm and column temperature 30°C. The analytical method was validated in terms of linearity, stability, repeatability, precision and recovery tests. While performing fingerprint analysis, we identified 11 peaks as characteristic peaks and assessed the similarities of 17 samples collected from different geological regions of China. The peak areas were used to evaluate the variation in the chemical composition of the tested samples. For this purpose, we performed hierarchical cluster analysis of the peak areas. Our results indicate that simultaneous determination of multiple ingredients could be done through chromatographic fingerprint analysis. Therefore, this high-performance liquid chromatography fingerprint method was readily utilized to evaluate the quality of leaves of M. officinalis var.biloba, which are used in several traditional herbal preparations.

Topics: Biphenyl Compounds; China; Chromatography; Chromatography, High Pressure Liquid; Glucosides; Lignans; Magnolia; Mannosides; Phenols; Plant Extracts; Plant Leaves; Proanthocyanidins; Quercetin; Reference Values; Reproducibility of Results; Rutin; Temperature

Trimethyltin (TMT), an organotin with potent neurotoxic effects by selectively damaging to hippocampus, is used as a tool for creating an experimental model of neurodegeneration. In the present study, we investigated the protective effects of magnolol, a natural biphenolic compound, on TMT-induced neurodegeneration and glial activation in vitro and in vivo. In HT22 murine neuroblastoma cells, TMT induced necrotic/apoptotic cell death and oxidative stress, including intracellular reactive oxygen species (ROS), protein carbonylation, induction of heme oxygenase-1 (HO-1), and activation of all mitogen-activated protein kinases (MAPKs) family proteins. However, magnolol treatment significantly suppressed neuronal cell death by inhibiting TMT-mediated ROS generation and activation of JNK and p38 MAPKs. In BV-2 microglial cells, magnolol efficiently attenuated TMT-induced microglial activation via suppression of ROS generation and activation of JNK, p38 MAPKs, and nuclear factor-κB (NF-κB) signaling. In an in vivo mouse study, TMT induced massive neuronal damage and enhanced oxidative stress at day 2. We also observed a concomitant increase in glial cells and inducible nitric oxide synthase (iNOS) expression on the same day. These features of TMT toxicity were reversed by treatment of magnolol. We observed that p-JNK and p-p38 MAPK levels were increased in the mouse hippocampus at day 1 after TMT treatment and that magnolol blocked TMT-induced JNK and p38 MAPK activation. Magnolol administration prevented TMT-induced hippocampal neurodegeneration and glial activation, possibly through the regulation of TMT-mediated ROS generation and MAPK activation.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Biphenyl Compounds; Cell Death; Cells, Cultured; Cytokines; DNA Fragmentation; Enzyme Inhibitors; Glial Fibrillary Acidic Protein; Hippocampus; Lignans; Male; Mice; Mice, Inbred ICR; Neuroglia; Neurons; Nitrites; Protein Carbonylation; Reactive Oxygen Species; Signal Transduction; Trimethyltin Compounds

Masiningan is a traditional medicine consisting of six crude drugs that have been used for treating constipation and diabetes mellitus in both Japan and China. Masiningan has been reported to have significant PTP1B inhibitory activity and to affect cells in the insulin-signaling pathway. The aim of the present study is to identify the PTP1B inhibitory compounds in Masiningan.. Bioactivity peaks were identified by analytical HPLC profiling and PTP1B inhibitory activity profiling of sub-fractions from Masiningan extract. The bioactive compounds were isolated by tracking two identified bioactive peaks, and the chemical structures were determined by spectroscopic analyses. The bioactive compounds were further investigated for their inhibitory effect against PTP1B by enzymatic kinetic analysis, molecular docking simulation, inhibitory selectivity against other PTPs, and cellular activity in the insulin signal transduction pathway.. From Masiningan, magnolol (1) and chrysophanol (2) were isolated as compounds that exhibited significant dose-dependent inhibitory activities against PTP1B, with IC50 values of 24.6 and 12.3μM, respectively. Kinetic analysis revealed that 1 is a non-competitive and that 2 is a competitive PTP1B inhibitor. In the molecular docking simulation, compound 2 was stably positioned in the active pocket of PTP1B, and the CDOCKER energy was calculated to be 24.3411kcal/mol. Both compounds demonstrated remarkably high selectivity against four PTPs and revealed cellular activity against the insulin signal transduction pathway.. Magnolol (1) and chrysophanol (2) were identified as the principle PTP1B inhibitory active compounds in Masiningan, and their actions were investigated in detail. These findings demonstrated the effectiveness of Masiningan on diabetes mellitus through the inhibition of PTP1B at a molecular level as well as the potential of magnolol (1) and chrysophanol (2) as lead compounds in future anti-diabetes drug development.

Topics: Anthraquinones; Biphenyl Compounds; Catalytic Domain; Humans; Japan; Kinetics; Lignans; Medicine, Kampo; Models, Molecular; Molecular Structure; Protein Conformation; Protein Tyrosine Phosphatase, Non-Receptor Type 1

Glioblastoma (GBM) is a malignant brain tumor associated with a high mortality rate. The aim of this study is to investigate the synergistic effects of honokiol (Hono) and magnolol (Mag), extracted from Magnolia officinalis, on cytotoxicity and inhibition of human GBM tumor progression in cellular and animal models. In comparison with Hono or Mag alone, co-treatment with Hono and Mag (Hono-Mag) decreased cyclin A, D1 and cyclin-dependent kinase 2, 4, 6 significantly, leading to cell cycle arrest in U87MG and LN229 human glioma cells. In addition, phosphorylated phosphoinositide 3-kinase (p-PI3K), p-Akt, and Ki67 were decreased after Hono-Mag treatment, showing proliferation inhibition. Hono-Mag treatment also reduced p-p38 and p-JNK but elevated p-ERK expression. Besides, Hono-Mag treatment induced autophagy and intrinsic and extrinsic apoptosis. Both ERK and autophagy inhibitors enhanced Hono-Mag-induced apoptosis in LN229 cells, indicating a rescuer role of ERK. In human GBM orthotopic xenograft model, the Hono-Mag treatment inhibited the tumor progression and induced apoptosis more efficiently than Temozolomide, Hono, or Mag group. In conclusion, the Hono-Mag exerts a synergistic anti-tumor effect by inhibiting cell proliferation and inducing autophagy and apoptosis in human GBM cells. The Hono-Mag may be applied as an adjuvant therapy to improve the therapeutic efficacy of GBM treatment.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Autophagy; Biphenyl Compounds; Brain Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Synergism; Glioblastoma; Humans; Lignans; Mice; Mice, Nude; Xenograft Model Antitumor Assays

The stem of Magnoliae officinalis (MO) cortex is always preliminarily processed before being applied in traditional Chinese medicine. The definite bioavailability of honokiol (HO) and magnolol (MA) in processed MO (PMO) and the effect of chemical profiling change on the pharmacokinetics of HO and MA are always a greater challenge compared with those of MO. Compared with that of MO, the pharmacokinetic profiling of HO and MA in the PMO was significantly changed and the mean Tmax of HO and MA was increased by 31 and 50% (P < 0.05), respectively; the mean AUC0-t and Cmax of HO were increased by 36 and 24% (P < 0.05), respectively. Subsequently, the chemical profiling of MO and PMO was investigated by a simple and rapid LC-Q/TOF-MS coupled with multivariate analysis method. Principal component analysis and hierarchical cluster analysis of the chromatographic data demonstrated that the chemical profiling of PMO was significantly different from that of MO. Eight marker components including six alkaloids (magnocurarine, magnoflorine, roemerine and three unidentified peaks) and two lignans (obovatol and MA) were screened out by partial least-squares discriminant analysis. The results indicated that the changes of eight marker components of PMO may have an effect on the pharmacokinetic profiles of HO and MA.

Topics: Alkaloids; Animals; Biphenyl Compounds; Chromatography, Liquid; Cluster Analysis; Drugs, Chinese Herbal; Humans; Lignans; Magnolia; Male; Multivariate Analysis; Plant Stems; Principal Component Analysis; Rats; Rats, Wistar; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

To investigate the effect of magnolol on proliferation and apoptosis of HL-60 cells and its mechanism.. MTT assay was used to measure the proliferation of HL-60 cells after treatment with different concentration of magnolol (5, 10, 20, 40, 80 and 160 µg/ml). The morphological changes of HL-60 cells were examined by light microscopy, and DAPI staining was performed to observe the nuclear morphology of HL-60 cells. The early cell apoptosis was detected by flow cytometry with Annexin V-FITC/PI double-staining. RT-PCR was carried out to examine the mRNA expression of BAX and BCL-2. Western blot was performed to detect the protein expression of caspase family.. The magnolol inhibited HL-60 cell proliferation, and the inhibitory rate of cell proliferation increased significantly in a dose- and time- dependent manner (P < 0.05). HL-60 cells became small, even apoptotic bodies appeared after treatment with magnolol. In addition, nuclear condensation or fragmentation could be observed, which is the typical morphological features of apoptosis. When HL-60 cells were treated with 40 µg/ml of magnolol for 24 h, the ratio of early apoptotic cells reached to (11.7 ± 2.4) %, which was significant different from control (1.4 ± 1.1) % (P < 0.05). RT-PCR results showed that treatment of HL-60 cells with magnolol up-regulated the expression of BAX, whereas down-regulated the expression of BCL-2. Western blot results showed that the cleavages of caspase-3, -8 and -9 were significantly enhanced by magnolol.. The magnolol can significantly inhibit the proliferation of HL-60 cells and induce the apoptosis of HL-60 cells, which may occur through up-regulation of BAX, down-regulation of BCL-2 and the activation of caspases.

Topics: Apoptosis; bcl-2-Associated X Protein; Biphenyl Compounds; Caspases; Cell Proliferation; Down-Regulation; Flow Cytometry; HL-60 Cells; Humans; Lignans; Proto-Oncogene Proteins c-bcl-2; Up-Regulation

As a continuing effort to elucidate the impact of structure modification upon cutaneous absorption behavior, we attempted to assess the skin permeation of magnolol by methylation and acetylation.. Diacetylmagnolol and 2-O-acetyl-2'-O-methylmagnolol (AMM) were designed and synthesized in this study. The anti-inflammatory activity against stimulated neutrophils and keratinocytes was evaluated to check the bioactivity of the analogues. In vitro skin absorption was investigated using nude mouse and pig skin models at both equimolar and saturated doses.. Magnolol generally showed the strongest anti-inflammatory potential, followed by diacetylmagnolol and AMM. The antibacterial activity was observed for magnolol and diacetylmagnolol but not AMM. Diacetylmagnolol and AMM could be partly hydrolyzed to magnolol and 2-O-methylmagnolol after entering the skin. The hydrolysis rate of diacetylmagnolol was faster than that of AMM. The lipophilicity played a crucial role in cutaneous absorption, with AMM exhibiting the highest skin deposition. AMM accumulation within nude mouse skin was about 2.5-fold greater than that of magnolol and diacetylmagnolol. On the other hand, the transdermal penetration across the skin was lessened by methylation and esterification. This led to a superior skin targeting of AMM. Although the pharmacological activity of AMM was low, the high skin uptake and bioconversion into 2-O-methylmagnolol in the skin contributed to a greater therapeutic index (TI, skin deposition x inflammatory inhibition percentage) compared to the others. The accumulation of AMM in the hair follicles was 77.12 nmol/cm(2), which was significantly greater than that with magnolol (44.84 nmol/cm(2)) and diacetylmagnolol (26.96 nmol/cm(2)). The synthetic analogues were tolerable to the nude mouse skin.. Based on the experimental results, we may suggest topically applied AMM as a potent and safe candidate for the treatment of cutaneous inflammation.

Topics: Administration, Cutaneous; Animals; Biphenyl Compounds; Dermatologic Agents; Esterification; Female; Hair Follicle; Humans; Keratinocytes; Lignans; Methylation; Mice; Mice, Nude; Neutrophils; Skin; Skin Absorption; Swine; Therapeutic Index

Heat stress (HS) is an important environmental stressor that adversely influences livestock during the summer. The aim of this study was to investigate whether magnolol protects against HS-induced intestinal epithelial cell injury.. An intestinal epithelial cell line (IEC-6) was subjected to HS at 42 °C, with and without magnolol pretreatment. Cell injury was detected by monitoring lactate dehydrogenase (LDH) release. MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay was used to assess cell proliferation and viability, including identifying effective concentrations of magnolol. Flow cytometry confirmed G1-phase cell-cycle arrest and its alleviation by magnolol. Active DNA synthesis was measured by incorporation of nucleic acid 5-ethynyl-2'-deoxyuridine (EdU). G1-phase cell-cycle-related gene expression was assessed by real-time reverse transcription polymerase chain reaction (RT-PCR) and levels of G1-phase-related proteins by Western blotting.. HS induced IEC-6 cell injury and decreased cell viability, as demonstrated by data from LDH and MTS assays, respectively. Based on a number of criteria, IEC-6 cells subjected to HS were arrested in the G1 phase of the cell cycle. Magnolol pretreatment decreased HS-induced cell injury through relief of this cell-cycle arrest.. Magnolol pretreatment attenuates HS-induced injury in IEC-6 cells. Magnolol is potentially promising as a protective strategy for HS in livestock.

Topics: Animals; Biphenyl Compounds; Cell Survival; Cells, Cultured; G1 Phase Cell Cycle Checkpoints; Hot Temperature; Humans; Intestinal Mucosa; L-Lactate Dehydrogenase; Lignans; Rats

Histone modifications play critical roles in the progression of non-small cell lung cancer (NSCLC), which accounts for almost 85% of all diagnosed lung cancers. Magnolol and polyphenol mixture (PM) derived from Magnolia officinalis exhibited remarkable antitumor activities in lung cancer. However, the epigenetic effects and molecular mechanisms of magnolol and PM in NSCLC have yet to be reported. In this study, the epigenetic effects of magnolol and PM in NSCLC were examined in vitro and in vivo. Results revealed that magnolol and PM significantly suppressed the expression levels and function of class I histone deacetylases (HDACs). In A549 and H1299 cells, magnolol and PM remarkably induced cell apoptosis by arresting the cell cycle in the G0/G1 phase while simultaneously activating various pro-apoptotic signals, including TRAIL-R2 (DR5), Bax, caspase 3, cleaved caspase 3, and cleaved PARP. However, these apoptosis-promoting effects could be attenuated by TSA, which is a specific class I HDACs inhibitor. ChIP assays also demonstrated that magnolol and PM significantly enriched the histone acetyl mark (H3K27ac) in the promoter region of DR5. In A549 xenograft model, magnolol and PM notably reduced tumor growth by 44.40% and 35.40%, respectively. Therefore, magnolol and PM, as potential inhibitors of class I HDACs, induced tumor cell apoptosis and suppressed tumor growth partially by epigenetically activating DR5, which is a key protein in death receptor signaling pathway.

Topics: A549 Cells; Acetylation; Animals; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Apoptosis Regulatory Proteins; Biphenyl Compounds; Carcinoma, Non-Small-Cell Lung; Cell Cycle Checkpoints; Cell Proliferation; Dose-Response Relationship, Drug; Epigenesis, Genetic; Female; Histone Deacetylase 1; Histone Deacetylase Inhibitors; Histones; Humans; Lignans; Lung Neoplasms; Magnolia; Mice, Inbred BALB C; Mice, Nude; Phytotherapy; Plant Extracts; Plants, Medicinal; Polyphenols; Promoter Regions, Genetic; Receptors, TNF-Related Apoptosis-Inducing Ligand; Signal Transduction; Time Factors; TNF-Related Apoptosis-Inducing Ligand; Tumor Burden; Xenograft Model Antitumor Assays

Magnolol has shown inhibitory effects on NO production and TNF-alpha production in lipopolysaccharide (LPS)-activated macrophages and LPS-induced acute lung injury; however, the poor solubility of magnolol has hindered its clinical success. In this study, magnolol-loaded microparticles were prepared via single emulsion method from a polyketal polymer, termed PK3. The particle sizes of magnolol-loaded PK3 microparticle is 3.73 ± 0.41 μm, and was suitable for phagocytosis by macrophages and pulmonary drug delivery. PK3 microparticles exhibited excellent biocompatibility both in vitro and in vivo. More importantly, intratracheal delivery of these magnolol-loaded microparticles significantly reduced the lung inflammatory responses at low dosage of magnolol (0.5 mg/kg), and have great clinical potential in treating acute lung injury.

Topics: Acute Lung Injury; Animals; Biphenyl Compounds; Drug Delivery Systems; Lignans; Lipopolysaccharides; Male; Mice; Rats; Rats, Sprague-Dawley; RAW 264.7 Cells

Magnolol is the main constituent of Magnolia bark and has been reported to exhibit antidepressant effects in rodent models. Hippocampal neurogenesis and neurotrophins such as brain-derived neurotrophic factor are integrally involved in the action of conventional antidepressants. Here, we investigated the effects of magnolol on depressive behaviours, impaired hippocampal neurogenesis and neurotrophin-related signal transduction in an olfactory bulbectomy (OBX) mouse model of depression. Mice were submitted to OBX to induce depressive behaviour, which was evaluated in the tail suspension test. Magnolol was administered orally by gavage needle. Neurogenesis was assessed by analysis of cells expressing NeuN, a neuronal marker, and 5-bromo-2'-deoxyuridine (BrdU) uptake. Phosphorylation levels of protein kinase B (Akt), extracellular signal-regulated kinase and cyclic AMP-responsive element-binding protein were evaluated by Western blot. Fourteen day treatment with magnolol (50 or 100 mg/kg/day) significantly improved OBX-induced depressive behaviour in tail suspension test. In agreement, magnolol significantly rescued impairments of hippocampal neurogenesis. Moreover, single treatments with magnolol (50 mg/kg) significantly increased phosphorylation of Akt, extracellular signal-regulated kinase and cyclic AMP-responsive element-binding protein after 3 h. The present data indicate that magnolol exerts antidepressant-like effects on behaviours by enhancing hippocampal neurogenesis and neurotrophin-related intracellular signalling in OBX mice. Copyright © 2016 John Wiley & Sons, Ltd.

Topics: Animals; Antidepressive Agents; Biphenyl Compounds; Depression; Disease Models, Animal; Hippocampus; Lignans; Male; Mice; Neurogenesis; Olfactory Bulb; Phosphorylation; Signal Transduction

Proliferation of vascular smooth muscle cells (VSMCs) contributes to the development of vascular remodeling. Recently, magnolol has been reported to have a potential role in regulating tumor necrosis factor α-induced proliferation of VSMCs. However, the role of magnolol in platelet-derived growth factor (PDGF)-induced proliferation of VSMCs remains unknown.. Our purpose was to elucidate the effect of magnolol on the proliferation of VSMCs induced by PDGF-BB and to investigate the underlying molecular mechanisms.. Our data demonstrated that magnolol inhibited rat VSMC proliferation and DNA synthesis stimulated by 20 ng/ml PDGF-BB without causing cell cytotoxicity. Flow cytometric analysis showed that magnolol inhibited S-phase entry of VSMCs. We also demonstrated that magnolol caused this effect by inhibiting the mRNA and protein expression of cyclin D1, cyclin E, and cyclin-dependent kinases 2 and 4 in PDGF-BB-stimulated VSMCs. Further analysis showed that the inhibitory effect of magnolol on the proliferation of VSMCs was associated with the inhibition of the PDGF-BB-stimulated production of intracellular reactive oxygen species (ROS) and Ras, MEK, and ERK1/2 activation.. These results demonstrate that magnolol can block the proliferation of VSMCs through inhibition of intracellular ROS production and Ras-MEK-ERK1/2 pathways. Magnolol, therefore, has a potential application in preventing atherosclerosis and restenosis.

Topics: Animals; Becaplermin; Biphenyl Compounds; Cell Proliferation; Cells, Cultured; Lignans; MAP Kinase Signaling System; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Neovascularization, Pathologic; Proto-Oncogene Proteins c-sis; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species

Honokiol and magnolol, as pharmacological biphenolic compounds of Magnolia officinalis, have been reported to have antioxidant and anti-inflammatory properties. Sterol regulatory element binding protein-1 c (SREBP-1 c) plays an important role in the development and processing of steatosis in the liver. In the present study, we investigated the effects of a combination of honokiol and magnolol on SREBP-1 c-dependent lipogenesis in hepatocytes as well as in mice with fatty liver due to consumption of high-fat diet (HFD). Liver X receptor α (LXRα) agonists induced activation of SREBP-1 c and expression of lipogenic genes, which were blocked by co-treatment of honokiol and magnolol (HM). Moreover, a combination of HM potently increased mRNA of fatty acid oxidation genes. HM induced AMP-activated protein kinase (AMPK), an inhibitory kinase of the LXRα-SREBP-1 c pathway. The role of AMPK activation induced by HM was confirmed using an inhibitor of AMPK, Compound C, which reversed the ability of HM to both inhibit SREBP-1 c induction as well as induce genes for fatty acid oxidation. In mice, HM administration for four weeks ameliorated HFD-induced hepatic steatosis and liver dysfunction, as indicated by plasma parameters and Oil Red O staining. Taken together, our results demonstrated that a combination of HM has beneficial effects on inhibition of fatty liver and SREBP-1 c-mediated hepatic lipogenesis, and these events may be mediated by AMPK activation.

Topics: AMP-Activated Protein Kinases; Animals; Biphenyl Compounds; Cell Line; Diet, High-Fat; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Enzyme Inhibitors; Fatty Liver; Hepatocytes; Humans; Lignans; Lipogenesis; Liver X Receptors; Male; Mice; Mice, Inbred C57BL; Orphan Nuclear Receptors; Signal Transduction; Sterol Regulatory Element Binding Protein 1

Mastitis comprises an inflammation of the mammary gland, which is almost always linked with bacterial infection. The treatment of mastitis concerns antimicrobial substances, but not very successful. On the other hand, anti-inflammatory therapy with Chinese traditional medicine becomes an effective way for treating mastitis. Magnolol is a polyphenolic binaphthalene compound extracted from the stem bark of Magnolia sp., which has been shown to exert a potential for anti-inflammatory activity. The purpose of this study was to investigate the protective effects of magnolol on inflammation in lipopolysaccharide (LPS)-induced mastitis mouse model in vivo and the mechanism of this protective effects in LPS-stimulated mouse mammary epithelial cells (MMECs) in vitro. The damage of tissues was determined by histopathology and myeloperoxidase (MPO) assay. The expression of pro-inflammatory cytokines was determined by enzyme-linked immunosorbent assay (ELISA). Nuclear factor-kappa B (NF-κB), inhibitory kappa B (IκBα) protein, p38, extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and Toll-like receptor 4 (TLR4) were determined by Western blot. The results showed that magnolol significantly inhibit the LPS-induced TNF-α, IL-6, and IL-1β production both in vivo and vitro. Magnolol declined the phosphorylation of IκBα, p65, p38, ERK, and JNK in LPS-stimulated MMECs. Furthermore, magnolol inhibited the expression of TLR4 in LPS-stimulated MMECs. In vivo study, it was also observed that magnolol attenuated the damage of mastitis tissues in the mouse models. These findings demonstrated that magnolol attenuate LPS-stimulated inflammatory response by suppressing TLR4/NF-κB/mitogen-activated protein kinase (MAPK) signaling system. Thereby, magnolol may be a therapeutic agent against mastitis.

Topics: Animals; Biphenyl Compounds; Cells, Cultured; Disease Models, Animal; Dose-Response Relationship, Drug; Epithelial Cells; Female; Humans; Inflammation; Lignans; Male; Mammary Glands, Animal; Mastitis; Mice; Mice, Inbred BALB C

Bioassay-guided fractionation of the MeOH extract of Magnolia grandiflora seeds resulted in the isolation of a new dimeric neolignan, named bishonokiol A (1), as well as two known neolignans magnolol (2) and honokiol (3). The structures of the compounds were determined on the basis of data obtained using NMR and MS. Bishonokiol A (1) showed potent anti-proliferative activities in four human cancer cell lines, with IC50 values ranging from 5.1 to 7.5 µM. Additionally, bishonokiol A (1) induced apoptosis, as well as down-regulated the expression of the anti-apoptotic protein Bcl-2 and caspase-3 cleavage in HepG2 cell line.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Biphenyl Compounds; Caspase 3; Cell Line, Tumor; Cell Proliferation; Cell Survival; Down-Regulation; Drug Screening Assays, Antitumor; Humans; Lignans; Magnolia; Molecular Conformation; Plant Extracts; Proto-Oncogene Proteins c-bcl-2; Seeds

In this study, a kind of green solvent named polyethylene glycol (PEG) was developed for the ultrasound-assisted extraction (UAE) of magnolol and honokiol from Cortex Magnoliae Officinalis. The effects of PEG molecular weight, PEG concentration, sample size, pH, ultrasonic power and extraction time on the extraction of magnolol and honokiol were investigated to optimise the extraction conditions. Under the optimal extraction conditions, the PEG-based UAE supplied higher extraction efficiencies of magnolol and honokiol than the ethanol-based UAE and traditional ethanol-reflux extraction. Furthermore, the correlation coefficient (R(2)), repeatability (relative standard deviation, n = 6) and recovery confirmed the validation of the proposed extraction method, which were 0.9993-0.9996, 3.1-4.6% and 92.3-106.8%, respectively.

Topics: Biphenyl Compounds; Chromatography, High Pressure Liquid; Drugs, Chinese Herbal; Lignans; Magnolia; Polyethylene Glycols; Ultrasonics

Application of a matrix-immobilised target enzyme for screening inhibitors is widely used in drug development, but there are few studies in insecticide discovery. In this paper, an economical and effective immobilised acetylcholinesterase (AChE) column was prepared using the sol-gel embedment method, which was further combined with high-performance liquid chromatography for screening the AChE inhibitors and insecticidal compounds from complex natural products.. AChE inhibitory constituents magnolol and honokiol were isolated from the ethanol extract of Magnolia officinalis, with IC50 values of 0.069 and 0.057 mM respectively. In an in vivo bioassay, magnolol and honokiol showed insecticidal activity against Nilaparvata lugens, with LC50 values of 0.324 and 0.137 mM, which are comparable with that of commonly used insecticide chlorpyrifos (0.233 mM). Moreover, molecular docking was carried out against a homology model of N. lugens AChE. The complexes showed that magnolol and honokiol placed themselves nicely into the active site of the enzyme and exhibited an interaction energy that was in accordance with our activity profile data.. These results demonstrate that magnolol and honokiol have great applied potential to be developed as natural insecticides, and an immobilised AChE column is very useful as a rapid screening tool for target enzymes towards potent inhibitors.

Topics: Acetylcholinesterase; Alkaloids; Animals; Biphenyl Compounds; Cholinesterase Inhibitors; Chromatography, High Pressure Liquid; Female; Hemiptera; Insecticides; Lignans; Magnolia; Plant Extracts; Sesquiterpenes

We present the synthesis of new derivatives of natural products magnolol (1) and honokiol (2) and their evaluation as allosteric ligands for modulation of GABAA receptor activity. New derivatives were prepared via metal assisted cross-coupling reactions in two consecutive steps. Compounds were tested by means of two-electrode voltage clamp electrophysiology at the α1β2γ2 receptor subtype at low GABA concentrations. We have identified several compounds enhancing GABA induced current (IGABA) in the range similar or even higher than the lead structures. At 3μM, compound 8g enhanced IGABA by factor of 443, compared to 162 and 338 of honokiol and magnolol, respectively. Furthermore, 8g at EC10-20 features a much bigger window of separation between the α1β2γ2 and the α1β1γ2 subtypes compared to honokiol, and thus improved subtype selectivity.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Biphenyl Compounds; GABA Modulators; Lignans; Metals; Molecular Structure; Oocytes; Patch-Clamp Techniques; Protein Subunits; Rats; Receptors, GABA-A; Recombinant Proteins; Structure-Activity Relationship; Xenopus

In this study, we evaluated the anti-photoaging activity of magnolol in UV-irradiated hairless mice, and hypothesized that magnolol would prevent photoaging in these animals. The inhibitory effect of magnolol on wrinkle formation was determined by analyzing the skin replica, histologically examining the epidermal thickness, and identifying damage to the collagen fibers. The protective effects of magnolol on UVB-induced skin photoaging were examined by determining the level of MMPs and mitogen-activated protein kinases (MAPKs). Exposure to UVB radiation significantly increased skin thickness and wrinkle grade, but magnolol treatment significantly reduced the average length and depth of wrinkles, and this was correlated with the inhibition of collagen fiber loss. The magnolol-treated group had remarkably decreased activity levels of MMP-1, -9, and -13 compared to the corresponding levels in the vehicle-treated UVB-irradiated group. These results indicate that magnolol prevents skin photoaging in UVB-irradiated hairless mice.

Topics: Animals; Biphenyl Compounds; Collagen; Lignans; Male; Matrix Metalloproteinases; Mice, Hairless; Mitogen-Activated Protein Kinases; Skin Aging; Ultraviolet Rays

Magnolol (1) isolated from Magnolia officinalis exhibits many beneficial effects such as anti-inflammatory and antioxidant activity. The aim of this study was to evaluate the effects of magnolol (1) on RANKL-induced osteoclast differentiation and investigate the underlying molecular mechanisms. Treatment with magnolol (1) significantly inhibited osteoclast differentiation of RAW 264.7 macrophages and bone-resorbing activity of osteoclasts in the RANKL-induced system. Moreover, RANKL-activated JNK/ERK/AP-1 and NF-κB signaling, ROS formation, and NFATc1 activation were attenuated by magnolol (1). A novel finding of this study is that magnolol (1) can increase heme oxygenase-1 (HO-1) expression and Nrf2 activation in RANKL-stimulated cells. Blocking HO-1 activity with tin protoporphyrin IX markedly reversed magnolol (1)-mediated inhibition of osteoclast differentiation, NFATc1 nuclear translocation, and MMP-9 activity, suggesting that HO-1 contributes to the attenuation of NFATc1-mediated osteoclastogenesis by magnolol (1). Therefore, the inhibitory effect of magnolol (1) on osteoclast differentiation is due to inhibition of MAPK/c-fos/AP-1 and NF-κB signaling as well as ROS production and up-regulation of HO-1 expression, which ultimately suppresses NFATc1 induction. These findings indicate that magnolol (1) may have potential to treat bone diseases associated with excessive osteoclastogenesis.

Topics: Biphenyl Compounds; Bone Diseases; Bone Marrow Cells; Heme Oxygenase-1; Lignans; Macrophages; Magnolia; Molecular Structure; NF-kappa B; Osteoclasts; RANK Ligand; Signal Transduction; Transcription Factor AP-1; Transcription Factors; Up-Regulation

Neuroprotective agents can rescue ischemic penumbra in cerebral ischemia. However, the clinically effective neuroprotective agents for cerebral ischemic injury remain deficient in clinic so far. This study was undertaken to investigate the brain protective effect of 002C-3 and its potential mechanisms in rats, and its preliminary toxicity in mice. A transient middle cerebral artery occlusion (tMCAO) model in rats was used to evaluate its effect and mechanism, a dose limited experiment was used to evaluate its preliminary toxicity. 10-50μg/kg of 002C-3 (single iv bolus after reperfusion) significantly reduced neurological scores, infarct volumes and brain water contents, and the effect was more potent than that of magnolol under the same mole dose; 50μg/kg of 002C-3 significantly decreased the number of TUNEL-positive cells, reduced the activity of caspase-3, and lowered the autophagy-related proteins LC3-II and Beclin-1 level in I-R cerebral tissue. At 1000 times' dose of high effective dose (ip) 002C-3 failed to show evident toxicity in mice, and the mean body weight of mice treated with 002C-3 was almost the same as that of the vehicle control, but magnolol caused evident toxicity and death. In conclusion, 002C-3 has significant protective effect against cerebral ischemia-reperfusion injury; the effect is more potent than magnolol; this effect is maybe associated with its inhibition of both apoptosis and autophagy; its toxicity is greatly reduced compared to magnolol. These results provided data for its further research and development.

Topics: Animals; Apoptosis; Autophagy; Biphenyl Compounds; Brain; Brain Infarction; Caspase 3; Infarction, Middle Cerebral Artery; Lignans; Male; Mice; Neuroprotective Agents; Rats, Sprague-Dawley; Reperfusion Injury

The emergence of antibiotic resistant strains such as methicillin-resistant Staphylococcus aureus (MRSA) reminds us an urgent need to develop a new immune-modulating agent for preventing S. aureus infection. In this study, we found that herbal medicines, honokiol and magnolol, caused a significant cellular immune modulatory effect during S. aureus infection. In mouse macrophages, these compounds drove upregulation of an antioxidant effect in response to S. aureus, resulting in a dampened total cellular reactive oxygen species (ROS) production and decreased production of inflammatory cytokines/chemokines, whereas honokiol induced increased types I and III interferon messenger RNA (mRNA) expression levels in response to MSSA infection. Moreover, the internalization of S. aureus by human alveolar epithelial cells was inhibited by these compounds. Furthermore, honokiol and magnolol treatment promoted a delay in killing during MSSA infection in Caenorhabditis elegans, suggesting antimicrobial function in vivo. In conclusion, honokiol and magnolol may be considered as attractive immune-modulating treatment for S. aureus infection.

Topics: Animals; Anti-Bacterial Agents; Biphenyl Compounds; Caenorhabditis elegans; Cytokines; Humans; Lignans; Macrophages; Methicillin; Methicillin-Resistant Staphylococcus aureus; Mice; Plant Extracts; Plants, Medicinal; Staphylococcal Infections; Staphylococcus aureus

The goal of this study was to investigate the synergic effects between magnolol and azoles, and the potential antifungal mechanisms.. Microdilution checkerboard, time-kill and agar diffusion assay were employed to evaluate the synergic effects between magnolol and fluconazole (FLC). Magnolol significantly decreased the efflux of rhodamine 123 (Rh123), leading to greater intracellular accumulation of Rh123 in Candida albicans cells. Compared to the Candida drug resistance (cdr) 2 or multidrug resistance (mdr) 1 deletion mutant, the growth of cdr1 strain was most sensitive to magnolol exposure. In the presence of magnolol, MDR1 overexpressing cells were sensitive to FLC, whereas CDR1 and CDR2 overexpressing cells displayed tolerance to FLC. Magnolol treatment correlated with up-regulation of transporter and ergosterol biosynthesis pathway genes, analyzed by real-time reverse transcription-polymerase chain reaction. The ergosterol content of C. albicansSC5314 was significantly decreased after magnolol exposure.. Magnolol synergizes with azoles for targeting of C. albicans by inducing a higher intracellular content of antifungals, by tapping into the competitive effect of ABC transporter Cdr1p substrates, and enhancing the effect by targeting of the ergosterol biosynthesis pathway.. Our results provide the first evidence that magnolol may function as a Cdr1p substrate and as an inhibitor of ergosterol biosynthesis. This function can thus be exploited in combination with azoles to reverse multidrug resistance of C. albicans strains.

Topics: Antifungal Agents; Azoles; Biphenyl Compounds; Candida albicans; Drug Synergism; Ergosterol; Fluconazole; Fungal Proteins; Lignans; Membrane Transport Proteins; Up-Regulation

The first step in infection by Candida albicans is adhesion to host cells or implanted medical devices and this followed by hyphal growth and biofilm formation. Yeast-to-hyphal transition has long been identified as a key factor in fungal virulence. Following biofilm formation, C. albicans is usually less sensitive or insensitive to antifungals. Therefore, development of new antifungals with inhibitory action on adhesion, yeast-hyphal transition and biofilm formation by C. albicans is very necessary.. The effects of magnolol and honokiol on hypha growth were investigated using different induction media. Their inhibitory effects were determined using the 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5- carboxanilide assay, and biofilm thickness and viability were observed by a confocal scanning laser microscope. Mammalian cells were used in adhesion assays. Genes related to hyphae development and cell adhesions were analyzed by real-time reverse transcription-polymerase chain reaction. The exogenous cyclic adenosine monophosphate was used to determine the mechanisms of action of magnolol and honokiol. Caenorhabditis elegans was used as an in vivo model to estimate the antifungal activities of magnolol and honokiol.. Magnolol and honokiol inhibited adhesion, the transition from yeast to hypha, and biofilm formation by C. albicans through the Ras1-cAMP-Efg1 pathway. Moreover, magnolol and honokiol prolonged the survival of nematodes infected by C. albicans. Magnolol and honokiol have potential inhibitory effects against biofilm formation by C. albicans.. This study provides useful information towards the development of new strategies to reduce the incidence of C. albicans biofilm-associated infection.

Topics: Animals; Antifungal Agents; Biofilms; Biphenyl Compounds; Caenorhabditis elegans; Candida albicans; Cell Adhesion; Cell Line; Drugs, Chinese Herbal; Fungal Proteins; Hyphae; Lignans; Microscopy, Confocal; Models, Animal; Rats; Signal Transduction; Titanium; Virulence

To explore the regulatory mechanisms of magnolol and honokiol on calcium-activated potassium channels signaling pathway in Enterotoxigenic Escherichia coli (ETEC)-induced diarrhea mice, the concentrations of serum chloride ion (Cl(-)), sodium ion (Na(+)), potassium ion (K(+)) and calcium ion (Ca(2+)) were measured. Additionally, the mRNA expressions of calmodulin 1 (CaM), calcium/calmodulin-dependent protein kinase II alpha subunit (CaMKIIα) and beta subunit (CaMKIIβ), ryanodine receptor 1, inositol 1,4,5-trisphosphate receptors (IP3 receptors), protein kinases C (PKC), potassium intermediate/small conductance calcium-activated channels (SK) and potassium large conductance calcium-activated channels(BK)were determined. A diarrhea mouse model was established using ETEC suspensions (3.29×10(9)CFU/ml) at a dosage of 0.02ml/g live body weight (BW). Magnolol or honokiol was intragastrically administered at dosages of 100 (M100 or H100), 300 (M300 or H300) and 500 (M500 or H500) mg/kg BW according to a 3×3 factorial arrangement. Magnolol and honokiol increased the Cl(-) and K(+) concentrations, further, upregulated the CaM, BKα1 and BKβ3 mRNA levels but downregulated the IP3 receptors 1, PKC, SK1, SK2, SK3, SK4 and BKβ4 mRNA expressions. Magnolol and honokiol did not alter the CaMKIIα, CaMKIIβ, ryanodine receptor 1, IP3 receptor 2, IP3 receptor 3, BKβ1 and BKβ2 mRNA expressions. These results clarify that magnolol and honokiol, acting through Ca(2+) channel blockade, inhibit the activation of IP3 receptor 1 to regulate the IP3-Ca(2+) store release, activate CaM to inhibit SK channels, and effectively suppress PKC kinases to promote BKα1 and BKβ3 channels opening and BKβ4 channel closing, which modulates the intestinal ion secretion.

Topics: Animals; Biphenyl Compounds; Calcium; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Calmodulin; Chlorides; Diarrhea; Enterotoxigenic Escherichia coli; Escherichia coli Infections; Ileum; Inositol 1,4,5-Trisphosphate Receptors; Lignans; Male; Mice; Potassium; Potassium Channels, Calcium-Activated; Protein Kinase C; Ryanodine Receptor Calcium Release Channel; Signal Transduction; Sodium

Drug efflux transporter P-glycoprotein plays an important role in cancer chemotherapy. The nuclear factor-κB (NF-κB) transcription factors play critical roles in development and progression of cancer. In this study, the effects of natural compounds that can inhibit NF-κB activation on the function of P-glycoprotein were investigated using human MDR1 gene-transfected KB/MDR1 cells. The accumulation of daunorubicin or rhodamine 123, fluorescent substrates of P-glycoprotein, in KB/MDR1 cells increased in the presence of caffeic acid phenetyl ester (CAPE), licochalcone A, anacardic acid, celastrol, xanthohumol, magnolol, and honokiol in a concentration-dependent manner. In contrast, lupeol, zerumbone, thymoquinone, emodin, and anethol had no effects. The ATPase activities of P-glycoprotein were stimulated by CAPE, licochalcone A, anacardic acid, celastrol, xanthohumol, magnolol, and honokiol. Tumor necrosis factor (TNF)-α stimulated NF-κB activation was inhibited by CAPE, licochalcone A, anacardic acid, and xanthohumol. KB/MDR1 cells were sensitized to vinblastine cytotoxicity by CAPE, licochalcone A, anacardic acid, xanthohumol, magnolol, and honokiol, showing that these natural NF-κB inhibitors reverse multidrug resistance. These results suggest that natural compounds, such as CAPE, licochalcone A, and anacardic acid, have dual inhibitory effects on the anticancer drug efflux transporter P-glycoprotein and NF-κB activation, and may become useful to enhance the efficacy of cancer chemotherapy.

Topics: Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Products; Biphenyl Compounds; Cell Line, Tumor; Flavonoids; Humans; Lignans; NF-kappa B; Propiophenones

Patients with prehypertension are more likely to progress to manifest hypertension than those with optimal or normal blood pressure. However, the mechanisms underlying the development from prehypertension to hypertension still remain largely elusive and the drugs for antihypertensive treatment in prehypertension are absent. Here we determined the effects of magnolol (MAG) on blood pressure and aortic vasodilatation to insulin, and investigated the underlying mechanisms. Four-week-old male spontaneous hypertensive rats (SHR) and age-matched normotensive Wistar-Kyoto (WKY) control rats were used. Our results shown that treatment of young SHRs with MAG (100 mg/kg/day, o.g.) for 3 weeks decreased blood pressure, improved insulin-induced aorta vasodilation, restored Akt and eNOS activation stimulated by insulin, and increased PPARγ and decreased TRB3 expressions. In cultured human umbilical vein endothelial cells (HUVECs), MAG incubation increased PPARγ, decreased TRB3 expressions, and restored insulin-induced phosphorylated Akt and eNOS levels and NO production, which was blocked by both PPARγ antagonist and siRNA targeting PPARγ. Improved insulin signaling in HUVECs by MAG was abolished by upregulating TRB3 expression. In conclusion, treatment of young SHRs with MAG beginning at the prehypertensive stage decreases blood pressure via improving vascular insulin resistance that is at least partly attributable to upregulated PPARγ, downregulated TRB3 and consequently increased Akt and eNOS activations in blood vessels in SHRs.

Topics: Animals; Aorta; Biphenyl Compounds; Blood Pressure; Blood Vessels; Densitometry; Human Umbilical Vein Endothelial Cells; Humans; Hypertension; Insulin; Insulin Resistance; Lignans; Nitric Oxide Synthase Type III; PPAR gamma; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Rats, Inbred SHR; Rats, Inbred WKY; Signal Transduction; Up-Regulation; Vasodilation

In this study, we aimed to determine the glucuronidation potential of psoralidin in humans and to perform validation on use of psoralidin-3-O-glucuronidation as a functional marker for UGT1A9. Glucuronidation kinetics was determined using human liver microsomes (HLMs), human intestine microsomes (HIM), and expressed UDP-glucuronosyltransferase (UGT) enzymes. The chemical structures of metabolites were determined by liquid chromatography-mass spectrometry and nuclear magnetic resonance spectroscopy analyses. Validation of psoralidin-3-O-glucuronidation as a UGT1A9 marker was performed using combined approaches including reaction phenotyping, chemical inhibition, activity correlation analysis, and determination of relative activity factor (RAF). HLM and UGT1A9 generated two monoglucuronides (9-O-glucuronide and 3-O-glucuronide) from psoralidin, whereas HIM, UGT1A1, UGT1A7, and UGT1A8 generated one only (9-O-glucuronide). Formation of 3-O-glucuronide in HLM was markedly inhibited by the UGT1A9-selective inhibitors magnolol and niflumic acid. Further, psoralidin-3-O-glucuronidation was strongly correlated with propofol-glucuronidation in a group of nine individual HLMs (r = 0.978, p < 0.001). Strong correlation was also observed between psoralidin-3-O-glucuronidation and the UGT1A9 protein levels measured by Western blotting (r = 0.944, p < 0.001). Moreover, UGT1A9 was responsible for 99.6% of psoralidin-3-O-glucuronidation in HLM based on the RAF approach. In conclusion, psoralidin was subjected to efficient glucuronidation, generating one or two monoglucuronides depending on UGT isozymes. Also, psoralidin-3-O-glucuronidation was an excellent in vitro marker for UGT1A9.

Topics: Benzofurans; Biomarkers; Biphenyl Compounds; Coumarins; Glucuronides; Glucuronosyltransferase; Humans; Intestinal Mucosa; Isoenzymes; Kinetics; Lignans; Microsomes, Liver; Niflumic Acid; UDP-Glucuronosyltransferase 1A9

Counter-current chromatography (CCC) is an efficient liquid-liquid chromatography technique for separation and purification of complex mixtures like natural products extracts and synthetic chemicals. However, CCC is still a challenging process requiring some special technical knowledge especially in the selection of appropriated solvent systems. In this work, we introduced a new 9 × 9 map-based solvent selection strategy for CCC isolation of targets, which permit more than 60 hexane-ethyl acetate-methanol-water (HEMWat) solvent systems as the start candidates for the selection of solvent systems. Among these solvent systems, there are clear linear correlations between partition coefficient (K) and the system numbers. Thus, an appropriate CCC solvent system (i.e., sweet spot for K = 1) may be hit by measurement of k values of the target only in two random solvent systems. Besides this, surprisingly, we found that through two sweet spots, we could get a line ("Sweet line") where there are infinite sweet solvent systems being suitable for CCC separation. In these sweet solvent systems, the target has the same partition coefficient (K) but different solubilities. Thus, the better sweet solvent system with higher sample solubility can be obtained for high capacity CCC preparation. Furthermore, we found that there is a zone ("Sweet zone") where all solvent systems have their own sweet partition coefficients values for the target in range of 0.4 < K< 2.5 or extended range of 0.25 < K < 16. All results were validated by using 14 pure GUESSmix mimic natural products as standards and further confirmed by isolation of several targets including honokiol and magnolol from the extracts of Magnolia officinalis Rehd. Et Wils and tanshinone IIA from Salvia miltiorrhiza Bunge. In practice, it is much easier to get a suitable solvent system only by making a simple screening two to four HEMWat two-phase solvent systems to obtain the sweet line or sweet zone without special knowledge or comprehensive standards as references. This is an important advancement for solvent system selection and also will be very useful for isolation of current natural products including Traditional Chinese Medicines.

Topics: Abietanes; Biological Products; Biphenyl Compounds; Chemistry Techniques, Analytical; Chromatography, High Pressure Liquid; Countercurrent Distribution; Hexanes; Lignans; Magnolia; Methanol; Reproducibility of Results; Salvia miltiorrhiza; Solvents; Water

Acute lung injury (ALI) has a high morbidity and mortality rate due to the serious inflammation and edema occurred in lung. Magnolol extracted from Magnolia officinalis, has been reported to exhibit anti-inflammatory, and antioxidant activities. Peroxisome proliferator-activated receptors (PPARs) are known to exert a cytoprotective effect against cellular inflammatory stress and oxidative injury. The aim of this study was to explore the involvement of PPAR-γ in the beneficial effect of magnolol in lipopolysaccharide (LPS)-induced ALI. We found that treatment with magnolol greatly improved the pathological features of ALI evidenced by reduction of lung edema, polymorphonuclear neutrophil infiltration, ROS production, the levels of pro-inflammatory cytokines in bronchoalveolar lavage fluid (BALF), the expression of iNOS and COX-2, and NF-κB activation in lungs exposed to LPS. Importantly, magnolol is capable of increasing the PPAR-γ expression and activity in lungs of ALI. However, blocking PPAR-γ activity with GW9662 markedly abolished the protective and anti-inflammatory effects of magnolol. Taken together, the present study provides a novel mechanism accounting for the protective effect of magnolol in LPS-induced ALI is at least partly attributed to induction of PPAR-γ in lungs, and in turn suppressing NF-κB-related inflammatory responses.

Topics: Acute Lung Injury; Anilides; Animals; Anti-Inflammatory Agents, Non-Steroidal; Biphenyl Compounds; Bronchoalveolar Lavage Fluid; Cytokines; Lignans; Lipopolysaccharides; Male; Neutrophil Infiltration; NF-kappa B; Oxidative Stress; Peroxidase; PPAR gamma; Pulmonary Edema; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species

Ma-Zi-Ren-Wan (MZRW) is a classic Chinese formula which has been used to treat human constipation in China for over 2000 years. In order to make good and rational use of this formula in the future, this paper presents the first attempt to track the pharmacokinetic features of MZRW in rat using rapid and sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Ten chemical components of MZRW, namely, rhein, emodin, aloe emodin, hesperidin, naringin, amygdalin, albiflorin, paeoniflorin, magnolol and honokiol, were simultaneously determined in rat plasma after a single oral administration (10g/kg body weight) of MZRW to rats. Geniposide and liquiritin were used as internal standards. The separation was performed on a Waters ACQUITY BEH C18 column (100mm×2.1mm, 1.7μm). The detection was conducted by multiple-reaction monitoring (MRM) in negative ionization mode. Two highest abundant MRM transitions without interference were optimized for each analyte. This method was well validated in terms of linearity, precision, accuracy, recovery, matrix effect and stability. All calibration curves had good linearity (r(2)>0.995) over the concentration range from 3.9 to 125.0ng/mL for emodin, 3.9-500.0ng/mL for amygdalin, 2.0-4000.0ng/mL for naringin and hesperidin, 3.9-2000.0ng/mL for magnolol, 7.8-2000.0ng/mL for rhein and 3.9-4000.0ng/mL for albiflorin, paeoniflorin, aloe emodin and honokiol. The intra-day and inter-day precision (relative standard deviation) was within 15%, the accuracy (relative error) ranged from -13.6% to 15.1%, and the lower limit of quantification in plasma ranged between 2.0ng/mL and 7.8ng/mL. Extraction recovery, matrix effect and stability were satisfactory. The validated method was successfully applied to a pharmacokinetic study of these ten compounds after oral administration of MZRW to rats. The pharmacokinetic parameters of each compound can facilitate clinical studies in the future.

Topics: Animals; Anthraquinones; Biphenyl Compounds; Chromatography, High Pressure Liquid; Drugs, Chinese Herbal; Flavonoids; Glycosides; Lignans; Linear Models; Male; Rats; Rats, Sprague-Dawley; Reproducibility of Results; Sensitivity and Specificity; Tandem Mass Spectrometry

Magnolol, the major active compound found in Magnolia officinalis has a wide range of clinical applications due to its anti-inflammation and anti-oxidation effects. This study investigated the effects of magnolol on the growth of human gallbladder carcinoma (GBC) cell lines. The results indicated that magnolol could significantly inhibit the growth of GBC cell lines in a dose- and time-dependent manner. Magnolol also blocked cell cycle progression at G0 /G1 phase and induced mitochondrial-related apoptosis by upregulating p53 and p21 protein levels and by downregulating cyclin D1, CDC25A, and Cdk2 protein levels. When cells were pretreated with a p53 inhibitor (pifithrin-a), followed by magnolol treatment, pifithrin-a blocked magnolol-induced apoptosis and G0 /G1 arrest. In vivo, magnolol suppressed tumor growth and activated the same mechanisms as were activated in vitro. In conclusion, our study is the first to report that magnolol has an inhibitory effect on the growth of GBC cells and that this compound may have potential as a novel therapeutic agent for the treatment of GBC.

Topics: Animals; Antineoplastic Agents; Apoptosis; Biphenyl Compounds; cdc25 Phosphatases; Cell Line, Tumor; Cell Proliferation; Cyclin D1; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinase Inhibitor p21; G1 Phase Cell Cycle Checkpoints; Gallbladder Neoplasms; Human Umbilical Vein Endothelial Cells; Humans; Lignans; Medicine, Chinese Traditional; Membrane Potential, Mitochondrial; Mice; Mice, Inbred BALB C; Mice, Nude; Nitric Oxide Synthase; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays

Amyloid formation is associated with multiple amyloidosis diseases. Human calcitonin (hCT) is a typical amyloidogenic peptide, its aggregation is associated with medullary carcinoma of the thyroid (MTC), and also limits its clinical application. Magnolia officinalis is a traditional Chinese herbal medicine; its two major polyphenol components, magnolol (Mag) and honokiol (Hon), have displayed multiple functions. Polyphenols like flavonoids and their derivatives have been extensively studied as amyloid inhibitors. However, the anti-amyloidogenic property of a biphenyl backbone containing polyphenols such as Mag and Hon has not been reported. In this study, these two compounds were tested for their effects on hCT aggregation. We found that Mag and Hon both inhibited the amyloid formation of hCT, whereas Mag showed a stronger inhibitory effect; moreover, they both dose-dependently disassembled preformed hCT aggregates. Further immuno-dot blot and dynamic light scattering studies suggested Mag and Hon suppressed the aggregation of hCT both at the oligomerization and the fibrillation stages, while MTT-based and dye-leakage assays demonstrated that Mag and Hon effectively reduced cytotoxicity caused by hCT aggregates. Furthermore, isothermal titration calorimetry indicated Mag and Hon both interact with hCT. Together, our study suggested a potential anti-amyloidogenic property of these two compounds and their structure related derivatives.

Topics: Biphenyl Compounds; Calcitonin; Calorimetry; Cell Line, Tumor; Dynamic Light Scattering; Humans; Lignans; Magnolia; Medicine, Chinese Traditional; Microscopy, Electron, Transmission; Polyphenols; Protein Binding

The antimicrobial killing activity toward methicillin-resistant Staphylococcus aureus (MRSA) has been a serious emerging global issue. In a continuing search for compounds with antibacterial activity against several microorganisms including S. aureus and MRSA, an n-hexane extract of Magnolia officinalis was found to contain magnolol. This compound exhibited potent activity against S. aureus, standard methicillin-susceptible S. aureus (MSSA), and MRSA as well as clinical MRSA isolates. When combined with oxacillin, the antibacterial activities of magnolol and honokiol against the MRSA strain were increased compared to single treatment without antibiotics at 10 µg/mL and 25 µg/mL, respectively. These activities of magnolol and honokiol were dose dependent. Also, magnolol showed synergistic effects with oxacillin against 13 clinical isolates of MRSA. It was determined that magnolol and honokiol had a synergistic effect with oxacillin against MRSA strain. Furthermore, the magnolol inhibited the expression of the resistant genes, mecA, mecI, femA, and femB, in mRNA. We concluded that the antibacterial activity of magnolol against MRSA strain is more related to the mecI's pathway and components of the cell wall than mecR1. Therefore, the results obtained in this study suggest that the combination of magnolol and antibiotics could lead to the development of new combination antibiotics against MRSA infection.

Topics: Anti-Infective Agents; Biphenyl Compounds; Hexanes; Lignans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Oxacillin; Plant Extracts

Magnolol isolated from Magnolia officinalis, a Chinese medical herb, exhibits an anti-inflammatory activity and a protective effect against periodontitis. The inflammation caused by lipopolysaccharide (LPS) from Porphyromonas gingivalis (P. gingivalis) has been considered a key inducer in the development of periodontitis. In this study, we investigated whether magnolol inhibits P. gingivalis LPS-evoked inflammatory responses in RAW 264.7 macrophages and the involvement of heme oxygenase-1 (HO-1). Magnolol significantly activated p38 MAPK, Nrf-2/HO-1 cascade and reactive oxygen species (ROS) formation. Notably, the Nrf-2 activation and HO-1 induction by magnolol were greatly diminished by blocking p38 MAPK activity and ROS production. Furthermore, in P. gingivalis LPS-stimulated macrophages, magnolol treatment remarkably inhibited the inflammatory responses evidenced by suppression of pro-inflammatory cytokine, prostaglandin E2, nitrite formation, and the expression of inducible nitric oxide synthase and cyclooxygenase-2, as well as NF-κB activation accompanied by a significant elevation of Nrf-2 nuclear translocation and HO-1 expression/activity. However, inhibiting HO-1 activity with tin protoporphyrin IX markedly reversed the anti-inflammatory effects of magnolol. Collectively, these findings provide a novel mechanism by which magnolol inhibits P. gingivalis LPS-induced inflammation in macrophages is at least partly mediated by HO-1 activation, and thereby promoting its clinical use in periodontitis.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Biphenyl Compounds; Cytokines; Enzyme Activation; Heme Oxygenase-1; Lignans; Lipopolysaccharides; Metalloporphyrins; Mice; NF-E2-Related Factor 2; p38 Mitogen-Activated Protein Kinases; Porphyromonas gingivalis; Protoporphyrins; RAW 264.7 Cells; Reactive Oxygen Species; Signal Transduction

Certain dietary agents, such as natural products, have been reported to show anti-cancer effects. However, the underlying mechanisms of these substances in human cancer remain unclear. We recently found that resveratrol exerts an anti-cancer effect by upregulating tumour-suppressor microRNAs (miRNAs). In the current study, we aimed to identify new dietary products that have the ability to activate tumour-suppressor miRNAs and that therefore may serve as novel tools for the prevention and treatment of human cancers. We describe the generation and use of an original screening system based on a luciferase-based reporter vector for monitoring miR-200c tumour-suppressor activity. By screening a library containing 139 natural substances, three natural compounds - enoxolone, magnolol and palmatine chloride - were identified as being capable of inducing miR-200c expression in breast cancer cells at 10 μM. Moreover, these molecules suppressed the invasiveness of breast cancer cells in vitro. Next, we identified a molecular pathway by which the increased expression of miR-200c induced by natural substances led to ZEB1 inhibition and E-cadherin induction. These results indicate that our method is a valuable tool for a fast identification of natural molecules that exhibit tumour-suppressor activity in human cancer through miRNA activation.

Topics: Antineoplastic Agents; Berberine Alkaloids; Biological Products; Biphenyl Compounds; Cadherins; Cell Line, Tumor; Cell Movement; Cell Proliferation; Dietary Supplements; Drug Screening Assays, Antitumor; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Genes, Tumor Suppressor; Glycyrrhetinic Acid; Homeodomain Proteins; Humans; Lignans; MicroRNAs; Phenotype; Small Molecule Libraries; Transcription Factors; Zinc Finger E-box-Binding Homeobox 1

Magnolol and honokiol, the bioactive phytochemicals contained in Magnolia officinalis, are uncommon antioxidants bearing isomeric bisphenol cores substituted with allyl functions. We have elucidated the chemistry behind their antioxidant activity by experimental and computational methods. In the inhibited autoxidation of cumene and styrene at 303 K, magnolol trapped four peroxyl radicals, with a kinh of 6.1 × 10(4) M(-1) s(-1) in chlorobenzene and 6.0 × 10(3) M(-1) s(-1) in acetonitrile, and honokiol trapped two peroxyl radicals in chlorobenzene (kinh = 3.8 × 10(4) M(-1) s(-1)) and four peroxyl radicals in acetonitrile (kinh = 9.5 × 10(3) M(-1) s(-1)). Their different behavior arises from a combination of intramolecular hydrogen bonding among the reactive OH groups (in magnolol) and of the OH groups with the aromatic and allyl π-systems, as confirmed by FT-IR spectroscopy and DFT calculations. Comparison with structurally related 3,3',5,5'-tetramethylbiphenyl-4,4'-diol, 2-allylphenol, and 2-allylanisole allowed us to exclude that the antioxidant behavior of magnolol and honokiol is due to the allyl groups. The reaction of the allyl group with a peroxyl radical (C-H hydrogen abstraction) proceeds with rate constant of 1.1 M(-1) s(-1) at 303 K. Magnolol and honokiol radicals do not react with molecular oxygen and produce no superoxide radical under the typical settings of inhibited autoxidations.

Topics: Acetonitriles; Anisoles; Antioxidants; Biphenyl Compounds; Hydrogen Bonding; Kinetics; Lignans; Molecular Structure; Oxidation-Reduction; Quantum Theory; Spectroscopy, Fourier Transform Infrared; Superoxides

Skeletal muscle atrophy, the most prominent phenotypic feature of cancer cachexia, is often observed in cancer patients undergoing chemotherapy. Magnolol (M) extracted from Magnolia officinalis exhibits several pharmacological effects including anti-inflammatory and anticancer activities. In this study, we investigated whether magnolol supplementation protects against the development of cachexia symptoms in bladder cancer-bearing mice undergoing chemotherapy. Combined treatment of magnolol with chemotherapeutic drugs, such as gemcitabine and cisplatin (TGCM) or gemcitabine (TGM), markedly attenuates the body weight loss and skeletal muscle atrophy compared with conventional chemotherapy (TGC). The antiatrophic effect of magnolol may be associated with inhibition of myostatin and activin A formation, as well as FoxO3 transcriptional activity resulting from Akt activation, thereby suppressing ubiquitin ligases MuRF-1 and MAFbx/atrogin-1 expression, as well as proteasomal enzyme activity. Notably, magnolol-induced insulin-like growth factor 1 (IGF-1) production and related protein synthesis may also contribute to its protective effects. The decreased food intake, and intestinal injury and dysfunction observed in the mice of TGC group were significantly improved in the TGCM and TGM groups. Moreover, the increased inflammatory responses evidenced by elevation of proinflammatory cytokine formation and NF-κB activation occurred in the atrophying muscle of TGC group were markedly inhibited in mice of combined treatment with magnolol. In summary, these findings support that magnolol is a promising chemopreventive supplement for preventing chemotherapy-induced skeletal muscle atrophy associated with cancer cachexia by suppressing muscle protein degradation, and inflammatory responses, as well as increasing IGF-1-mediated protein synthesis.

Topics: Animals; Biphenyl Compounds; Body Weight; Forkhead Box Protein O3; Forkhead Transcription Factors; Insulin-Like Growth Factor I; Interleukin-6; Lignans; Male; Mice; Mice, Nude; Muscular Atrophy; NF-kappa B; Proteasome Endopeptidase Complex; Tumor Necrosis Factor-alpha; Urinary Bladder Neoplasms

To improve the water solubility and biological activity of neoligans (magnolol and honokiol) and test the antitumor activity of the modified compounds.. The glycosylated products of magnolol and honokiol were obtained by enzymatic synthesis using a UDP-glycosyltransferase (YjiC) from Bacillus. The products were characterized by high-performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LC-MS), and nuclear magnetic resonance (NMR) analysis. MTT assay was used to detect the growth inhibition of 4 human cancer cell lines induced by the compounds.. We obtained two glucosides of neolignans (magnolol and honokiol) for the first time by enzymatic synthesis using a UDP-glycosyltransferase. Based on the spectroscopic data, the glucosides were identified as magnolol-2- O-β-D-glucopyranoside (1) and honokiol-4'-O-β-D-glucopyranoside (2). Compounds 1-4 exhibited moderate anti-proliferative activities against the 4 human cancer cell lines, with IC50 values ranging from 9.41 to 111.21 µmol/L.. The glycoslated products show enhanced water solubility and drug sensitivity against SMMC7721 cells, suggesting their value as potential therapeutic drugs.

Topics: Antineoplastic Agents, Phytogenic; Biphenyl Compounds; Cell Line, Tumor; Chromatography, High Pressure Liquid; Glucosides; Glycosylation; Humans; Lignans; Magnetic Resonance Spectroscopy; Mass Spectrometry

Methicillin-resistant Staphylococcus aureus (MRSA) is a problematic pathogen posing a serious therapeutic challenge in the clinic. It is often multidrug-resistant (MDR) to conventional classes of antibacterial agents and there is an urgent need to develop new agents or strategies for treatment. Magnolol (ML) and honokiol (HL) are two naturally occurring diallylbiphenols which have been reported to show inhibition of MRSA. In this study their synergistic effects with antibacterial agents were further evaluated via checkerboard and time-kill assays.. The susceptibility spectrum of clinical MRSA strains was tested by the disk diffusion method. The minimal inhibitory concentrations (MICs) and minimal bactericidal concentrations (MBCs) of ML and HL were assayed by broth microdilution. The synergy was evaluated through checkerboard microdilution and time-killing experiments.. ML and HL showed similar activity against both MSSA and MRSA with MIC/MBC at 16 ~ 64 mg/L, with potency similar to amikacin (AMK) and gentamicin (GEN). When they were used in combination with conventional antibacterial agents, they showed bacteriostatic synergy with FICIs between 0.25 ~ 0.5, leading to the combined MICs decreasing to as low as 1 ~ 2 and 1 ~ 16 mg/L for ML (HL) and the agents, respectively. MIC50 of the combinations decreased from 16 mg/L to 1 ~ 4 mg/L for ML (HL) and 8 ~ 128 mg/L to 2 ~ 64 mg/L for the antibacterial agents, which exhibited a broad spectrum of synergistic action with aminoglycosides (AMK, etilmicin (ETM) and GEN), floroquinolones (levofloxacin (LEV), ciprofloxacin and norfloxacin), fosfomycin (FOS) and piperacillin. The times of dilution (TOD, the extent of decreasing in MIC value) were determined up to 16 for the combined MIC. A more significant synergy after combining was determined as ML (HL) with AMK, ETM, GEN and FOS. ML (HL) combined with antibacterial agents did not show antagonistic effects on any of the ten MRSA strains. Reversal effects of MRSA resistance to AMK and GEN by ML and HL were also observed, respectively. All the combinations also showed better dynamic bactericidal activity against MRSA than any of single ML (HL) or the agents at 24 h incubation. The more significant synergy of combinations were determined as HL (ML) + ETM, HL + LEV and HL + AMK (GEN or FOS), with △LC24 of 2.02 ~ 2.25.. ML and HL showed synergistic potentiation of antibacterial agents against clinical isolates of MRSA and warrant further pharmacological investigation.

Topics: Anti-Bacterial Agents; Biphenyl Compounds; Drug Synergism; Lignans; Methicillin; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests

Near infrared (NIR) spectroscopy assignment of Magnolol was performed using deuterated chloroform solvent and two-dimensional correlation spectroscopy (2D-COS) technology. According to the synchronous spectra of deuterated chloroform solvent and Magnolol, 1365~1455, 1600~1720, 2000~2181 and 2275~2465 nm were the characteristic absorption of Magnolol. Connected with the structure of Magnolol, 1440 nm was the stretching vibration of phenolic group O-H, 1679 nm was the stretching vibration of aryl and methyl which connected with aryl, 2117, 2304, 2339 and 2370 nm were the combination of the stretching vibration, bending vibration and deformation vibration for aryl C-H, 2445 nm were the bending vibration of methyl which linked with aryl group, these bands attribut to the characteristics of Magnolol. Huoxiangzhengqi Oral Liduid was adopted to study the Magnolol, the characteristic band by spectral assignment and the band by interval Partial Least Squares (iPLS) and Synergy interval Partial Least Squares (SiPLS) were used to establish Partial Least Squares (PLS) quantitative model, the coefficient of determination Rcal(2) and Rpre(2) were greater than 0.99, the Root Mean of Square Error of Calibration (RM-SEC), Root Mean of Square Error of Cross Validation (RMSECV) and Root Mean of Square Error of Prediction (RMSEP) were very small. It indicated that the characteristic band by spectral assignment has the same results with the Chemometrics in PLS model. It provided a reference for NIR spectral assignment of chemical compositions in Chinese Materia Medica, and the band filters of NIR were interpreted.

Topics: Biphenyl Compounds; Drugs, Chinese Herbal; Least-Squares Analysis; Lignans; Models, Theoretical; Phenols; Spectroscopy, Near-Infrared

To study the quality suitability rank dividing of Magnolia officinalis on the basis of investigation on the correlation between the ratio of magnolol and honokiol in Magnoliae Officinalis Cortex and ecological factors, in order to provide scientific basis for its planting area of high-quality medicinal materials.. Based on the samples' quality analysis of 43 sampling points of Magnolia officinalis,the relationship between the ratio of magnolol and honokiol in Magnoliae officinalis Cortex and ecological factors was analyzed by statistical analysis. The geographic information system(GIS) was applied to assess the quality suitability rank dividing of Magnolia officinalis in China.. There were 12 ecological factors mainly affecting the quality of Magnoliae Officinalis Cortex; The ratio of magnolol and honokiol had obvious characteristics of regional quality. Conclusion: Magnoliae Officinalis Cortex which produced in Hubei and Chongqing is dao-di herbs.

Topics: Biphenyl Compounds; China; Geographic Information Systems; Lignans; Magnolia

Magnolol, a hydroxylated biphenyl agent isolated from herbal planet Magnolia officinalis, is a component of traditional Asian herbal teas. It has been reported to have anti-microbial, anti-inflammatory, and anti-cancer activity. Non-small cell lung cancer (NSCLC) cell lines (A549, H441 and H520) and normal human bronchial epithelial cells (HBECs) were used to evaluate the cytotoxic effect of magnolol. We show that magnolol inhibited cellular proliferation, increased DNA fragmentation, and decreased mitochondrial membrane potential in all NSCLC cells, but had no cytotoxic effect on HBECs. Magnolol triggered the release of pro-apoptotic proteins: Bid, Bax and cytochrome c from mitochondria, but did not activate the caspase-3, -8, and -9, suggesting that magnolol induces apoptosis of NSCLC cell lines via a caspase-independent pathway. The caspase-independent pathway is mediated through the activation of nuclear translocation of apoptosis-inducing factor, endonuclease G and cleaved poly(ADP-ribose) polymerase, which played important roles in mediating cell death. Furthermore, magnolol inhibited PI3K/AKT and ERK1/2 activity, but up-regulated p38 and JNK activity in A549 cell lines. The results of this study provided a basis for understanding and developing magnolol as a novel treatment of NSCLC.

Topics: Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; Biphenyl Compounds; Carcinoma, Non-Small-Cell Lung; Caspases; Cell Line, Tumor; Cell Proliferation; DNA Fragmentation; Drug Screening Assays, Antitumor; Humans; Lignans; Membrane Potential, Mitochondrial; Mitochondria; Respiratory Mucosa; Signal Transduction

Cancer prevention remains a high priority for the scientific world. Magnolia dealbata Zucc (Magnoliaceae), a Mexican endemic species, is used for the empirical treatment of cancer.. To evaluate the cytotoxic and cancer chemopreventive effects of an ethanol extract of Magnolia dealbata seeds (MDE).. The cytotoxic effect of MDE, at concentrations ranging from 1 to 200 µg/ml, on human cancer cells and human nontumorigenic cells was evaluated using the MTT assay for 48 h. The apoptotic activities of MDE 25 μg/ml on MDA-MB231 breast cancer cells were evaluated using the TUNEL assay and the detection of caspase 3 using immunofluorescence analysis for 48 h, each. The chemopreventive effect was evaluated by administrating different doses of MDE, between 1 and 50 mg/kg, injected intraperitoneally daily into athymic mice which were implanted with MDA-MB231 cells during 28 days. The growth and weight of tumors were measured.. MDE showed cytotoxic effects on MDA-MB231 cells (IC₅₀ = 25 µg/ml) and exerted pro-apoptotic activities as determined by DNA fragmentation in MDA-MB231 cells. MDE 25 µg/ml also induces the activation of caspase 3 in MDA-MB231 cells. These results suggest that Magnolia dealbata may be an optimal source of the bioactive compounds: honokiol (HK) and magnolol (MG). MDE 50 mg/kg i.p. exerted chemopreventive effects by inhibiting the growth of MDA-MB231 tumor by 75% in athymic mice, compared to the control group.. MDE exerts cytotoxic, apoptotic and chemopreventive activities on MDA-MB231 human cancer cells.

Topics: Animals; Anticarcinogenic Agents; Antineoplastic Agents, Phytogenic; Apoptosis; Biphenyl Compounds; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Humans; In Situ Nick-End Labeling; Inhibitory Concentration 50; Lignans; Magnolia; Mammary Neoplasms, Experimental; Mice, Nude; Seeds

A polymeric film modified glassy carbon electrode was electrochemically fabricated with potential step technique using 1-butyl-3-[3-(N-pyrrole)propyl] imidazolium tetrafluoroborate ionic liquid as a monomer. Followed by being treated with sodium dodecyl sulfonate solution, a hydrophobic film bearing poly{1-butyl-3-[3-(N-pyrrolyl)propyl]imidazolium dodecyl sulfonate} moiety was modified onto electrode surface. The substitution was confirmed by X-ray photoelectron spectroscopy. The morphology of the polymeric film electrode surface was characterized with scanning electron microscopy. Electrochemical behaviors of magnolol at the hydrophobic polymeric film electrode were systematically investigated with voltammetry. Compared with the unmodified glassy carbon electrode, the oxidation peak shift slightly towards positive potential and the oxidation peak current significantly increased. Under optimal conditions, the oxidation peak current was linearly related to the magnolol concentration in the range of 1.0 × 10(-8) to 1.0 × 10(-6) mol L(-1) and 1.0 × 10(-6) to 5.0 × 10(-5) mol L(-1). The detection limit was estimated to be 4.55 × 10(-9) mol L(-1) (S/N=3). The polymerized ionic liquid film electrode was successfully used to analysis magnolol in M. officinalis. The result was consistent with that obtained by high performance liquid chromatography.

Topics: Biphenyl Compounds; Electrodes; Hydrogen-Ion Concentration; Hydrophobic and Hydrophilic Interactions; Ionic Liquids; Lignans; Limit of Detection; Microscopy, Electron, Scanning; Nanotechnology; Photoelectron Spectroscopy; Polymerization; Reproducibility of Results

In this paper, multiwalled-carbon-nanotube-based matrix solid-phase dispersion coupled to HPLC with diode array detection was used to extract and determine honokiol and magnolol from Magnoliae Cortex. The extraction efficiency of the multiwalled-carbon-nanotube-based matrix solid-phase dispersion was studied and optimized as a function of the amount of dispersing sorbent, volume of elution solvent, and flow rate of elution solvent, with the aid of response surface methodology. An amount of 0.06 g of carboxyl-modified multiwalled carbon nanotubes and 1.5 mL of methanol at a flow rate of 1.1 mL/min were selected. The method obtained good linearity (r(2) > 0.9992) and precision (RSD < 4.7%) for honokiol and magnolol, with limits of detection of 0.045 and 0.087 μg/mL, respectively. The recoveries obtained from analyzing in triplicate spiked samples were determined to be from 90.23 to 101.10% and the RSDs from 3.5 to 4.8%. The proposed method that required less samples and reagents was simpler and faster than Soxhlet and maceration extraction methods. The optimized method was applied for analyzing five real samples collected from different cultivated areas.

Topics: Biphenyl Compounds; Chromatography, High Pressure Liquid; Lignans; Magnolia; Nanotubes, Carbon; Plant Extracts; Solid Phase Extraction

Diarrhea is a big problem in piglets. Cangpo Oral Liquid (COL) is a compound of Chinese herbal medicine. The preparation was fed to piglets had diarrheal disease in order to determine its anti-diarrhea activity and potential applications in vivo.. The contents of Berberine hydrochloride, Magnolol and Honokiol in COL were performed on HPLC analysis. Organ bath was used to investigate the effect of COL on peristaltic reflexes and peristaltic waves in vitro. And anti-diarrhea activity of COL was evaluated in clinical.. Thin layer chromatography (TLC) and HPLC analyses showed that the contents of Berberine hydrochloride, Magnolol and Honokiol in COL were 970µg/mL, 130µg/mL and 300µg/mL, respectively. Administration of the COL to the organ bath caused a concentration-dependent inhibition of intestinal peristalsis. When the COL concentration in the bath was cumulatively increased, the amplitude and frequency of the peristaltic waves was lowered. The result of clinical efficacy of COL was very effective to diarrheic piglets. COL can possibly inhibit the curve of peristaltic waves in vitro; and clinical trial showed a statistically significant therapeutic effect in vivo.. In conclusion, COL can be used as an effective therapeutic agent. However, the ingredients, pharmacokinetics and specific signaling pathways of COL need to be further studied.

Topics: Animals; Antidiarrheals; Berberine; Biphenyl Compounds; Coptis; Diarrhea; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Female; Intestines; Lignans; Magnolia; Male; Peristalsis; Phytotherapy; Swine

Expression of cell adhesion molecules by the endothelium and the attachment of leukocytes to these cells play major roles in inflammation and cardiovascular disorders. Magnolol, a major active component of Magnolia officinalis, has antioxidative and anti-inflammatory properties. In the present study, the effects of magnolol on the expression of vascular cell adhesion molecule-1 (VCAM-1) in human aortic endothelial cells (HAECs) and the related mechanisms were investigated. TNF-α induced VCAM-1 protein expression and mRNA stability were significantly decreased in HAECs pre-treated with magnolol. Magnolol significantly reduced the phosphorylation of ERK, JNK, and p38 in TNF-α-treated HAECs. The decrease in VCAM-1 expression in response to TNF-α treatment was affected by JNK and p38 inhibitors, not by an ERK inhibitor. Magnolol also attenuates NF-κB activation and the translocation of HuR (an RNA binding protein) in TNF-α-stimulated HAECs. The VCAM-1 expression was weaker in the aortas of TNF-α-treated apo-E deficient mice with magnolol treatment. These data demonstrate that magnolol inhibits TNF-α-induced JNK/p38 phosphorylation, HuR translocation, NF-κB activation, and thereby suppresses VCAM-1 expression resulting in reduced leukocyte adhesion. Taken together, these results suggest that magnolol has an anti-inflammatory property and may play an important role in the prevention of atherosclerosis and inflammatory responses.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Aorta; Apolipoproteins E; Atherosclerosis; Biphenyl Compounds; Cells, Cultured; Endothelial Cells; Gene Expression; Humans; Lignans; MAP Kinase Signaling System; Mice; NF-kappa B; Phosphorylation; Phytotherapy; Signal Transduction; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1

Magnolol is a traditional Chinese medicine from the root and bark of Magnolia officinalis. It has long been used to treat anxiety, cough, headache and allergies, as well as a variety of inflammations. Lung inflammation is a key event in the pathogenesis of asthma and chronic obstructive pulmonary disease. The present study sought to examine the effects of magnolol on tumor necrosis factor (TNF)-α-induced upregulation of intercellular adhesion molecule-1 (ICAM-1), activation of the nuclear factor (NF)-κB and mitogen-activated protein kinase (MAPK) signaling pathway in cultured human pulmonary epithelial cells, and adhesion of human macrophage-like U937 cells to A549 cells. A549 cells were incubated with magnolol at 25 and 50 μmol/l. Then, 20 ng/ml TNF-α was used to activate the cells. Magnolol inhibited the growth of human pulmonary epithelial A549 cells in a dose- and time-dependent manner. Magnolol suppressed the adhesion of U937 cells to TNF-α-induced A549 cells. In cultured human pulmonary epithelial A549 cells, magnolol decreased TNF-α-induced upregulation of ICAM-1. Magnolol repressed TNF-α-induced activation of NF-κB and mitogen-activated protein kinase (MAPK) signaling pathways in A549 cells by inhibiting phosphorylation of NF-κB, p38, extracellular signal-regulated kinase (ERK) 1/2, and stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK). These findings support the hypothesis that magnolol inhibits the inflammatory process in lung epithelial A549 cells by suppressing the ICAM-1 and NF-κB and MAPK signaling pathways. Taken together, these results indicate that magnolol offers significant potential as a therapeutic treatment for inflammatory diseases of the lungs including asthma, sepsis, and chronic obstructive pulmonary disease.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Biphenyl Compounds; Cell Survival; Dose-Response Relationship, Drug; Humans; Intercellular Adhesion Molecule-1; Lignans; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase Kinases; NF-kappa B; Respiratory Mucosa; Tumor Necrosis Factor-alpha; U937 Cells

The effects of magnolol (Mag) on hyperglycemia and hyperlipemia, hepatic oxidative stress and cytochrome P4502E1 (CYP2E1) activity of diabetic rats induced by high-fat diet (HFD) and streptozotocin (STZ) were studied. After oral administration of Mag (25, 50 and 100 mg x kg(-1) x d(-1)) for continuous 10 weeks, the blood glucose and lipids (TC, TG and LDL-C) levels, as well as the hepatic CYP2E1 activity and MDA content of diabetic rats, decreased significantly (P < 0.05 or P < 0.01), whereas the oral glucose tolerance and hepatic antioxidant enzymatic activities (CAT and GSH-Px) of diabetic rats, increased significantly (P < 0.05 or P < 0.01). The results indicated that Mag was effective against the hepatic oxidative damage, hyperglycemia and hyperlipemia of diabetic rats induced by HFD and STZ, and the inhibition of Mag on hepatic CYP2E1 activity could be an important mechanism of Mag against hepatic insulin resistance and oxidative damage.

Topics: Animals; Biphenyl Compounds; Blood Glucose; Cholesterol; Cholesterol, LDL; Cytochrome P-450 CYP2E1; Diabetes Mellitus, Experimental; Diet, High-Fat; Glucose Tolerance Test; Hypoglycemic Agents; Lignans; Liver; Magnolia; Male; Oxidative Stress; Plants, Medicinal; Protective Agents; Rats; Rats, Wistar; Streptozocin; Triglycerides

Magnolol is isolated from the herb Magnolia officinalis, which has been demonstrated to exert pharmacological effects. Our aim was to investigate whether magnolol is able to act as an anti-inflammatory agent that brings about neuroprotection using a global ischemic stroke model and to determine the mechanisms involved. Rats were treated with and without magnolol after ischemia reperfusion brain injury by occlusion of the two common carotid arteries. The inflammatory cytokine production in serum and the volume of infarction in the brain were measured. The proteins present in the brains obtained from the stroke animal model (SAM) and control animal groups with and without magnolol treatment were compared. Magnolol reduces the total infarcted volume by 15% and 30% at dosages of 10 and 30mg/kg, respectively, compared to the untreated SAM group. The levels of acute inflammatory cytokines, including interleukin-1 beta, tumor necrosis factor alpha, and interleukin-6 were attenuated by magnolol. Magnolol was also able to suppress the production of nitrotyrosine, 4-hydroxy-2-nonenal (4-HNE), inducible NO synthase (iNOS), various phosphorylated p38 mitogen-activated protein kinases and various C/EBP homologues. Furthermore, this modulation of ischemia injury factors in the SAM model group treated with magnolol seems to result from a suppression of reactive oxygen species production and the upregulation of p-Akt and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). These findings confirm the anti-oxidative properties of magnolol, including the inhibition of ischemic injury to neurons; this protective effect seems to involve changes in the in vivo activity of Akt, GSK3β and NF-κB.

Topics: Animals; Biphenyl Compounds; Blotting, Western; Brain; Brain Ischemia; Cell Death; Endoplasmic Reticulum Stress; Immunohistochemistry; Indicators and Reagents; Ischemic Attack, Transient; Lignans; Male; Neurons; Neuroprotective Agents; NF-kappa B; Nitric Oxide Synthase Type II; Oncogene Protein v-akt; p38 Mitogen-Activated Protein Kinases; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Stroke; Transcription Factor CHOP; Tyrosine

Magnolia officinalis is one of the commonly used in traditional Chinese medicine for the treatment of fever, chronic bronchitis and stomach ailments. Magnolol and honokiol are isomers with hydroxylated biphenol compound in the extract of Magnolia officinalis. This study aims to determine the isomers in rat plasma and evaluate their pharmacokinetic pattern after administration emulsion.. Sprague Dawley male rats received either an intravenous (i.v.25, mg/kg) or oral (50mg/kg) dose of the emulsion of the isomer. A sensitive and specific ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) method was developed for the investigation of the pharmacokinetics of magnolol and honokiol in rats. Kaempferol was employed as an internal standard.. The plasma samples were deproteinized with acetonitrile, the post-treatment samples were analyzed on an Agela C18 column interfaced with a triple quadrupole tandem mass spectrometer in negative electrospray ionization mode. Acetonitrile and 5 mmol/L ammonium acetate buffer solution (65: 35, v/v) was used as the mobile phase at a flow rate of 0.2 mL/min. Following oral administration of emulsion to rats, magnolol attained mean peak plasma concentrations of 426.4 ± 273.8 ng/mL at 1.20 h, whereas honokiol reached peak plasma concentrations of 40.3 ± 30.8 ng/mL at 0.45 h. The absolute bioavailability of magnolol and honokiol is 17.5 ± 9.7% and 5.3 ± 11.7%. By comparison, the AUC0-∞ of magnolol was 5.4 times higher than that of honokiol after intravenous administration, but AUC0-∞ of magnolol was about 18-fold higher than honokiol after oral administration.

Topics: Administration, Intravenous; Administration, Oral; Animals; Biphenyl Compounds; Chromatography, Liquid; Emulsions; Lignans; Male; Rats; Reproducibility of Results; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry

Magnolol, a major active constituent in herbal medicine, potently inhibits propofol glucuronidation in human liver microsomes, with inhibition constants in the nanomolar range. This study was conducted to investigate magnolol-induced inhibition of propofol glucuronidation in liver microsomes from Swiss-Hauschka mice, Sprague-Dawley rats, Chinese Bama pigs, and cynomolgus macaques. Results indicated that magnolol (10 μM) inhibited propofol glucuronidation in liver microsomes from Bama pigs and cynomolgus macaques but not in those from mice or rats. Data from liver microsomes from Bama pigs indicated a competitive inhibition mechanism, with a Ki of 1.7 μM. In contrast to that of pig liver microsomes, the inhibition of microsomes from cynomolgus macaques followed a noncompetitive mechanism, with a Ki of 3.4 μM. In summary, this study indicates that magnolol-induced inhibition of propofol glucuronidation varies substantially among species, and the Ki values determined by using liver microsomes from various experimental animal species far exceed that for human liver microsomes. The inhibition of propofol glucuronidation by magnolol in liver microsomes from all animal species tested was significantly lower than the inhibition previously demonstrated in human liver microsomes. Hepatic microsomes from Swiss-Hauschka mice, Sprague-Dawley rats, Chinese Bama pigs, and cynomolgus macaques are not effective models of the inhibition of glucuronidation induced by magnolol in humans.

Topics: Animals; Biphenyl Compounds; Drug Interactions; Glucuronides; Lignans; Macaca fascicularis; Mice; Microsomes, Liver; Propofol; Rats; Rats, Sprague-Dawley; Species Specificity; Swine

Prostate cancer, one of the most common cancers in the Western world, affects many men worldwide. This study investigated the effects of magnolol, a compound found in the roots and bark of the magnolia tree Magnolia officinalis, on the behavior of 2 androgen insensitive human prostate cancer cell lines, DU145 and PC3, in vitro. Magnolol, in a 24-h exposure at 40 and 80 μM, was found to be cytotoxic to cells. Magnolol also affected cell cycle progression of DU145 and PC3 cells, resulting in alterations to the cell cycle and subsequently decreasing the proportion of cells entering the G2/M-phase of the cell cycle. Magnolol inhibited the expression of cell cycle regulatory proteins including cyclins A, B1, D1, and E, as well as CDK2 and CDK4. Protein expression levels of pRBp107 decreased and pRBp130 protein expression levels increased in response to magnolol exposure, whereas p16(INK4a), p21, and p27 protein expression levels were apparently unchanged post 24-h exposure. Magnolol exposure at 6 h did increase p27 protein expression levels. This study has demonstrated that magnolol can alter the behavior of androgen insensitive human prostate cancer cells in vitro and suggests that magnolol may have potential as a novel anti-prostate cancer agent.

Topics: Antineoplastic Agents, Phytogenic; Biphenyl Compounds; Cell Cycle; Cell Cycle Proteins; Cell Line, Tumor; Cyclin A; Cyclin B1; Cyclin D1; Cyclin E; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase Inhibitor p27; Humans; Lignans; Magnolia; Male; Plant Extracts; Prostatic Neoplasms

This study investigated the effects of magnolol, a compound from Magnolia officinalis, on the behavior of LNCaP and PC3 human prostate cancer cells in vitro.. In vitro cell culture approach with biochemical tests and Western blot analyses was used.. Magnolol, (80 μM, 6 hour exposure) was found to affect the expression of insulin-like growth factor-1 (IGF-1) and associated proteins. In both cell lines, protein expression of IGF-1 and insulin-like growth factor binding protein-5 (IGFBP-5) were significantly decreased, while protein expression of IGFBP-3 was significantly increased. Additionally, protein expression of insulin-like growth factor-1 receptor (IGF-1R) was significantly increased and the phosphorylated form of IGF-1 (p-IGF-1R) was significantly decreased in PC3 cells, while IGFBP-4 protein expression was significantly increased in LNCaP cells.. This study has demonstrated for the first time that magnolol can alter the expression of IGF-1 and associated proteins in human prostate cancer cells in vitro and suggests that magnolol may have a potential role as a novel anti-prostate cancer agent.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Biphenyl Compounds; Blotting, Western; Humans; In Vitro Techniques; Insulin-Like Growth Factor Binding Proteins; Insulin-Like Growth Factor I; Lignans; Male; Prostatic Neoplasms; Receptor, IGF Type 1; Tumor Cells, Cultured

Biphenylic compounds related to the natural products magnolol and 4'-O-methylhonokiol were synthesized, evaluated and optimized as positive allosteric modulators (PAMs) of GABA(A) receptors. The most efficacious compounds were the magnolol analog 5-ethyl-5'-hexylbiphenyl-2,2'-diol (45) and the honokiol analogs 4'-methoxy-5-propylbiphenyl-2-ol (61), 5-butyl-4'-methoxybiphenyl-2-ol (62) and 5-hexyl-4'-methoxybiphenyl-2-ol (64), which showed a most powerful potentiation of GABA-induced currents (up to 20-fold at a GABA concentration of 3μM). They were found not to interfere with the allosteric sites occupied by known allosteric modulators, such as benzodiazepines and N-arachidonoylglycerol. These new PAMs will be useful as pharmacological tools and may have therapeutic potential for mono-therapy, or in combination, for example, with GABA(A) receptor agonists.

Topics: Allosteric Regulation; Animals; Biological Products; Biphenyl Compounds; Lignans; Oocytes; Patch-Clamp Techniques; Protein Binding; Protein Isoforms; Receptors, GABA-A; Structure-Activity Relationship; Xenopus

In recent years, epidemiological data confirm that cannabis-related emergencies, cannabis-use disorders and dependence are significantly increased. Cannabis is generally considered a little dangerous substances of abuse, however, chronic consumption has been associated to the development of mental disorders, cognitive deficits, chronic bronchitis, emphysema, increased risk of myocardial infarction in the hour after use, increased mortality after myocardial infarction, liver inflammation and steatosis in patients affected by hepatitis C. In this article we described the pharmacological characteristics of Magnolia officinalis bark active principles suggesting a potential application in the treatment of both cannabis dependence and cannabis-related disorders.

Topics: Animals; Biphenyl Compounds; Cannabis; Humans; Inflammation; Lignans; Magnolia; Marijuana Abuse; Plant Bark; Plant Extracts; Polyphenols; Rats; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Receptors, Cannabinoid; Receptors, G-Protein-Coupled

Cell division protein, FtsZ, has been identified as a new potential antimicrobial target against multidrug-resistant (MDR) and methicillin-resistant Staphylococcus aureus (MRSA). By using computer-aided simulation, the phenolic compounds magnolol and honokiol from Magnolia officinalis were shown to have high anchor energies to FtsZ of S. aureus. The calculated binding energies of magnolol and honokiol for this FtsZ (PDB Code: 4DXD) were established to be -7.6 kcal/mol and -8.2 kcal/mol, respectively. Both of them showed polymerization inhibition efficacy for this FtsZ at 100 ppm, which confirmed the simulation results. Their antibacterial activity against S. aureus including multidrug-resistant (MDR) and methicillin-resistant S. aureus (MRSA) with minimum inhibitory concentration (MIC) values in the range of 8-16 ppm. These findings support the use of computer-aided simulation to screen natural compounds for this cell division protein, FtsZ, and this method can be a quick and promising approach for the development of antimicrobial agents against multi-drug resistant S. aureus.

Topics: Anti-Bacterial Agents; Biphenyl Compounds; Humans; Lignans; Magnolia; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Plant Exudates; Staphylococcal Infections; Staphylococcus aureus

Preparation of magnolol-loaded amorphous solid dispersion was investigated for improving the bioavailability.. A solid dispersion of magnolol was prepared with polyvinylpyrrolidone K-30 (PVP) by melting method, and the physical properties were characterized by using differential scanning calorimetry, powder X-ray diffractometry, Fourier transformation-infrared spectroscopy and scanning electron microscope. In addition, dissolution test was also performed. Subsequently, the bioavailability of magnolol pure compound, its physical mixture and solid dispersion were compared in rabbits. The blood samples withdrawn via marginal ear vein at specific time points were assayed by HPLC method.. Oral administration of the solid dispersion of magnolol with PVP significantly increased the systemic exposures of magnolol and magnolol sulfates/glucuronides by 80.1% and 142.8%, respectively, compared to those given with magnolol pure compound.. Magnolol-loaded amorphous solid dispersion with PVP has demonstrated enhanced bioavailability of magnolol in rabbits.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Biological Availability; Biphenyl Compounds; Chemistry, Pharmaceutical; Chromatography, High Pressure Liquid; Drug Carriers; Drug Compounding; Lignans; Male; Povidone; Rabbits; Solubility

Magnolol, an orally available compound from Magnolia officinalis used widely in traditional herbal medicine against a variety of neuronal diseases, possesses potent antioxidant properties and protects the brain against oxidative damage. The aim of the work is to examine the protective mechanisms of magnolol on human neuroblastoma SH-SY5Y cells against apoptosis induced by the neurotoxin acrolein, which can cause neurodegenerative disorders by inducing oxidative stress. By investigating the effect of magnolol on neural cell damage induced by the neurotoxin acrolein, we found that magnolol pretreatment significantly attenuated acrolein-induced oxidative stress through inhibiting reactive oxygen species accumulation caused by intracellular glutathione depletion and nicotinamide adenine dinucleotide phosphate oxidase activation. We next examined the signaling cascade(s) involved in magnolol-mediated antiapoptotic effects. The results showed that acrolein induced SH-SY5Y cell apoptosis by activating mitochondria/caspase and MEK/ERK signaling pathways. Our findings provide the first evidence that magnolol protects SH-SY5Y cells against acrolein-induced oxidative stress and prolongs SH-SY5Y cell survival through regulating JNK/mitochondria/caspase, PI3K/MEK/ERK, and PI3K/Akt/FoxO1 signaling pathways.

Topics: Acrolein; Apoptosis; Biphenyl Compounds; Cell Line, Tumor; Cell Survival; Humans; Lignans; MAP Kinase Signaling System; Membrane Potential, Mitochondrial; Mitochondria; Neurons; Neuroprotective Agents; Oxidative Stress; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt

The hypoxic environment in tumors is an important factor causing tumor angiogenesis by activating the key transcription factor, hypoxia-inducible factors-1α (HIF-1α). Magnolol isolated from Magnolia officinalis has been reported to exhibit an anticancer activity via elevation of apoptosis. However, whether magnolol inhibits tumor angiogenesis remains unknown. In the present study, we demonstrated that magnolol significantly inhibited angiogenesis in vitro and in vivo evidenced by the attenuation of hypoxia and vascular endothelial growth factor (VEGF)-induced tube formation of human umbilical vascular endothelial cells, vasculature generation in chicken chorioallantoic membrane and Matrigel plug. In hypoxic human bladder cancer cells (T24), treatment with magnolol inhibited hypoxia-stimulated H2O2 formation, HIF-1α induction including mRNA, protein expression, and transcriptional activity as well as VEGF secretion. Additionally, the enhanced degradation of HIF-1α protein via enhancing prolyl hydroxylase activity and the decreased newly-synthesized HIF-1α protein in hypoxic T24 cells may involve the reduction of HIF-1α protein accumulation by magnolol. Interestingly, magnolol also acts as a VEGFR2 antagonist, and subsequently attenuates the down-stream AKT/mTOR/p70S6K/4E-BP-1 kinase activation both in hypoxic T24 cells and tumor tissues. As expected, administration of magnolol greatly attenuated tumor growth, angiogenesis and the protein expression of HIF-1α, VEGF, CD31, a marker of endothelial cells, and carbonic anhydrase IX, an endogenous marker for hypoxia, in the T24 xenograft mouse model. Collectively, these findings strongly indicate that the anti-agngiogenic activity of magnolol is, at least in part, mediated by suppressing HIF-1α/VEGF-dependent pathways, and suggest that magnolol may be a potential drug for human bladder cancer therapy.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents, Phytogenic; Biphenyl Compounds; Cell Hypoxia; Cell Line, Tumor; Chickens; Chorioallantoic Membrane; Female; Human Umbilical Vein Endothelial Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Lignans; Mice; Mice, Nude; Neoplasm Transplantation; Neovascularization, Pathologic; Neovascularization, Physiologic; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases; Transcription, Genetic; Urinary Bladder Neoplasms; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2

The purpose of this study was to investigate the mechanism by which magnolol treatment prevents lipopolysaccharide (LPS)-induced septic dysmotility in mice. Sepsis was induced by intravenous tail vein injection of LPS (4 mg/kg body weight). Animals were divided into three groups: the magnolol-treated septic group, the placebo-treated septic group, and the control group. Intestinal transit and circular smooth muscle contraction were measured 12 h after LPS injection, and immunocytochemisty was performed to study the morphology of interstitial cells of Cajal (ICCs). Stem cell factor (SCF) expression and c-kit phosphorylation were determined by Western blot analysis, and the mRNA levels of inducible NO synthase (iNOS) were determined by RT-PCR. Nitric oxide (NO) content, superoxide dismutase (SOD) activity, and malondialdehyde (MDA) concentration were detected using commercial kits. Intestinal transit and muscular contractility were significantly lower in the LPS-treated group than in the control group. Immunocytochemical experiments showed that the total number of ICCs, and the total and average lengths of the ICC processes were significantly decreased in the LPS-treated group compared with those in the control group. In LPS-treated animals, magnolol pretreatment significantly accelerated intestinal transit, increased circular muscle contraction, and prevented ICC morphology changes. Phosphorylation of c-kit and expression of SCF were significantly downregulated in LPS-treated animals compared with control animals. Magnolol pretreatment prevented sepsis-induced decreases in c-kit phosphorylation and SCF expression in LPS-treated animals. Magnolol pretreatment prevented the sepsis-induced increase in NO concentration, iNOS expression, and MDA concentration, and decrease in SOD activity in LPS-treated animals. Our results suggest that magnolol treatment prevents sepsis-induced intestinal dysmotility by regulating SCF/c-kit and NO signaling to maintain functional ICCs.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Biphenyl Compounds; Cell Count; Gastrointestinal Motility; Gerbillinae; Interstitial Cells of Cajal; Lignans; Lipopolysaccharides; Male; Malondialdehyde; Mice; Muscle Contraction; Nitric Oxide; Nitric Oxide Synthase Type II; Phosphorylation; Proto-Oncogene Proteins c-kit; RNA, Messenger; Sepsis; Stem Cell Factor; Superoxide Dismutase; Up-Regulation

Alzheimer's disease (AD), one of the most common forms of dementia, is primarily ascribed to the cholinergic deficits and neuronal dysfunction. Magnolol (Mag), a bioactivator extracted from Magnolia officinalis, has protective effects on cholinergic neurons, but the specific mechanism remains unknown. To further evaluate the therapeutic effects of Mag on the learning and memory impairment in a scopolamine (Scop)-induced mouse model, the passive avoidance and the Morris water maze tests, the measurement of the ratio of brain/hippocampus to body weight, activities of acetyl cholinesterase (AChE), superoxide dismutase (SOD), total nitric oxide synthase (total NOS) and the content of methane dicarboxylic aldehyde (MDA) in hippocampus homogenate as well as the immunefluorescence staining of the AChE positive nerve fibers were performed. Therapeutically treated with Mag, the impaired abilities of learning and memory of the Scop-induced mice were almost restored to the native levels. The restored AChE, total NOS and SOD activities and the MDA level were observed, with a relatively normal density of AChE positive nerve fibers in hippocampus CA3 molecular layer. The improving efficacy of Mag on learning and memory impairment induced by Scop is dose-dependent, indicating that Mag has potential neuroprotective effects against neuronal impairment and memory dysfunction induced by Scop in mice. The underlying mechanisms may be associated with the anti-oxidative effects of Mag and its protective effects on hippocampus cholinergic neurons.

Topics: Acetylcholine; Animals; Avoidance Learning; Biphenyl Compounds; Brain; Cholinergic Neurons; Lignans; Male; Malondialdehyde; Maze Learning; Memory Disorders; Mice; Nerve Fibers; Neuroprotective Agents; Nitric Oxide Synthase; Organ Size; Scopolamine; Superoxide Dismutase

Previously, we demonstrated that magnolol, a hydroxylated biphenyl compound isolated from the bark of Magnolia officinalis, at low concentrations (3-10 μM) exerted an antiproliferation effect in colon cancer, hepatoma, and glioblastoma (U373) cell lines through upregulation of the p21/Cip1 protein. Magnolol at a higher concentration of 100 μM, however, induced apoptosis and upregulated p27/Kip1 expression in U373. In the present study, we further studied whether the increased p27/Kip1 expression contributes to the magnolol-induced apoptosis in U373. Our data show that knock-down of p27/Kip1 expression significantly suppressed the magnolol-induced apoptosis, suggesting that p27/Kip1 might play an important role in the regulation of magnolol-induced apoptosis. This notion was further supported by demonstrating that magnolol induced an increase of the caspase activity in U373 in vitro and in vivo, and these effects were abolished by pretransfection of the cell with p27/Kip1 siRNA. To delineate the possible signaling pathways involved in the magnolol-induced increases of p27/Kip1 expression and apoptosis, we found that magnolol (100 μM) increased the levels of phosphorylated cSrc (p-cSrc), p-ERK, p-p38 MAP kinase (p-p38 MAPK), and p-AKT but not p-JNK in U373. Moreover, pretreatment of U373 with a cSrc inhibitor (PP2), a PI3K inhibitor (LY294002), an ERK inhibitor (PD98059), or a p38 MAPK inhibitor (SB203580) but not a JNK inhibitor (SP600125) significantly reduced the magnolol-induced increases of p27/Kip1 protein levels and apoptosis. Taken together, our data suggest that magnolol at a higher concentration of 100 μM induced apopotosis in U373 cells through cSrc-mediated upregulation of p27/Kip1.

Topics: Animals; Apoptosis; Biphenyl Compounds; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p27; Female; Glioblastoma; Humans; Lignans; Magnolia; Male; Mice; Mice, Nude; Plant Extracts; Signal Transduction; Up-Regulation

In the course of screening for neuroprotective natural products, Magnoliae Cortex showed potent inhibition of hippocampal neuronal HT22 cell death. Obovatol, honokiol, and magnolol were isolated from the ethanolic extract of Magnoliae Cortex. Isolated compounds obovatol, honokiol, and magnolol were protective against 5mM glutamate-induced cell death. When cells were stressed using glutamate, cell viability decreased to 16.98±4.58% over the control (100.00±10.15%). In contrast, 10 μM obovatol, 10 μM honokiol, and 50 μM magnolol increased cell viability to 91.80±1.70%, 93.59±1.93%, and 85.36±7.40%, respectively. The neuroprotective effects of obovatol and honokiol were attributable to the inhibition of intracellular reactive oxygen species production, followed by protection of the mitochondrial membrane potential (ΔΨm), recovery of Bcl-2 and Bid levels, inhibition of apoptosis-inducing factor expression, and phosphorylation of mitogen-activated protein kinases such as p38 kinases, extracellular signal-regulated kinases, and c-Jun N-terminal kinases. On the contrary, magnolol did not show any significant effect on the ΔΨm and apoptotic factors. Among three compounds, obovatol most strongly scavenged 2,2-diphenyl-1-picrylhydrazyl radicals and inhibited the elevation of intracellular reactive oxygen species levels in glutamate-stressed HT22 cells. These data suggest that obovatol and honokiol may have clinical applications for preventing neurodegenerative disorders.

Topics: Animals; Apoptosis; Apoptosis Inducing Factor; BH3 Interacting Domain Death Agonist Protein; Biphenyl Compounds; Cell Death; Cell Line; Cell Survival; Extracellular Signal-Regulated MAP Kinases; Glutamic Acid; JNK Mitogen-Activated Protein Kinases; Lignans; Magnoliaceae; Membrane Potential, Mitochondrial; Mice; Neurons; Neuroprotective Agents; Oxidative Stress; p38 Mitogen-Activated Protein Kinases; Phenyl Ethers; Phosphorylation; Picrates; Plant Extracts; Reactive Oxygen Species; Signal Transduction

This study describes the mechanism of trolox and tiron induced potentiation of cytotoxicity caused by Ery5, an analog of magnolol, in human myeloid leukemia HL-60 cells. Ery5 induced cytotoxicity in HL-60 cells by involving activation of bax and cleavage of caspase 3, which contributed towards activation of both apoptotic and autophagic pathways. Trolox and tiron, even at non-toxic concentrations, contributed to the cytotoxicity of Ery5 by activation of autophagic proteins like ATG7, ATG12 and LC3-II. Z-VAD-fmk mediated reduction in the cytotoxicity and expression of autophagic proteins, further suggested that autophagy induced by Ery5 is largely dependent upon caspases. Interestingly, Ery5 induced autophagy was accompanied by the downregulation of PI3K/AKT pathway whereas, trolox and tiron strongly enhanced this effect. In addition to that treatment of cells with Ery5, trolox and tiron individually, displayed a marked upregulation of Bax. The involvement of Bax in trolox and tiron induced enhancement of the cytotoxicity of Ery5 was confirmed, when siRNA induced silencing of Bax led to increased viability of the cells and exerted a strong inhibitory effect on LC3-II accumulation and p62 degradation in case of cells treated by the combination of Ery5 with trolox or tiron. Additionally, an important role of PARP in Ery5 mediated cell death has been suggested by PARP silencing experiments, however, potentiation of autophagic cytotoxicity by trolox and tiron did not seem to be dependent on PARP-1. Therefore, Bax seems to play a vital role in trolox and tiron mediated potentiation of autophagic cell death by Ery5 in HL-60 cells.

Topics: 1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt; Amino Acid Chloromethyl Ketones; Antineoplastic Agents; Apoptosis; Autophagy; Autophagy-Related Protein 12; Autophagy-Related Protein 7; bcl-2-Associated X Protein; Biphenyl Compounds; Caspases; Chromans; Drug Synergism; Gene Expression Regulation, Neoplastic; HL-60 Cells; Humans; Lignans; Microtubule-Associated Proteins; Phenols; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-ret; Signal Transduction; Small Ubiquitin-Related Modifier Proteins; Ubiquitin-Activating Enzymes

Endometritis is an inflammation of the uterine lining that is commonly initiated at parturition. The uterine epithelial cells play an important role in defending against invading pathogens. Magnolol, a hydroxylated biphenyl compound isolated from Magnolia officinalis, has been shown to have anti-inflammatory effects. The aim of this study was to investigate the anti-inflammatory effect of magnolol in modifying lipopolysaccharide (LPS)-induced signal pathways in mouse uterine epithelial cells. We found that magnolol inhibited TNF-α and IL-6 production in LPS-stimulated mouse uterine epithelial cells. We also found that magnolol inhibited LPS-induced NF-κB activation, IκBα degradation, phosphorylation of ERK, JNK, and P38. Furthermore, magnolol could significantly inhibit the expression of TLR4 stimulating by LPS. These results suggest that magnolol exerts an anti-inflammatory property by downregulating the expression of TLR4 upregulated by LPS, thereby attenuating TLR4-mediated NF-κB and MAPK signaling and the release of pro-inflammatory cytokines. These findings suggest that magnolol may be a therapeutic agent against endometritis.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Biphenyl Compounds; Cell Survival; Cells, Cultured; Down-Regulation; Endometritis; Enzyme Activation; Epithelial Cells; Extracellular Signal-Regulated MAP Kinases; Female; I-kappa B Proteins; Inflammation; Interleukin-6; JNK Mitogen-Activated Protein Kinases; Lignans; Lipopolysaccharides; MAP Kinase Signaling System; Mice; Mice, Inbred BALB C; NF-kappa B; NF-KappaB Inhibitor alpha; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha; Uterus

Growing evidence indicates that glia atrophy contributes to the pathophysiology and the pathogenesis of major depressive disorder. Magnolol is the main constituent identified in the bark of Magnolia officinalis, which has been used for the treatment of mental disorders, including depression, in Asian countries. In this study, we investigated the antidepressant-like effect and the possible mechanisms of magnolol in rats subjected to unpredictable chronic mild stress (UCMS). The ameliorative effect of magnolol on depression symptoms was investigated through behavior tests, including sucrose preference test, open-field test and forced-swimming test. In addition, the levels of glial fibrillary acidic protein (GFAP), an astrocyte marker, in the hippocampus and prefrontal cortex were determined by immunohistochemistry, Western blot, and reverse transcription-polymerase chain reaction (RT-PCR). Exposure to UCMS resulted in a decrease of behavioral activity, whereas magnolol (20, 40 mg/kg) and fluoxetine (20mg/kg) administration significantly reversed the depressive-like behaviors (P<0.05).Moreover, treatment with magnolol effectively increased GFAP mRNA and protein levels in UCMS rats. These results confirmed the antidepressant-like effect of magnolol, which maybe primarily mediated by reversing the glial atrophy in the UCMS rat brain.

Topics: Animals; Antidepressive Agents; Behavior, Animal; Biphenyl Compounds; Depression; Disease Models, Animal; Dose-Response Relationship, Drug; Fluoxetine; Food Preferences; Glial Fibrillary Acidic Protein; Hippocampus; Lignans; Male; Motor Activity; Neuroglia; Prefrontal Cortex; Rats; Rats, Sprague-Dawley; RNA, Messenger; Stress, Psychological; Swimming

Two honokiol dimers, houpulins A and B (1 and 2), and two magnolol derivatives, houpulins C and D (3 and 4), were isolated and characterized from an ethanol extract obtained from the roots of Magnolia officinalis. The chemical structures were determined based on spectroscopic and physicochemical analyses, which included 1D and 2D NMR, as well as mass spectrometry data. These four oligomers possess new carbon skeletons postulated to be biosynthesized from the coupling of three or four C6-C3 subunits. In addition, the new oligomers were evaluated for inhibition of superoxide anion generation and elastase release, and houpulin B (2) was identified as a new anti-inflammatory lead compound.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Biphenyl Compounds; Carbon; Dimerization; Ethanol; Humans; Inhibitory Concentration 50; Lignans; Magnolia; Neutrophils; Pancreatic Elastase; Plant Roots; Superoxides; Young Adult

Magnolol, a neolignan from the traditional medicinal plant Magnolia obovata, has been shown to possess neuroprotective, anti-inflammatory, anticancer and anti-angiogenic activities. However, the precise mechanism of the anti-angiogenic activity of magnolol remains to be elucidated. In the present study, the anti-angiogenic effect of magnolol was evaluated in mouse embryonic stem (mES)/embryoid body (EB)-derived endothelial-like cells. The endothelial-like cells were obtained by differentiation from mES/EB cells. Magnolol (20 µM) significantly suppressed the transcriptional and translational expression of platelet endothelial cell adhesion molecule (PECAM), an endothelial biomarker, in mES/EB-derived endothelial-like cells. To further understand the molecular mechanism of the suppression of PECAM expression, signaling pathways were analyzed in the mES/EB-derived endothelial-like cells. Magnolol induced the generation of reactive oxygen species (ROS) by mitochondria, a process that was associated with the induction of apoptosis as determined by positive Annexin V staining and the activation of cleaved caspase-3. The involvement of ROS generation by magnolol was confirmed by treatment with an antioxidant, N-acetyl-cysteine (NAC). NAC inhibited the magnolol-mediated induction of ROS generation and suppression of PECAM expression. In addition, magnolol suppressed the activation of MAPKs (ERK, JNK and p38) and the PI3K/AKT/mTOR signaling pathway in mES/EB-derived endothelial-like cells. Taken together, these findings demonstrate for the first time that the anti-angiogenic activity of magnolol may be associated with ROS-mediated apoptosis and the suppression of the PI3K/AKT/mTOR signaling pathway in mES/EB-derived endothelial-like cells.

Topics: Acetylcysteine; Angiogenesis Inhibitors; Animals; Apoptosis; Biphenyl Compounds; Caspase 3; Cell Differentiation; Cell Line; Embryonic Stem Cells; Endothelial Cells; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; JNK Mitogen-Activated Protein Kinases; Lignans; MAP Kinase Signaling System; Membrane Potential, Mitochondrial; Mice; Mitochondria; Neovascularization, Pathologic; Nitric Oxide Synthase; p38 Mitogen-Activated Protein Kinases; Phosphatidylinositol 3-Kinases; Platelet Endothelial Cell Adhesion Molecule-1; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; TOR Serine-Threonine Kinases

The purpose of the present study was to determine whether magnolol, a free radical scavenger, mitigates the deleterious effects of traumatic brain injury (TBI).. Traumatic brain injuries were induced in anesthetized male Sprague-Dawley rats using fluid percussion, and the rats were divided into groups treated with magnolol (2 mg/kg, intravenously) or vehicle. A group of rats that did not undergo TBI induction was also studied as controls. Biomarkers of TBI, including glycerol and 2,3-dihydroxybenzoic acid, were evaluated by microdialysis. Infraction volume, extent of neuronal apoptosis, and antiapoptosis factor transforming growth factor β1 (TGF-β1) were also measured. Functional outcomes were assessed by motor assays.. Compared with the rats without TBI, the animals with TBI exhibited higher hippocampal glycerol and 2,3-dihydroxybenzoic acid. Relative to the vehicle-treated group, the magnolol-treated group showed decreased hippocampal levels of glycerol and hydroxyl radical levels. The magnolol-treated rats also exhibited decreased cerebral infarction volume and neuronal apoptosis and increased antiapoptosis-associated factor TGF-β1 expression. These effects were translated into improved motor function post TBI.. Our results suggest that intravenous magnolol injection mitigates the deleterious effects of TBI in rats based on its potent free radical scavenging capability, and the mechanism of anti-neuronal apoptosis is partly due to an increase in TGF-β1 expression in the ischemic cortex.

Topics: Animals; Apoptosis; Biphenyl Compounds; Brain Injuries; Disease Models, Animal; Free Radical Scavengers; Glycerol; Hippocampus; Hydroxybenzoates; Lignans; Male; Models, Animal; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Resuscitation; Transforming Growth Factor beta1

The medicinal herb formulation Da-Cheng-Qi decoction (DCQD) has been shown to ameliorate the severity of acute pancreatitis by regulating an apoptosis-necrosis switch in cells. The active components responsible for this effect and their detailed mechanism of action remain unclear. Here we determine the pharmacokinetic characteristics of the four most abundant compounds in DCQD using a rat model of severe acute pancreatitis. Acute pancreatitis-like symptoms were first induced in rats and then they were given DCQD orally. Rhein was found in rat serum at much higher levels than magnolol, hesperidin, or naringin, even though it was the least abundant of the four compounds in the DCQD. We also examined pharmacodynamics in AR42J cells stimulated with 10(-8) M cerulein as a cellular model of acute pancreatitis. After pretreating AR42J cells with individual compounds and then exposing them to cerulein, we determined cell viability, levels of apoptosis and necrosis, and numbers of cells positive for reactive oxygen species (ROS). Pretreatment with any of the four DCQD compounds increased cell viability and the apoptosis index, while also reducing necrosis and ROS generation. The compounds showed maximal effect in AR42J cells around the same time that they showed maximum serum concentration in rats. Although all four components appear to play a role in an apoptosis-necrosis cellular switch in vitro, rhein may be the most bioactive DCQD ingredient.

Topics: Animals; Anthraquinones; Apoptosis; Biphenyl Compounds; Cells, Cultured; Disease Models, Animal; Drugs, Chinese Herbal; Flavanones; Hesperidin; Lignans; Male; Necrosis; Pancreas; Pancreatitis, Acute Necrotizing; Phytotherapy; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species

This study investigated the effect of honokiol (HON) and magnolol (MAG), phenolic compounds in Magnolia plants, on adiposity and adiposity-related metabolic disturbances in mice fed high-fat diet (HFD), and the potential underlying mechanisms focusing on the lipid metabolism and inflammatory response.. C57BL/6J mice were fed HFD (45 kcal% fat) with or without HON (0.02%, w/w) or MAG (0.02%, w/w) for 16 wk. Despite no changes in body weight, food intake, and hepatic fat accumulation, HON and MAG significantly lowered the weight of white adipose tissue (WAT) as well as adipocyte size and protected against insulin resistance induced by HFD. These effects were associated with increases in energy expenditure and adipose fatty acid oxidation and decreases in fatty acid synthase activity and expression of genes related to fatty acid synthesis, desaturation, and uptake, as well as adipocyte differentiation in WAT. Moreover, HON and MAG significantly lowered the expression of proinflammatory genes in WAT and elevated the plasma IL-10 level. Particularly, HON significantly decreased the plasma resistin level and increased the plasma adiponectin level compared to the control group.. HON and MAG have potential as novel agents for amelioration of adiposity and associated insulin resistance and inflammation.

Topics: Adipogenesis; Adiponectin; Adipose Tissue, White; Adiposity; Animals; Biphenyl Compounds; Blood Glucose; Body Weight; Chemokine CCL2; Cholesterol; Diet, High-Fat; Dietary Supplements; Energy Metabolism; Glucose Tolerance Test; Inflammation; Insulin Resistance; Interleukin-10; Interleukin-6; Lignans; Liver; Male; Mice; Mice, Inbred C57BL; Triglycerides; Tumor Necrosis Factor-alpha

Increased proliferation and migration of vascular smooth muscle cells (VSMCs) contribute importantly to the formation of both atherosclerotic and restenotic lesions. The objective of this study was to investigate the effect of magnolol on VSMC migration.. The proteolytic activity of matrix metalloproteinases (MMPs) in tumor necrosis factor alpha (TNF-α) stimulated VSMCs was performed by gelatin zymography. VSMC migration was assessed by wound healing and Boyden chamber methods. Collagen induced VSMC adhesion was determined by spectrofluorimeter and stress fibers formation was evaluated by fluorescence microscope. The expression of signaling molecules involved in stress fibers formation was determined by western blot. The phosphorylation of myosin light chain (MLC20) was determined by urea-glycerol polyacrylamide gel electrophoresis. Immunohistochemistry was performed to determine the expression of β1-integrin and collagen type I in the injured carotid arteries of rats on day 35 after vascular injury.. VSMC migration was strongly inhibited by magnolol without affecting MMPs expression. Also, magnolol inhibited β1-integrin expression, FAK phosphorylation and RhoA and Cdc42 activation to inhibit the collagen induced stress fibers formation. Moreover, magnolol inhibited the phosphorylation of MLC20. Our in vivo results showed that magnolol inhibited β1-integrin expression, collagen type I deposition and FAK phosphorylation in injured carotid arteries without affecting MMP-2 activity.. Magnolol inhibited VSMC migration via inhibition of cytoskeletal remodeling pathway to attenuate neointima formation.. This study provides a rationale for further evaluation of magnolol for the management of atherosclerosis and restenosis.

Topics: Animals; Biphenyl Compounds; Carotid Arteries; Cell Adhesion; Cell Movement; Cells, Cultured; Cytoskeleton; Dose-Response Relationship, Drug; Lignans; Magnolia; Muscle, Smooth, Vascular; Neointima; Rats; Structure-Activity Relationship

α-Santalol is active component of sandalwood oil and has been shown to have chemopreventive effects against chemically and UVB-induced skin cancer development in mice. α-Santalol is also shown to have skin permeation enhancing effects. Honokiol and magnolol isolated from Magnolia officinalis bark extract have also been shown to have chemopreventive effects against chemically and UVB-induced skin cancer in mice. This study was conducted to investigate the combination effects of α-santalol, honokiol and magnolol to study any additive/synergistic effects to lower the doses required for chemoprevention. Pretreatment of combinations of α-santalol with honokiol and magnolol significantly decreased tumor multiplicity upto 75% than control, α-santalol, honokiol and magnolol alone in SKH-1 mice. Combination of α-santalol with honokiol and magnolol also decreased cell viability, proliferation, and enhanced apotosis in comparison to α-santalol, honokiol and magnolol alone in Human epidrmoid carcinoma A431 cells. Overall, the results of present study indicated combinations of α-santalol with honokiol and magnolol could provide chemoprevention of skin cancer at lower doses than given alone.

Topics: Animals; Anticarcinogenic Agents; Apoptosis; Biphenyl Compounds; Cell Proliferation; Drug Therapy, Combination; Female; Lignans; Mice; Neoplasms, Radiation-Induced; Polycyclic Sesquiterpenes; Sesquiterpenes; Skin Neoplasms; Ultraviolet Rays

This study aimed to investigate the effect of magnolol (5,5'-diallyl-2,2'-biphenyldiol) on contraction in distal colonic segments of rats and the underlying mechanisms. Colonic segments were mounted in organ baths for isometric force measurement. Whole-cell voltage-sensitive L-type Ca(2+) currents were recorded on isolated single colonic smooth muscle cells using patch-clamp technique. The spontaneous contractions and acetylcholine (ACh)- and Bay K 8644-induced contractions were inhibited by magnolol (3-100 μM). In the presence of Bay K8644 (100 nM), magnolol (10-100 μM) inhibited the contraction induced by 10 μM ACh. By contrast, tetrodotoxin (100 nM) and Nώ-nitro-L-arginine methyl ester (L-NAME 100 μM) did not change the inhibitory effect of magnolol (10 μM). In addition, magnolol (3-100 μM) inhibited the L-type Ca(2+) currents. The present results suggest that magnolol inhibits colonic smooth muscle contraction through downregulating L-type Ca(2+) channel activity.

Topics: Acetylcholine; Animals; Biphenyl Compounds; Calcium Channel Blockers; Calcium Channels, L-Type; Colon; Down-Regulation; Drugs, Chinese Herbal; Lignans; Magnolia; Male; Muscle Contraction; Muscle, Smooth; Myocytes, Smooth Muscle; Rats; Rats, Sprague-Dawley

Magnolol, a hydroxylated biphenyl compound isolated from Magnolia officinalis, has been reported to possess anticancer activity. Recent studies have also demonstrated that magnolol inhibits cell growth and induces the apoptosis of cancer cells. However, the effects of magnolol on vascular endothelial growth factor (VEGF)-induced angiogenesis in endothelial cells have not been studied. In the present study, we have used human umbilical vein endothelial cells (HUVECs) to investigate the antiangiogenic effect and molecular mechanism of magnolol. Magnolol inhibited the VEGF-induced proliferation, chemotactic motility and tube formation of HUVECs in vitro as well as the vessel sprouting of the aorta ex vivo. Furthermore, magnolol inhibited VEGF-induced Ras activation and subsequently suppressed extracellular signal-regulated kinase (ERK), phosphatidylinositol-3-kinase (PI3K)/Akt and p38, but not Src and focal adhesion kinase (FAK). Interestingly, the knockdown of Ras by short interfering RNA produced inhibitory effects that were similar to the effects of magnolol on VEGF-induced angiogenic signaling events, such as ERK and Akt/eNOS activation, and resulted in the inhibition of proliferation, migration, and vessel sprouting in HUVECs. In combination, these results demonstrate that magnolol is an inhibitor of angiogenesis and suggest that this compound could be a potential candidate in the treatment of angiogenesis-related diseases.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Biphenyl Compounds; Cell Proliferation; Extracellular Signal-Regulated MAP Kinases; Human Umbilical Vein Endothelial Cells; Humans; Lignans; Magnolia; Male; Neovascularization, Pathologic; Nitric Oxide Synthase Type III; Phosphatidylinositol 3-Kinase; Plant Extracts; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Signal Transduction; Vascular Endothelial Growth Factors

To study the chemical constituents of the dichloromethane extract from pine needles of Cedrus deodara.. The chemical constituents were isolated and purified from the dichloromethane extract of pine needles by chromatography on silica gel and Sephadex LH-20. Their structures were elucidated by analysis of spectral data and chemical properties.. Seven compounds were isolated and their chemical structures were identified as ferulic acid (1), osthole (2), beta-phenylacrylic acid (3), paeonol (4), beta-sitosterol (5), magnolol (6) and honokiol (7).. Compounds 1 - 4, 6 and 7 are isolated from this plant for the first time.

Topics: Acetophenones; Biphenyl Compounds; Cedrus; Chromatography, Thin Layer; Coumaric Acids; Coumarins; Lignans; Methylene Chloride; Molecular Structure; Plant Leaves

Magnolol, a small-molecule hydroxylated biphenol, isolated from the root and stem bark of Magnolia officinalis, has been shown to possess antiproliferative effect on various cancer cell lines. In the current study, we found that magnolol potently inhibited proliferation and induced apoptosis in MCF-7 human breast cancer cells. Further mechanistic studies revealed that induction of apoptosis is associated with cell cycle arrest at G2/M phase, increased generation of reactive oxygen species (ROS), reduced mitochondrial membrane potential (MMP), release of cytochrome c (Cyto c) and apoptosis inducing factor (AIF) from mitochondria to cytosol, upregulation of Bax, p21 and p53, and down-regulation of Bcl-2, cyclin B1 and cyclin-dependent kinase 1 (CDK1). Our findings indicated that magnolol induced apoptosis in MCF-7 cells via the intrinsic pathway with release of AIF from mitochondrial and G2/M phase arrest pathway. Therefore, magnolol might be a potential lead compound in the therapy of breast cancer.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Apoptosis Inducing Factor; Biphenyl Compounds; Bisbenzimidazole; Breast Neoplasms; Caspases; Cell Division; Cell Line, Tumor; Cell Proliferation; Coloring Agents; Cytochromes c; Female; Flow Cytometry; G2 Phase; Genes, bcl-2; Humans; Indicators and Reagents; Lignans; Membrane Potential, Mitochondrial; Mitochondria; Reactive Oxygen Species; Tetrazolium Salts; Thiazoles

Angiogenesis has a key role in the tumor progression and metastasis; targeting endothelial cell proliferation has emerged as a promising therapeutic strategy for the prevention of cancer. Previous studies have revealed a complex association between the process of angiogenesis and autophagy and its outcome on tumorigenesis. Autophagy, also known as type-II cell death, has been identified as an alternative way of cell killing in apoptotic-resistant cancer cells. However, its involvement in chemoresistance and tumor promotion is also well known. In this study, we used a derivate of natural product magnolol (Ery5), a potent autophagy inducer, to study the association between the autophagy and angiogenesis in both in vitro and in vivo model system. We found that the robust autophagy triggered by Ery5, inhibited angiogenesis and caused cell death independent of the apoptosis in human umbilical cord vein endothelial cells and PC-3 cells. Ery5 induced autophagy effectively inhibited cell proliferation, migration, invasion and tube formation. We further demonstrated that Ery5-mediated autophagy and subsequent inhibition of angiogenesis was reversed when autophagy was inhibited through 3-methyl adenine and knocking down of key autophagy proteins ATG7 and microtubule-associated protein light chain 3. While evaluating the negative regulation of autophagy on angiogenesis, it was interesting to find that angiogenic environment produced by the treatment of VEGF and CoCl2 remarkably downregulated the autophagy and autophagic cell death induced by Ery5. These studies, while disclosing the vital role of autophagy in the regulation of angiogenesis, also suggest that the potent modulators of autophagy can lead to the development of effective therapeutics in apoptosis-resistant cancer.

Topics: Animals; Autophagy; Biphenyl Compounds; Cell Cycle; Cell Death; Cell Line; Cell Proliferation; Cobalt; Human Umbilical Vein Endothelial Cells; Humans; Lignans; Microtubule-Associated Proteins; Neovascularization, Pathologic; Phenols; Rats; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2

To develop a UPLC method for the simultaneous determination of liquiritin, narirutin, hesperidin, ammonium glycyrrhetate, honokiol and magnolol in Huoxiang Zhengqi oral liquid.. A Zorbax Eclipse C18 column was used with the mobile phase of acetonitrile and 0. 05% phosphate acid by gradient elution at the detection wavelength of 220 nm. The flow rate was 0.42 mL x min(-1) and the column temperature was 30 degrees C.. The calibration curves were linear in the ranges of 0.001 7-0.034, 0.003 4-0.068, 0.006 4-0.128, 0.012 8-0.256, 0.003 2-0.064, 0.006 4-0.128 microg, respectively. The average recoveries were 103.3%, 98.39%, 98.29%, 102.1%, 98.45%, 102.2% with RSDs of 2.1%,1.0%, 0.50%, 2.3%, 0.9%, 2.0%, respectively.. The UPLC method was simple, rapid and accurate, it could be used for quality control of Huoxiang Zhengqi oral liquid.

Topics: Administration, Oral; Biphenyl Compounds; Chromatography, High Pressure Liquid; Disaccharides; Drugs, Chinese Herbal; Flavanones; Glucosides; Hesperidin; Lignans; Pharmaceutical Solutions

Magnolol (4-allyl-2-(5-allyl-2-hydroxyphenyl)phenol), the main bioactive constituent of the medicinal plant Magnolia officinalis, and its main metabolite tetrahydromagnolol were recently found to activate cannabinoid (CB) receptors. We now investigated the structure-activity relationships of (tetrahydro)magnolol analogs with variations of the alkyl chains and the phenolic groups and could considerably improve potency. Among the most potent compounds were the dual CB1/CB2 full agonist 2-(2-methoxy-5-propyl-phenyl)-4-hexylphenol (61a, K(i) CB1:0.00957 µM; K(i) CB2:0.0238 µM), and the CB2-selective partial agonist 2-(2-hydroxy-5-propylphenyl)-4-pentylphenol (60, K(i) CB1:0.362 µM; K(i ) CB2:0.0371 µM), which showed high selectivity versus GPR18 and GPR55. Compound 61b, an isomer of 61a, was the most potent GPR55 antagonist with an IC50 value of 3.25 µM but was non-selective. The relatively simple structures, which possess no stereocenters, are easily accessible in a four- to five-step synthetic procedure from common starting materials. The central reaction step is the well-elaborated Suzuki-Miyaura cross-coupling reaction, which is suitable for a combinatorial chemistry approach. The scaffold is versatile and may be fine-tuned to obtain a broad range of receptor affinities, selectivities and efficacies.

Topics: Animals; Biological Products; Biphenyl Compounds; Cannabinoid Receptor Agonists; CHO Cells; Cricetulus; Lignans; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Structure-Activity Relationship

Invasion and metastasis are the main causes of treatment failure and death in breast cancer. Thus, novel invasion-based therapies such as those involving natural agents are urgently required. In this study, we examined the effects of magnolol (Mag), a compound extracted from medicinal herbs, on breast cancer cells in vitro and in vivo. Highly invasive cancer cells were found to be highly sensitive to treatment. Mag markedly inhibited the activity of highly invasive MDA-MB-231 cells. Furthermore, Mag significantly downregulated matrix metalloproteinase-9 (MMP-9) expression, an enzyme critical to tumor invasion. Mag also inhibited nuclear factor-κB (NF-κB) transcriptional activity and the DNA binding of NF-κB to MMP-9 promoter. These results indicate that Mag suppresses tumor invasion by inhibiting MMP-9 through the NF-κB pathway. Moreover, Mag overcame the promoting effects of phorbol 12-myristate 13-acetate (PMA) on the invasion of MDA-MB-231 cells. Our findings reveal the therapeutic potential and mechanism of Mag against cancer.

Topics: Animals; Antineoplastic Agents; Biological Products; Biphenyl Compounds; Breast Neoplasms; Cell Adhesion; Cell Line, Tumor; Cell Movement; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Heterografts; Humans; Lignans; Matrix Metalloproteinase 9; Neoplasm Invasiveness; NF-kappa B; Signal Transduction; Tumor Burden

To investigate the absorption and transport mechanism of magnolol in Caco-2 cell model.. A human intestinal epithelial cell model Caco-2 cell in vitro cultured was applied to study the absorption and transport of magnolol, the effects of time, donor concentration, P-gp inhibitor verapamil, pH and temperature on the absorption and transport of magnolol were investigated. The determination of magnolol was performed by high performance liquid chromatography, then the values of apparent permeability coefficient (P app ) and P ratio Basolateral-to-Apical (BL-to-AP)/Apical-to-Basolateral (AP-to-BL) were calculated.. In Caco-2 cell model, comparing the amounts of transport of AP-to-BL and BL-to-AP, the latter was larger. At the same donor concentration, either the amounts of transport of AP-to-BL or BL-to-AP increased with increase in donor concentration and incubation time. Verapamil could significantly improve the amounts of transport of AP-to-BL. The transport of AP-to-BL and BL-to-AP depended on temperature, and there was no significant effect of pH on the transport of AP-to-BL.. Magnolol could be transported through the intestinal mucosa via a passive diffusion mechanism primarily, coexisting with a carrier-mediated transport, at the same time, the efflux mechanism could be involved.

Topics: Biological Transport; Biphenyl Compounds; Caco-2 Cells; Chromatography, High Pressure Liquid; Humans; Hydrogen-Ion Concentration; Intestinal Absorption; Lignans; Models, Biological; Temperature; Time Factors; Verapamil

An approach was established to analyze the chemical profiling of Xiao-Cheng-Qi Decoction (XCQD) using liquid chromatography coupled with electrospray ionization tandem mass spectrometry. XCQD consisted of three herbal medicines (Rhubarb, Fructus Aurantii Immaturus and Cortex Magnoliae Officinalis). The traditional water extractive method was applied in the sample preparation, which was identical with clinical use. The characteristic fragmentation pathways of 17 reference compounds were comprehensively studied, including precursors of tannins, flavonones, anthraquinones and lignan. In total, 71 constituents were identified or tentatively characterized based on their mass spectrometry fragmentations and chromatographic behaviors. By comparing their relative contents, flavanones and anthraquinones were supposed to be used together for the quality control of XCQD. Further pharmacology and pharmacokinetics investigations should be performed on the basis of the present chemical profiling study.

Topics: Anthraquinones; Biphenyl Compounds; Catechin; Chromatography, Liquid; Cinnamates; Drugs, Chinese Herbal; Flavanones; Gallic Acid; Lignans; Spectrometry, Mass, Electrospray Ionization; Tannins

Magnolia officinalis as a traditional Chinese herb has long been used for the treatment of anxiety, cough, headache and allergic diseases, and also have been used in traditional Chinese medicine to treat a variety of mental disorders including depression.. Magnolol, a hydroxylated biphenyl compound isolated from Magnolia officinalis, has been reported to have anti-inflammatory properties. However, the underlying molecular mechanisms are not well understood. The aim of this study was to investigate the molecular mechanism of magnolol in modifying lipopolysaccharide (LPS)-induced signal pathways in RAW264.7 cells.. The purity of magnolol was determined by high performance liquid chromatography. RAW264.7 cells were stimulated with LPS in the presence or absence of magnolol. The expression of proinflammatory cytokines were determined by ELISA and reverse transcription-PCR. Nuclear factor-κB (NF-κB), inhibitory kappa B (IκBα) protein, p38, extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and Toll-like receptor 4 (TLR4) were determined by Western blot. Further analyses were performed on mTLR4 and mMD2 co-transfected HEK293 cells.. The result showed that the purity of magnolol used in this study was 100%. Magnolol inhibited the expression of TNF-α, IL-6 and IL-1β in LPS-stimulated RAW264.7 cells in a dose-dependent manner. Western blot analysis showed that magnolol suppressed LPS-induced NF-κB activation, IκBα degradation, phosphorylation of ERK, JNK and P38. Magnolol could significantly down-regulated the expression of TLR4 stimulating by LPS. Furthermore, magnolol suppressed LPS-induced IL-8 production in HEK293-mTLR4/MD-2 cells.. Our results suggest that magnolol exerts an anti-inflammatory property by down-regulated the expression of TLR4 up-regulated by LPS, thereby attenuating TLR4 mediated the activation of NF-κB and MAPK signaling and the release of pro-inflammatory cytokines. These findings suggest that magnolol may be a therapeutic agent against inflammatory diseases.

Topics: Animals; Anti-Inflammatory Agents; Biphenyl Compounds; Cell Survival; Cells, Cultured; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Gene Expression Regulation; HEK293 Cells; Humans; Inflammation; Interleukin-8; Lignans; Lipopolysaccharides; MAP Kinase Signaling System; Mice; NF-kappa B; Signal Transduction; Toll-Like Receptor 4; Transfection

Endovascular injury induces switching of contractile phenotype of vascular smooth muscle cells (VSMCs) to synthetic phenotype, thereby causing proliferation of VSMCs leading to intimal thickening. The purpose of this study was to assess the effect of magnolol on the proliferation of VSMCs in vitro and neointima formation in vivo, as well as the related cell signaling mechanisms.. Tumor necrosis factor alpha (TNF-alpha) induced proliferation ofVSMCs was assessed using colorimetric assay. Cell cycle progression and mRNA expression of cell cycle associated molecules were determined by flow cytometry and reverse transcription polymerase chain reaction (RT-PCR) respectively. The signaling molecules such as ERK1/2,JNK, P38 and NF-kappaB were determined by Western blot analysis. In addition, rat carotid artery balloon injury model was performed to assess the effect of magnolol on neointima formation in vivo.. Oral administration of magnolol significantly inhibited intimal area and intimal/medial ratio (I/M). Our in vitro assays revealed magnolol dose dependently induced cell cycle arrest at G0/G1. Also, magnolol inhibited mRNA and protein expression of cyclin D1, cyclin E, CDK4 and CDK2 in vitro and in vivo. The cell cycle arrest was associated with inhibition of ERK1/2 phosphorylation and NF-kappaB translocation.. Magnolol suppressed proliferation of VSMCs in vitro and attenuated neointima formation in vivo by inducing cell cycle arrest at G0/G1 through modulation of cyclin D1, cyclin E, CDK4 and CDK2 expression.. Thus, the results suggest that magnolol could be a potential therapeutic candidate for the prevention of restenosis and atherosclerosis.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Biphenyl Compounds; Carotid Arteries; Carotid Artery Injuries; Cell Cycle Checkpoints; Cell Cycle Proteins; Cell Proliferation; Cells, Cultured; Gene Expression Regulation; Lignans; Male; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Neointima; NF-kappa B; Rats; Rats, Sprague-Dawley; Signal Transduction; Tumor Necrosis Factor-alpha

Magnolol and honokiol, predominant active compounds in the family Magnoliaceae, are known to exhibit strong anti-inflammatory activities against dermal disorders. We attempted to modify the structures of magnolol and honokiol by methoxylation to optimize the skin delivery ability. Absorption of these permeants into and through the skin was performed at both an infinite dose and saturated solubility. Superoxide anion and elastase released from human neutrophils were the biomarkers used to examine anti-inflammatory potencies of these permeants. The safety of the permeants was evaluated by keratinocyte viability and in vivo bioengineering techniques. Topical magnolol and honokiol at an infinite dose (7.5 mM) showed skin accumulations of 0.22 and 0.16 nmol/mg, respectively. Methoxylation significantly enhanced their skin absorption. Deposition amounts of dimethylmagnolol and dimethylhonokiol were respectively 15- and 7-fold greater than those of magnolol and honokiol. Contrary to the skin accumulation results, the transdermal penetration across skin decreased following methoxylation. No transdermal delivery occurred for dimethylhonokiol. Skin uptake of 4'-O-methylhonokiol was 2-fold higher than that of 2-O-methylhonokiol, although they are isomers. Methoxylated permeants demonstrated selective absorption into follicles, which showed 3-5-fold higher follicular amounts compared to magnolol and honokiol. The relative order of anti-inflammatory activities was honokiol>2-O-methylmagnolol>dimethylhonokiol>magnolol. The other compounds exhibited negligible or negative responses in activated neutrophils. Magnolol and honokiol induced slight but significant keratinocyte cytotoxicity and stratum corneum disruption. Daily administration of methoxylated permeants, especially dimethylhonokiol, produced no skin irritation for up to 7 days. Methoxylated magnolol and honokiol can be efficient and safe candidates for treating inflammatory skin disorders.

Topics: Adult; Animals; Anti-Inflammatory Agents; Biphenyl Compounds; Cell Survival; Cells, Cultured; Female; Humans; In Vitro Techniques; Keratinocytes; Lignans; Mice; Mice, Nude; Neutrophils; Pancreatic Elastase; Skin; Skin Absorption; Skin Irritancy Tests; Superoxides; Swine; Young Adult

Most of the anti-breast cancer drugs are often limited owing to drug resistance and serious adverse reactions. Therefore, development of more targeted and low toxic drugs from traditional Chinese medicines for breast cancer are needed. At the same time, establishment of fast and effective drug screening methods are urgently required. We describe here a 2D LC method of MDA-MB-231 cell membrane chromatography combined with HPLC/MS for recognition, separation, and identification of target components from traditional Chinese medicine Cortex Magnolia officinalis. The MDA-MB-231 cells membrane was used to prepare the chromatographic stationary phase in the first dimension. The active compounds had a retention characteristic on the cell membrane chromatography model (10 × 2.0 mm, 5 μm). The retention fractions were enriched using an online C(18) column (10 × 1.0 mm, 5 μm) and were analyzed by the second dimension RP chromatography. Finally, the activity of the retention fractions was tested through in vitro experiments. Results showed that the retention fractions were honokiol and magnolol and the inhibition rate on MDA-MB-231 cell growth were 23 and 64 μM, respectively. These results support the conclusion that this coupled analytical technique could be an efficient method in drug discovery.

Topics: Antineoplastic Agents, Phytogenic; Biphenyl Compounds; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Chromatography, Liquid; Drug Screening Assays, Antitumor; Drugs, Chinese Herbal; Female; Humans; Lignans; Magnolia; Mass Spectrometry

To investigate the chemical constituents of Elephantopus mollis.. Compounds were separated and purified by various column chromatographies including macroporous resin, ODS, Sephadex LH-20 and silica gel columns. The structures were identified by their physicochemical properties and spectroscopic data.. Nine compounds were identified as 2beta-deethoxy-2-hydroxyphantomolin (1), 2beta-methoxy-2-deethoxyphantomolin (2), 2beta-methoxy-2-deethoxy-8-O-deacylphantomolin-8-O-tigli-nate (3), molephantinin (4), betulinic acid (5), magnolol (6), honokiol (7), dibutly phthalate (8) and tricin (9).. Compounds 5-9 are isolated from this plant for the first time.

Topics: Asteraceae; Betulinic Acid; Biphenyl Compounds; Dibutyl Phthalate; Flavonoids; Lignans; Magnetic Resonance Spectroscopy; Molecular Structure; Pentacyclic Triterpenes; Triterpenes

Hypertonic saline (HTS) administration can decrease the inflammation following ischemia reperfusion. Magnolol is a potent antioxidant. The present study investigated whether combined treatment of magnolol and HTS could provide further protection in mesenteric ischemia reperfusion injury.. Male C3H/HeOuJ mice were randomly segregated into the following groups: sham-operated (sham), vehicle treatment and mesenteric ischemia reperfusion (MSIR) (vehicle-treated), magnolol treatment and MSIR (magnolol-treated), HTS treatment and MSIR (HTS-treated), as well as co-administration of magnolol plus HTS and MSIR (combined-treated). In MSIR, mice were subjected to mesenteric ischemia for 60 min followed by reperfusion for 30 min. Lung injury was evaluated by lung edema (water ratio) and myeloperoxide (MPO) activity; RNA expression of inducible nitric oxide synthetase (iNOS), TNF-α, and IL-6 were assayed by real time RT-PCR. The formation of peroxynitrite in plasma was assayed by the peroxynitrite-dependent oxidation of dihydrorhodamine 123 (DHR 123) to rhodamine.. Compared with those in the sham-treated group, lung edema and MPO activity, expressions of iNOS, TNF-α and IL-6, and plasma peroxynitrite were significantly increased in the vehicle-treated group. Significant attenuations of these parameters were found in the magnolol-treated or HTS-treated animals. Combined treatment of magnolol and HTS further suppressed the lung edema, iNOS, and TNF-α expressions, and plasma peroxynitrite, compared with the results of a single treatment of magnolol or HTS.. Compared with single-agent use, co-administration of magnolol and HTS further decreases iNOS expression and plasma peroxynitrite as well as the degree of lung injury from MISR. These results may provide another treatment measure for post-injury immunomodulation.

Topics: Animals; Antioxidants; Biphenyl Compounds; Interleukin-6; Lignans; Lung; Male; Mesentery; Mice; Mice, Inbred C3H; Models, Animal; Nitric Oxide Synthase Type II; Peroxides; Peroxynitrous Acid; Pulmonary Edema; Regional Blood Flow; Reperfusion Injury; Saline Solution, Hypertonic; Tumor Necrosis Factor-alpha

Interleukin-8 (IL-8) and tumour necrosis factor-alpha (TNF-α) from keratinocyte play important roles in initiating the inflammatory process of acne. They are used as major elements to evaluate the anti-inflammatory activity of drugs. In this study, various active constituents extracted from Chinese medicinal herbs were tested for their anti-inflammatory effects against P. acnes using ELISA. Among the constituents, matrine, baicalin, ursolic acid, sodium danshensu, magnolol, honokiol, hesperidin and andrographolide significantly reduced IL-8 and TNF-α by human HaCaT keratinocyte cells pretreated with heat-killed P. acnes. Excepting hesperidin, these active constituents presented dose-dependent inhibitory effects. Our studies showed that all of them exhibited low cytotoxicity at 5 µg mL⁻¹ in tested cell lines, and even at 50 µg mL⁻¹, in the cases of matrine, baicalin, ursolic acid and sodium danshensu. Based on the obtained results, it can be suggested that these active constituents are potential acne-mitigating candidates for cosmetic applications.

Topics: Anti-Inflammatory Agents; Biphenyl Compounds; Cell Line; Drugs, Chinese Herbal; Flavonoids; Humans; Interleukin-8; Keratinocytes; Lignans; Propionibacterium acnes; Triterpenes; Ursolic Acid

1. Magnolol (5,5'-diallyl-2,2'-dihydroxybiphenyl) is a major phenolic compound purified from Magnolia officinalis. The aim of the present study was to elucidate the effects of magnolol on vascular contractions. 2. Rat aortic rings were mounted in organ baths. Magnolol was added cumulatively (0.3-30 μmol/L) to elicit relaxation in endothelium-intact and -denuded rat aortic rings precontracted with U46619 (30 nmol/L, 20 min), NaF (8.0 mmol/L, 40 min), phenylephrine (1.0 or 0.1 μmol/L, 15 min) or phorbol-12,13-dibutyrate (PDBu, 0.3 or 0.1 μmol/L, 40 min). In separate experiments, cumulative concentrationresponse curves were obtained for NaF (2.0-12 mmol/L), U46619 (1.0 nmol/L1.0 μmol/L) or PDBu (1.0 nmol/L1.0 μmol/L) after pretreatment with either magnolol or vehicle for 30 min in endothelium-denuded aortic rings. After completion of the functional study, we measured the amount of guanosine triphosphate (GTP) RhoA by using a G-LISA RhoA Activation Assay, as well as the phosphorylation of 20 kDa myosin light chain (MLC₂₀), myosin phosphatase-targeting subunit 1 (MYPT1) and protein kinase C-potentiated inhibitory protein for heterotrimeric myosin light-chain phosphatase of 17 kDa (CPI-17) by immunobloting. 3. Magnolol (0.3-30 μmol/L) reduced vascular tension induced by the thromboxane A₂ agonist U46619 (30 nmol/L), sodium fluoride (NaF) (8.0 mmol/L) and the α₁ -adrenoceptor agonist phenylephrine (1.0 or 0.1 μmol/L) in both endothelium-intact and -denuded rings. The magnitude of the relaxation effects of magnolol on the contraction induced by each of the drugs were similar. The magnitude of the effect of magnolol in endothelium-intact and -denuded rings were similar. 4. Pretreatment of rat aortic rings with 1.0, 3.0 or 10 μmol/L magnolol for 30 min dose-dependently inhibited the maximum response on the concentration-response curves to NaF and U46619, but not to phorbol-12,13-dibutyrate (PDBu). 5. Magnolol (3.0 or 10 μmol/L) decreased RhoA activation, as well as the phosphorylation of MLC₂₀ , MYPT1(Thr855) and CPI-17(Thr38) induced by either 8.0 mmol/L NaF or 30 nmol/L U46619. In contrast, magnolol did not affect PDBu (0.1 μmol/L)-induced phosphorylation of CPI-17(Thr38) . 6. In conclusion, magnolol reduces vascular contraction by inhibiting the RhoA/Rho kinase pathway in endothelium-denuded rat aorta.

Topics: Animals; Aorta, Thoracic; Biphenyl Compounds; In Vitro Techniques; Lignans; Male; Molecular Weight; Muscle Proteins; Muscle, Smooth, Vascular; Myosin Light Chains; Osmolar Concentration; Phosphoproteins; Phosphorylation; Protein Phosphatase 1; Protein Processing, Post-Translational; Rats; Rats, Sprague-Dawley; rho-Associated Kinases; rhoA GTP-Binding Protein; Signal Transduction; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

Gastric cancer is the fourth most commonly diagnosed cancer with the second highest mortality rate worldwide. Surgery, chemotherapy and radiation therapy are generally used for the treatment of stomach cancer but only limited clinical response is shown by these therapies and still no effectual therapy for advanced gastric adenocarcinoma patients is available. Therefore, there is a need to identify other therapeutic agents against this life-threatening disease. Plants are considered as one of the most important sources for the development of anticancer drugs. Magnolol, a natural compound possesses anticancer properties. However, effects of Magnolol on human gastric cancer remain unexplored. The effects of Magnolol on the viability of SGC-7901 cells were determined by the MTT assay. Apoptosis, mitochondrial membrane potential and cell cycle were evaluated by flow cytometry. Protein expression of Bcl-2, Bax, caspase-3 and PI3K/Akt was analysed by Western blotting. Magnolol induced morphological changes in SGC-7901 cells and its cytotoxic effects were linked with DNA damage, apoptosis and S-phase arrest in a dose-dependent manner. Magnolol triggered the mitochondrial-mediated apoptosis pathway as shown by an increased ratio of Bax/Bcl-2, dissipation of mitochondrial membrane potential (ΔΨm), and sequential activation of caspase-3 and inhibition of PI3K/Akt. Additionally, Magnolol induced autophagy in SGC-7901 cells at high concentration but was not involved in cell death. Magnolol-induced apoptosis of SGC-7901 cells involves mitochondria and PI3K/Akt-dependent pathways. These findings provide evidence that Magnolol is a promising natural compound for the treatment of gastric cancer and may represent a candidate for in vivo studies of monotherapies or combination antitumor therapies.

Topics: Adenocarcinoma; Apoptosis; bcl-2-Associated X Protein; Biphenyl Compounds; Caspase 3; Cell Growth Processes; Down-Regulation; Enzyme Activation; Humans; Lignans; Mitochondria; Phosphatidylinositol 3-Kinases; Platelet Aggregation Inhibitors; Proto-Oncogene Proteins c-bcl-2; S Phase; Signal Transduction; Stomach Neoplasms

Two new phenylethanoid glycosides magnoloside D (1) and E (2), together with nine known compounds, were isolated from the polar part of methanol extract of the stem bark of Magnolia officinalis. The structures of the new compounds were established on the basis of spectral analysis. Anti-spasmodic activity of four major constituents (3, 4, 9 and 11) was tested in isolated colon of rat, compounds 3, 4, and 9 showed inhibition against acetylcholine, with the effect similar to that of magnolol and honokiol. At the same time, antioxidant activity of the isolated compounds was investigated using a DPPH and an ORAC assay. All of the compounds, except compound 8 showed potent antioxidant capacity in the ORAC assay, while compounds 1-5 and 11 exhibited potent antioxidant activity in the DPPH assay.

Topics: Acetylcholine; Animals; Antioxidants; Biphenyl Compounds; Colon; Glycosides; Lignans; Magnolia; Parasympatholytics; Phenylethyl Alcohol; Plant Bark; Plant Extracts; Rats

Molecularly imprinted membranes (MIMs) for selective separation of magnolol were prepared by thermal polymerization using magnolol as the template, ethylene glycol dimethacrylate (EGDMA) as the cross-linker, 2,2-azobisisobutyronitrile (AIBN) as the initiator, organic solvent as the porogen, methacrylamide (MAM) and acrylic acid (AA) as the functional monomers and cellulose acetate as the agglutinant. Commercial filter paper was used as the supporting material. The effects of different porogens and the ratio of functional monomers on the binding and recognition capacity of MIMs were investigated, and the morphology of the membranes was examined by scanning electron microscopy (SEM). The results showed that the MIMs have the highest selectivity to magnolol when the ratio of MAM/AA was 1:4 and tetrahydrofuran (THF) with dimethyl sulfoxide (DMSO) was used as the porogen. The morphology of the imprinted membranes after template extracting is much rougher with big cavities than that of the non-imprinted membranes (NIMs) and the imprinted membranes before template extracting. The MIMs can selectively separate the magnolol.

Topics: Acrylamides; Acrylates; Biphenyl Compounds; Drugs, Chinese Herbal; Lignans; Membranes, Artificial; Microscopy, Electron, Scanning; Molecular Imprinting; Polymerization

Magnolol is a food additive that is often found in mints and gums. Human exposure to this compound can reach a high dose; thus, characterization of magnolol disposition in humans is very important. Previous studies indicated that magnolol can undergo extensive glucuronidation in humans in vivo. In this study, in vitro assays were used to characterize the glucuronidation pathway in human liver and intestine. Assays with recombinant human UDP-glucuronosyltransferase enzymes (UGTs) revealed that multiple UGT isoforms were involved in magnolol glucuronidation, including UGT1A1, -1A3, -1A7, -1A8, -1A9, -1A10, and -2B7. Magnolol glucuronidation by human liver microsomes (HLM), human intestine microsomes (HIM), and most recombinant UGTs exhibited strong substrate inhibition kinetics. The degree of substrate inhibition was relatively low in the case of UGT1A10, whereas the reaction catalyzed by UGT1A9 followed biphasic kinetics. Chemical inhibition studies and the relative activity factor (RAF) approach were used to identify the individual UGTs that played important roles in magnolol glucuronidation in HLM and HIM. The results indicate that UGT2B7 is mainly responsible for the reaction in HLM, whereas UGT2B7 and UGT1A10 are significant contributors in HIM. In summary, the current study clarifies the glucuronidation pathway of magnolol and demonstrates that the RAF approach can be used as an efficient method for deciphering the roles of individual UGTs in a given glucuronidation pathway in the native tissue that is catalyzed by multiple isoforms with variable and atypical kinetics.

Topics: Biphenyl Compounds; Glucuronides; Glucuronosyltransferase; Humans; Intestinal Mucosa; Kinetics; Lignans; Liver; Microsomes; Microsomes, Liver; Protein Isoforms; Recombinant Proteins

A versatile synthetic route is reported towards the preparation of new analogues for potent neurotrophic agent biaryl-type lignan honokiol. A focused 24-membered library of derivatives containing five different groups at 5'-position of honokiol has been prepared in fair to good overall yields. Compared to the natural product, or to analogues with a short alkyl chain in this position, these new derivatives have lost most of the neurotrophic activity.

Topics: Animals; Biphenyl Compounds; Cells, Cultured; Humans; Immunohistochemistry; Lignans; Molecular Structure; Nerve Growth Factors; Neurites; Neurogenesis; Small Molecule Libraries; Structure-Activity Relationship

Magnolol is the main constituent identified in the barks of Magnolia officinalis, which has been used for the treatment of mental disorders including depression in China. In this study, we investigated the antidepressant-like effect of magnolol, and its possible mechanisms in rats subjected to unpredictable chronic mild stress (UCMS). High performance liquid chromatography with electrochemical detection (HPLC-ECD) and immunohistochemical staining analysis were applied to explore the mechanisms underlying the antidepressant-like effect of magnolol. Magnolol (20, 40 mg/kg) significantly reversed UCMS-induced reduction in sucrose consumption and deficiency in locomotor activity. In addition, it was observed that administration of magnolol (20, 40 mg/kg) restored brain-derived neurotrophic factor (BDNF) expression, and normalized the serotonergic system changes in the UCMS-treated rats. These results confirmed the antidepressant-like effect of magnolol, which might be based primarily on its ability to increase the BDNF expression and enhance the activity of the serotonergic system in rat brains.

Topics: Animals; Antidepressive Agents; Biphenyl Compounds; Brain-Derived Neurotrophic Factor; Chromatography, High Pressure Liquid; Disease Models, Animal; Exploratory Behavior; Food Preferences; Hippocampus; Immunohistochemistry; Lignans; Magnolia; Male; Motor Activity; Phytotherapy; Prefrontal Cortex; Rats; Rats, Sprague-Dawley; Stress, Physiological; Sucrose

Antimycin A treatment of cells blocks the mitochondrial electron transport chain and leads to elevated ROS generation. In the present study, we investigated the protective effects of magnolol, a hydroxylated biphenyl compound isolated from Magnolia officinalis, on antimycin A-induced toxicity in osteoblastic MC3T3-E1 cells. Osteoblastic MC3T3-E1 cells were pre-incubated with magnolol before treatment with antimycin A. Cell viability and mineralization of osteoblasts were assessed by MTT assay and Alizarin Red staining, respectively. Mitochondrial dysfunction in cells was measured by mitochondrial membrane potential (MMP), complex IV activity, and ATP level. The cellular antioxidant effect of magnolol in osteoblastic MC3T3-E1 cells was assessed by measuring cardiolipin oxidation, mitochondrial superoxide levels, and nitrotyrosine content. Phosphorylated cAMP-response element-binding protein (CREB ) was evaluated using ELISA assay. Pretreatment with magnolol prior to antimycin A exposure significantly reduced antimycin A-induced osteoblast dysfunction by preventing MMP dissipation, ATP loss, and CREB inactivation. Magnolol also reduced cardiolipin peroxidation, mitochondrial superoxide, and nitrotyrosine production induced by antimycin A. These results suggest that magnolol has a protective effect against antimycin A-induced cell damage by its antioxidant effects and the attenuation of mitochondrial dysfunction. All these data indicate that magnolol may reduce or prevent osteoblast degeneration in osteoporosis or other degenerative disorders.

Topics: Animals; Antimycin A; Antioxidants; Biphenyl Compounds; Cardiolipins; Cell Line; CREB-Binding Protein; Electron Transport; Lignans; Magnolia; Membrane Potential, Mitochondrial; Mice; Mitochondria; Osteoblasts; Osteoporosis; Oxidative Stress; Plant Extracts; Protective Agents; Reactive Oxygen Species; Tyrosine

A method for the separation and determination of honokiol and magnolol in Magnolia officinalis and its medicinal preparation is developed by capillary zone electrophoresis and response surface methodology. The concentration of borate, content of organic modifier, and applied voltage are selected as variables. The optimized conditions (i.e., 16 mmol/L sodium tetraborate at pH 10.0, 11% methanol, applied voltage of 25 kV and UV detection at 210 nm) are obtained and successfully applied to the analysis of honokiol and magnolol in Magnolia officinalis and Huoxiang Zhengqi Liquid. Good separation is achieved within 6 min. The limits of detection are 1.67 µg/mL for honokiol and 0.83 µg/mL for magnolol, respectively. In addition, an artificial neural network with "3-7-1" structure based on the ratio of peak resolution to the migration time of the later component (R(s)/t) given by Box-Behnken design is also reported, and the predicted results are in good agreement with the values given by the mathematic software and the experimental results.

Topics: Biphenyl Compounds; Computational Biology; Drugs, Chinese Herbal; Electrophoresis, Capillary; Lignans; Magnolia; Models, Statistical; Neural Networks, Computer; Plant Bark; Reproducibility of Results

A simple LC-MS/MS method was developed for determination and pharmacokinetic study of magnolol in rat blood. Blood sample pretreatment involved a one-step extraction with methanol of 100 µL blood. The chromatographic separation was carried out on a Agilent Zobax SB C18 column with a mobile phase consisting of acetonitrile-0.2% formic acid (55:45, v/v) at a flow rate of 0.3 mL/min. The detection was performed on a triple quadrupole tandem mass spectrometer by multiple reaction monitoring via electro spray ionization source with positive mode. A high throughput was achieved with a run time of 4 min per sample. The standard curve for magnolol was linear (r > 0.999) over the concentration range of 2-1 000 ng/mL, with a lower limit of quantification of 2 ng/mL. The intra- and inter-day precision (relative standard deviation) values were not higher than 12% and the accuracy (relative error) was <5% at three quality control levels. This simple, fast and highly sensitive method was fully validated and successfully applied to a clinical pharmacokinetic study of magnolol in rats after oral administration.

Topics: Animals; Antineoplastic Agents, Phytogenic; Biphenyl Compounds; Chromatography, High Pressure Liquid; Female; Freezing; Indicators and Reagents; Lignans; Limit of Detection; Male; Quality Control; Rats; Rats, Sprague-Dawley; Reference Standards; Reproducibility of Results; Specimen Handling; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry

Fibroblast-like synoviocytes (FLS) play an important role in the pathologic processes of destructive arthritis by producing a number of catabolic cytokines and metalloproteinases (MMPs). The expression of these mediators is controlled at the transcriptional level. The purposes of this study were to evaluate the anti-arthritic effects of magnolol (5,5'-Diallyl-biphenyl-2,2'-diol), the major bioactive component of the bark of Magnolia officinalis, by examining its inhibitory effects on inflammatory mediator secretion and the NF-κB and AP-1 activation pathways and to investigate its therapeutic effects on the development of arthritis in a rat model. The in vitro anti-arthritic activity of magnolol was tested on interleukin (IL)-1β-stimulated FLS by measuring levels of IL-6, cyclooxygenase-2, prostaglandin E(2), and matrix metalloproteinases (MMPs) by ELISA and RT-PCR. Further studies on how magnolol inhibits IL-1β-stimulated cytokine expression were performed using Western blots, reporter gene assay, electrophoretic mobility shift assay, and confocal microscope analysis. The in vivo anti-arthritic effects of magnolol were evaluated in a Mycobacterium butyricum-induced arthritis model in rats. Magnolol markedly inhibited IL-1β (10 ng/mL)-induced cytokine expression in a concentration-dependent manner (2.5-25 µg/mL). In clarifying the mechanisms involved, magnolol was found to inhibit the IL-1β-induced activation of the IKK/IκB/NF-κB and MAPKs pathways by suppressing the nuclear translocation and DNA binding activity of both transcription factors. In the animal model, magnolol (100 mg/kg) significantly inhibited paw swelling and reduced serum cytokine levels. Our results demonstrate that magnolol inhibits the development of arthritis, suggesting that it might provide a new therapeutic approach to inflammatory arthritis diseases.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis; Biphenyl Compounds; Cytokines; Disease Models, Animal; Fibroblasts; Humans; Inflammation Mediators; Interleukin-1beta; Lignans; Matrix Metalloproteinases; Rats; Synovial Membrane; Treatment Outcome

Magnolol, a polyphenolic compound isolated from Houpu, a Chinese herb from the bark of Magnolia officinalis, has been reported to have in vitro and in vivo neuroprotective effects. In spite of these reported beneficial effects, studies on the direct impact of magnolol on neuronal ion channels have been scarce. Whether magnolol affects voltage-gated Na(+) channels (VGSC) and voltage-gated K(+) (Kv) channels is unknown. Using the whole-cell voltage-clamp method, we studied the effects of magnolol on voltage-gated ion channels in neuronal NG108-15 cells. Magnolol inhibited VGSC channels with mild state-dependence (IC(50) of 15 and 30 μM, at holding potentials of -70 and -100 mV, respectively). No frequency-dependence was observed in magnolol block. Magnolol caused a left-shift of 18 mV in the steady-state inactivation curve but did not affect the voltage-dependence of activation. Magnolol inhibited Kv channels with an IC(50) of 21 μM, and it caused a 20-mV left-shift in the steady-state inactivation curve without affecting the voltage-dependence of activation. In conclusion, magnolol is an inhibitor of both VGSC and Kv channels and these inhibitory effects may in part contribute to some of the reported neuroprotective effects of magnolol.

Topics: Biphenyl Compounds; Cell Line, Tumor; Humans; Ion Channel Gating; Lignans; Neurons; Neuroprotective Agents; Potassium Channel Blockers; Potassium Channels, Voltage-Gated; Sodium Channel Blockers; Sodium Channels

A series of novel magnolol derivatives were synthesised and evaluated for in vitro antimicrobial and antiproliferative activities. We found that most of the compounds were effective inhibitors of Staphylococcus aureus, MRSA and VRE with MIC in the range of 1-64 μg/mL and MBC in the range of 1-128 μg/mL. Few derivatives also exhibited promising antifungal activity. Some magnolol analogues exhibited promising antiproliferative activity than parent magnolol when tested against three human cancer cell lines.

Topics: Anti-Infective Agents; Antifungal Agents; Antineoplastic Agents; Bacteria; Biological Products; Biphenyl Compounds; Cell Line, Tumor; Cell Proliferation; Chemistry Techniques, Synthetic; DNA Fragmentation; Drug Design; Humans; Lignans

The National Center for Complementary and Alternative Medicine (NCCAM) estimates that nearly 40% of adults in the United States use alternative medicines, often in the form of an herbal supplement. Extracts from the tree bark of magnolia species have been used for centuries in traditional Chinese and Japanese medicines to treat a variety of neurological diseases, including anxiety, depression, and seizures. The active ingredients in the extracts have been identified as the bi-phenolic isomers magnolol and honokiol. These compounds were shown to enhance the activity of GABA(A) receptors, consistent with their biological effects. The GABA(A) receptors exhibit substantial subunit heterogeneity, which influences both their functional and pharmacological properties. We examined the activity of magnolol and honokiol at different populations of both neuronal and recombinant GABA(A) receptors to characterize their mechanism of action and to determine whether sensitivity to modulation was dependent upon the receptor's subunit composition. We found that magnolol and honokiol enhanced both phasic and tonic GABAergic neurotransmission in hippocampal dentate granule neurons. In addition, all recombinant receptors examined were sensitive to modulation, regardless of the identity of the α, β, or γ subunit subtype, although the compounds showed particularly high efficacy at δ-containing receptors. This direct positive modulation of both synaptic and extra-synaptic populations of GABA(A) receptors suggests that supplements containing magnolol and/or honokiol would be effective anxiolytics, sedatives, and anti-convulsants. However, significant side-effects and risk of drug interactions would also be expected.

Topics: Animals; Biphenyl Compounds; Drugs, Chinese Herbal; GABA Agents; HEK293 Cells; Hippocampus; Humans; Inhibitory Postsynaptic Potentials; Lignans; Neurons; Rats; Receptors, GABA-A; Synaptic Transmission

In the present study, the ability of magnolol, a hydroxylated biphenyl compound isolated from Magnolia officinalis, to stimulate osteoblast function and inhibit the release of bone-resorbing mediators was investigated in osteoblastic MC3T3-E1 cells.. Osteoblast function was measured by cell growth, alkaline phosphatase activity, collagen synthesis, and mineralization. Glutathione content was also measured in the cells. Bone-resorbing cytokines, receptor activator of nuclear factor-κB ligand (RANKL), TNF-α, and IL-6 were measured with an enzyme immunoassay system.. Magnolol caused a significant elevation of cell growth, alkaline phosphatase activity, collagen synthesis, mineralization, and glutathione content in the cells (P < 0.05). Skeletal turnover is orchestrated by a complex network of regulatory factors. Among cytokines, RANKL, TNF-α, and IL-6 were found to be key osteoclastogenetic molecules produced by osteoblasts. Magnolol significantly (P < 0.05) decreased the production of osteoclast differentiation inducing factors such as RANKL, TNF-α, and IL-6 in the presence of antimycin A, which inhibits mitochondrial electron transport and has been used as an ROS generator.. Magnolol might be a candidate as an agent for the prevention of bone disorders such as osteoporosis.

Topics: Alkaline Phosphatase; Animals; Antimycin A; Biphenyl Compounds; Cell Line; Collagen; Cytokines; Glutathione; Interleukin-6; Lignans; Mice; Osteoblasts; RANK Ligand; Tumor Necrosis Factor-alpha

In this study, the binding modes of honokiol (HK) and magnolol (MG) with human serum albumin (HSA) have been established under imitated physiological condition, which was very important to understand the pharmacokinetics and toxicity of HK or MG. The experimental results proved that the fluorescence of HSA was quenched by HK or MG through a static quenching procedure. The binding constants of HK-HSA and MG-HSA complexes were 5.304 and 263.755×10(4) L mol(-1) at 298 K, respectively. The binding process was a spontaneous molecular interaction procedure, in which the hydrophobic interaction played a major role in the formation of the HK-HSA complex, whereas, the binding interaction between MG and HSA might involve the hydrophobic interaction strongly and electrostatic interaction. In addition, the effect of HK/MG on the secondary structure of HSA was analyzed using CD, UV-vis absorption, Fourier transform infrared (FT-IR), synchronous fluorescence and three-dimensional fluorescence spectra. According to Förster no-radiation energy transfer theory, the binding distance of HSA to HK or MG was calculated to be 1.842 or 1.238 nm. Besides, the effects of common ions on the binding constants of HSA-HK/MG systems were also discussed.

Topics: Biphenyl Compounds; Circular Dichroism; Humans; Hydrophobic and Hydrophilic Interactions; Lignans; Protein Binding; Serum Albumin; Spectrometry, Fluorescence; Spectroscopy, Fourier Transform Infrared; Static Electricity

Abnormal activation of the canonical Wnt/β-catenin pathway and up-regulation of the β-catenin/T-cell factor (TCF) response to transcriptional signaling play a critical role early in colorectal carcinogenesis. Therefore, Wnt/β-catenin signaling is considered an attractive target for cancer chemotherapeutic or chemopreventive agents. Small molecules derived from the natural products were used in our cell-based reporter gene assay to identify potential inhibitors of Wnt/β-catenin signaling. Magnolol, a neolignan from the cortex of Magnolia obovata, was identified as a promising candidate because it effectively inhibited β-catenin/TCF reporter gene (TOPflash) activity. Magnolol also suppressed Wnt3a-induced β-catenin translocation and subsequent target gene expression in human embryonic kidney 293 cells. To further investigate the precise mechanisms of action in the regulation of Wnt/β-catenin signaling by magnolol, we performed Western blot analysis, real-time reverse transcriptase-polymerase chain reactions, and an electrophoretic mobility shift assay in human colon cancer cells with aberrantly activated Wnt/β-catenin signaling. Magnolol inhibited the nuclear translocation of β-catenin and significantly suppressed the binding of β-catenin/TCF complexes onto their specific DNA-binding sites in the nucleus. These events led to the down-regulation of β-catenin/TCF-targeted downstream genes such as c-myc, matrix metalloproteinase-7, and urokinase-type plasminogen activator in SW480 and HCT116 human colon cancer cells. In addition, magnolol inhibited the invasion and motility of tumor cells and exhibited antitumor activity in a xenograft nude mouse model bearing HCT116 cells. These findings suggest that the growth inhibition of magnolol against human colon cancer cells can be partly attributed to the regulation of the Wnt/β-catenin signaling pathway.

Topics: Animals; Antineoplastic Agents, Phytogenic; beta Catenin; Biphenyl Compounds; Colorectal Neoplasms; Female; HCT116 Cells; HEK293 Cells; Humans; Lignans; Mice; Mice, Inbred BALB C; Mice, Nude; Signal Transduction; Wnt3A Protein; Xenograft Model Antitumor Assays

1. Human exposure to magnolol can reach a high dose in daily life. Our previous studies indicated that magnolol showed high affinities to several UDP-glucuronosyltransferases (UGTs) This study was designed to examine the in vitro inhibitory effects of magnolol on UGTs, and further to evaluate the possibility of the in vivo inhibition that might happen. 2. Assays with recombinant UGTs and human liver microsomes (HLM) indicated that magnolol (10 µM) can selectively inhibit activities of UGT1A9 and extra-hepatic UGT1A7. Inhibition of magnolol on UGT1A7 followed competitive inhibition mechanism, while the inhibition on UGT1A9 obeyed either competitive or mixed inhibition mechanism, depending on substrates. The K(i) values for UGT1A7 and 1A9 are all in nanomolar ranges, lower than possible magnolol concentrations in human gut lumen and blood, indicating the in vivo inhibition on these two enzymes would likely occur. 3. In conclusion, UGT1A7 and 1A9 can be strongly inhibited by magnolol, raising the alarm for safe application of magnolol and traditional Chinese medicines containing magnolol. Additionally, given that UGT1A7 is an extra-hepatic enzyme, magnolol can serve as a selective UGT1A9 inhibitor that will act as a new useful tool in future hepatic glucuronidation phenotyping.

Topics: Biocatalysis; Biomarkers; Biphenyl Compounds; Enzyme Inhibitors; Gastrointestinal Tract; Glucuronosyltransferase; Humans; Kinetics; Lignans; Microsomes, Liver; Recombinant Proteins; UDP-Glucuronosyltransferase 1A9

Magnolol, a hydroxylated biphenyl compound isolated from Magnolia officinalis has been reported to have anti-inflammatory properties. The purpose of this study was to evaluate the effect of magnolol on acute lung injury induced by lipopolysaccharide in mice. Male BALB/c mice were pretreated with dexamethasone or magnolol 1 h before intranasal instillation of lipopolysaccharide (LPS). 7 h after LPS administration, the myeloperoxidase in lung tissues, lung wet/dry weight ratio and inflammatory cells in the bronchoalveolar lavage fluid were determined. The levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) in the bronchoalveolar lavage fluid were measured by enzyme-linked immunosorbent assay (ELISA). The extent of phosphorylation of nuclear factor of inhibitory kappa B alpha (IκB-α), nuclear factor kappa-B (NF-κB) p65 and the expression of Toll-like receptor-4 (TLR4) were detected by western blot. The results showed that magnolol markedly attenuated the histological alterations in the lung; reduced the number of total cells, neutrophils, and macrophages in the bronchoalveolar lavage fluid; decreased the wet/dry weight ratio of lungs in the bronchoalveolar lavage fluid; down-regulated the level of pro-inflammatory mediators, including TNF-α, IL-1β and IL-6; inhibited the phosphorylation of IκB-α, NF-κB p65 and the expression of TLR4, caused by LPS. Taken together, our results suggest that anti-inflammatory effects of magnolol against the LPS-induced acute lung injury may be due to its ability of inhibition TLR4 mediated NF-κB signaling pathways. Magnolol may be a promising potential therapeutic reagent for acute lung injury treatment.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents, Non-Steroidal; Biphenyl Compounds; Lignans; Lipopolysaccharides; Male; Mice; Mice, Inbred BALB C; NF-kappa B; Random Allocation; Signal Transduction; Toll-Like Receptor 4; Treatment Outcome

Activation of peroxisome proliferator-activated receptor (PPAR) isoforms (α, β/δ, and γ) is known to inhibit platelet aggregation. In the present study, we examined whether PPARs-mediated pathways contribute to the antiplatelet activity of magnolol, a compound purified from Magnolia officinalis. Magnolol (20-60 μM) dose-dependently enhanced the activity and intracellular level of PPAR-β/γ in platelets. In the presence of selective PPAR-β antagonist (GSK0660) or PPAR-γ antagonist (GW9662), the inhibition of magnolol on collagen-induced platelet aggregation and intracellular Ca(2+) mobilization was significantly reversed. Moreover, magnolol-mediated up-regulation of NO/cyclic GMP/PKG pathway and Akt phosphorylation leading to increase of eNOS activity were markedly abolished by blocking PPAR-β/γ activity. Additionally, magnolol significantly inhibited collagen-induced PKCα activation through a PPAR-β/γ and PKCα interaction manner. The arachidonic acid (AA) or collagen-induced thromboxane B(2) formation and elevation of COX-1 activity caused by AA were also markedly attenuated by magnolol. However, these above effects of magnolol on platelet responses were strongly reduced by simultaneous addition of GSK0660 or GW9662, suggesting that PPAR-β/γ-mediated processes may account for magnolol-regulated antiplatelet mechanisms. Similarly, administration of PPAR-β/γ antagonists remarkably abolished the actions of magnolol in preventing platelet plug formation and prolonging bleeding time in mice. Taken together, we demonstrate for the first time that the antiplatelet and anti-thrombotic activities of magnolol are modulated by up-regulation of PPAR-β/γ-dependent pathways.

Topics: Animals; Biphenyl Compounds; Blood Platelets; Calcium; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Cyclooxygenase 1; Fibrinolytic Agents; Guanylate Cyclase; Lignans; Mice; Mice, Inbred ICR; Nitric Oxide; Nitric Oxide Synthase Type III; Phosphorylation; Platelet Aggregation; Platelet Aggregation Inhibitors; PPAR gamma; PPAR-beta; Protein Kinase C-alpha; Proto-Oncogene Proteins c-akt; Rabbits; Receptors, Cytoplasmic and Nuclear; Signal Transduction; Soluble Guanylyl Cyclase; Thromboxane B2; Up-Regulation

Magnolol (6,6',7,12-tetramethoxy-2,2'-dimethyl-1-beta-berbaman, C(18)H(18)O(2)), an active ingredient of the bark of Magnolia officinalis, has been reported to exert potent anti-epileptic effects via the GABA(A) receptor. The receptor also mediates sleep in humans and animals. The aim of this study was to determine whether magnolol could modulate sleep behaviors by recording EEG and electromyogram in mice. The results showed that magnolol administered i.p. at a dose of 5 or 25 mg/kg could significantly shorten the sleep latency, increase the amount of non-rapid eye movement (non-REM, NREM) and rapid eye movement (REM) sleep for 3 h after administration with an increase in the number of NREM and REM sleep episodes. Magnolol at doses of 5 and 25 mg/kg increased the number of bouts of wakefulness but decreased their duration. On the other hand, magnolol increased the number of state transitions from wakefulness to NREM sleep and subsequently from NREM sleep to wakefulness. Immunohistochemical study showed that magnolol increased c-Fos expression in the neurons of ventrolateral preoptic area, a sleep center in the anterior hypothalamus, and decreased c-Fos expression in the arousal tuberomammillary nucleus, which was located in the caudolateral hypothalamus. The sleep-promoting effects and changes in c-Fos induced by magnolol were reversed by flumazenil, an antagonist at the benzodiazepine site of the GABA(A) receptor. These results indicate that magnolol increased NREM and REM sleep via the GABA(A) receptor.

Topics: Animals; Arousal; Biphenyl Compounds; Diazepam; Drug Interactions; Electroencephalography; Electromyography; Flumazenil; GABA Modulators; Gene Expression; Genes, fos; Hypothalamic Area, Lateral; Immunohistochemistry; Lignans; Magnolia; Male; Mice; Mice, Inbred C57BL; Plant Bark; Polysomnography; Preoptic Area; Receptors, GABA-A; Sleep; Sleep, REM

Neuroprotective efficacy of magnolol, 5,5'-dially-2,2'-dihydroxydiphenyl, was investigated in a model of stroke and cultured neurons exposed to glutamate-induced excitotoxicity. Rats were subjected to permanent middle cerebral artery occlusion (pMCAO). Magnolol or vehicle was administered intraperitoneally, at 1 hr pre-insult or 1-6 hrs post-insult. Brain infarction was measured upon sacrifice. Relative to controls, animals pre-treated with magnolol (50-200 mg/kg) had significant infarct volume reductions by 30.9-37.8% and improved neurobehavioral outcomes (P<0.05, respectively). Delayed treatment with magnolol (100 mg/kg) also protected against ischemic brain damage and improved neurobehavioral scores, even when administered up to 4 hrs post-insult (P<0.05, respectively). Additionally, magnolol (0.1 µM) effectively attenuated the rises of intracellular Ca(2+) levels, [Ca(2+)](i), in cultured neurons exposed to glutamate. Consequently, magnolol (0.1-1 µM) significantly attenuated glutamate-induced cytotoxicity and cell swelling (P<0.05). Thus, magnolol offers neuroprotection against permanent focal cerebral ischemia with a therapeutic window of 4 hrs. This neuroprotection may be, partly, mediated by its ability to limit the glutamate-induced excitotoxicity.

Topics: Animals; Biphenyl Compounds; Brain; Calcium; Cells, Cultured; Cerebral Infarction; Dose-Response Relationship, Drug; Glutamic Acid; Infarction, Middle Cerebral Artery; Injections, Intraperitoneal; Lignans; Male; Neurons; Neuroprotective Agents; Neuropsychological Tests; Rats; Rats, Sprague-Dawley; Time Factors

Magnolia officinalis has been widely used in traditional Chinese medicine. Magnolol, an active component isolated from Magnolia officinalis, is known to be a cardiovascular protector since 1994. The multiplex mechanisms of magnolol on cardiovascular protection depends on cell types and dosages, and will be reviewed and discussed in this article. Magnolol under low and moderate dosage possesses the ability to protect heart from ischemic/reperfusion injury, reduces atherosclerotic change, protects endothelial cell against apoptosis and inhibits neutrophil-endothelial adhesion. The moderate to high concentration of magnolol mainly acts on smooth muscle cells and platelets. Magnolol induces apoptosis in vascular smooth muscle cells at moderate concentration and inhibits proliferation at moderate and high concentration. High concentration of magnolol also abrogates platelet activation, aggregation and thrombus formation. Magnolol also serves as an smooth muscle relaxant only upon the high concentration. Oral intake of magnolol to reach the therapeutic level for cardiovascular protection is applicable, thus makes magnolol an agent of great potential for preventing cardiovascular diseases in high-risk patients.

Topics: Apoptosis; Biphenyl Compounds; Cardiovascular System; Drugs, Chinese Herbal; Humans; Inflammation; Lignans; Magnolia; Muscle, Smooth, Vascular; Myocytes, Cardiac; Myocytes, Smooth Muscle

To investigate the effect of prescription compatibility on the pharmacokinetics of components from Dachengqi Decoction (DCQD, ) in rats.. Twenty-four male rats were randomly and equally divided into the DCQD group, Dahuang (Radix et Rhizoma Rhei, Polygonaceae) group, Houpo (Magnolia officinalis Rehd., Magnoliaceae) group, and Zhishi (Fructus Aurantii Immaturus, Rutaceae) group. The blood samples were collected before dosing and subsequently at 10, 15, 20, 30, 45 min, 1, 2, 4, 8, and 12 h following gavage. The levels of aloe-emodin, rhein, emodin, chrysophanol, honokiol, magnolol, hesperidin, and naringin in rat serum were quantified using a liquid chromatography tandem mass spectrometry (LC-MS/MS) method for pharmacokinetic study.. The area under the curve (AUC), mean retention time (MRT), the peak concentration (C(max)) of aloe-emodin, rhein, emodin, and chrysophanol in the DCQD group were significantly different compared with the Dahuang group (P <0.05, respectively). The mean plasma concentration, C(max), and the absorption of Dahuang's component in the DCQD group were obviously lower at each time point than those in the Dahuang group, while the elimination process of Dahuang's component was obviously delayed (P <0.05). Half-lives of aloe-emodin, chrysophanol, and rhein were also extended in the DCQD group (P <0.05, respectively). In the DCQD group, the mean plasma concentration, AUC, C(max) and absorption of honokiol, and magnolol were significantly lower (P <0.01, respectively) at each time point than those in the Houpo group, while the drug distribution half-life time (T(1/2α)), the drug eliminated half-life time (T(1/2β)), MRT, and time of peak concentration (T(max)) were significantly delayed (P <0.05, respectively). Pharmacokinetic parameters of hesperidin and naringin in the Zhishi group were not significantly different as compared with the DCQD group (P >0.05, respectively), while the MRT of naringin was significantly longer.. The compatibility in Chinese medicine could affect the drug's pharmacokinetics in DCQD, which proves that the prescription compatibility principle of Chinese medicine formulations has its own pharmacokinetic basis.

Topics: Administration, Oral; Animals; Anthraquinones; Biphenyl Compounds; Drug Incompatibility; Emodin; Flavanones; Hesperidin; Lignans; Male; Plant Extracts; Rats; Rats, Sprague-Dawley

Colon cancer is the third most common malignancy around the world. Surgery, chemotherapy, and radiotherapy are generally used to treat colon cancer, but no effective therapy for advanced colon carcinoma is available. Therefore, there is a need to identify other therapeutic agents against this disease. Magnolol, a hydroxylated biphenyl compound present in Magnolia officinalis, exerts anticancer potential and low toxicity. Emerging evidence has suggested that activation of AMP-activated protein kinase (AMPK), a potential cancer therapeutic target is involved in apoptosis in colon cancer cells. However, the effects of magnolol on human colon cancer through activation of AMPK remain unexplored. In this study, we explored whether magnolol exerts an antiproliferative effect, and induces apoptosis in HCT-116 human colon cancer cells. Magnolol displayed several apoptotic features, including propidium iodide labeling, DNA fragmentation, and caspase-3 and poly(ADP-ribose) polymerase cleavages. We showed that magnolol induced the phosphorylation of AMPK in dose- and time-dependent manners. The selective AMPK inhibitor compound C abrogated the effect of magnolol on AMPK activation, suppression of proliferation, and caspase-3 cleavage. Magnolol downregulated expression of the antiapoptotic protein Bcl2, upregulated expression of pro-apoptotic protein p53 and Bax, and caused the release of mitochondrial cytochrome c. Magnolol-induced p53 and Bcl2 expression was abolished in the presence of compound C. Magnolol inhibited migration and invasion of HCT-116 cells through AMPK activation. These findings demonstrate that AMPK mediates the anticancer effects of magnolol through apoptosis in HCT-116 cells.

Topics: AMP-Activated Protein Kinases; Antineoplastic Agents, Phytogenic; Apoptosis; bcl-2-Associated X Protein; Biphenyl Compounds; Caspase 3; Cell Movement; Colonic Neoplasms; Cytochromes c; DNA Fragmentation; Dose-Response Relationship, Drug; HCT116 Cells; Humans; Lignans; Magnolia; Mitochondria; Phosphorylation; Phytotherapy; Plant Extracts; Poly(ADP-ribose) Polymerases; Propidium; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Tumor Suppressor Protein p53

Magnolol, a tradition Chinese herb, displays an array of activities including antifungal, antibacterial, and antioxidant effects. To investigate the protective effect of magnolol on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. ALI was induced in mice by intratracheal instillation of LPS (1 mg/kg). The mice received intratracheal instillation of magnolol (5 μg/kg) 30 min before LPS administration. Pulmonary histological changes were evaluated by hematoxylin-eosin stain and lung wet/dry weight ratios were observed. Concentrations of tumor necrosis factor (TNF)-α and interleukin (IL)-1β, and myeloperoxidase (MPO) activity were measured by enzyme-linked immunosorbent assay. Expression of cyclooxygenase (COX)-2 in lung tissues was determined by Western blot analysis. Magnolol pretreatment significantly attenuated the severity of lung injury and inhibited the production of TNF-α and IL-1β in mice with ALI. After LPS administration, the lung wet/dry weight ratios, as an index of lung edema, and MPO activity were also markedly reduced by magnolol pretreatment. The expression of COX-2 was significantly suppressed by magnolol pretreatment. Magnolol potently protected against LPS-induced ALI and the protective effects of magnolol may attribute partly to the suppression of COX-2 expression.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents, Non-Steroidal; Biphenyl Compounds; Bronchoalveolar Lavage Fluid; Cyclooxygenase 2; Disease Models, Animal; Edema; Interleukin-1beta; Lignans; Lipopolysaccharides; Lung; Male; Mice; Mice, Inbred BALB C; Peroxidase; Respiratory Distress Syndrome; Tumor Necrosis Factor-alpha

This study aimed to evaluate the effect of honokiol and its structural analogs on the functional activity and gene expression of P-glycoprotein (P-gp) in order to identify effective P-gp inhibitors from natural products which have additional health-promoting effects.. The interaction characteristics of honokiol, magnolol and 4-O-methylhonokiol with P-gp were determined in NCI/ADR-RES cells overexpressing P-gp.. All three compounds down-regulated the expression of P-gp in a concentration- and time-dependent manner, leading to 2.5- to 4.1-fold reductions of P-gp expression in NCI/ADR-RES cells. Accordingly, down-regulation of P-gp resulted in the significant enhancement of the intracellular accumulation of calcein, a P-gp substrate. Furthermore, pre-treatment with honokiol, magnolol or 4-O-methylhonokiol significantly increased the susceptibility of cancer cells to daunorubicin-induced cytotoxicity in NCI/ADR-RES cells.. The present study suggests that honokiol, magnolol and 4-O-methylhonokiol could be promising agents for reducing the multidrug resistance of cancer cells to anticancer drugs via the down-regulation of P-gp expression.

Topics: Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biphenyl Compounds; Cell Line, Tumor; Daunorubicin; Down-Regulation; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Lignans; Magnolia; Plant Extracts

To reveal the relationship between the quality and the leaf shape of Magnolia officinalis produced in Hubei Enshi.. Determined the content of magnolol and honokiol by HPLC with methanol-water (78:22) and the detective wavelength was 294 nm.. The content of magnolol and honokiol in the leaf of Magnolia officinalis was usually higher if the leaf apex was convex and the leaves were short. In certain years, the content of magnolol and honokiol in Cortex Magnoliae officinalis was positively correlated with the bark thickness.. The leaf shape of Magnolia officinalis produced in Hubei Enshi is directly related to the phenolic content of leaf itself. But it has nothing to do with the content of magnolol and honokiol in Cortex Magnoliae officinalis.

Topics: Biphenyl Compounds; China; Chromatography, High Pressure Liquid; Lignans; Magnolia; Plant Bark; Plant Leaves; Plants, Medicinal; Quality Control

A new magnolol-bonded silica gel stationary phase (MSP) was used to separate the basic drugs including four purines, eight pyrimidines, four pterins and five flavonoids as polar representative samples by high performance liquid chromatography (HPLC). To clarify the separation mechanism, a commercial ODS column was also tested under the same chromatographic conditions. The high selectivities and fast baseline separations of the above drugs were achieved by using simple mobile phases on MSP. Although there is no end-caped treatment, the peak shapes of basic drugs containing nitrogen such as purines, pyrimidines and pterins were rather symmetrical on MSP, which indicated the the magnolol as ligand with multi-sites could shield the side effect of residual silanol groups on the surface of silica gel. Although somewhat different in the separation resolution, it was found that the elution orders of some drugs were generally similar on both MSP and ODS. The hydrophobic interaction should play a significant role in the separations of the above basic drugs, which was attributed to their reversed-phase property in the nature. However, MSP could provide the additional sites for many polar solutes, which was a rational explanation for the high selectivity of MSP. For example, in the separation of purines, pyrimidines and pterins on MSP, hydrogen-bonding and dipole-dipole interactions played leading roles besides hydrophobic interaction. Some solute molecules (such as mercaptopurine, vitexicarpin) and MSP can form the strong pi-pi stacking in the separation process. All enhanced the retention and improved the separation selectivity of MSP, which facilitated the separation of the basic drugs.

Topics: Biphenyl Compounds; Chromatography, High Pressure Liquid; Chromatography, Reverse-Phase; Flavonoids; Lignans; Pterins; Purines; Pyrimidines; Silica Gel

Honokiol, 5,5'-diallyl-2,4'-dihydroxy- biphenyl, by comparison with its isomer magnolol, 5,5'-diallyl- 2,2'-dihydroxy- biphenyl, has been characterized by steady-state and time-resolved spectroscopy as well as (1)H NMR. Honokiol shows more complex pH dependence of absorption and fluorescence characteristics compared with magnolol. Honokiol possesses much weaker acidity than magnolol both in the ground and excited states. Its weak photoacidity is similar to that of 4-hydroxy- biphenyl or 4, 4'-dihydroxy- biphenyl rather than 2-hydroxy- biphenyl or 2, 2'-hydroxy- biphenyl. The electron effect and geometry configuration of substitution has been discussed.

Topics: Acids; Biphenyl Compounds; Hydrogen-Ion Concentration; Lignans; Magnetic Resonance Spectroscopy; Photochemistry; Spectrometry, Fluorescence

Parkinson's disease (PD) is one of the most common neurodegenerative disorders. The aim of the present study was to investigate the protective and restorative potential of magnolol, a major bioactive biphenolic from the bark of Magnolia officinalis, for alleviating the motor deficits induced by 6-hydroxydopamine (6-OHDA) in a mouse model of PD. Before or after unilateral striatal 6-OHDA lesion induction, mice were administered magnolol subchronically; then the apomorphine-induced rotational behaviors of the hemiparkinsonian mice and tyrosine hydroxylase (TH) expression in striatum were determined. Magnolol that was administered 30 min before 6-OHDA lesion induction and then applied daily for 14 days significantly ameliorated apomorphine-induced contralateral rotation in 6-OHDA-lesioned mice, and consistently protected the decreased levels of TH protein expression in striatum. One week after termination of the 7-day subchronic pretreatment, magnolol also remarkably prevented the dopaminergic neuronal loss as identified by TH immunohistochemistry staining in striatum, associated with rotational behavioral protection in 6-OHDA-lesioned mice. Importantly, daily subchronic posttreatment with magnolol for 14 days efficiently reduced apomorphine-induced rotation, but did not restore the neuronal impairment in striatum damaged by 6-OHDA. Taken together, these findings suggest that magnolol may possess neuronal protective activity and behavioral restoration against 6-OHDA-induced toxicity in the PD model.

Topics: Animals; Biphenyl Compounds; Corpus Striatum; Disease Models, Animal; Drug Administration Schedule; Lignans; Male; Mice; Neuroprotective Agents; Oxidopamine; Parkinsonian Disorders; Tyrosine 3-Monooxygenase

Some Magnolia (Magnoliaceae) species are used for the empirical treatment of diabetes mellitus, but the antidiabetic properties of Magnolia dealbata have not yet been experimentally validated. Here we report that an ethanolic extract of Magnolia dealbata seeds (MDE) and its active principles honokiol (HK) and magnolol (MG) induced the concentration-dependent 2-NBDG uptake in murine 3T3-F442A and human subcutaneous adipocytes. In insulin-sensitive adipocytes, MDE 50 μg/ml induced the 2-NBDG uptake by 30% respect to insulin, while HK and MG, 30 μM each, did it by 50% (murine) and 40% (human). The simultaneous application of HK and MG stimulated 2-NBDG uptake by 70% in hormone-sensitive cells, on which Magnolia preparations exerted synergic effects with insulin. In insulin-resistant adipocytes, MDE, HK and MG induced 2-NBDG uptake by 57%, 80% and 96% respect to Rosiglitazone (RGZ), whereas HK and MG simultaneously applied stimulated 2-NBDG uptake more efficiently than RGZ (120%) in both murine and human adipocytes. Inhibitors of the insulin-signaling pathway abolished the glucose uptake induced by Magnolia dealbata preparations, suggesting that their antidiabetic effects are mediated by this signaling pathway. In addition, MDE, HK and MG exerted only mild to moderate proadipogenic effects on 3T3-F442A and human preadipocytes, although the combined application of HK and MG markedly increased the lipid accumulation in both cell types. In summary, Magnolia dealbata and its active principles HK and MG stimulate glucose uptake in insulin-sensitive and insulin-resistant murine and human adipocytes using the insulin signaling pathway.

Topics: 3T3 Cells; 4-Chloro-7-nitrobenzofurazan; Adipocytes; Adipogenesis; Animals; Biphenyl Compounds; Cell Survival; Deoxyglucose; Drug Synergism; Glucose; Humans; Hypoglycemic Agents; Insulin; Lignans; Lipid Metabolism; Magnolia; Mice; Plant Extracts; Signal Transduction

The aim of this study was to evaluate the anti-convulsant effects of magnolol (6, 6', 7, 12-tetramethoxy-2, 2'-dimethyl-1-β-berbaman, C18H18O2) and the mechanisms involved.. Mice were treated with magnolol (20, 40 and 80 mg·kg(-1)) 30 min before injection with pentylenetetrazol (PTZ, 60 mg·kg(-1), i.p.). The anti-seizure effects of magnolol were analysed using seizure models of behaviour, EEG and in vitro electrophysiology and c-Fos expression in the hippocampus and cortex.. Magnolol at doses of 40 and 80 mg·kg(-1) significantly delayed the onset of myoclonic jerks and generalized clonic seizures, and decreased the seizure stage and mortality compared with those of the vehicle-treated animals. EEG recordings showed that magnolol (40 and 80 mg·kg(-1)) prolonged the latency of seizure onset and decreased the number of seizure spikes. The anti-epileptic effect of magnolol was reversed by the GABA(A)/benzodiazepine receptor antagonist flumazenil. Pretreatment with flumazenil decreased the effects of magnolol on prolongation of seizure latency and decline of seizure stage. In a Mg(2+)-free model of epileptiform activity, using multi-electrode array recordings in mouse hippocampal slices, magnolol decreased spontaneous epileptiform discharges. Magnolol also significantly decreased seizure-induced Fos immunoreactivity in the piriform cortex, dentate gyrus and hippocampal area CA1. These effects were attenuated by pretreatment with flumazenil.. These findings indicate that the inhibitory effects of magnolol on epileptiform activity were mediated by the GABA(A) /benzodiazepine receptor complex.

Topics: Animals; Anticonvulsants; Behavior, Animal; Biphenyl Compounds; Cerebral Cortex; Dose-Response Relationship, Drug; Electroencephalography; Excitatory Postsynaptic Potentials; Hippocampus; Lignans; Magnolia; Male; Mice; Mice, Inbred Strains; Molecular Structure; Plant Bark; Receptors, GABA-A; Seizures

Lung malignancy is a major cause of human mortality. As such, safe pharmacological agents that can detect lung cancer are urgently required. Magnolol has been reported to have anticancer property. However, it is still unclear whether magnolol induces apoptosis of lung carcinoma cells. In this study, magnolol inhibited cell growth, increased lactate dehydrogenase release, and modulated cell cycle in human lung carcinoma A549 cells. Magnolol induced the activation of caspase-3 and cleavage of Poly-(ADP)-ribose polymerase, and decreased the expression level of nuclear factor-κB/Rel A in the nucleus. In addition, magnolol inhibited basic fibroblast growth factor-induced proliferation and capillary tube formation of human umbilical vein endothelial cells. These data indicate that magnolol is a potential candidate for treating of human lung carcinoma.

Topics: Antineoplastic Agents; Apoptosis; Biphenyl Compounds; Blotting, Western; Carcinoma, Non-Small-Cell Lung; Caspase 3; Cell Culture Techniques; Cell Cycle; Cell Line, Tumor; Cell Nucleus; Cell Proliferation; Cell Survival; Endothelial Cells; Endothelium, Vascular; Flow Cytometry; Humans; Lignans; Lung Neoplasms; Neovascularization, Pathologic; NF-kappa B; Poly(ADP-ribose) Polymerases

Magnolol (M) is a polyphenol antioxidant abundant in the bark of Magnolia officinalis Rehder & E. Wilson, a popular Chinese herb. To understand the pharmacokinetics and bioavailability of M, Sprague-Dawley rats were intravenously injected with a bolus of M (20 mg/kg) and orally given a single dose and seven doses of M (50 mg/kg). Blood samples were withdrawn via cardiopuncture at specific times. Organs including the liver, kidney, brain, lung, and heart were collected at 30 min after the 7th oral dose. The serum and tissue specimens were assayed by HPLC before and after hydrolysis with β-glucuronidase and sulfatase. The results showed that after intravenous bolus, the systemic exposure of magnolol glucuronides (MG) was comparable with that of M while after oral administration, magnolol sulfates/glucuronides (M S/G) were predominant in the bloodstream. Conversely, M was predominant in the liver, kidney, brain, lung, and heart. Among the studied organs, the liver contained the highest concentrations of M and MG. In conclusion, M S/G was the major form in circulation, whereas M was predominant in the liver, kidney, brain, lung, and heart after oral administration of M; among these organs, the liver contained the highest concentrations of M and MG.

Topics: Administration, Oral; Animals; Biological Availability; Biphenyl Compounds; Calibration; Chromatography, High Pressure Liquid; Drugs, Chinese Herbal; Injections, Intravenous; Lignans; Magnolia; Male; Medicine, Chinese Traditional; Plant Bark; Plants, Medicinal; Rats; Rats, Sprague-Dawley; Reproducibility of Results; Taiwan; Time Factors; Tissue Distribution

The antioxidant properties of magnolol and honokiol were evaluated in the experimental systems of reducing ONOO(-) and (1)O(2), bleaching β-carotene in linoleic acid (LH) emulsion, and trapping 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonate) cationic radical (ABTS(+)*) and 2,2'-diphenyl-1-picrylhydrazyl radical (DPPH), and then were applied to inhibit the oxidation of DNA induced by Cu(2+)/glutathione (GSH) and 2,2'-azobis(2-amidinopropane hydrochloride) (AAPH). Magnolol and honokiol were active to reduce ONOO(-) and (1)O(2). Honokiol showed a little higher activity to protect LH and to inhibit Cu(2+)/GSH-induced oxidation of DNA than magnolol. In addition, honokiol exhibited higher activities to trap ABTS(+)* and DPPH than magnolol. In particular, honokiol trapped 2.5 radicals while magnolol only trapped 1.8 radicals in protecting DNA against AAPH-induced oxidation. The obtained results suggested that low antioxidant ability of magnolol may be related to the intramolecular hydrogen bond formed between di-ortho-hydroxyl groups, which hindered the hydrogen atom in hydroxyl group to be abstracted by radicals. Therefore, the antioxidant capacity of magnolol was lower than that of honokiol.

Topics: Antioxidants; Biphenyl Compounds; DNA; Free Radical Scavengers; Lignans

Overexpression of the HER2 oncogene contributes to tumor cell invasion, metastasis and angiogenesis and correlates with poor prognosis. Magnolol has been reported to exhibit anti-tumor activities. However, the molecular mechanism of action of magnolol has not been investigated in HER2-positive cancer cells. Therefore, we examined the anti-cancer effects of magnolol on HER2-overexpressing ovarian cancer cells. Magnolol treatment caused a dose-dependent inhibition of HER2 gene expression at the transcriptional level, potentially in part through suppression of NF-κB activation. Treatment of HER2-overexpressing ovarian cancer cells with magnolol down-regulated the HER2 downstream PI3K/Akt signaling pathway, and suppressed the expression of downstream target genes, vascular endothelial growth factor (VEGF), matrix metalloproteinase 2 (MMP2) and cyclin D1. Consistently, magnolol-mediated inhibition of MMP2 activity could be prevented by co-treatment with epidermal growth factor. Migration assays revealed that magnolol treatment markedly reduced the motility of HER2-overexpressing ovarian cancer cells. Furthermore, magnolol-induced apoptosis in HER2-overexpressing ovarian cancer cells was characterized by the up-regulation of cleaved poly(ADP-ribose) polymerase (PARP) and activated caspase 3. These findings suggest that magnolol may act against HER2 and its downstream PI3K/Akt/mTOR-signaling network, thus resulting in suppression of HER2-mediated transformation and metastatic potential in HER2-overexpressing ovarian cancers. These results provide a novel mechanism to explain the anti-cancer effect of magnolol.

Topics: Biphenyl Compounds; Caspase 3; Cell Growth Processes; Cell Line, Tumor; Cell Transformation, Neoplastic; Cyclin D1; Down-Regulation; Female; Gene Expression Regulation, Neoplastic; Genes, erbB-2; Humans; Lignans; Neoplasm Metastasis; Ovarian Neoplasms; Phosphatidylinositol 3-Kinases; Poly(ADP-ribose) Polymerases; Proto-Oncogene Proteins c-akt; Receptor, ErbB-2; Signal Transduction; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

Multi-drug resistance is of great concern for public health worldwide and necessitates the search for new antimicrobials from sources such as plants. Several Magnolia (Magnoliaceae) species have been reported to exert antimicrobial effects on sensitive and multidrug-resistant microorganisms. However, the antimicrobial properties of Magnolia dealbata have not been experimentally evaluated. The antimicrobial effects of an ethanol extract of Magnolia dealbata seeds (MDE) and its active compounds honokiol (HK) and magnolol (MG) were tested against the phytopathogen Clavibacter michiganensis subsp. michiganensis and several human multi-drug resistant pathogens using the disk-diffusion assay. The effects of MDE and its active compounds on the viability of human peripheral blood mononuclear cells (PBMC) were evaluated using MTT assay. MDE and its active compounds had antimicrobial activity (inhibition zone > 10 mm) against C. michiganensis, Pseudomonas aeruginosa, Acinetobacter baumannii, Acinetobacter lwoffii, Candida albicans, Candida tropicalis and Trichosporon belgeii. The results suggest that M. dealbata and its active compounds have selective antimicrobial effects against drug-resistant fungal and Gram (-) bacteria and exert minimal toxic effects on human PMBC.

Topics: Anti-Bacterial Agents; Antifungal Agents; Bacteria; Biphenyl Compounds; Fungi; Humans; Leukocytes, Mononuclear; Lignans; Magnolia; Plant Extracts

Encapsulation and release behavior of a water-insoluble drug, magnolol, using a core-shell polysaccharide-based nanoparticle, manipulating the cellular internalization and controlled cytotoxic effect of magnolol-loaded nanoparticles over the A10 vascular smooth muscle cells (VSMCs) was reported. A magnolol-polyvinylpyrrolidone (PVP) core phase was prepared, followed encapsulating by an amphiphilic carboxymethyl-hexanoyl chitosan (CHC) shell to form a magnolol-loaded core-shell hydrogel nanoparticles (termed magnolol-CHC nanoparticles). The resulting magnolol-CHC nanoparticles were employed for evaluation of drug release and controlled cytotoxic inhibition of VSMCs migration in vitro. A sustained release of the magnolol from the nanoparticles was determined. The magnolol-CHC nanoparticles exhibited outstanding cellular uptake efficiency, and under a cytotoxic evaluation, an increased antiproliferative effect and effective inhibition of VSMC migration as a result of efficient intracellular delivery of the encapsulated magnolol in comparison to free magnolol was achieved. We then envision a potential intracellular medication strategy with improved biological and therapeutic efficacy using the magnolol-CHC nanoparticles illustrated in this work.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Biphenyl Compounds; Cell Line; Cell Movement; Cell Survival; Delayed-Action Preparations; Hydrogel, Polyethylene Glycol Dimethacrylate; Lignans; Microscopy, Confocal; Myocytes, Smooth Muscle; Nanoparticles; Solubility; Water

Magnolol, a plant lignan isolated from the bark and seed cones of Magnolia officinalis, has been shown to have chemopreventive effects on chemically-induced skin cancer development. The objectives of this investigation are to study the anticarcinogenic effects of magnolol on UVB-induced skin tumor development in SKH-1 mice, a model relevant to humans, and determine the possible role of apoptosis and cell cycle arrest involved in the skin tumor development.. UVB-induced skin carcinogenesis model in SKH-1 mice was used for determining the preventive effects of magnolol on skin cancer development. Western blottings and flow cytometric analysis were used to study the effects of magnolol on apoptosis and cell cycle.. Magnolol pretreated groups (30, 60 μ g) before UVB treatments (30 mJ/cm2, 5 days/week) resulted in 27-55% reduction in tumor multiplicity as compared to control group in SKH-1 mice. Magnolol pretreatment increased the cleavage of caspase-8 and poly-(-ADP-ribose) polymerase (PARP), increased the expression of p21, a cell cycle inhibitor, and decreased the expression of proteins involved in the G2/M phase of cell cycle in skin samples from SKH-1 mice.Treatment of A431 cells with magnolol decreased cell viability and cell proliferation in a concentration dependent manner. Magnolol induced G2/M phase cell cycle arrest in A431 cells at 12 h with a decreased expression of cell cycle proteins such as cyclin B1, cyclin A, CDK4, Cdc2 and simultaneous increase in the expression of Cip/p21, a cyclin-dependent kinase inhibitor. Magnolol induced apoptosis in vivo and in vitro with an increased cleavage of caspase-8 and PARP. Phospho-signal transducers and activators of transcription 3 (Tyr705), B-Raf, p-MEK, and p-AKT were down-regulated, whereas phosphorylation of ERK was induced by magnolol in A431 cells.. Magnolol pretreatments prevent UVB-induced skin cancer development by enhancing apoptosis, causing cell cycle arrest at G2/M phase, and affecting various signaling pathways. Magnolol could be a potentially safe and potent anticarcinogenic agent against skin cancer.

Topics: Animals; Anticarcinogenic Agents; Apoptosis; Biphenyl Compounds; Blotting, Western; Carcinoma, Squamous Cell; Caspases; Cell Cycle Checkpoints; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cyclin-Dependent Kinases; Cyclins; Flow Cytometry; Intracellular Signaling Peptides and Proteins; Lignans; Mice; Neoplasms, Radiation-Induced; Phosphorylation; Skin Neoplasms; STAT3 Transcription Factor; Ultraviolet Rays

The targeting of Staphylococcus aureus biofilm structures are now gaining interest as an alternative strategy for developing new types of antimicrobial agents. Magnolol (MOL) shows inhibitory activity against S. aureus biofilms and Triton X-100-induced autolysis in vitro, although there are no data regarding the molecular mechanisms of MOL action in bacteria.. The molecular basis of the markedly reduced autolytic phenotype and biofilm inhibition triggered by MOL were explored using transcriptomic analysis, and the transcription of important genes were verified by real-time RT-PCR. The inhibition of autolysis by MOL was evaluated using quantitative bacteriolytic assays and zymographic analysis, and antibiofilm activity assays and confocal laser scanning microscopy were used to elucidate the inhibition of biofilm formation caused by MOL in 20 clinical isolates or standard strains. The reduction in cidA, atl, sle1, and lytN transcript levels following MOL treatment was consistent with the induced expression of their autolytic repressors lrgA, lrgB, arlR, and sarA. MOL generally inhibited or reversed the expression of most of the genes involved in biofilm production. The growth of S. aureus strain ATCC 25923 in the presence of MOL dose-dependently led to decreases in Triton X-100-induced autolysis, extracellular murein hydrolase activity, and the amount of extracellular DNA (eDNA). MOL may impede biofilm formation by reducing the expression of cidA, a murein hydrolase regulator, to inhibit autolysis and eDNA release, or MOL may directly repress biofilm formation.. MOL shows in vitro antimicrobial activity against clinical and standard S. aureus strains grown in planktonic and biofilm cultures, suggesting that the structure of MOL may potentially be used as a basis for the development of drugs targeting biofilms.

Topics: Anti-Bacterial Agents; Autolysis; Bacteriolysis; Biofilms; Biphenyl Compounds; Lignans; Octoxynol; Staphylococcus aureus; Transcriptome

Nuclear receptors retinoic X receptor α (RXRα) and peroxisome proliferator activated receptor γ (PPARγ) function potently in metabolic diseases, and are both important targets for anti-diabetic drugs. Coactivation of RXRα and PPARγ is believed to synergize their effects on glucose and lipid metabolism. Here we identify the natural product magnolol as a dual agonist targeting both RXRα and PPARγ. Magnolol was previously reported to enhance adipocyte differentiation and glucose uptake, ameliorate blood glucose level and prevent development of diabetic nephropathy. Although magnolol can bind and activate both of these two nuclear receptors, the transactivation assays indicate that magnolol exhibits biased agonism on the transcription of PPAR-response element (PPRE) mediated by RXRα:PPARγ heterodimer, instead of RXR-response element (RXRE) mediated by RXRα:RXRα homodimer. To further elucidate the molecular basis for magnolol agonism, we determine both the co-crystal structures of RXRα and PPARγ ligand-binding domains (LBDs) with magnolol. Structural analyses reveal that magnolol adopts its two 5-allyl-2-hydroxyphenyl moieties occupying the acidic and hydrophobic cavities of RXRα L-shaped ligand-binding pocket, respectively. While, two magnolol molecules cooperatively accommodate into PPARγ Y-shaped ligand-binding pocket. Based on these two complex structures, the key interactions for magnolol activating RXRα and PPARγ are determined. As the first report on the dual agonist targeting RXRα and PPARγ with receptor-ligand complex structures, our results are thus expected to help inspect the potential pharmacological mechanism for magnolol functions, and supply useful hits for nuclear receptor multi-target ligand design.

Topics: Biphenyl Compounds; Crystallography, X-Ray; HEK293 Cells; Humans; Lignans; Models, Biological; Molecular Targeted Therapy; PPAR gamma; Protein Structure, Tertiary; Response Elements; Retinoid X Receptor alpha; Transcription, Genetic

Although magnolol is cytoprotective against warm ischemia/reperfusion injury, its effect on cold preservation has not been fully investigated. This study aimed at examining whether magnolol maintains the liver graft integrity after cold preservation and elucidating the underlying mechanisms in terms of apoptotic signaling under both normothermic and hypothermic conditions. After being preserved in Ringer's lactate (RL) at 4 degrees C for 6h ex vivo, the magnolol-treated grafts demonstrated significantly higher AST, ALT, and LDH levels in perfusates than those from negative controls. TUNEL staining showed no difference in the number of apoptotic nuclei in both groups, whereas a more intense apoptotic signal in magnolol-treated grafts was shown as compared with the controls. In vitro data showed no significant difference in viability of RL-preserved clone-9 hepatocytes between the magnolol-treated and control groups, while magnolol pretreatment at 30min before cold preservation prominently induced hepatocyte cell death. RT-PCR and Western blotting analyses revealed a suppression in Bcl-2, but an up-regulation in Bax expression in clone-9 cells after magnolol treatment. Magnolol suppressed the ratios of NF-kappaB to I-kappaBalpha protein contents and I-kappaBalpha phosphorylation induced by TNF-alpha, and potentiated mitochondrial cytochrome c release and subsequent caspase-3 cleavage. Conversely, caspase-3 inhibitor attenuated magnolol-induced hepatotoxicity. We concluded that magnolol could not protect liver grafts from cold ischemia/reperfusion injury. High concentration of magnolol under serum-reduced conditions attenuates NF-kappaB-mediated signaling and induces intrinsic apoptotic pathway, thereby inducing in vitro hepatotoxicity.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Biphenyl Compounds; Blotting, Western; Caspase 3; Chemical and Drug Induced Liver Injury; Cold Temperature; Cryopreservation; Cytochromes c; I-kappa B Proteins; In Situ Nick-End Labeling; Lignans; Liver; Liver Transplantation; Magnolia; Male; Mitochondria; NF-kappa B; Plant Bark; Plant Extracts; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Reverse Transcriptase Polymerase Chain Reaction; Serum; Signal Transduction; Tumor Necrosis Factor-alpha

A rapid expansion of supercritical solution (RESS) technology was presented for the micronization of Chinese medicinal material. Magnolia bark extract (MBE) obtained by supercritical carbon dioxide (scCO(2)) extraction technology was chosen as the experimental material. RESS process produced 4.7 microm size MBE microparticles (size distribution, 0.2-24.1 microm), which was significantly smaller than the 55.3 microm size particles (size distribution, 8.3-102.4 microm) obtained from conventional mechanical milling. Dissolution rate study showed that drug dissolution was significantly enhanced by the RESS progress. At 90 min, the amount dissolved of mechanical milling MBE was 6.37 mg x l(-1), which was significantly lower than that of micronized MBE (14.77 mg x l(-1)), according to the results of ANOVA (p<0.01). The effect of extraction temperature (30, 40, 50 degrees Celsius), extraction pressure (200, 250, 300 bar) and nozzle size (50, 100, 200 microm) on the size distribution of microparticles was investigated. The characteristics of microparticles were also studied by differential scanning calorimetry (DSC), infrared spectroscopy (IR), scanning electron microscopy (SEM), and image analysis. This study demonstrates that RESS is applicable for preparing microparticles of MBE at low operating temperature; the process is simple without residual solvent.

Topics: Biphenyl Compounds; Calorimetry, Differential Scanning; Carbon Dioxide; Drugs, Chinese Herbal; Equipment Design; Lignans; Magnolia; Molecular Structure; Particle Size; Plant Bark; Solubility; Solutions; Spectrophotometry, Infrared; Technology, Pharmaceutical; Time Factors

Magnolol has been reported to have an anti-inflammatory and antitumor effect in vitro and in vivo. Herein, we report the investigation of the inhibitory effects of magnolol on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in mouse skin. We found that the topical application of magnolol effectively inhibited the transcriptional activation of iNOS and COX-2 mRNA and proteins in mouse skin stimulated by TPA. Pretreatment with magnolol resulted in the reduction of TPA-induced nuclear translocation of the nuclear factor-kappaB (NFkappaB) subunit and DNA binding by blocking the phosphorylation of IkappaBalpha and p65 and subsequent degradation of IkappaBalpha. In addition, magnolol can suppress TPA-induced activation of extracellular signal-regulated kinase (ERK)1/2, p38 mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase (PI3K)/Akt, which are upstream of NFkappaB. Moreover, magnolol significantly inhibited 7,12-dimethylbene[a]anthracene (DMBA)/TPA-induced skin tumor formation by reducing the tumor multiplicity, tumor incidence, and tumor size of papillomas at 20 weeks. All these results revealed that magnolol is an effective antitumor agent and that its inhibitory effect is through the down-regulation of inflammatory iNOS and COX-2 gene expression in mouse skin, suggesting that magnolol is a novel functional agent capable of preventing inflammation-associated tumorigenesis.

Topics: Animals; Base Sequence; Biphenyl Compounds; Carcinogens; Dermatitis, Contact; DNA Primers; Electrophoretic Mobility Shift Assay; Lignans; Mice; Neoplasms, Experimental; Reverse Transcriptase Polymerase Chain Reaction; Tetradecanoylphorbol Acetate

An efficient protocol for the in vitro propagation of Magnolia dealbata Zucc., an important medicinal plant that is the source of the anxiolytic and anticancer compounds honokiol and magnolol, was established. This plant is wild-crafted, and conservationists have expressed concerns with regard to the sustainability of production. In the present work, two factors were found to be of importance for the regeneration of M. dealbata and the production of honokiol and magnolol. These factors were the type of explants and the combination and concentration of plant-growth regulators. Green, compact, nodular organogenic callus was obtained from leaf explants in a medium fortified with Murashige and Skoog salts and supplemented with 1.5 mg/L 2,4-dicholorophenoxyacetic acid and 1.5 mg/L kinetin. Shoots multiplication from callus cultures was achieved in the Murashige and Skoog (MS) medium with 1.5 mg/L thidiazuron (TDZ). Phenol secretion was controlled by the addition of 250 mg/L of activated charcoal. For rooting, shoots were transferred to MS medium supplemented with several auxins. After root induction, the plants were hardened in earthen pots containing sand, soil, and vermiculite. The contents of honokiol (HK) and magnolol (MG) were determined in different plant materials by high-performance liquid chromatography-diode-array detection techniques. This analysis revealed that the honokiol and magnolol content in aerial and underground parts of micropropagated M. dealbata were higher than that observed in wild plants (both 6 months old). Our results suggest that conservation of M. dealbata is possible by means of in vitro multiplication of leaf-derived callus. The usefulness of M. dealbata regeneration and production of HK and MG may be attributed to the proper selection of explant sourcing and identification of the correct growth medium to support adequate growth. This careful selection of explants and growth medium leads to a very useful source of plant material for pharmacological and phytomedicinal screening applications and, above all, would safeguard this plant species from the threat of extinction.

Topics: Biphenyl Compounds; Conservation of Natural Resources; Culture Media; Lignans; Magnolia; Mexico; Plant Roots; Plant Shoots; Tissue Culture Techniques

In this study we investigated the antimicrobial activity of magnolol on Staphylococcus aureus. The minimal inhibitory concentrations of magnolol against 31 S. aureus strains ranged from 4-32 microg/mL. In addition, hemolysin assays, Western blotting, and real-time RT-PCR were performed to investigate the effect of magnolol on alpha-toxin secretion by both methicillin-sensitive S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA). The results indicated that sub-inhibitory concentrations of magnolol dose-dependently inhibited the transcription of hla (the gene encoding alpha-toxin) in S. aureus, resulting in a reduction of alpha-toxin secretion and, thus, hemolytic activities.

Topics: Animals; Bacterial Toxins; Biphenyl Compounds; Blotting, Western; Hemolysin Proteins; Hemolysis; Lignans; Rabbits; Reverse Transcriptase Polymerase Chain Reaction; Staphylococcus aureus

To study the immunologic mechanism in pathogenesis of the acute pancreatitis (AP) and the intervention effects of sandostatin and magnolol.. Ninety BALB/c mice were divided into negative control group, caerulein-induced model group, sandostatin-treatment group, magnolol-treatment group, combined sandostatin- and magnolol-treatment group by means of random number table, with 18 mice in each group. AP model was reproduced by seven intraperitoneal injections of caerulein at an interval of 1 hour. Every 30 minutes before the caerulein challenge, sandostatin was injected sub- cutaneously. Magnolol was injected intravenously immediately after the AP model was reproduced. Then at 9, 12, 24 hours after modelling, blood was drawn from orbital vein and serum was separated. Serum amylase (SA), interleukin-10 (IL-10) and gamma-interferon (IFN-gamma) were determined after the mice were sacrificed, and pancreas and spleen were harvested . The pathological changes of pancreas were observed, and the number and the ratio of myeloid- dendritic cells (MDCs) to lymphoid dendritic cells (LDCs) were measured with flow cytometry.. Compared with control group [SA (1.12 + or - 0.05) kU/L, pancreatic score (PS) 0.09 + or - 0.10], both indexes increased progressively in the model group [SA (26.11 + or - 1.96) kU/L, PS 5.32 + or - 0.19, both P<0.01]. The ratio of MDCs/LDCs showed downward tendency at every time-point especially at 9th hour (0.421 + or - 0.049 vs. 1.712 + or - 0.372, P<0.05), while the ratio of IL-10 to IFN-gamma did not show significant differences. Compared with model group, both SA and PS significantly decreased in all the three drug intervention groups [SA (kU/L): 18.25 + or - 1.09, 17.32 + or - 1.26, 17.62 + or - 0.56, PS: 4.55 + or - 0.15, 4.16 + or - 0.18, 4.10 + or - 0.13, all P<0.01]. There was no significant difference in the two ratios of MDCs/LDCs and IL-10/IFN-gamma between sandostatin-treatment group and model group. However, the ratio of MDCs/LDCs of the magnolol-treatment group was higher than that in sandostatin-treatment group 9, 12, 24 hours after modelling (9 hours: 4.694 + or - 0.527 vs. 0.819 + or - 0.182, 12 hours: 2.566 + or - 0.463 vs. 1.421 + or - 0.163, 24 hours : 2.343 + or - 0.359 vs. 1.421 + or - 0.113, P<0.05 or P<0.01). At every time-point, the ratio of IL-10/IFN-gamma in the magnolol-treatment group was significantly higher compared with the model group, and at the 12-hour point, it was higher than that of sandostatin-treatment group (8.000 + or - 1.738 vs. 3.558 + or - 0.362, P<0.05 ). The combined treatment group showed similar changes as the magnolol-treatment group.. When AP occurs, the differentiation from T helper (Th0) to Th1 is augmented, while differentiation of Th0 to Th2 decreases, thus inducing an imbalance in the relationship of pro- and anti-inflammatory response. Magnolol can induce the differentiation from Th0 to Th2 by modulating the different subtype dendritic cells, thus improving the anti-inflammatory response, resulting in attenuating local and systemic inflammatory response in AP. However, sandostatin did not show such effect.

Topics: Amylases; Animals; Biphenyl Compounds; Ceruletide; Dendritic Cells; Disease Models, Animal; Interferon-gamma; Interleukin-10; Lignans; Mice; Mice, Inbred BALB C; Octreotide; Pancreas; Pancreatitis

Magnolol, a hydroxylated biphenyl compound isolated from the root and stem bark of Magnolia officinalis, has been reported to have anticancer activity, but little is known about its molecular mechanisms of action. Increased expression of cyclooxygenase-2 (COX-2), a key enzyme in arachidonic acid metabolism, has been identified in many cancer types. Matrix metalloproteinases (MMPs) are enzymes involved in various steps of metastasis development. The objective of this study was to study the effects of magnolol on cancer invasion and metastasis using PC-3 human prostate carcinoma cells. Cellular proliferation was determined by MTT colorimetric assay. Magnolol inhibited cell growth in a dose-dependent manner. In an invasion assay conducted in Transwell chambers, magnolol showed 33 and 98% inhibition of cancer cell at 10 microM and 20 microM concentrations, respectively, compared to the control. The expression of MMP-2/-9 and COX-1/-2 was assessed by gelatin zymography and Western blot respectively. The protein and mRNA levels of both MMP-2 and MMP-9 were down-regulated by magnolol treatment in a dose-dependent manner. These results demonstrate the antimetastatic properties of magnolol in inhibiting the adhesion, invasion, and migration of PC-3 human prostate cancer cells.

Topics: Biphenyl Compounds; Cell Adhesion; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cyclooxygenase 1; Cyclooxygenase 2; Down-Regulation; Gene Expression Regulation, Neoplastic; Humans; Lignans; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Neoplasm Invasiveness; Neoplasm Metastasis; Prostatic Neoplasms

The hydrophobic ionic liquid of [BMIM][PF(6)] was successfully used for the ultrasound-assisted extraction of hydrophobic magnolol and honokiol from cortex Magnoliae officinalis. To obtain the best extraction efficiencies, some ultrasonic parameters including the concentration of [BMIM][PF(6)], pH, ultrasonic power and ultrasonic time were evaluated. The results obtained indicated that the [BMIM][PF(6)]-based ultrasound-assisted extraction efficiencies of magnolol and honokiol were greater than those of the [BMIM][BF(4)]-based ultrasound-assisted extraction (from 48.6 to 45.9%) and the traditional ethanol reflux extraction (from 16.2 to 13.3%). Furthermore, the proposed extraction method is validated by the recovery, correlation coefficient (R(2)) and reproducibility (RSD, n=5), which were 90.8-102.6, 0.9992-0.9998, and 1.6-5.4%, respectively.

Topics: Biphenyl Compounds; Drugs, Chinese Herbal; Hydrogen-Ion Concentration; Hydrophobic and Hydrophilic Interactions; Imidazoles; Ionic Liquids; Lignans; Magnolia; Molecular Structure; Solvents; Ultrasonics

Magnolol is a compound extracted from the Chinese medicinal herb Magnolia officinalis. It has multiple pharmacological effects, notably as an anti-oxidant. The aim of this study was to evaluate the effects of magnolol on sepsis induced by intravenous (i.v.) administration of lipopolysaccharide (LPS; 10 mg/kg) in anaesthetized Wistar rats. Magnolol (4 microg/kg, i.v.) was administered at 30 min after LPS injection. Post-treatment with magnolol significantly attenuated the deleterious haemodynamic changes (e.g., hypotension and bradycardia) caused by LPS. Meanwhile, magnolol significantly inhibited the elevation of plasma levels of tumor necrosis factor alpha, glutamate-oxaloacetate transaminase, glutamate-pyruvate transaminase and blood urine nitrogen caused by LPS. The induction of inducible nitrous oxide (NO) synthase and the overproduction of NO and superoxide anions by LPS were also significantly reduced by post-treatment with magnolol. Moreover, the plasma level of the thrombin-antithrombin complex following administration of LPS was also reduced by post-treatment with magnolol. Thus, the beneficial effects of magnolol on LPS-induced sepsis result from its anti-inflammatory, anti-coagulatory, and anti-oxidant effects.

Topics: Animals; Antithrombin III; Biphenyl Compounds; Blood Pressure; Disease Models, Animal; Gene Expression Regulation, Enzymologic; Heart Rate; Kidney; Lignans; Lipopolysaccharides; Liver; Lung; Male; Nitrates; Nitric Oxide Synthase Type II; Nitrites; Peptide Hydrolases; Rats; Rats, Wistar; Shock, Septic; Superoxides; Survival Rate; Tumor Necrosis Factor-alpha

Da-Cheng-Qi decoction (DCQD) is a purgative compound prescription used in China and East Asia. In this paper, pharmacokinetic differences of six major active components (rhein, emodin, aloe-emodin, magnolol, naringenin and hesperetin) between DCQD and its three constitutional herbal medicines, i.e., Radix et Rhizoma Rhei, Cortex Magnoliae officinalis and Fructus Aurantii Immaturus were investigated in rats after oral administration. Plasma samples were analyzed for the quantification of the six active components using validated LC-MS/MS methods. Unpaired Student's t-test was used for statistical comparison. Significant differences (p < 0.05) in the main pharmacokinetic parameters for rhein, emodin, aloeemodin, magnolol, naringenin and hesperetin were found between DCQD and the decoction of its constitutional single herbal medicines, which demonstrated the presence of drug-drug interactions between these constitutional raw materials of DCQD occurring either in the procedure of decoction or during ADME process.

Topics: Animals; Anthraquinones; Area Under Curve; Biphenyl Compounds; Chromatography, Liquid; Drugs, Chinese Herbal; Emodin; Female; Flavanones; Hesperidin; Lignans; Male; Plant Extracts; Rats; Rats, Sprague-Dawley; Tandem Mass Spectrometry

In the course of a study on lignan profiles of tropical and subtropical members of the Magnoliaceae, Magnolia garrettii, an evergreen tree known from northern Thailand, Vietnam, and southern Yunnan (China), was investigated. The work resulted in the isolation of two dimeric lignans from the dichloromethane extract of the leaves of M. garrettii, garrettilignan A (1) and garrettilignan B (2), each substituted with two additional p-allylphenolic moieties. Garrettilignans A (1) and B (2) represent new skeletal types within the neolignan class. Additionally, four known neolignans, magnolol, honokiol, 4'-methylhonokiol, and obovatol, were identified.

Topics: Austria; Biphenyl Compounds; Lignans; Magnolia; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Phenyl Ethers; Plant Leaves

Recently, intermittent counter-current extraction (ICcE) has been developed and shown its advantage in improving resolution between targeted compounds. However, how to choose suitable parameters to increase the throughput has not been systematically studied yet. In present work, we first calculated theoretically the conditions to carry out ICcE elution mode. Then, honokiol and magnolol were separated as model compounds using ICcE elution mode to confirm our conclusion. After parameters like sample concentration and sample feed were optimized in analytical high-performance counter-current chromatography (HPCCC), the separation process was scaled up to preparative HPCCC successfully. 12.8 g honokiol and 16.1g magnolol were separated from 30 g mixture with purities of 98.6% and 93.7%. And the throughput of target isolation of ICcE elution mode was at least 3.75 x higher than isocratic elution mode with the same HPCCC instruments. Our results confirmed our theory calculation and demonstrated the enormous potential of ICcE on preparative separation of binary mixture.

Topics: Biphenyl Compounds; Chemical Fractionation; Countercurrent Distribution; Drugs, Chinese Herbal; Lignans; Models, Chemical

Amyloid β peptide (Aβ) induced toxicity is a well-established pathway of neuronal cell death which might play a role in Alzheimer's disease. In this regard, the toxic effect of Aβ on a cultured Aβ-sensitive neuronal cell line was used as a primary screening tool for potential anti-Alzheimer's therapeutic agents. The effects of nine pure compounds (vitamin E, α-asarone, salidroside, baicolin, magnolol, gastrodin, bilobalide, honokiol and β-asarone) from selected Chinese herbs on neuronal cell death induced by Aβ in NGF-differentiated PC12 cells were examined. Only two of the studied compounds, honokiol and magnolol, significantly decreased Aβ-induced cell death. Further experiments indicated that their neuroprotective effects are possibly mediated through reduced ROS production as well as suppression of intracellular calcium elevation and inhibition of caspase-3 activity. The results provide for the first time a scientific rationale for the clinical use of honokiol and magnolol in the treatment of Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Apoptosis; Biphenyl Compounds; Calcium; Caspase 3; Cell Survival; Drugs, Chinese Herbal; Lignans; Magnolia; Neuroprotective Agents; PC12 Cells; Rats; Reactive Oxygen Species

This study examined the pharmacological property of magnolol, a phenolic compound purified from Magnolia officinalis, on the GI motility using the rat isolated gastrointestinal (GI) strips. Magnolol (0.3-30 microM) dose-dependently stimulated the tone and amplitude of spontaneous contractions in ileum longitudinal muscles. Magnolol at 3 microM significantly increased the contractions of jejunum longitudinal and colon circular muscles, but not the longitudinal muscle contractions in fundus, antrum and colon. Pretreatment of ileum strips with either atropine (0.5 microM) or 4-diphenyllacetoxy-N(2-chloriethyl)-piperidine (4-DAMP, 0.5 microM) dramatically inhibited the acetylcholine (ACh, 0.1 microM)- and magnolol (3 microM)-induced longitudinal muscle contractions, but they were not affected by methoctramine (0.5 microM) and hexamethonium (0.5 microM). Ondansetron (0.1 microM) and GR113808 (2 microM) significantly reduced the tone of ileum longitudinal muscle contractions stimulated by 5-HT (10 microM), but not the amplitude. Magnolol (3 microM)-induced ileum longitudinal muscle contractions, both tone and amplitude, were significantly blocked by GR113808, but not by ondansetron. Taken together, magnolol differently regulates the spontaneous GI motility according to the region of GI tracts and orientation of smooth muscles, and magnolol-induced regulation of smooth muscle contractions in rat GI strips is likely to be mediated, at least in part, by activation of ACh and 5-HT receptors, possibly the M(3) and/or 5-HT(4) receptors.

Topics: Animals; Atropine; Biphenyl Compounds; Calcium Channels; Dose-Response Relationship, Drug; Gastrointestinal Motility; Gastrointestinal Tract; Ileum; In Vitro Techniques; Lignans; Male; Muscle Contraction; Rats; Rats, Sprague-Dawley; Receptor, Muscarinic M2; Receptors, Serotonin, 5-HT4

Magnolol has been reported to strongly inhibit the mutagenicity induced by indirect mutagens in the Ames test as well as the clastogenicity induced by benzo(a)pyrene (B(a)P) in the mice micronucleus test. Here, we evaluated the inhibitory effect of magnolol on the DNA damage induced by 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2) in various organs using the mice alkaline single cell gel electrophoresis (SCG) assay. Animals were treated with a single oral administration of magnolol (0.01, 0.1, 1, 10, and 100 mg/kg), followed by a single intraperitoneal injection of Trp-P-2 (10 mg/kg). The liver, lung, and kidney were removed at 3 h after treatment and used in SCG assay. The results indicated that magnolol inhibited Trp-P-2-induced DNA damage in various organs. To elucidate the mechanism of this inhibitory effect against Trp-P-2, we investigated the inhibitory effect of magnolol on in vivo CYP1A2 activity using the zoxazolamine paralysis test. Magnolol significantly prolonged zoxazolamine paralysis time and showed an inhibitory effect on in vivo CYP1A2 activity. These results indicate that magnolol has an inhibitory effect on the DNA damage induced by Trp-P-2 in various organs in vivo. This inhibitory mechanism is considered due to in vivo CYP1A2 inhibition.

Topics: Animals; Antimutagenic Agents; Biphenyl Compounds; Carbolines; Comet Assay; Cytochrome P-450 CYP1A2; DNA Damage; Kidney; Lignans; Liver; Lung; Male; Mice; Mice, Inbred ICR; Mutagens; Zoxazolamine

This study was performed to investigate whether magnolol enhances pentobarbital-induced sleeping behaviors through the GABAergic systems. Magnolol prolonged the sleeping time induced by pentobarbital. In addition, magnolol increased chloride influx in primary cultured cerebellar granule cells. The expression of the GABA(A) receptor alpha-subunit was increased selectively by magnolol, but magnolol had no effect on the abundance of beta- or gamma-subunits. The expression of glutamic acid decarboxylase (GAD) was not influenced by magnolol. It is suggested that magnolol may enhance pentobarbital-induced sleeping behaviors through the activation of GABAergic systems.

Topics: Animals; Biphenyl Compounds; Cells, Cultured; Cerebellum; Chlorides; Glutamate Decarboxylase; Lignans; Magnolia; Male; Mice; Mice, Inbred ICR; Molecular Structure; Pentobarbital; Rats; Rats, Sprague-Dawley; Receptors, GABA-A; Sleep

1. Accumulating evidence suggests that oxidative stress plays a key role in the development of cardiac fibrosis. Urotensin-II (U-II) has been reported to play an important role in cardiac remodelling and fibrosis. Recently, we demonstrated the involvement of reactive oxygen species (ROS) production in U-II-induced cardiac fibroblast proliferation. Magnolol is an anti-oxidant compound extracted from the cortices of Magnolia officinalis. Thus, it is feasible that magnolol may attenuate cardiac fibroblast proliferation by inhibiting ROS production. Therefore, the aims of the present study were to determine whether magnolol alters U-II-induced cell proliferation and to identify the putative underlying signalling pathways in rat cardiac fibroblasts. 2. Cultured rat cardiac fibroblasts were pretreated with magnolol (1, 3 and 10 micromol/L) for 30 min, followed by exposure to U-II (30 nmol/L) for 24 h, after which cell proliferation and endothelin-1 (ET-1) protein secretion was examined. The effects of magnolol on U-II-induced ROS formation and extracellular signal-regulated kinase (ERK) phosphorylation were examined to elucidate the intracellular mechanisms by which magnolol affects cell proliferation and ET-1 expression. 3. Urotensin-II (30 nmol/L) stimulated cell proliferation, ET-1 protein secretion and ERK phosphorylation, all of which were inhibited by magnolol (10 micromol/L). Pretreatment of cardiac fibroblasts with N-acetylcysteine (5 mmol/L) for 30 min prior to exposure to U-II resulted in inhibition of U-II increased ROS formation. Similar effects were observed with 10 micromol/L magnolol. 4. In conclusion, the results suggest that magnolol inhibits cardiac fibroblast proliferation by interfering with ROS generation. Thus, the present study provides important new insights into the molecular pathways involved, which may contribute to our understanding of the effects of magnolol on the cardiovascular system.

Topics: Animals; Animals, Newborn; Biphenyl Compounds; Cell Proliferation; Cells, Cultured; Fibroblasts; Growth Inhibitors; Lignans; Myocardium; Nitric Oxide Synthase; Rats; Rats, Sprague-Dawley; Urotensins

We observed that treatment of prostate cancer cells for 24 h with magnolol, a phenolic component extracted from the root and stem bark of the oriental herb Magnolia officinalis, induced apoptotic cell death in a dose- and time-dependent manner. A sustained inhibition of the major survival signal, Akt, occurred in magnolol-treated cells. Treatment of PC-3 cells with an apoptosis-inducing concentration of magnolol (60 microM) resulted in a rapid decrease in the level of phosphorylated Akt leading to inhibition of its kinase activity. Magnolol treatment (60 microM) also caused a decrease in Ser((136)) phosphorylation of Bad (a proapoptotic protein), which is a downstream target of Akt. Protein interaction assay revealed that Bcl-xL, an anti-apoptotic protein, was associated with Bad during treatment with magnolol. We also observed that during treatment with magnolol, translocation of Bax to the mitochondrial membrane occurred and the translocation was accompanied by cytochrome c release, and cleavage of procaspase-8, -9, -3, and poly(ADP-ribose) polymerase (PARP). Similar results were observed in human colon cancer HCT116Bax(+/-) cell line, but not HCT116Bax(-/-) cell line. Interestingly, at similar concentrations (60 microM), magnolol treatment did not affect the viability of normal human prostate epithelial cell (PrEC) line. We also observed that apoptotic cell death by magnolol was associated with significant inhibition of pEGFR, pPI3K, and pAkt. These results suggest that one of the mechanisms of the apoptotic activity of magnolol involves its effect on epidermal growth factor receptor (EGFR)-mediated signaling transduction pathways.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; bcl-2-Associated X Protein; bcl-Associated Death Protein; bcl-X Protein; Biphenyl Compounds; Cell Line, Tumor; Cytochromes c; Epidermal Growth Factor; ErbB Receptors; Humans; Lignans; Male; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; Signal Transduction

To characterize antifungal principles from the methanol extract of Magnolia obovata and to evaluate their antifungal activities against various plant pathogenic fungi.. Four neolignans were isolated from stem bark of M. obovata as antifungal principles and identified as magnolol, honokiol, 4-methoxyhonokiol and obovatol. In mycelial growth inhibition assay, both magnolol and honokiol displayed more potent antifungal activity than 4-methoxyhonokiol and obovatol. Both magnolol and honokiol showed similar in vivo antifungal spectrum against seven plant diseases tested; both compounds effectively suppressed the development of rice blast, tomato late blight, wheat leaf rust and red pepper anthracnose. 4-Methoxyhonokiol and obovatol were highly active to only rice blast and wheat leaf rust respectively.. The extract of M. obovata and four neolignans had potent in vivo antifungal activities against plant pathogenic fungi.. Neolignans from Magnolia spp. can be used and suggested as a novel antifungal lead compound for the development of new fungicide and directly as a natural fungicide for the control of plant diseases such as rice blast and wheat leaf rust.

Topics: Allyl Compounds; Antifungal Agents; Biphenyl Compounds; Chromatography, Thin Layer; Fungi; Lignans; Magnolia; Microbial Sensitivity Tests; Mycelium; Phenyl Ethers; Plant Bark; Plant Diseases; Plant Extracts

Acute liver failure (ALF), an often fatal condition characterized by massive hepatocyte necrosis, is frequently caused by drug poisoning, particularly with acetaminophen (N-acetyl-p-aminophenol/APAP). Hepatocyte necrosis is consecutive to glutathione (GSH) depletion and mitochondrial damage caused by reactive oxygen species (ROS) overproduction. Magnolol, one major phenolic constituent of Magnolia officinalis, have been known to exhibit potent antioxidative activity. In this study, the anti-hepatotoxic activity of magnolol on APAP-induced toxicity in the Sprague-Dawley rat liver was examined. After evaluating the changes of several biochemical parameters in serum, the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) were elevated by APAP (500 mg/kg) intraperitoneal administration (8 and 24 h) and reduced by treatment with magnolol (0.5 h after APAP administration; 0.01, 0.1, and 1 mug/kg). Histological changes around the hepatic central vein, lipid peroxidation (thiobarbituric acid-reactive substance/TBARS), and GSH depletion in liver tissue induced by APAP were also recovered by magnolol treatment. The data show that oxidative stress followed by lipid peroxidation may play a very important role in the pathogenesis of APAP-induced hepatic injury; treatment with lipid-soluble antioxidant, magnolol, exerts anti-hepatotoxic activity. Our study points out the potential interest of magnolol in the treatment of toxic ALF.

Topics: Acetaminophen; Animals; Antioxidants; Biphenyl Compounds; Glutathione; Lignans; Lipid Peroxidation; Liver; Liver Failure, Acute; Magnolia; Male; Rats; Rats, Sprague-Dawley

Topics: Antineoplastic Agents, Phytogenic; Biphenyl Compounds; Humans; Lignans; Magnolia; Neoplasms; Plant Extracts

Ethanol induces hepatic steatosis via a complex mechanism that is not well understood. Among the variety of molecules that have been proposed to participate in this mechanism, the sterol regulatory element (SRE)-binding proteins (SREBPs) have been identified as attractive targets for therapeutic intervention. In the present study, we evaluated the effects of honokiol on alcoholic steatosis and investigated its possible effect on the inhibition of SREBP-1c maturation. In in vitro studies, H4IIEC3 rat hepatoma cells developed increased lipid droplets when exposed to ethanol, but co-treatment with honokiol reversed this effect. Honokiol inhibited the maturation of SREBP-1c and its translocation to the nucleus, the binding of nSREBP-1c to SRE or SRE-related sequences of its lipogenic target genes, and the expression of genes for fatty acid synthesis. In contrast, magnolol, a structural isomer of honokiol, had no effect on nSREBP-1c levels. Male Wistar rats fed with a standard Lieber-DeCarli ethanol diet for 4 weeks exhibited increased hepatic triglyceride and decreased hepatic glutathione levels, with concomitantly increased serum alanine aminotransferase and TNF-alpha levels. Daily administration of honokiol (10 mg/kg body weight) by gavage during the final 2 weeks of ethanol treatment completely reversed these effects on hepatotoxicity markers, including hepatic triglyceride, hepatic glutathione, and serum TNF-alpha, with efficacious abrogation of fat accumulation in the liver. Inhibition of SREBP-1c protein maturation and of the expression of Srebf1c and its target genes for hepatic lipogenesis were also observed in vivo. A chromatin immunoprecipitation assay demonstrated inhibition of specific binding of SREBP-1c to the Fas promoter by honokiol in vivo. These results demonstrate that honokiol has the potential to ameliorate alcoholic steatosis by blocking fatty acid synthesis regulated by SREBP-1c.

Topics: Active Transport, Cell Nucleus; Animals; Biphenyl Compounds; Cell Line, Tumor; Cytoprotection; Disease Models, Animal; Dose-Response Relationship, Drug; Ethanol; fas Receptor; Fatty Acids; Fatty Liver, Alcoholic; Genes, Reporter; Glutathione; Lignans; Lipogenesis; Liver; Male; Promoter Regions, Genetic; Protective Agents; Rats; Rats, Wistar; Sterol Regulatory Element Binding Protein 1; Transcription, Genetic; Transfection; Triglycerides; Tumor Necrosis Factor-alpha

The nuclear receptor peroxisome proliferator-activated receptor (PPAR) gamma plays an important role in adipocyte differentiation. Its ligands, including thiazolidinediones, improve insulin sensitivity in type 2 diabetes. We investigate the effect of magnolol, an ingredient of Magnolia officinalis on adipogenesis and glucose uptake using 3T3-L1 cells.. The effect of magnolol on adipocyte differentiation was quantified by measuring Oil Rd O staining using 3T3-L1 cells and C3H10T1/2 cells. And real-time PCR and western blot were used to determine the expression of PPARgamma or PPARgamma target genes, respectively. The effect of magnolol on glucose uptake was performed using 3T3-L1 adipocytes.. Magnolol dose-dependently enhanced adipocyte differentiation in 3T3-L1 cells and C3H10T1/2 cells. In the early stage of adipogenesis, magnolol induced gene expression of C/EBPdelta, C/EBPalpha and PPARgamma2 and during adipocyte differentiation, it also induced the expression of PPARgamma target genes such as aP2, LPL and adiponectin. In addition, magnolol it also increase expression of PAPRgamma target gene such as C/EBPalpha and aP2 at mRNA and aP2 protein level in mature adipocytes. In PPARgamma ligand binding assays, magnolol exhibited binding affinity to PPARgamma but its activity was weaker than rosiglitazone. At the same time, magnolol-induced adipogenesis was inhibited by co-treatment of GW9662 both 3T3-L1 cells and C3H10T1/2 cells. In mature 3T3-L1 adipocytes, magnolol increased basal and insulin-stimulated glucose uptake accompanied by the up-regulation of mRNA and protein level of Glut4.. Our results suggest that magnolol could improve insulin sensitivity through the activation of PPARgamma as a ligand.

Topics: 3T3-L1 Cells; Adipocytes; Animals; Biphenyl Compounds; Cell Differentiation; Cell Membrane Permeability; Gene Expression Regulation; Glucose; Insulin; Ligands; Lignans; Magnolia; Mice; Peroxisome Proliferator-Activated Receptors; Pluripotent Stem Cells; Protein Binding; RNA, Messenger

Magnolol was previously shown to inhibit genotoxicity induced by environmental mutagens both in vitro and in vivo. Here, we investigate the effects of the magnolol-containing kampo (traditional) medicines Hange-koboku-to, Dai-joki-to, and Goshaku-san, as well as Magnoliae Cortex, on the clastogenesis induced by benzo(a)pyrene (B(a)P) using the mouse micronucleus test. The mice were first treated with a single intraperitoneal injection of B(a)P, followed by a single oral dose of Hange-koboku-to, Dai-joki-to, Goshaku-san, or Magnoliae Cortex. Peripheral blood specimens were prepared 48 h after B(a)P administration and analyzed using the acridine orange (AO) technique. The anti-clastogenic mechanisms employed by the kampo medicines and Magnoliae Cortex were also investigated by evaluating in vivo CYP1A1 activity using the zoxazolamine paralysis test. Results show that Hange-koboku-to, Dai-joki-to, and Magnoliae Cortex, which contain high levels of magnolol, significantly inhibited the clastogenesis induced by B(a)P and sufficiently inhibited in vivo CYP1A1 activity. In contrast, Goshaku-san, which contains low levels of magnolol, had little inhibitory effect on clastogenicity and in vivo CYP1A1 activity. These findings suggest that magnolol is a major contributor to the inhibition of B(a)P-induced clastogenesis, and that kampo medicines exert significant anti-clastogenic effects.

Topics: Animals; Antimutagenic Agents; Benzo(a)pyrene; Biphenyl Compounds; Cytochrome P-450 CYP1A1; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Lignans; Magnolia; Medicine, Kampo; Mice; Mice, Inbred ICR; Micronucleus Tests; Mutagens; Plant Bark

We investigated the protective effects of magnolol, an active antioxidant and free radical scavenger extracted from Magnolia officinalis, in a hind limb ischemic-reperfusion animal model. Adult male Sprague-Dawley rats were subjected to hind limb ischemic insult for 2 hours and were intravenously treated with magnolol at 0.01 mg/kg (n=8), 0.3 mg/kg (n=8) mg/kg or 1 mg/kg (n=8) mg/kg, or vehicle (n=8). At 24 h post-insult, the levels of nitrite/nitrate (NOX), malondialdehyde (MDA) and myeloperoxidase (MPO), as well as the degree of muscle damage, were assessed. Relative to controls, animals treated with magnolol (0.3 and 1 mg/kg) had attenuated muscular inflammation, edema and damage. Magnolol (0.3-1 mg/kg) also effectively reduced postischemic rises in the MDA, NOx and MPO levels (p<0.05, respectively). Magnolol administrated at 0.01 mg/kg, however, failed to protect against the ischemic-perfusion limb injury. In addition, magnolol (0.01-1 mg/kg) did not affect local muscular blood reperfusion or other physiological parameters, including hematocrit, glucose, arterial blood gases and mean arterial blood pressure. Thus, intravenous administration with magnolol at 0.3-1 mg/kg protects against ischemic limb damage in rats. This cytoprotection may be attributed to its antioxidant, anti-nitrosative and anti-inflammatory actions.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Biphenyl Compounds; Body Temperature; Drug Evaluation, Preclinical; Hindlimb; Lignans; Magnolia; Male; Malondialdehyde; Nitric Oxide; Peroxidase; Phytotherapy; Plant Extracts; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Reperfusion Injury

The purpose of this study is to explore the feasibility and superiority of using rapid expansion of supercritical solution (RESS) technology in the field of traditional Chinese medicine. The extract of magnolia bark (EMB) was obtained by supercritical carbon dioxide (SCF-CO2) extraction technology. Microparticles of EMB were manufactured by RESS technology. The effects of operating temperature and pressure on the contents of the active ingredient in the particles were evaluated by HPLC. The effect of expansion conditions on the particle size distribution of EMB particles was investigated. The smallest sample (mean size: 4.7 microm) was obtained under the RESS condition: pressure of 25 MPa, temperature of 50 degrees C and a nozzle size of 100 microm. The characteristics of microparticles were also studied by differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and image analysis. The dissolution rate study showed that microparticles had a significantly faster dissolution rate than normal material particles. After oral raw EMB suspension, the mean areas under the plasma concentration-time curves (AUC(0-t)) of honokiol and magnolol were found to be (4.23 +/- 0.36) and (5.46 +/- 0.57) mg x h x L(-1), respectively, which were increased significantly, i.e. (5.41 +/- 0.63) and (7.24 +/- 0.83) mg x h x L(-1) when micronized EMB suspension was administered orally in SD rats (P < 0.05). Similarly, the mean maximum plasma concentrations of honokiol and magnolol increased from (1.55 +/- 0.22) and (2.35 +/- 0.14) mg x L(-1) (raw EMB) to (2.31 +/- 0.17) and (2.84 +/- 0.21) mg x L(-1) (micronized EMB), respectively. The results of t-test demonstrated that AUC(0-t) and Cmax value for honokiol and magnolol was significantly increased with the micronization compared to raw EBM (P < 0.05). This study demonstrated that the RESS was applicable for preparing microparticles of EMB at low operating temperature. The process was simple, free of environment pollution and without residual solvent.

Topics: Administration, Oral; Animals; Area Under Curve; Biphenyl Compounds; Drug Compounding; Drugs, Chinese Herbal; Lignans; Magnolia; Male; Microspheres; Particle Size; Plant Bark; Plants, Medicinal; Rats; Rats, Sprague-Dawley; Solubility

Previously, we demonstrated that magnolol isolated from the bark of Magnolia officinalis has anticancer activity in colon, hepatoma, and leukemia cell lines. In this study, we show that magnolol concentration dependently (0-40 microM) decreased the cell number in a cultured human glioblastoma cancer cell line (U373) and arrested the cells at the G0/G1 phase of the cell cycle. Magnolol treatment decreased the protein levels of cyclins A and D1 and increased p21/Cip1, but not cyclins B and D3, cyclin-dependent kinase (CDK)2, CDK4, CDC25C, Weel, p27/Kip1, and p53. The CDK2-p21/Cip1 complex was increased, and the CDK2 kinase activity was decreased in the magnolol-treated U373. Pretreatment of U373 with p21/Cip1 specific antisense oligodeoxynucleotide prevented the magnolol-induced increase of p21/Cip1 protein levels and the decrease of DNA synthesis. Magnolol at a concentration of 100 microM induced DNA fragmentation in U373. Our findings suggest the potential applications of magnolol in the treatment of human brain cancers.

Topics: Biphenyl Compounds; Cell Cycle; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p21; Down-Regulation; Glioblastoma; Humans; Lignans; Magnolia; Plant Extracts

Oxidative stress plays a significant role in the progression of cataract. We aimed to investigate the protective effect of magnolol, a compound extracted from the Chinese herb Magnolia officinalis, against oxidative stress in human lens epithelial (HLE) cells as well as the possible molecular mechanism involved. In this study, magnolol was observed to protect against H2O2-induced cytotoxicity in HLE B-3 cells. Magnolol inhibited the generation of reactive oxygen species (ROS), loss of mitochondrial membrane potential (Delta psi m) and release of cytochrome c from mitochondria caused by H2O2 into cytosol in HLE B-3 cells. Magnolol also inhibited H2O2-induced expressions of caspase-9 and caspase-3 and reduction of Bcl-2/Bax ratio. Moreover, magnolol attenuated the deactivation of ERK/MAPK (extracellular signal-regulated kinase/mitogen activated protein kinase) and the enhanced activation of p38, JNK (c-Jun N-terminal kinase) induced by H2O2. Magnolol could be useful in protecting against oxidative stress in HLE cells, suggesting a potential protective effect against cataractogenesis effect against cataractogenesis.

Topics: bcl-2-Associated X Protein; Biphenyl Compounds; Blotting, Western; Caspase 3; Caspase 9; Cell Line; Cell Survival; Cytochromes c; Dose-Response Relationship, Drug; Enzyme Activation; Epithelial Cells; Flow Cytometry; Humans; Hydrogen Peroxide; Lens, Crystalline; Lignans; Magnolia; MAP Kinase Signaling System; Membrane Potential, Mitochondrial; Oxidants; Oxidative Stress; Protective Agents; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species

Honokiol and magnolol, important anxiolytic and anti-cancer agents, have been produced in cell-suspension cultures of the endangered Mexican plant Magnolia dealbata Zucc. In vitro cultures of the plant were established, and the accumulation of honokiol and magnolol in callus and cell-suspension cultures was measured. Leaf samples were the best explants for callus establishment and metabolite production, and Murashige and Skoog medium supplemented with 1 mg/L 2, 4-dichlorophenoxyacetic acid and 1 mg/L kinetin yielded 2.3 mg/g of honokiol and 5.9 mg/g of magnolol. Bacterial and fungal contamination was inhibited with a multiple-step tissue sterilization procedure. Oxidation was inhibited with 1 g/L activated charcoal. Cell-suspension batch cultures derived from friable callus obtained from leaves of this species were grown for 30 days in shaker flasks containing Murashige and Skoog medium. Throughout the growth cycle, honokiol and magnolol levels, fresh and dry weight, and sucrose uptake were determined. The effects of carbon source concentration on biomass accumulation and the synthesis of bioactive compounds were studied. By using 3 mL of inocula supplemented with 3% (w/v) sucrose, maximum yields of honokiol (8.1 mg/g) and magnolol (13.4 mg/g) were obtained after 25 days. These yields were 300% and 382%, respectively, of the yields of honokiol and magnolol obtained from field-grown plants.

Topics: Anti-Anxiety Agents; Antineoplastic Agents, Phytogenic; Biomass; Biphenyl Compounds; Carbohydrates; Cells, Cultured; Chromatography, High Pressure Liquid; Kinetics; Lignans; Magnolia; Mexico

Magnolia bark combined with ginger rhizome is a common drug pair in traditional Chinese prescriptions for the treatment of depression. In the present study, we examined antidepressant-like effects of the mixture of honokiol and magnolol (HMM) from magnolia bark and essential oil from ginger rhizome (OGR) alone and in combination in chronic unpredictable mild stress (CUMS) of rats. Behavioral (sucrose intake, immobility time of forced swimming test) and biochemical parameters [serotonin (5-HT) in prefrontal cortex, hippocampus, and striatum, gastric mucosa cholecystokinin (CCK) and serum gastrin (GAS) levels] were simultaneously examined in the CUMS rats. 20 mg/kg HMM alone, but not OGR, significantly increased sucrose intake and reduced immobility time in the CUMS rats. Moreover, 20 mg/kg HMM and 14 mg/kg OGR in combination exhibited significant synergistic effects on sucrose intake increase and immobility time reduction in the CUMS rats. HMM elevated 5-HT levels in various brain regions, and OGR reduced gastric mucosa CCK and serum GAS levels in the CUMS rats. These results suggested that the synergistic antidepressant-like effects of compatibility of HMM with OGR might be mediated simultaneously by regulation of the serotonergic and gastroenteric system functions. These findings also provided a pharmacological basis for the clinical application of this drug pair of magnolia bark and ginger rhizome in traditional Chinese medicine.

Topics: Animals; Antidepressive Agents; Biphenyl Compounds; Brain; Cholecystokinin; Depression; Drug Synergism; Drug Therapy, Combination; Gastric Mucosa; Gastrins; Lignans; Male; Oils, Volatile; Rats; Rats, Wistar; Serotonin; Swimming; Zingiber officinale

The antinociceptive effects of honokiol and magnolol, two major bioactive constituents of the bark of Magnolia officinalis, were investigated on animal paw licking responses and thermal hyperalgesia induced by glutamate receptor agonists including glutamate, N-methyl-D-aspartate (NMDA), and metabotropic glutamate 5 receptor (mGluR5) activator (RS)-2-chloro-5-hydroxyphenylglycine (CHPG), as well as inflammatory mediators such as substance P and prostaglandin E2 (PGE2) in mice. The actions of honokiol and magnolol on glutamate-induced c-Fos expression in the spinal cord dorsal horn were also examined. Our data showed that honokiol and magnolol blocked glutamate-, substance P- and PGE2-induced inflammatory pain with similar potency and efficacy. Consistently, honokiol and magnolol significantly decreased glutamate-induced c-Fos protein expression in superficial (I-II) laminae of the L4-L5 lumbar dorsal horn. However, honokiol was more selective than magnolol for inhibition of NMDA-induced licking behavioral and thermal hyperalgesia. In contrast, magnolol was more potent to block CHPG-mediated thermal hyperalgesia. These results demonstrate that honokiol and magnolol effectively decreased the inflammatory pain. Furthermore, their different potency on inhibition of nociception provoked by NMDA receptor and mGluR5 activation should be considered.

Topics: Analgesics; Animals; Anti-Infective Agents; Biphenyl Compounds; Dinoprostone; Excitatory Amino Acid Agents; Glycine; Immunohistochemistry; Inflammation; Lignans; Male; Mice; N-Methylaspartate; Phenylacetates; Proto-Oncogene Proteins c-fos; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate

To investigate the effect of severe acute pancreatitis (SAP) on pharmacokinetics of Da-Cheng-Qi Decoction (DCQD) components in rats.. Rats were divided into SAP group and sham-operation group as a control group (n = 6). Rhein, chrysophanol, rheochrysidin, magnolol, hesperidin and naringin in DCQD were quantified in rat serum by high performance liquid chromatography tandem mass spectrometry for studying their pharmacokinetics.. Early absorption of each DCQD component was tended to degrade in SAP group after treatment with DCQD by gavage. The C(max) (chrysophanol, P = 0.0059; rheochrysidin, P = 0.0288; magnolol, P = 0.0487; hesperidin, P = 0.0277; naringin, P = 0.0023) and AUC (rhein, P = 0.0186; chrysophanol, P = 0.0013; magnolol, P = 0.001; hesperidin, P = 0.0081; naringin, P = 0.0272) of DCQD component were obviously lower in SAP group than in control group. The T(1/2alpha) of chrysophanol and rheochrysidin (P = 0.0467 and 0.0005, respectively) and T(max) of chrysophanol and rheochrysidin (P = 0.0101 and 0.0037, respectively) lasted longer in SAP group than in control group.. SAP can significantly impact the absorption of DCQD components in rats and their pharmacokinetic parameters.

Topics: Animals; Anthraquinones; Anti-Inflammatory Agents, Non-Steroidal; Biphenyl Compounds; Enzyme Inhibitors; Flavanones; Glucosides; Hesperidin; Humans; Lignans; Male; Molecular Structure; Mutagens; Pancreatitis, Acute Necrotizing; Plant Extracts; Random Allocation; Rats; Rats, Sprague-Dawley

Magnolol inhibited proliferation of human malignant melanoma A375-S2 cells. The drug induced oligonucleosomal fragmentation of DNA in A375-S2 cells and increased caspase-3, 8, 9 activities followed by the degradation of caspase-3 substrates, inhibitor of caspase dependent DNase (ICAD) and poly-(ADP-ribose) polymerase (PARP). Pan-caspase inhibitor (z-VADfmk), caspase-3 inhibitor (z-DEVD-fmk), capase-8 inhibitor (z-IETD-fmk), caspase-9 inhibitor (z-LEHD-fmk) and caspase-10 inhibitor (z-AEVD-fmk) inhibited magnolol-induced A375-S2 cell apoptosis. The level of anti-apoptotic mitochondrial protein Bcl-2 was up-regulated while the level of pro-apoptotic protein Bax was down-regulated. Taken together, our results indicate that magnolol induces apoptosis by activation of both mitochondrial and death receptor pathways in A375-S2 cells.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; bcl-2-Associated X Protein; Biphenyl Compounds; Bisbenzimidazole; Blotting, Western; Caspase 3; Caspase 8; Caspase 9; Cell Line, Tumor; Cell Nucleus; Cell Survival; Coloring Agents; DNA Fragmentation; DNA, Neoplasm; fas Receptor; Humans; Lignans; Melanoma, Experimental; Mitochondria; Proto-Oncogene Proteins c-bcl-2; Receptors, Death Domain; Signal Transduction

The enhancement effect of mesoporous Al-doped silica (Al/SiO(2))-modified electrode was investigated. Due to the properties such as large surface area, strong adsorptive ability and numerous active sites, mesoporous Al/SiO(2) alters the structure and property of electrode/solution interface, then greatly improves the electrochemical response of magnolol. The electrochemical behavior of magnolol was examined in detail. It is found that the oxidation peak current of magnolol remarkably increases at the mesoporous Al/SiO(2)-modified electrode. Based on this, a sensitive and convenient electrochemical method was developed for the determination of magnolol. The linear range is over the range from 7.5 x 10(-8) to 2.0 x 10(-5) mol L(-1). The limit of detection (S/N=3) is as low as 2.5 x 10(-8) mol L(-1). Finally, this novel method was successfully used to determine the magnolol in Chinese traditional medicines.

Topics: Alkaline Phosphatase; Aluminum; Biphenyl Compounds; Catalysis; Electrodes; Enzymes, Immobilized; Lignans; Medicine, Chinese Traditional; Microscopy, Electron, Scanning; Microscopy, Electron, Transmission; Nanotubes; Reproducibility of Results; Silicon Dioxide

To study the phenols in Cortex of Magnolia officinalis of biernial seedings produced in Enshi, Hubei.. The content of magnolol and honokiol in cortexes were determined by HPLC. The chromatograms of 10 samples seedling cortexes were recorded and compared.. The content of magnolol and honokiol in Cortex of Magnolia officinalis of the seedlings from Enshi was higher than other samples. There were ten characteristic absorption bands in the HPLC chromatograms, which differed from the cortex of adult trees.. The results can be used to identify the quality of the seedlings for the breeding.

Topics: Age Factors; Biphenyl Compounds; China; Chromatography, High Pressure Liquid; Lignans; Magnolia; Plant Bark; Plant Stems; Plants, Medicinal; Seedlings

Magnolol, an active component extracted from Magnolia officinalis, has been reported to have protective effect on ischemia and reperfusion (I/R)-induced injury in experimental animals. The aim of the present investigation was to further evaluate the mechanism(s) by which magnolol reduces I/R-induced myocardial injury in rats in vivo. Under anesthesia, left anterior descending (LAD) coronary artery was occluded for 30 min followed by reperfusion for 24 h (for infarct size and cardiac function analysis). In some experiments, reperfusion was limited to 1 h or 6 h for analysis of biochemical and molecular events. Magnolol and DMSO solution (vehicle) were injected intra-peritoneally 1 h prior to I/R insult. The infarct size was measured by TTC technique and heart function was monitored by Millar Catheter. Apoptosis related events such as p-ERK, p-Bad, Bcl-xl and cytochrome c expression were evaluated by Western blot analysis and myocardial caspase-3 activity was also measured. Magnolol (10 mg/kg) reduced infarct size by 50% (P < 0.01 versus vehicle), and also improved I/R-induced myocardial dysfunction. Left ventricular systolic pressure and positive and negative maximal values of the first derivative of left ventricular pressure (dP/dt) were significantly improved in magnolol-treated rats. Magnolol increased the expression of phosphor ERK and Bad which resulted in inhibition of myocardial apoptosis as evidenced by TUNEL analysis and DNA laddering experiments. Application of PD 98059, a selective MEK1/2 inhibitor, strongly antagonized the effect of magnolol. Taken together, we concluded that magnolol inhibits apoptosis through enhancing the activation of ERK1/2 and modulation of the Bcl-xl proteins which brings about reduction of infarct size and improvement of cardiac function in I/R-induced injury.

Topics: Animals; Apoptosis; Biphenyl Compounds; Caspase 3; Disease Models, Animal; Flavonoids; Heart; Lignans; Male; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Myocardial Infarction; Myocardial Reperfusion Injury; Plant Extracts; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; Signal Transduction

To study the chemical constituents and volatile oil of Xiaochengqi decoction.. The constituents in decoction were separated by means of column chromatography and their structures were identified by spectral data and compared with literature data. As well as the volatile oil of Xiaochengqi Fang were analyzed and identified by GC-MS.. Eleven compounds were isolated and identified as chrysophanol (1), physcion (2), magnolol (3), beta-sitosterol (4), sitosterol trans-cinnamic acid (5), emodin (6), aloe emodin (7), rhein (8), gallic acid (9), chrysophanol-8-O-beta-D-glucopyranoside (10), aurantiamarin (11). The volatile oils extracted with steam distillation from Xiaochengqi were identified 67 components, and the main components are including.. All of the eleven compounds were isolated from Xiaochengqi decoction for the first time and the study on their activities in Chinese prescription is being carried out. D-limonene (42.61%), p-cymene (16.43%), and 8-terpinene (14.46%).

Topics: Anthraquinones; Biphenyl Compounds; Cinnamates; Cyclohexenes; Cymenes; Drugs, Chinese Herbal; Emodin; Gallic Acid; Gas Chromatography-Mass Spectrometry; Lignans; Limonene; Monoterpenes; Oils, Volatile; Sitosterols; Terpenes

We investigated the molecular mechanisms involved in the expression of matrix metalloproteinase-9 (MMP-9) and the inhibition of MMP expression by magnolol in 5637 human urinary bladder cancer cells. Tumor necrosis factor-alpha (TNF-alpha) stimulated the secretion of MMP-9 in 5637 cells, as shown by zymography and promoter assay. The transcription factor nuclear factor kappaB (NF-kappaB) binding site was identified by gel-shift assay to be a cis-element for TNF-alpha activation of the MMP-9 promoter. Our results also demonstrated that TNF-alpha stimulates MMP-9 expression via the p38 MAP kinase signaling pathway in 5637 cells. Moreover, p38 MAP kinase-mediated MMP-9 gene regulation in response to TNF-alpha is involved in the NF-kappaB response element in 5637 cells. In addition, magnolol inhibited TNF-alpha-induced expression of the MMP-9, as determined by zymography and immunoblot, in 5637 cells. The TNF-alpha-induced invasion and migration of cells was inhibited by magnolol, as assessed by a modified boyden chamber and wound-healing assays, respectively. Finally, magnolol blocked MMP-9 expression, at least in part, by decreasing the binding of transcription factor NF-kappaB to DNA. In conclusion, TNF-alpha induced MMP-9 expression in 5637 cells by activating the transcription factor NF-kappaB, which is involved in the p38 MAP kinase-mediated control of MMP-9 regulation. Magnolol inhibited MMP-9 expression through the transcription factor NF-kappaB in TNF-alpha-induced 5637 cells.

Topics: Antineoplastic Agents; Biphenyl Compounds; Cell Line, Tumor; Cell Movement; Enzyme Inhibitors; Humans; Imidazoles; Lignans; Matrix Metalloproteinase Inhibitors; NF-kappaB-Inducing Kinase; p38 Mitogen-Activated Protein Kinases; Protein Serine-Threonine Kinases; Pyridines; Signal Transduction; Tumor Necrosis Factor-alpha; Urinary Bladder Neoplasms

An HPLC-photodiode array (PDA) detection method was established for the simultaneous determination of 12 components in Xiao-Yao-San-Jia-Wei (XYSJW): geniposide, puerarin, paeoniflorin, ferulic acid, liquiritin, hesperidin, naringin, paeonol, daidzein, glycyrrhizic acid, honokiol, and magnolol. These were separated in less than 70 min using a Waters Symmetry Shield RP 18 column with gradient elution using (A) acetonitrile, (B) water, and (C) acetic acid at a flow rate of 1 ml/min, and with a PDA detector. All calibration curves showed good linear regression (r(2)>0.9992) within the test ranges. The method was validated for specificity, accuracy, precision, and limits of detection. The proposed method enables in a single run the simultaneous identification and determination for quality control of 12 multi-structural components of XYSJW forming the basis of its therapeutic effect.

Topics: Acetophenones; Benzoates; Biphenyl Compounds; Bridged-Ring Compounds; Coumaric Acids; Drugs, Chinese Herbal; Flavanones; Glucosides; Glycyrrhizic Acid; Hesperidin; Iridoids; Isoflavones; Lignans; Medicine, Chinese Traditional; Molecular Structure; Monoterpenes; Quality Control; Reference Standards; Reproducibility of Results; Sensitivity and Specificity

To reveal the relationship between the storage time of the bark of Magnolia officinalis and the content of phenols in it, and lay a theoretical foundation for the harvest, processing, management and storage.. The contents of magnolol and honokoiol in 15 bark samples, collected from the main producing areas in China, were determined in the time of freshly harvest and 3 and 10 years after respectively by HPLC method.. It showed that within a certain period of time, bark storage was favorable to conversion and accumulation of phenols, that the content of magnolol tended to increase from year 0 to year 3, then followed by slight decrease with years on account of volatilization of phenols, but was still higher when the bark was stored for 10 years than that that when the bark was freshly harvested, and the content of honokoiol still tended to increase when the bark had been stored for 10 years.. The phenols in bark of M. officinalis is quite stable and the bark can be stored for 10 years or longer.

Topics: Biphenyl Compounds; Drug Storage; Drugs, Chinese Herbal; Lignans; Magnolia; Plant Bark; Time Factors

To investigate the protective effects of magnolol on sepsis-induced inflammation and intestinal dysmotility.. Sepsis was induced by a single intraperitoneal injection of lipopolysaccharide (LPS). Male Wistar rats were randomly assigned to one of three treatment groups: magnolol prior to LPS injection (LPS/Mag group); vehicle prior to LPS injection (LPS/Veh group); vehicle prior to injection of saline (Control/Veh). Intestinal transit and circular muscle mechanical activity were assessed 12 h after LPS injection. Tumor necrosis factor-alpha (TNF-alpha), interleukin-10 (IL-10), monocyte chemoattractant protein-1 (MCP-1) and inducible nitric oxide synthase (iNOS) mRNA in rat ileum were studied by RT-PCR 2 h after LPS injection. Nuclear factor-kappaB (NF-kappaB) activity in the intestine was also investigated at this time using electrophoretic mobility shift assay. In addition, antioxidant activity was determined by measuring malondialdehyde (MDA) concentration and superoxide dismutase (SOD) activity in the intestine 2 h after LPS injection.. Magnolol significantly increased intestinal transit and circular muscle mechanical activity in LPS-treated animals. TNF-alpha, MCP-1 and iNOS mRNA expression in the small intestine were significantly reduced after magnolol treatment in LPS-induced septic animals, compared with untreated septic animals. Additionally, magnolol significantly increased IL-10 mRNA expression in septic rat ileum. Magnolol also significantly suppressed NF-kappaB activity in septic rat intestine. In addition, magnolol significantly decreased MDA concentration and increased SOD activity in rat ileum.. Magnolol prevents sepsis-induced suppression of intestinal motility in rats. The potential mechanism of this benefit of magnolol appears to be modulation of self-amplified inflammatory events and block of oxidative stress in the intestine.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Biphenyl Compounds; Chemokine CCL2; Disease Models, Animal; Gastrointestinal Diseases; Gastrointestinal Motility; Ileum; Inflammation Mediators; Interleukin-10; Lignans; Lipopolysaccharides; Male; Malondialdehyde; NF-kappa B; Nitric Oxide Synthase Type II; Rats; Rats, Wistar; RNA, Messenger; Sepsis; Superoxide Dismutase; Tumor Necrosis Factor-alpha

It was previously reported that magnolol strongly inhibited the mutagenicity induced by the indirect mutagens [benzo(a)pyrene (B(a)P), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-aminodipyrido[1,2-a:3',2'-d]imidazole (Glu-P-2), 2-aminoanthracene (2AA), and 7,12-dimethylbenz[a]anthracene (DMBA)] in Salmonella typhimurium TA98 and TA100 in the Ames test, and that the mechanism of this anti-mutagenic effect may involve the inhibition of the metabolic activation of indirect mutagen enzymes. In this study, the in vivo anti-clastogenic effect of magnolol against clastogenicity induced by B(a)P was evaluated using the micronucleus test in mice. Animals were treated with an oral administration of magnolol (1, 10, and 100 mg/kg) at -24, 0, 24, 48, 72, and 96 h before a single intraperitoneal injection of B(a)P. Peripheral blood specimens were prepared 48 h after administration of B(a)P, and analyzed by the acridine orange (AO) technique. The results indicated that magnolol inhibited clastogenicity induced by B(a)P at various administration times. In order to elucidate the mechanism behind this effect, we measured the activity of the detoxifying enzymes [UDP-glucuronosyltransferase (UGT) and glutathione-S-transferase (GST)] and antioxidative enzymes [superoxide dismutase (SOD) and catalase] in the liver when treated with an oral administration of magnolol at various administration times. Its effect on clastogenicity created by exposure to oxidative DNA damage-inducing X-ray irradiation was also evaluated using the micronucleus test in mice. Results showed that magnolol increased the activity of both UGT and SOD enzymes, and also inhibited the clastogenicity induced by X-ray irradiation. Magnolol had an anti-clastogenic effect on B(a)P in the micronucleus test as well as an anti-mutagenic effect on indirect mutagens in the Ames test. The anti-clastogenic effect of magnolol was also suggested by the increases in UGT and SOD enzyme activity, and by the attenuation of oxidative damage induced by X-ray irradiation.

Topics: Animals; Benzo(a)pyrene; Biphenyl Compounds; Enzyme Activation; Lignans; Liver; Male; Mice; Mice, Inbred ICR; Micronucleus Tests; Mutagens

Honokiol and magnolol are the main constituents simultaneously identified in the barks of Magnolia officinalis, which have been used in traditional Chinese medicine to treat a variety of mental disorders including depression. In the present study, we reported on the antidepressant-like effects of oral administration of the mixture of honokiol and magnolol in well-validated models of depression in rodents: forced swimming test (FST), tail suspension test (TST) and chronic mild stress (CMS) model. The mixture of honokiol and magnolol significantly decreased immobility time in the mouse FST and TST, and reversed CMS-induced reduction in sucrose consumption to prevent anhedonia in rats. However, this mixture was unable to affect ambulatory or rearing behavior in the mouse open-field test. CMS induced alterations in 5-hydroxytryptamine (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) levels in various brain regions of rats. An increase in serum corticosterone concentrations and a reduction in platelet adenylyl cyclase (AC) activity were simultaneously found in the CMS rats. The mixture of honokiol and magnolol at 20 and 40 mg/kg significantly attenuated CMS-induced decreases of 5-HT levels in frontal cortex, hippocampus, striatum, hypothalamus and nucleus accumbens. And it markedly increased 5-HIAA levels in frontal cortex, striatum and nucleus accumbens at 40 mg/kg and in frontal cortex at 20 mg/kg in the CMS rats. A subsequent reduction in 5-HIAA/5-HT ratio was found in hippocampus and nucleus accumbens in the CMS rats receiving this mixture. Furthermore, the mixture of honokiol and magnolol reduced elevated corticosterone concentrations in serum to normalize the hypothalamic-pituitary-adrenal (HPA) hyperactivity in the CMS rats. It also reversed CMS-induced reduction in platelet AC activity, via upregulating the cyclic adenosine monophosphate (cAMP) pathway. These results suggested that the mixture of honokiol and magnolol possessed potent antidepressant-like properties in behaviors involved in normalization of biochemical abnormalities in brain 5-HT and 5-HIAA, serum corticosterone levels and platelet AC activity in the CMS rats. Our findings could provide a basis for examining directly the interaction of the serotonergic system, the HPA axis and AC-cAMP pathway underlying the link between depression and treatment with the mixture of honokiol and magnolol.

Topics: Animals; Antidepressive Agents; Behavior, Animal; Biphenyl Compounds; Corticosterone; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Exploratory Behavior; Hindlimb Suspension; Hydroxyindoleacetic Acid; Lignans; Magnolia; Male; Mice; Mice, Inbred ICR; Phytotherapy; Rats; Rats, Wistar; Serotonin; Stress, Physiological; Swimming

A rapid, sensitive and specific liquid chromatography-electrospray ionization/tandem mass spectrometry (LC-ESI/MS/MS) method has been developed and validated for simultaneous determination of five active constituents (including magnolol, honokiol, rhein, emodin and aloe-emodin) from Da-Cheng-Qi decoction (DCQD) in rat plasma. After the addition of gliquidone as the internal standard (IS), plasma samples were prepared by one-step protein precipitation using methanol and separated by HPLC on a short reversed phase C(18) column packed with smaller particles (100 mm x 3.0 mm, 3.5 microm) using a mobile phase of methanol-0.1% formic acid aqueous solution (70:30, v/v). Analytes were determined in a triple-quadrupole mass spectrometer in the selected reaction-monitoring (SRM) mode using electrospray source with negative mode. The method was proved to be rapid, sensitive, specific, accurate and reproducible and has been successfully applied to the determination of the five compounds in rat plasma after oral administration of low dose DCQD for pharmacokinetic study.

Topics: Administration, Oral; Animals; Anthraquinones; Biphenyl Compounds; Chromatography, High Pressure Liquid; Drugs, Chinese Herbal; Emodin; Female; Lignans; Male; Plant Extracts; Rats; Rats, Sprague-Dawley; Tandem Mass Spectrometry

Magnolol has been reported to play a role in antitumor activity. However, the relevant pathway integrating cell cycle regulation and signaling pathways involved in growth inhibition in cancer cells remains to be identified. In the present study, magnolol treatment of these cells resulted in significant dose-dependent growth inhibition together with apoptosis, G1- and G2/M-phase cell cycle arrest at a 60 microM (IC50) dose in 5637 bladder cancer cells. In addition, magnolol treatment strongly induced p27KIP1 expression, and down-regulated expression of cyclin-dependent kinases (CDKs) and cyclins. Moreover, treatment with magnolol-induced phosphorylation of ERK, p38 MAP kinase, and JNK. Among the pathway inhibitors examined, only PD98059, an ERK-specific inhibitor, blocked magnolol-dependent p27KIP1 expression. Blockade of ERK function consistently reversed magnolol-mediated inhibition of cell proliferation and decreased G2/M cell cycle proteins, but not G1 cell cycle proteins. Furthermore, magnolol treatment increased both Ras and Raf activation. Transfection of cells with dominant negative Ras (RasN17) and Raf (RafS621A) mutant genes suppressed magnolol-induced ERK activity and p27KIP1 expression. Finally, the magnolol-induced reduction in cell proliferation and G2/M cell cycle proteins was also abolished in the presence of RasN17 and RafS621A mutant genes. These data demonstrate that the Ras/Raf/ERK pathway participates in p27KIP1 induction, leading to a decrease in the levels of cyclin B1/Cdc2 complexes and magnolol-dependent inhibition of cell growth. Overall, these novel findings concerning the molecular mechanisms of magnolol in 5637 bladder cancer cells provide a theoretical basis for therapeutic treatment of malignancies.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Biphenyl Compounds; Cell Cycle; Cell Division; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cyclin-Dependent Kinase Inhibitor p27; Dose-Response Relationship, Drug; Enzyme Inhibitors; Extracellular Signal-Regulated MAP Kinases; G2 Phase; Humans; Lignans; Phosphorylation; Signal Transduction; Urinary Bladder Neoplasms

Magnolia officinalis is a commonly used traditional Chinese medicine for treating gastrointestinal disorders. HPLC quantification analysis revealed that magnolol and honokiol were the most abundant constituents of M. officinalis extracts, with their contents in the ethanol extract being the highest, the water extract the least and the 50 % ethanol extract in between. In guinea pig isolated ileum, both magnolol and honokiol inhibited contraction to acetylcholine. The herbal extracts also produced inhibitory responses, in an order of decreasing efficacy: ethanol extract > 50 % ethanol extract > water extract. The differences in inhibitory efficacies among the three extracts were similar to the differences in their magnolol and honokiol contents. Further examination demonstrated that two mixtures containing solely magnolol and honokiol at concentrations identical to those determined in the ethanol and water extracts exhibited similar levels of anti-spasmodic effects as their respective extracts while a "blank" ethanol extract free of magnolol and honokiol failed to produce any response. These observations suggest that the magnolol and honokiol contents account for the anti-spasmodic effects of M. officinalis extracts in guinea pig isolated ileum.

Topics: Animals; Biphenyl Compounds; Guinea Pigs; Ileum; Lignans; Magnolia; Molecular Structure; Muscle Contraction; Muscle, Smooth; Plant Extracts

We investigated the effect of magnolol (5,5'-diallyl-2,2'-dihydroxybiphenyl), a marker compound isolated from the cortex of Magnolia officinalis, in non-obese type 2 diabetic Goto-Kakizaki (GK) rats. The rats were treated orally with magnolol (100 mg/kg body weight) once a day for 13 weeks. In magnolol-treated GK rats, fasting blood glucose and plasma insulin were significantly decreased, and the pancreatic islets also showed strong insulin antigen positivity. Urinary protein and creatinine clearance (Ccr) were significantly decreased. Pathological examination revealed the prevention of the glomeruli enlargement in magnolol-treated GK rats. The overproduction of renal sorbitol, advanced glycation endproducts (AGEs), type IV collagen, and TGF-beta1 mRNA were significantly reduced in magnolol-treated GK rats. Thus based on our findings, the use of magnolol could result in good blood glucose control and prevent or retard development of diabetic complications such as diabetic nephropathy.

Topics: Animals; Biphenyl Compounds; Blood Glucose; Collagen Type IV; Creatinine; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Glycation End Products, Advanced; Hypoglycemic Agents; Immunohistochemistry; Insulin; Islets of Langerhans; Kidney Cortex; Lignans; Magnolia; Male; Plant Bark; Plant Roots; Proteinuria; Rats; Rats, Inbred Strains; Sorbitol; Transforming Growth Factor beta1

Magnolol, a compound extracted from the Chinese medicinal herb Magnolia officinalis, has several biological effects. However, its protective effects against endothelial injury remain unclear. In this study, we examined whether magnolol prevents oxidized low density lipoprotein (oxLDL)-induced vascular endothelial apoptosis. Incubation of oxLDL with magnolol (2.5-20 microM) inhibited copper-induced oxidative modification via diene formation, thiobarbituric acid reactive substances (TBARS) assay and electrophoretic mobility assay. Apoptotic cell death as characterized by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) stain. We measured the production of reactive oxygen species (ROS) by using the fluorescent probe 2',7'-dichlorofluorescein acetoxymethyl ester (DCF-AM), and observed the activity of antioxidant enzymes. Furthermore, several apoptotic signaling pathways which showed NF-kappaB activation, increased cytosolic calcium, alteration of mitochondrial membrane potential, cytochrome c release and activation of caspase 3 were also investigated. We demonstrated that magnolol prevented the copper-induced oxidative modification of LDL. Magnolol attenuated the oxLDL-induced ROS generation and subsequent NF-kappaB activation. Furthermore, intracellular calcium accumulation and subsequent mitochondrial membrane potential collapse, cytochome c release and activation of caspase 3 caused by oxLDL were also inhibited by magnolol. Our results suggest that magnolol may have clinical implications in the prevention of atherosclerotic vascular disease through decreasing the oxLDL-induced ROS production.

Topics: Antioxidants; Apoptosis; Biphenyl Compounds; Calcium; Caspase 3; Cell Survival; Cells, Cultured; Copper Sulfate; Cytochromes c; Dose-Response Relationship, Drug; Endothelial Cells; Humans; Lignans; Lipid Peroxidation; Lipoproteins, LDL; Membrane Potential, Mitochondrial; Mitochondria; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; NF-kappa B; Oxidation-Reduction; Reactive Oxygen Species; Signal Transduction; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances; Time Factors

In this paper, a rapid separation approach has been developed using high-capacity high-speed counter-current chromatography (high-capacity HSCCC) to isolate and purify honokiol and magnolol, which are the main bioactive constituents from Houpu. The optimization of the solvent selection process, sample loading volume and flow rate is systematically studied using analytical high-capacity HSCCC. The optimized parameters obtained rapidly at analytical scale were used for a 1000 x scale-up preparative run using pilot scale high-capacity HSCCC in a MAXI-DE centrifuge. A crude sample of 43 g was successfully separated and the fractions were analysed by high-performance liquid chromatography (HPLC). This large scale preparative single step run yielded 16.9 and 19.4 g of honokiol and magnolol with purities of 98.6 and 99.9%, in only 20 min. This is the first time that high-performance counter-current chromatography has been used to purify multiple gram grade bioactive compounds in less than 1h and at such high concentrations of final products (10.8 g/l for magnolol and 7.0 g/l for honokiol).

Topics: Biphenyl Compounds; Chromatography, High Pressure Liquid; Countercurrent Distribution; Lignans; Pilot Projects

Capillary zone electrophoresis (CZE) method was used for analysis of magnolol and honokiol. Under the optimized condition, CZE with UV absorption detection provided that the limit of detection was at microM level. To enhance detection sensitivity of magnolol and honokiol, CZE separation system was coupled with a laser-induced fluorescence (LIF) detector for the first time. The limits of detection of magnolol and honokiol were 12 nM (3.20 ng ml(-1)) and 18 nM (4.79 ng ml(-1)), respectively, showing that the CZE-LIF system provides greater than 100-fold sensitivity improvements than does the CZE-UV system. The developed method was applied to analyze magnolol and honokiol in spiked human plasma samples, microsome incubation samples as a preliminary demonstration of its potential in pharmacokinetic studies.

Topics: Animals; Biphenyl Compounds; Electrophoresis, Capillary; Fluorescence; Humans; Lignans; Microsomes, Liver; Rats; Reference Standards; Sensitivity and Specificity; Spectrophotometry, Ultraviolet

The mis-regulation of nuclear factor-kappa B (NF-kappaB) signal pathway is involved in a variety of inflammatory diseases that leds to the production of inflammatory mediators. Our studies using human U937 promonocytes cells suggested that magnolol, a low molecular weight lignan isolated from the medicinal plant Magnolia officinalis, differentially down-regulated the pharmacologically induced expression of NF-kappaB-regulated inflammatory gene products MMP-9, IL-8, MCP-1, MIP-1alpha, TNF-alpha. Pre-treatment of magnolol blocked TNF-alpha-induced NF-kappaB activation in different cell types as evidenced by EMSA. Magnolol did not directly affect the binding of p65/p50 heterodimer to DNA. Immunoblot analysis demonstrated that magnolol inhibited the TNF-alpha-stimulated phosphorylation and degradation of the cytosolic NF-kappaB inhibitor IkappaBalpha and the effects were dose-dependent. Mechanistically, a non-radioactive IkappaB kinases (IKK) assay using immunoprecipitated IKKs protein demonstrated that magnolol inhibited both intrinsic and TNF-alpha-stimulated IKK activity, thus suggesting a critical role of magnolol in abrogating the phosphorylation and degradation of IkappaBalpha. The involvement of IKK was further verified in a HeLa cell NF-kappaB-dependent luciferase reporter system. In this system magnolol suppressed luciferase expression stimulated by TNF-alpha and by the transient transfection and expression of NIK (NF-kappaB-inducing kinase), wild type IKKbeta, constitutively active IKKalpha and IKKbeta, or the p65 subunit. Magnolol was also found to inhibit the nuclear translocation and phosphorylation of p65 subunit of NF-kappaB. In line with the observation that NF-kappaB activation may up-regulate anti-apoptotic genes, it was shown in U937 cells that magnolol enhanced TNF-alpha-induced apoptotic cell death. Our results suggest that magnolol or its derivatives may have potential anti-inflammatory actions through IKK inactivation.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Biphenyl Compounds; Cell Line, Tumor; Cytokines; Dimerization; Down-Regulation; Gene Expression Regulation; Humans; I-kappa B Kinase; Lignans; Lipopolysaccharides; Matrix Metalloproteinase 9; NF-kappa B; NF-kappa B p50 Subunit; Phosphorylation; Transcription Factor RelA; Tumor Necrosis Factor-alpha

Previously, we showed that magnolol induces cell-cycle arrest in cultured colon and liver cancer cells through an upregulation of the p21 protein. The aim of this study was to delineate the molecular mechanism underlying this magnolol-induced increase of p21 protein. Thus our RT-PCR analysis demonstrated that the mRNA levels of p21 were increased at 1 h after magnolol treatment and sustained for at least 24 h. The p21 promoter activity was also increased by magnolol treatment. Western blot analysis demonstrated that treatment of COLO-205 cells with magnolol increased the levels of phosphorylation of extracellular signal-regulated kinase (ERK). Pretreatment of the cells with PD98059 abolished the magnolol-induced upregulation of p21 protein, suggesting the involvement of an ERK pathway in the magnolol-induced upregulation of p21 in COLO-205 cells. Ras inhibitor peptide abolished the magnolol-induced increase of phosphorylated ERK protein levels, increase of p21 protein, and decrease of thymidine incorporation. Moreover, treatment of COLO-205 with magnolol increased the phosphorylated Raf-1 protein (the Ras target molecule). Pretreatment of the cells with Raf-1 inhibitor reversed the magnolol-induced decrease in thymidine incorporation. Treatment of the cells with CaM kinase inhibitor, but not protein kinase A (PKA) inhibitor or phosphatidylinosital 3-kinase (PI3K) inhibitor, abolished the magnolol-induced activation of ERK and decrease of thymidine incorporation. Taken together, our results suggest that magnolol activates ERK phosphorylation through a Ras/Raf-1-mediated pathway. Subsequently, p21 expression is increased, and finally thymidine incorporation is decreased.

Topics: Biphenyl Compounds; Cell Cycle; Cell Line, Tumor; Colonic Neoplasms; Extracellular Signal-Regulated MAP Kinases; Humans; Lignans; Nitric Oxide Synthase; Phosphorylation; Proto-Oncogene Proteins c-raf; Proto-Oncogene Proteins p21(ras); Signal Transduction; Up-Regulation

Magnolol, a natural product isolated from Magnolia officinalis, has various pharmacological effects, such inhibition of effect on inflammation and tumor metastasis, protection against cerebral ischaemic injury, and potent antioxidant activity. In this present study, we evaluated the inhibitory effects of magnolol on transforming growth factor-beta1 (TGF-beta1) and fibronectin expression induced by high concentrations of glucose or S100b (a specific receptor of advance glycation end products ligand) in human retinal pigment epithelial cells (human RPE cells). No effect on cell growth was found with magnolol (up to 20 microg/ml) using a colorimetric 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltertrazolium bromide (MTT) assay. High glucose (25 mM) or S100b (5 microg/ml) induced increases in expression of TGF-beta1 and fibronectin. The increases in TGF-beta1 and fibronectin expression with high glucose or S100b were prevented by magnolol in a dose-dependent manner. Also, magnolol inhibited extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK)/Akt activation. The present study demonstrates that high glucose- or S100b-induced TGF-beta1 and fibronectin expression, but this increased expression is inhibited by magnolol via the ERK/MAPK/Akt signaling pathway in human RPE cells.

Topics: Biphenyl Compounds; Blotting, Western; Cell Line; Cell Survival; Dose-Response Relationship, Drug; Extracellular Signal-Regulated MAP Kinases; Fibronectins; Gene Expression; Glucose; Humans; Hyperglycemia; Lignans; Lipid Peroxidation; Magnolia; Molecular Structure; Nerve Growth Factors; Phosphorylation; Pigment Epithelium of Eye; Proto-Oncogene Proteins c-akt; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; S100 Calcium Binding Protein beta Subunit; S100 Proteins; Transforming Growth Factor beta

Transcriptional activity of nuclear factor kappaB (NF-kappaB) is induced by environmental signals including inflammation, UV irradiation and oxidative stress. It was shown that the NF-kappaB activity greatly contributes to the skin photoaging process. Thus, it is plausible that NF-kappaB inhibitors could directly prevent skin photoaging. In this study, we found that Magnolia ovovata extract inhibited NF-kappaB-mediated gene expression and demonstrated that external swabbing with Magnolia extract preventing skin photoaging processes through keratinocyte hyperproliferation and degradation of collagen fibers in mice skin. We have identified magnolol as the solely responsible active compound in Magnolia extract. Magnolol effectively inhibited the NF-kappaB-dependent transcription, but no effect was observed with other inducible transcription factors such as activator protein-1 (AP-1) and cyclic-AMP responsive element-binding protein (CREB). In addition, magnolol was effective in inhibiting the production of basic fibroblast growth factor (bFGF) and matrix metalloprotease-1 (MMP-1) from the cells overexpressing p65, a major subunit of NF-kappaB. Although magnolol did not affect the phosphorylation and degradation of IkappaBalpha, it inhibited the nuclear translocation of the activated NF-kappaB. These findings suggest that Magnolia extract and its active component magnolol can be used to prevent the skin photoaging via inhibiting NF-kappaB by external topical application.

Topics: Animals; Biphenyl Compounds; Cell Proliferation; Cells, Cultured; Collagen; Epidermis; Fibroblast Growth Factor 2; Humans; Lignans; Magnolia; Male; Matrix Metalloproteinase 1; Mice; Mice, Hairless; NF-kappa B; Plant Extracts; Skin Aging; Ultraviolet Rays

Spectroscopy is useful tool for aggregation studies on fluorephores. One of the major problems with this technique is that the inner filter effect becomes unavoidable since the samples are used at high concentration. In this work, our investigation on magnolol spectroscopic properties shows that the inner filter effect (IFE) of fluorescence plays a critical role in the spectra of magnolol. The strong dependence of the fluorescence parameters on the concentration accounts for the apparent experimental evidence of magnolol aggregation at high concentrations. There are some questions despite the aggregation model based on fluorescent aggregates seems to describe the behavior of the system. The mathematical correction on the emission intensities shows the linear fluorescence-concentration relationship. Furthermore, we propose a mathematic model of excitation spectrum based on the primary IFE (absorption of light of excitation wavelength), which provide a correct explanation of the unusual spectral shift and spectral narrowing in the excitation spectra of magnolol at high concentrations. The shapes of spectra are completely independent on magnolol aggregation and are due only to experimental artifacts, i.e. IFE.

Topics: Biphenyl Compounds; Ethanol; Fluorescence; Hydrogen-Ion Concentration; Light; Lignans; Models, Chemical; Solutions; Spectrum Analysis; Water

Magnolol, a substance purified from the bark of Magnolia officialis, inhibits cell proliferation and induces apoptosis in a variety of cancer cells. The aim of this study was to study the effects of magnolol on CGTH W-2 thyroid carcinoma cells. After 24 h treatment with 80 microM magnolol in serum-containing medium, about 50% of the cells exhibited apoptotic features and 20% necrotic features. Cytochrome-c staining was diffused in the cytoplasm of the apoptotic cells, but restricted to the mitochondria in control cells. Western blot analyses showed an increase in levels of activated caspases (caspase-3 and -7) and of cleaved poly (ADP-ribose) polymerase (PARP) by magnolol. Concomitantly, immunostaining for apoptosis inducing factor (AIF) showed a time-dependent translocation from the mitochondria to the nucleus. Inhibition of either PARP or caspase activity blocked magnolol-induced apoptosis, supporting the involvement of the caspases and PARP. In addition, magnolol activated phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and inactivated Akt by decreasing levels of phosphorylated PTEN and phosphorylated Akt. These data suggest that magnolol promoted apoptosis probably by alleviating the inhibitory effect of Akt on caspase 9. Furthermore, inhibition of PARP activity, but not of caspase activity, completely prevented magnolol-induced necrosis, suggesting the notion that it might be caused by depletion of intracellular ATP levels due to PARP activation. These results show that magnolol initiates apoptosis via the cytochrome-c/caspase 3/PARP/AIF and PTEN/Akt/caspase 9/PARP pathways and necrosis via PARP activation.

Topics: Apoptosis; Apoptosis Inducing Factor; Biphenyl Compounds; Blotting, Western; Caspase 3; Caspase 7; Cell Line, Tumor; Cytochromes c; Flow Cytometry; Humans; Immunohistochemistry; Lignans; Necrosis; Poly(ADP-ribose) Polymerases; Signal Transduction; Thyroid Neoplasms

Magnolol, an active component extracted from Magnolia officinalis, has been reported to inhibit the development of atherosclerotic disease. However, it is not known whether magnolol exerts similar cardioprotective effects in cells treated with TNF-alpha. In the present study, magnolol treatment was found to show potent inhibitory effects on cell proliferation in cultured VSMC in the presence of TNF-alpha. These inhibitory effects were associated with reduced extracellular signal-regulated kinase (ERK) 1/2 activity and G1 cell cycle arrest. Magnolol treatment strongly induced the expression of p21WAF1, but resulted in a decrease in cyclin-dependent kinases (CDKs) and cyclins involved in G1 progression. In addition to G1 cell cycle arrest and growth inhibition in VSMC, magnolol also caused the strong inhibition of TNF-alpha-induced matrix metalloproteinase-9 (MMP-9) expression in a dose-dependent manner as determined by zymography and immunoblot. Moreover, magnolol treatment strongly decreased MMP-9 promoter activity in response to TNF-alpha. We further demonstrated that magnolol reduced the transcriptional activity of NF-kappaB and activation protein-1 (AP-1), two important nuclear transcription factors that are involved in MMP-9 expression. Collectively, these results show that magnolol inhibits cell proliferation, G1 to S phase cell cycle progress and MMP-9 expression through the transcription factors NF-kappaB and AP-1 in TNF-alpha-induced VSMC. The findings of the present study reveal a potential mechanism that explains the anti-atherogenic activity of magnolol.

Topics: Biphenyl Compounds; Cell Proliferation; Cells, Cultured; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinases; Dose-Response Relationship, Drug; G1 Phase; Gene Expression; Humans; Immunoblotting; Lignans; Magnolia; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; NF-kappa B; Plant Extracts; Transcription Factor AP-1; Tumor Necrosis Factor-alpha; Up-Regulation

A series of new bisphenol derivatives bearing allylic moieties were synthesized as potential analogs of honokiol and/or magnolol. Certain compounds exhibited specific anti-proliferation activity against SVR cells and moderate anti-HIV-1 activity in primary human lymphocytes. Compound 5h was the most potent compound and its anti-tumor activity was evaluated in vivo.

Topics: Antineoplastic Agents; Antiviral Agents; Biphenyl Compounds; HIV-1; Lignans; Molecular Structure

To investigate the effects of the principal biologically active compounds of M. officinalis on the growth and acid generation of the main cariogenic bacteria.. Streptococcus mutans, Streptococcus sanguis, Actinomyces naeslundii, Actinomyces viscosus, Lactobacillus rhamnosus were chosen as the experimental bacteria. The active compounds (Magnolol and Honokiol) were separated from M. officinalis and then the effects of the two agents on the growth and acid generation of the bacteria were assessed. The minimal inhibitory concentration (MIC) and the minimal biofilm eradication concentration (MBEC) of the test strains were determined by MBEC-Device.. It was found that the growth of not only plantonic bacteria but also the biofilm were efficiently inhibited by Magnolol and Honokiol. The two agents could also inhibit the acid production of the test strains.. M. officinalis may be an effective anti-caries agent, and further researches will be necessary to define its usefulness in this aspect.

Topics: Acids; Bacteria; Biofilms; Biphenyl Compounds; Dental Caries; Lignans; Magnolia; Plant Extracts

Magnolia bark extract (MBE) is an extract of the dried stem, root, or branch bark of magnolia trees that has been used historically in traditional Chinese and Japanese medicines, and more recently as a component of dietary supplements and cosmetic products. To study the genotoxic potential of MBE, a bacterial reverse mutation assay and an in vivo micronucleus test were conducted. Compositional analysis of the test substance revealed that MBE contains 94% magnolol and 1.5% honokiol. MBE exerted no mutagenic activity in various bacterial strains of Salmonella typhimurium and in Escherichia coli WP2 uvrA, either in the absence or presence of metabolic activation at all doses tested. In the micronucleus test, various doses of MBE did not affect the proportions of immature to total erythrocytes, nor did it increase the number of micronuclei in the immature erythrocytes of Swiss albino mice. The results of these studies demonstrate that MBE is not genotoxic under the conditions of the in vitro bacterial reverse mutation assay and the in vivo micronucleus test, and support the safety of MBE for dietary consumption.

Topics: Administration, Oral; Animals; Biphenyl Compounds; Bone Marrow Cells; Chromatography, High Pressure Liquid; Cyclophosphamide; Dose-Response Relationship, Drug; Escherichia coli; Female; Lignans; Magnolia; Male; Mice; Mice, Inbred Strains; Micronucleus Tests; Mutagenicity Tests; Mutation; Plant Bark; Plant Extracts; Reproducibility of Results; Salmonella typhimurium

The aim is to investigate the effect of Magnolol preserved H460 cells from an oxidative agent tert-butylhydroperoxide (TBHP)-induced cell death. Magnolol augmented cell survival ratio after TBHP challenged. The protective action of this drug was more efficacious than that of N-acetylcysteine (NAC) which is a putative antioxidant. DNA damage, detected by the comet assay, was diminished after treatment of Magnolol. The cells viability decreased after treatment with 0.15 mM TBHP for 24 h, accompanied by inducing apoptotic death of the cells. Cytotoxicity and apoptosis induced by TBHP were significantly inhibited or attenuated after pretreatment with 20 microM Magnolol. Magnolol contributes to the cells survival through downregulated the p53 phosphorylation and PTEN expression, and upregulated Akt phosphorylation. Taken together, Magnolol was effective against DNA single strand breaks (SSB) formation, cytotoxicity and lipid peroxidation induced by TBHP, and its effects on p53 phosphorylation, PTEN and Akt phosphorylation were due to its antioxidative function, and partially via a p53 dependent mechanism in this protective effects.

Topics: Antioxidants; Apoptosis; Biphenyl Compounds; Blotting, Western; Cell Culture Techniques; Cell Line, Tumor; Cell Survival; DNA Fragmentation; Humans; Lignans; Lipid Peroxidation; Oxidants; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; tert-Butylhydroperoxide; Tumor Suppressor Protein p53

The antinociceptive actions of honokiol and magnolol, two major bioactive constituents of the bark of Magnolia officinalis, were evaluated using tail-flick, hot-plate and formalin tests in mice. The effects of honokiol and magnolol on the formalin-induced c-Fos expression in the spinal cord dorsal horn as well as motor coordination and cognitive function were examined. Data showed that honokiol and magnolol did not produce analgesia in tail-flick, hot-plate paw-shaking and neurogenic phase of the overt nociception induced by intraplantar injection of formalin. However, honokiol and magnolol reduced the inflammatory phase of formalin-induced licking response. Consistently, honokiol and magnolol significantly decreased formalin-induced c-Fos protein expression in superficial (I-II) laminae of the L4-L5 lumbar dorsal horn. However, honokiol and magnolol did not elicit motor incoordination and memory dysfunction at doses higher than the analgesic dose. These results demonstrate that honokiol and magnolol effectively alleviate the formalin-induced inflammatory pain without motor and cognitive side effects, suggesting their therapeutic potential in the treatment of inflammatory pain.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Biphenyl Compounds; Central Nervous System Depressants; Disease Models, Animal; Drug Evaluation, Preclinical; Fixatives; Formaldehyde; Inflammation; Lignans; Lumbosacral Region; Magnolia; Memory; Mice; Pain; Posterior Horn Cells; Proto-Oncogene Proteins c-fos

The antiallergic effects of magnolol and honokiol, isolated from the bark of Magnolia obovata (family Magnoliaceae), were investigated both in vitro and in vivo. Magnolol and honokiol potently inhibited passive cutaneous anaphylaxis reactions in mice induced by IgE-antigen complex as well as compound 48/80-induced scratching behaviors. These constituents exhibited not only potent inhibitory activity on the degranulation of RBL-2H3 cells induced by IgE-antigen complex, with IC(50) values of 45 and 55 muM, respectively, but also inhibited the protein expressions of IL-4 and TNF-alpha. Based on these findings, magnolol and honokiol may improve IgE-induced allergic diseases.

Topics: Animals; Anti-Allergic Agents; beta-N-Acetylhexosaminidases; Biphenyl Compounds; Cell Line, Tumor; Dose-Response Relationship, Drug; Immunoglobulin E; Inhibitory Concentration 50; Lignans; Male; Mast Cells; Mice; Mice, Inbred BALB C; Mice, Inbred ICR; Molecular Structure; p-Methoxy-N-methylphenethylamine; Passive Cutaneous Anaphylaxis; Pruritus; Rats

We have reported that the protective effect of Magnolol on TBHP-induced injury in human nonsmall lung cancer H460 cells is partially via a p53 dependent mechanism. In this study, we found that Magnolol displayed a stimulatory effect at low concentrations (< or = 20 microM) whilst inhibitory effect at high concentrations (> or = 40 microM) in H460 cells. To investigate the mechanism of inducing the biphasic effect in H460 cells with Magnolol, we showed that Magnolol stimulated DNA synthesis at low concentrations and displayed an inhibition effect at high concentrations in H460 cells. More importantly, the inhibition of DNA synthesis was accompanied by the S phase cell cycle arrest and the appearance of intense intracytoplasmic vacuoles. These vacuoles can be labeled by autophagic marker monodansylcadaverin (MDC), 3-methyladenine (3-MA), an inhibitor of autophagy, was able to inhibit the occurrence of autophagy. The results of the LDH activity assay and TUNEL assay also showed that Magnolol at high concentrations inhibiting H460 cell growth was not via apoptotic pathway. Furthermore, accompanied by the occurrence of autophagy, the expression of phospho-Akt was down-regulated but PTEN significantly was up-regulated. In conclusion, Magnolol induces H460 cells death by autophagy but not apoptotic pathway. Blockade of PI3K/PTEN/Akt pathway is maybe related to Magnolol-induced autophagy. Autophagic cells death induction by Magnolol underlines the potential utility of its induction as a new cancer treatment modality.

Topics: Antineoplastic Agents; Apoptosis; Autophagy; Biphenyl Compounds; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; DNA; Humans; Lignans; Lung Neoplasms; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase

Magnolol (Mag), an active constituent isolated from the Chinese herb Hou p'u (Magnolia officinalis) has long been used to suppress inflammatory processes. Chronic inflammation is well known to be involved in vascular injuries such as atherosclerosis in which interleukin (IL)-6 may participate. Signal transducer and activator of transcription protein 3 (STAT3), a transcription factor involved in inflammation and the cell cycle, is activated by IL-6. In this study, we evaluated whether Mag can serve as an anti-inflammatory agent during endothelial injuries. The effects of Mag on IL-6-induced STAT3 activation and downstream target gene induction in endothelial cells (ECs) were examined. Pretreatment of ECs with Mag dose dependently inhibited IL-6-induced Tyr705 and Ser727 phosphorylation in STAT3 without affecting the phosphorylation of JAK1, JAK2, and ERK1/2. Mag pretreatment of these ECs dose dependently suppressed IL-6-induced promoter activity of intracellular cell adhesion molecule (ICAM)-1 that contains functional IL-6 response elements (IREs). An electrophoretic mobility shift assay (EMSA) revealed that Mag treatment significantly reduced STAT3 binding to the IRE region. Consistently, Mag treatment markedly inhibited ICAM-1 expression on the endothelial surface. As a result, reduced monocyte adhesion to IL-6-activated ECs was observed. Furthermore, Mag suppressed IL-6-induced promoter activity of cyclin D1 and monocyte chemotactic protein (MCP)-1 for which STAT3 activation plays a role. In conclusion, our results indicate that Mag inhibits IL-6-induced STAT3 activation and subsequently results in the suppression of downstream target gene expression in ECs. These results provide a therapeutic basis for the development of Mag as an anti-inflammatory agent for vascular disorders including atherosclerosis.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Biphenyl Compounds; Blotting, Western; Cattle; Cell Adhesion; Cell Line; Cells, Cultured; Chemokine CCL2; Cyclin D1; Dose-Response Relationship, Drug; Electrophoretic Mobility Shift Assay; Endothelial Cells; Gene Expression; Intercellular Adhesion Molecule-1; Interleukin-6; Lignans; Luciferases; Phosphorylation; Promoter Regions, Genetic; Protein Binding; Recombinant Fusion Proteins; STAT3 Transcription Factor

A simple, rapid, and accurate method for the separation and determination of honokiol and magnolol in Magnolia officinalis and related herbal medicines was developed by combination of flow injection (FI) and capillary zone electrophoresis (CZE). The analysis was carried out using an unmodified fused-silica capillary (50-microm I.D.; total length 7.5 cm; effective length 4.5 cm). A series of optimization steps afforded the following conditions: the sample solvent consisted of 150 mM NaOH and a running buffer composed of 10 mM sodium tetraborate/10 mM sodium dihydrogenphosphate (NaH2PO4) at pH 12 was applied for the separation of the analytes. The separation could be achieved within 5 min with a sample throughput rate of up to 28 h(-1). The repeatability (defined as the relative standard deviation, RSD) for honokiol and magnolol was 2.0% and 1.6% with peak area evaluation, 3.6% and 2.0% with peak height evaluation, and 2.0% and 1.4% with migration time evaluation, respectively. Regression equations revealed linear relationships (r = 0.9991-0.9998) between the peak area of each analyte and the concentration.

Topics: Biphenyl Compounds; Buffers; Chemistry Techniques, Analytical; Chemistry, Pharmaceutical; Electrophoresis, Capillary; Equipment Design; Herbal Medicine; Hydrogen-Ion Concentration; Lignans; Magnolia; Models, Chemical; Phosphates; Plant Extracts; Regression Analysis; Time Factors

A comparative study of preparative isolation and purification of the phenolic compounds magnolol and honokiol from the Chinese medicinal plant Magnoliae officinalis by upright counter-current chromatography (CCC) and semi-preparative HPLC is presented. The comparison reveals that with a two-phase solvent system composed of light petroleum (bp 60-90 degrees C)-ethyl acetate-tetrachloromethane-methanol-water (1:1:8:6:1, v/v), 1250 mg of honokiol and 520 mg of magnolol, with a purity of 98.7 and 99.5%, respectively, were obtained from 2.0 g of a crude sample of Magnoliae officinalis in a single CCC separation. In contrast, semi-preparative HPLC allowed isolation and purification of these two phenolic compounds with significantly lower productivity and higher solvent consumption. Structures of the purified compounds were identified by 1H and 13C NMR.

Topics: Biphenyl Compounds; Chromatography; Lignans; Magnetic Resonance Spectroscopy; Magnolia; Molecular Structure; Solvents

An optimized high-performance liquid chromatographic method coupled with tandem mass spectrometric detection (LC-MS/MS) was developed for the simultaneous determination of honokiol and magnolol in Magnolia officinalis. Honokiol and magnolol were separated from the extracts using a reversed-phase C(18) column with a mobile phase consisted of acetonitrile and water (75:25, v/v) at a flow-rate of 0.8 mL/min. Selected reaction monitoring (SRM) mode was used for all sample quantification by the precursor-ion/product ion pair m/z 265 --> m/z 224 for honokiol and m/z 265 --> m/z 247 for magnolol. Validation data showed that this method has good linearity (r(2) > 0.995) over the concentration range of 0.0025-0.5 microg/mL for honokiol and magnolol, and both intra- and inter-day variability were acceptable within 15% at the lowest concentrations for this method. This proposed method provides excellent specificity, higher sensitivity and shorter run time than conventional methods and was applied successfully to determine the contents of honokiol and magnolol in M. officinalis.

Topics: Biphenyl Compounds; Chromatography, High Pressure Liquid; Lignans; Magnolia; Mass Spectrometry; Molecular Structure; Plant Bark; Reproducibility of Results

The influence of plant product magnolol (0-100 microM) on the contractile activity of isolated colonic muscle strips in guinea pig and related mechanism were investigated. Magnolol did not affect the base tone of colon muscle strips, but it dose-dependently inhibited 40 mM KCl-, 1 microM carbachol (CCh)- and 10 microM serotonin (5-HT)-induced contractions at concentrations higher than 10 microM. And also, magnolol inhibited the 5-HT- or CCh-induced muscle contraction in calcium-free buffer. Furthermore, magnolol inhibited the KCl-induced contraction under the condition of procaine. In addition, inhibition rate of nifedipine plus magnolol on muscle strips was lower than that of nifedipine alone. Moreover, magnolol dose-dependently decreased the velocity of pellet propulsion in the concentration range of 0.1-10 microM, and totally inhibited pellet propulsion at the concentration higher than 30 microM. Thus, it can be concluded that magnolol may 1) block receptor-operated cation channels and the voltage dependent Ca2+ channel, and 2) inhibit calcium release from the sarcolemmal membrane (SR) through blocking InsP3-sensitive and ryanodine-sensitive pathways. This explains, at least partially, that Cortex magnoliae officinalis exerts therapeutic effects on gastrointestinal disease through relaxation of GI tract smooth muscles.

Topics: Anesthetics, Local; Animals; Biphenyl Compounds; Calcium Channel Blockers; Carbachol; Colon; Dose-Response Relationship, Drug; Gastrointestinal Agents; Gastrointestinal Transit; Guinea Pigs; In Vitro Techniques; Lignans; Male; Muscarinic Agonists; Muscle Contraction; Muscle, Smooth; Nifedipine; Potassium Chloride; Procaine; Serotonin

The aim of the present study was to investigate the neuroprotective effects of honokiol and magnolol, two major bioactive constituents of the bark of Magnolia officinalis, against neuron toxicity induced by glucose deprivation, excitatory amino acids and hydrogen peroxide (H(2)O(2)) in cultured rat cerebellar granule cells. Cell membrane damage was measured with a lactate dehydrogenase (LDH) release assay and 3-(4,5-dimethyl-2 thiazoyl)-2,5-diphenyl-tetrazolium bromide (MTT) assay was used to assess mitochondrial activity, reflecting cell survival. Results showed that honokiol and magnolol alone did not affect mitochondrial function and cell damage, but significantly reversed glucose deprivation-induced mitochondrial dysfunction and cell damage. The glutamate receptor blocker MK-801 and antioxidant vitamin E also provided protection against this damage. Furthermore, honokiol was more potent than magnolol in protecting against glutamate-, N-methyl-D-aspartate (NMDA)- and H(2)O(2)-induced mitochondrial dysfunction. These results demonstrated that the neuroprotective effects of honokiol and magnolol may be related to their anti-oxidative actions and antagonism of excitotoxicity induced by excitatory amino acids, suggesting that both compounds may be potential therapeutic agents for neurodegenerative diseases.

Topics: Animals; Antioxidants; Biphenyl Compounds; Cells, Cultured; Cerebellum; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Glucose; Glutamic Acid; Hydrogen Peroxide; L-Lactate Dehydrogenase; Lignans; Mitochondria; N-Methylaspartate; Neurons; Neuroprotective Agents; Oxidative Stress; Rats; Rats, Sprague-Dawley; Vitamin E

Capillary electrophoresis with electrochemical detection has been employed for the determination of honokiol and magnolol in Cortex Magnoliae Officinalis (i.e. Magnolia Bark) for the first time. Effects of several important factors such as the concentration and the acidity of the running buffer, separation voltage, injection time, and detection potential were investigated to acquire the optimum conditions. The detection electrode was a 300 microm diameter carbon disc electrode at a working potential of +0.90 V (versus saturated calomel electrode (SCE)). The two analytes can be well separated within 6 min in a 40 cm length fused silica capillary at a separation voltage of 18 kV in a 50mM borate buffer (pH 9.2). The relation between peak current and analyte concentration was linear over about three orders of magnitude with the detection limits (S/N=3) of 0.38 and 0.51 microM for honokiol and magnolol, respectively. The proposed method has been successfully applied to monitor the two bioactive constituents in the real plant samples with satisfactory assay results.

Topics: Anti-Arrhythmia Agents; Biphenyl Compounds; Drugs, Chinese Herbal; Electrochemistry; Electrodes; Electrophoresis, Capillary; Hydrogen-Ion Concentration; Lignans; Magnolia; Plant Bark; Regression Analysis

A separation of honokiol 1 from the closely structurally related magnolol 2 was developed. Honokiol demonstrated weak activity against HIV-1 in human lymphocytes.

Topics: Animals; Antineoplastic Agents, Phytogenic; Antiviral Agents; Biphenyl Compounds; Cell Line, Tumor; Chlorocebus aethiops; Drug Screening Assays, Antitumor; Humans; In Vitro Techniques; Leukocytes, Mononuclear; Lignans; Vero Cells

Dental caries has been an intractable disease in spite of intense dental research. Glucosyltransferase (GTF) enzyme plays the most important role in the development of dental caries. In our previous studies, magnolol, a compound from Magnolia officinalis Rehder et Wilson (Magnoliaceae), was shown to possess a strong anti-GTF activity. The purpose of the present study was to examine the effect of magnolol on the functional domains of GTF for the purpose of defining its anti-GTF activity mechanism. GTF-I which was prepared from Streptococcus milleri transformant KSB8 cells expressing the gtfB gene was used. The results demonstrated magnolol reduced total glucan synthesis, depending on the magnolol concentration. There were no significant differences in Michaelis constant (K(m)) values between the presence and absence of magnolol as determined by Lineweaver-Burk plot, and maximum velocity (V(m)) in the presence of magnolol was lower than that in its absence. Magnolol significantly inhibited both sucrose hydrolysis and glucosyl transfer to glucan by GTF-I. Free glucose in the presence of magnolol was reduced by 33-48% as compared to in its absence, while the quantity of glucan was reduced by 75-82%. These findings suggested that magnolol inhibited both two sequential reaction phases of GTF non-competitively by operating on the glucan-binding domain, but not on the catalytic domain. Magnolol could be a valuable resource for the exploration of novel bioactive compounds in natural products.

Topics: Biphenyl Compounds; Cariostatic Agents; Dose-Response Relationship, Drug; Electrophoresis, Polyacrylamide Gel; Enzyme Inhibitors; Glucans; Glucosyltransferases; Humans; Lignans; Streptococcus milleri Group; Sucrose

This paper describes the development and the application of a novel carbon nanotube/poly(methyl methacrylate) (CNT/PMMA) composite electrode as a sensitive amperometric detector of CE. The composite electrode was fabricated on the basis of the in situ polymerization of a mixture of CNT and prepolymerized methylmethacrylate in the microchannel of a piece of fused-silica capillary under heat. The performance of this unique system has been demonstrated by separating and detecting honokiol and magnolol in traditional Chinese medicine, Cortex Magnoliae Officinalis. Factors influencing their separation and detection processes were examined and optimized. Honokiol and magnolol were well separated within 7 min in a 40 cm long capillary at a separation voltage of 15 kV using a 50 mM borate buffer (pH 9.2). The new CNT-based CE detector offered significantly lower operating potentials, yielded substantially enhanced S/N characteristics, and exhibited resistance to surface fouling and hence enhanced stability. It demonstrated long-term stability and reproducibility with RSDs of less than 5% for the peak current (n = 9) and should also find a wide range of applications in microchip CE, flowing injection analysis, and other microfluidic analysis systems.

Topics: Biphenyl Compounds; Catalysis; Drugs, Chinese Herbal; Electrodes; Electrophoresis, Capillary; Hydrogen-Ion Concentration; Lignans; Magnolia; Nanotubes, Carbon; Polymethyl Methacrylate; Sensitivity and Specificity

Magnolol, a component of the bark of Magnolia obovata, has been reported to possess various biological activities, such as anti-carcinogenicity, anti-promotion activity and anti-oxidative activity. These findings suggest potential for this compound in cancer chemoprevention. Interestingly, there have been no reports to date on the potential anti-mutagenic activity of magnolol, involving inhibition of initiation processes of the primary stage of carcinogenicity. In this study, anti-mutagenic activity of magnolol against mutagenicity induced by direct mutagens [1-nitropyrene (1-NP), N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG)] and indirect mutagens [2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-aminodipyrido[1,2-a:3',2'-d]imidazole (Glu-P-2), benzo(a)pyrene (B(a)P), 2-aminoanthracene (2-AA) and 7,12-dimethylbenz[a]anthracene (DMBA)] were investigated using the bacterial mutagenicity test (Ames test). Results show that magnolol strongly inhibits mutagenicity induced by indirect mutagens, but does not affect direct mutagens. To elucidate the mechanism of this effect against indirect mutagens, effect of magnolol on CYP1A1- and CYP1A2-related enzyme activities of ethoxyresorufin-O-deethylase (EROD) and methoxyresorufin-O-demethylase (MROD) were investigated. Magnolol strongly and competitively suppressed these enzyme activities, suggesting it inhibited mutation induced by indirect mutagens through suppression of CYP1A1 and CYP1A2 activity.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Anthracenes; Antimutagenic Agents; Benzo(a)pyrene; Biphenyl Compounds; Cytochrome P-450 CYP1A1; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP1A2 Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Imidazoles; Kinetics; Lignans; Male; Methylnitronitrosoguanidine; Microsomes, Liver; Molecular Structure; Mutagenicity Tests; Mutagens; Oxidoreductases; Quinoxalines; Rats; Rats, Sprague-Dawley; Salmonella typhimurium

To evaluate the efficiency of 17 Chinese herbs on periodontal pathogenic microbes.. 17 efficient substances from Chinese herbs were purchased from Chinese Drug Identification Bureau, including magnesium lithospermate B, magnolol, tetramethyl pyrazine, matrine, dycyrrhizin, gentiopicrin, aloperin, baicalin, oleanolic acid, ginkgo seed, total glucosides of paeony capsules, anisldehyde, archin, cablin patchouli, hydrochloric acid Berberine, forsythin, and kakonein. Antimicrobial sensitivity tests of broth microdilution methods on 96-microwell plate were carried out for identification of the antimicrobial activity of extracts against six species of microorganisms: Actinobacillus actinomycete mitans(Aa) Y4, Actinomycetes viscosus(Av) 19246, Porphyromonas gingivalis(Pg) 33277, Fusobacterium necrophorum(Fn) 25286, Actinomyces naeslundii(An) wvl 45 and Prevotella nigrescens(Pn).. It was found that magnesium lithospermate B and magnolol showed the most efficient inhibition on microorganism of Pn and Fn, with the MIC being 0.053 and 0.313 mg/ml for Pn and Fn, respectively. Tetramethyl pyrazine, matrine, dycyrrhizin, gentiopicrin, aloperin, baicalin, and oleanolic acid had better inhibition than total glucosides of paeony capsules, anisldehyde, archin, cablin patchouli, hydrochloric acid berberine, forsythin, and kakonein.. The Chinese herbs, magnesium lithospermate B and magnolol are efficient agents for inhibition against periodontal pathogenic microbes.

Topics: Actinomyces; Actinomyces viscosus; Aggregatibacter actinomycetemcomitans; Anti-Infective Agents; Biphenyl Compounds; Drugs, Chinese Herbal; Fusobacterium necrophorum; Lignans; Periodontal Diseases; Porphyromonas gingivalis; Prevotella nigrescens

Recent reports have indicated that honokiol can induce apoptosis, suppress tumor growth, and inhibit angiogenesis. In this report, we found that honokiol potentiated the apoptosis induced by tumor necrosis factor (TNF) and chemotherapeutic agents, suppressed TNF-induced tumor cell invasion, and inhibited RANKL-induced osteoclastogenesis, all of which are known to require nuclear factor-kappaB (NF-kappaB) activation. Honokiol suppressed NF-kappaB activation induced by a variety of inflammatory stimuli, and this suppression was not cell type specific. Further studies showed that honokiol blocked TNF-induced phosphorylation, ubiquitination, and degradation of IkappaBalpha through the inhibition of activation of IkappaBalpha kinase and of Akt. This led to suppression of the phosphorylation and nuclear translocation of p65 and NF-kappaB-dependent reporter gene expression. Magnolol, a honokiol isomer, was equally active. The expression of NF-kappaB-regulated gene products involved in antiapoptosis (IAP1, IAP2, Bcl-x(L), Bcl-2, cFLIP, TRAF1, and survivin), proliferation (cyclin D1, cyclooxygenase-2, and c-myc), invasion (matrix metalloproteinase-9 and intercellular adhesion molecule-1), and angiogenesis (vascular endothelial growth factor) were also down-regulated by honokiol. Honokiol also down-regulated NF-kappaB activation in in vivo mouse dorsal skin model. Thus, overall, our results indicate that NF-kappaB and NF-kappaB-regulated gene expression inhibited by honokiol enhances apoptosis and suppresses osteoclastogenesis and invasion.

Topics: Animals; Apoptosis; Biphenyl Compounds; Carrier Proteins; Cyclin D1; Cyclooxygenase 2; Dose-Response Relationship, Drug; Drug Synergism; Genes, myc; Humans; I-kappa B Proteins; Lignans; Matrix Metalloproteinase 9; Membrane Glycoproteins; Membrane Proteins; Mice; Molecular Structure; NF-kappa B; NF-KappaB Inhibitor alpha; Osteoclasts; Osteogenesis; Phosphorylation; Promoter Regions, Genetic; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Synaptotagmin I; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

High-performance liquid chromatography was employed to determine the contents of the eight marker components liquiritin, naringin, hesperidin, thymol, imperatorin, honokiol, isoimperatorin, and magnolol in the traditional Chinese medicinal preparation Huoxiang-zhengqi liquid. The separation was performed on a C(18) column by stepwise gradient elution with water-methanol-acetonitrile (0.01 min, 68:30:2; 20 min, 60:38:2; 50 min, 34:64:2; 65 min, 34:64:2; 75 min, 28:70:2; 85 min, 68:30:2) as the mobile phase at a flow rate of 1 ml/min, with UV detection at 283 nm. Eight regression equations showed good linear relationships between the peak area ratio of each marker to internal standard and amounts. The recoveries of the markers listed above were 97.4, 98.5, 97.4, 98.6, 97.8, 99.2, 97.0, and 97.5%, respectively. The repeatability and reproducibility (relative standard deviation) of the method were less than 2.2 and 3.0%, respectively.

Topics: Biphenyl Compounds; Chromatography, High Pressure Liquid; Drugs, Chinese Herbal; Flavanones; Furocoumarins; Glucosides; Hesperidin; Lignans; Reproducibility of Results; Solutions; Thymol

Magnolol has been reported to have an inhibitory effect on tumor invasion in vitro and in vivo. In this study, we found that treatment with 30 microM magnolol exhibited growth inhibition partly by inducing apoptosis in cultured human leukemia U937 cells and that the apoptosis was induced via the sequential ordering of molecular events; 1) a transient decrease of phosphorylated extracelluar signal-requlated kinase (ERK), 2) translocation of apoptosis inducing factor (AIF) from mitochondria to cytosol concurrent with a decreased membrane potential, and 3) downregulation of bcl-2 protein. Pretreatment of the cells with a pan-caspase inhibitor Z-Val-Ala-Asp-fluoromethyl ketone (Z-VAD-FMK) did not prevent the apoptosis induced by magnolol. These findings indicated that the above-mentioned sequence of intracellular signaling events led to apoptosis in magnolol-treated U937 cells, which was caspase-independent.

Topics: Apoptosis; Apoptosis Inducing Factor; Biphenyl Compounds; Humans; Lignans; Mitochondria; Mitogen-Activated Protein Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; U937 Cells

To evaluate the antioxidant capacity and quality of traditional Chinese medicines using TLC-bioautography.. Two chromatograms of each crude drug sample were obtained, after developing, by spraying with 1,1-diphenyl-2-picrylhydrazyl (DPPH) solution in ethanol and classical stained reagents, separately. The images sprayed with DPPH solution were captured under light after the plates were heated at 40 degrees C for 30 min, and scanned using video scan software to get peak areas of active compounds.. Total peak areas of the spots on TLC were calculated to evaluate the antioxidant capacity of the tested crude drugs from different habitats and sources. The results indicated that Radix Linderae cultivated in Tiantai (Zhejiang province), Cortex Magnoliae Officinalis cultivated in Liangshan (Sichuan province), and Fructus Perillae acquired in Shanghai have the highest scavenging properties towards DPPH in their respective TLC-autographic assays. Norisoboldine, magnolol and honokiol, luteolin, apigenin and an unknown compound "U" proved to be the major antioxidant components in the corresponding crude drugs as they contribute the dominating peak areas to the total ones.. TLC-bioautography can not only be used for screening of the components with antioxidant potency but also for the purpose of quality evaluation of traditional Chinese medicines at the same time, and the method proved to be selective, simple and reproducible.

Topics: Alkaloids; Antioxidants; Biphenyl Compounds; China; Chromatography, Thin Layer; Drugs, Chinese Herbal; Hydrazines; Lignans; Lindera; Luteolin; Magnolia; Perilla; Picrates; Plants, Medicinal; Quality Control; Reproducibility of Results

To optimize preparative technique for banxia-houpu effervescent tablets.. Based on the pH, disintegration time limited, taste, and rigidity of effervescent tablets, the proper proportion between citric acid and sodium bicarbonate, as well as the proper quantity of polyethylene glycol 6000 and sodium cyclamate in the effervescent tablets were determined by using orthogonal design. The content of magnolol and honokiol in effervescent tablets were measured by HPLC.. The optimal preparative technique was: cirtic acid: sodium bicarbonate = 0.65:1. The percentage of polyethylene glycol 6000 was 85%, and the percentage of sodium cyclamate was 1.0%.. The preparative technique is stable, reliable and suitable for practical use.

Topics: Biphenyl Compounds; Chemistry, Pharmaceutical; Chromatography, High Pressure Liquid; Citric Acid; Drugs, Chinese Herbal; Hydrogen-Ion Concentration; Lignans; Pinellia; Plants, Medicinal; Polyethylene Glycols; Sodium Bicarbonate; Tablets; Technology, Pharmaceutical

Investigate into transport rate and retention rate transference of principal effective constituent in Shujin Kechuang capsule, a new development Chinese patent medicine for theraphy asthma.. HPLC was applied to analyze the content of ephedrine hydrochloride and honokiol and magnolol in crude drugs and 60% ethanol extracting solution and 25% concentrated solution,50% concentrated solution, 100% concentrated solution and finished product ( Shujin Kechuang capsule).. The transport rate of ephedrine hydrochloride and honokiol and magnolol is 56. 32%, 14. 43%, 14. 56% in the finished product respectively.. should be concentrate and desiccation in the condition that decompress and low temperature.

Topics: Asthma; Biphenyl Compounds; Capsules; Chromatography, High Pressure Liquid; Drug Combinations; Drugs, Chinese Herbal; Ephedra sinica; Ephedrine; Lignans; Magnolia; Plant Structures; Plants, Medicinal; Technology, Pharmaceutical

Magnolol (MG) and honokiol (HK), two lignans showing anti-inflammatory and anti-oxidant properties and abundantly available in the medicinal plants Magnolia officinalis and M. obovata, were found to enhance HL-60 cell differentiation initiated by low doses of 1,25-dihydroxyvitamin D3 (VD3) and all-trans-retinoic acid (ATRA). Cells expressing membrane differentiation markers CD11b and CD14 were increased from 4% in non-treated control to 8-16% after being treated with 10-30 microM MG or HK. When added to 1 nM VD3, MG or HK increased markers expressing cells from approximately 30% to 50-80%. When either MG or HK was added to 20 nM ATRA, only CD11b, but not CD14, expressing cells were increased from 9% to 24-70%. Under the same conditions, adding MG or HK to VD3 or ATRA treatment further enlarged the G0/G1 cell population and increased the expression of p27(Kip1), a cyclin-dependent kinase inhibitor. Pharmacological studies using PD098059 (a MEK inhibitor), SB203580 (a p38 MAPK inhibitor) and SP600125 (a JNK inhibitor) suggested that the MEK pathway was important for VD3 and ATRA-induced differentiation and also its enhancement by MG or HK, the p38 MAPK pathway had a inhibitory effect and the JNK pathway had little influence. It is evident that MG and HK are potential differentiation enhancing agents which may allow the use of low doses of VD3 and ATRA in the treatment for acute promyelocytic leukemia.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents, Phytogenic; Biphenyl Compounds; Calcitriol; Calcium Channel Agonists; CD11b Antigen; Cell Differentiation; G1 Phase; HL-60 Cells; Humans; Lignans; Lipopolysaccharide Receptors; MAP Kinase Signaling System; Resting Phase, Cell Cycle; Tretinoin

The neolignans, magnolol 1 and honokiol 2 have been reported to inhibit the growth of several tumor cell lines in vitro and in vivo. The chemical structure of magnolol and honokiol consists of biphenyl skeleton with phenolic and allylic functionalities. Analogs of 1 and 2 containing different substitution have been studies for their effect on the growth of Hep-G2 and their structure-activity relationships were reported in this work.

Topics: Antineoplastic Agents; Biphenyl Compounds; Cell Line, Tumor; Humans; Lignans; Structure-Activity Relationship

This study investigated the effect of magnolol, a compound isolated from Magnolia officinalis, on lipolysis in lipid-laden RAW 264.7 macrophages. Treatment of macrophages with magnolol led to dissolution of lipid droplets. This phenomenon was accompanied by a dose-dependent release of glycerol and cholesterol and a concomitant reduction in intracellular levels of glycerol and cholesterol. Furthermore, adipose differentiation-related protein (ADRP), a lipid droplet-associated protein, was down-regulated by magnolol in a dose- and time-dependent manner by Western blot analysis. Immunofluorescence studies also showed that ADRP became detached from the surface of lipid droplets after magnolol treatment. The lipolytic effect of magnolol was not mediated through the cAMP-protein kinase A (PKA) system, an authentic lipolytic pathway for macrophages, since magnolol did not induce an increase of intracellular cAMP levels, and pretreatment with either of PKA inhibitors, PKI and KT5720, did not abrogate the lipolytic response to magnolol. We conclude that magnolol induce-lipolysis of lipid-laden macrophages by down-regulation of ADRP expression and detachment of ADRP from the lipid droplet surface by a cAMP-independent mechanism. Lipolysis of lipid-laden macrophages may occur when the amount of ADRP on the surface of lipid droplets is not enough to stabilize the lipid droplets.

Topics: Animals; Biphenyl Compounds; Down-Regulation; Lignans; Lipid Metabolism; Lipolysis; Macrophages; Mice; Microscopy, Fluorescence; Rats

A simple and sensitive method has been developed for determining honokiol and magnolol in fresh Magnolia obovata (M. obovata) by micro high-performance liquid chromatography with electrochemical detection (microHPLC-ECD). Chromatography was performed using a Capcell Pak C-18 UG 120 microbore octadecylsilica (ODS) column, methanol-water-phosphoric acid (65 : 35 : 0.5, v/v/v), as a mobile phase and applied potential at +0.8 V vs. Ag/AgCl. Peak heights were found linearly related to the amounts of honokiol and magnolol injected from 0.67 pg to 2.0 ng (r>0.999). The detection limits (S/N=3) were 0.13 pg, respectively. Honokiol and magnolol of 0.27 ng were detected with relative standard deviation (RSD) of 0.73 and 1.17% (n=5), respectively. Honokiol and magnolol in Magnolia Bark of the Japanese Pharmacopoeia were extracted with 70% methanol, diluted with a mobile phase, and injected into the microHPLC-ECD for determination. Recoveries of honokiol and magnolol in Magnolia Bark exceeded 98.7% with RSD, less than 0.93% (n=5). Determination of the distributions of honokiol and magnolol in bark, phloem, wood, leaf blades, and petioles of fresh M. obovata were made using weight samples of 40-238 mg. This method is useful to determine honokiol and magnolol in M. obovata, which is a candidate for crude magnolia bark for traditional Japanese herbal medicines.

Topics: Biphenyl Compounds; Chromatography, High Pressure Liquid; Electrochemistry; Lignans; Magnolia; Medicine, Kampo; Microfluidics; Plant Components, Aerial; Plant Extracts; Plant Leaves

Magnolol stimulates adrenal steroidogenesis and induces the distributional changes of p160 and adipose differentiation-related protein (ADRP) in rat adrenal cells. This study investigated the underlying signaling mechanisms involved in these processes. Magnolol (30 microM) caused a time-dependent increase in the phosphorylation of extracellular signal-related kinase (ERK) in cultured adrenal cells. The following evidence supports a link between ERK activation and p160 translocation. First, the magnolol-induced redistribution of p160 from the lipid droplet surface to the cytosol, resulting in the decrease in the percentages of p160-positive cells, and this decrease in p160-positive cells was completely blocked by pretreatment with either of the MAPK-ERK kinase (MEK) inhibitors PD98059 or U0126. Second, magnolol did not significantly decrease total p160 protein levels but caused an increase in threonine phosphorylation of p160, which reached a maximum after 5 min of magnolol treatment, and this magnolol-induced phosphorylation of p160 was prevented by pretreatment with U0126, suggesting the involvement of ERK. In addition, magnolol decreased both ADRP immunostaining intensity at the lipid droplet surface and the percentage of ADRP-positive cells. This was further confirmed biochemically by the decrease in ADRP levels in total cell homogenates and in lipid droplet fractions. Magnolol-induced decrease in ADRP staining at the lipid droplet surface was not affected by pretreatment with PD98059 or U0126, indicating that ERK signaling was not involved in this event. Furthermore, treatment with 30 microM magnolol for 6 h resulted in about 50% decrease in ADRP protein level. Therefore, decreased protein levels of p160 and ADRP at the lipid droplet surface induced by magnolol were mediated via two different mechanisms: phosphorylation of p160 and downregulation of ADRP expression, respectively.

Topics: Adrenal Glands; Animals; Biphenyl Compounds; Blotting, Western; Butadienes; Cells, Cultured; Cytoplasmic Granules; Enzyme Inhibitors; Extracellular Signal-Regulated MAP Kinases; Female; Flavonoids; Fluorescent Antibody Technique; Histone Acetyltransferases; Lignans; Lipid Metabolism; Marine Toxins; Membrane Proteins; Microscopy, Fluorescence; Nitriles; Nuclear Receptor Coactivator 1; Oxazoles; Perilipin-2; Phosphoprotein Phosphatases; Phosphorylation; Protein Transport; Pyrans; Rats; Rats, Wistar; Spiro Compounds; Time Factors; Transcription Factors

Propionibacterium acnes, an anaerobic pathogen, plays an important role in the pathogenesis of acne and seems to initiate the inflammatory process by producing proinflammatory cytokines. In order to demonstrate the anti-inflammatory effects and action mechanisms of magnolol and honokiol, several methods were employed. Through DPPH and SOD activity assays, we found that although both magnolol and honokiol have antioxidant activities, honokiol has relatively stronger antioxidant activities than magnolol {[for DPPH assay, % of DPPH bleaching of magnolol and honokiol (500 microM magnolol: 19.8%; 500 microM honokiol: 67.3%)]; [for SOD assay, SOD activity (200 microM magnolol: 53.4%; 200 microM honokiol: 64.3%)]}. Moreover, the production of interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-alpha) induced by P. acnes in THP-1 cells, a human monocytic cell line, was reduced by magnolol and honokiol {[for IL-8 (10 microM magnolol: 42.7% inhibition; 10 microM honokiol: 51.4% inhibition)]; [for TNF-alpha (10 microM magnolol: 20.3% inhibition; 10 microM honokiol: 39.0% inhibition)]}. Cyclooxygenase-2 (Cox-2) activity was also suppressed by them [(15 microM magnolol: 45.8% inhibition), (15 microM honokiol: 66.3% inhibition)]. Using a nuclear factor-kappaB (NF-kappaB) luciferase reporter assay system and Western analysis, we identified that magnolol and honokiol exert their anti-inflammatory effects by inhibiting the NF-kappaB element, which exists in Cox-2, IL-8, and TNF-alpha promoters [(15 microM magnolol: 44.8% inhibition), (15 microM honokiol: 42.3% inhibition)]. Of particular note is that magnolol and honokiol operate downstream of the MEKK-1 molecule. Together with their previously known antibacterial activity against P. acnes and based on these results, we suggest that magnolol and honokiol may be introduced as possible acne-mitigating agents.

Topics: Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Biphenyl Compounds; Cytokines; Humans; Interleukin-8; Lignans; Magnolia; MAP Kinase Kinase Kinase 1; Microbial Sensitivity Tests; Monocytes; NF-kappa B; Phytotherapy; Picrates; Plant Extracts; Propionibacterium acnes; Superoxide Dismutase; Tumor Necrosis Factor-alpha

The effects of honokiol and magnolol, two major bioactive constituents of the bark of Magnolia officinalis, on Ca(2+) and Na(+) influx induced by various stimulants were investigated in cultured rat cerebellar granule cells by single-cell fura-2 or SBFI microfluorimetry. Honokiol and magnolol blocked the glutamate- and KCl-evoked Ca(2+) influx with similar potency and efficacy, but did not affect KCl-evoked Na(+) influx. However, honokiol was more specific for blocking NMDA-induced Ca(2+) influx, whereas magnolol influenced with both NMDA- and non-NMDA activated Ca(2+) and Na(+) influx. Moreover, the anti-convulsant effects of these two compounds on NMDA-induced seizures were also evaluated. After honokiol or magnolol (1 and 5 mg/kg, i.p.) pretreatment, the seizure thresholds of NMRI mice were determined by tail-vein infusion of NMDA (10 mg/ml). Data showed that both honokiol and magnolol significantly increased the NMDA-induced seizure thresholds, and honokiol was more potent than magnolol. These results demonstrated that magnolol and honokiol have differential effects on NMDA and non-NMDA receptors, suggesting that the distinct therapeutic applications of these two compounds for neuroprotection should be considered.

Topics: Analysis of Variance; Animals; Anti-Anxiety Agents; Biphenyl Compounds; Calcium; Cells, Cultured; Cerebellum; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Ion Channels; Lignans; Mice; N-Methylaspartate; Neurons; Platelet Aggregation Inhibitors; Potassium Chloride; Quinoxalines; Rats; Rats, Sprague-Dawley; Seizures; Sodium

To study the effects of magnolol and honokiol on isolated smooth muscle of gastrointestinal tract and their relationship with Ca2+, and on the gastric emptying and the intestinal propulsive activity in mice.. Routine experimental methods using isolated gastric fundus strips of rats and isolated ileum segments of guinea pigs were adopted to measure the smooth muscle tension. The effects of magnolol 10(-3), 10(-4), 10(-5) mol/L, and honokiol 10(-4), 10(-5), 10(-6) mol/L on the contractility of gastric fundus strips of rats and ileum of guinea pigs induced by acetylcholine (Ach) and 5-hydroxytryptamine (5-HT) was assessed respectively. The method using nuclein and pigment methylene blue was adopted to measure the gastric retention rate of nuclein and the intestinal propulsive ratio of a nutritional semi-solid meal for assessing the effect of magnolol and honokiol (0.5, 2, 20 mg/kg) on gastric emptying and intestinal propulsion.. Magnolol and honokiol significantly inhibited the contractility of isolated gastric fundus strips of rats treated with Ach or 5-HT and isolated ileum guinea pigs treated with Ach or CaCl2, and both of them behaved as non-competitive muscarinic antagonists. Magnolol and honokiol inhibited the contraction induced by Ach in Ca2+-free medium and extracellular Ca2+-dependent contraction induced by Ach. Each group of magnolol and honokiol experiments significantly decreased the residual rate of nuclein in the stomach and increased the intestinal propulsive ratio in mice.. The inhibitory effect of magnolol and honokiol on contractility of the smooth muscles of isolated gastric fundus strips of rats and isolated ileum of guinea pigs is associated with a calcium-antagonistic effect. Magnolol and honokiol can improve the gastric emptying of a semi-solid meal and intestinal propulsive activity in mice.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Biphenyl Compounds; Drugs, Chinese Herbal; Female; Gastric Emptying; Gastrointestinal Agents; Gastrointestinal Motility; Guinea Pigs; Lignans; Male; Mice; Muscle, Smooth; Rats

This study focused on identifying the signalling mediating the effect of magnolol on corticosterone production. Magnolol-induced corticosterone production was completely inhibited by mitogen-activated protein kinase kinase (MEK)-inhibitor PD98059, tyrosine kinase (TK)-inhibitor genistein or Janus tyrosine kinase 2 (JAK2)-inhibitor AG490, suggesting that extracellular signal-regulated kinase (ERK) and JAK2 are both involved in this signaling cascade. Further, magnolol induced the transient phosphorylation of MEK, ERK, cAMP response-element binding protein (CREB) and the expression of 32 and 30 kDa steroidogenic acute regulatory protein (StAR) in a time-dependent manner. Inhibition of TK or JAK2 activities blocked magnolol-induced phosphorylation of MEK and ERK, again supporting the upstream role of JAK2. The activation of JAK2 or MEK apparently mediated the magnolol-induced phosphorylation of CREB and the upregulation of StAR. These findings demonstrate a novel pathway for magnolol to induce the expression of StAR, which regulates the rate-limiting step in sterodiogenesis.

Topics: Adrenal Cortex; Animals; Biphenyl Compounds; Corticosterone; Cyclic AMP Response Element-Binding Protein; Extracellular Signal-Regulated MAP Kinases; Female; Janus Kinase 2; Lignans; Phosphoproteins; Phosphorylation; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Rats; Rats, Wistar; Signal Transduction

Magnolol has neurotrophic effects in primary cultured rat cortical neurons, which are expressed as the promotion of neurite outgrowth and neuronal survival. In this study, we investigated the protective effect of magnolol against age-related neuronal loss in the hippocampus using senescence-accelerated mouse (SAMP1). Magnolol (5, 10 mg/kg) was orally administered once a day for 14 d to 2- or 4-month-old mice, and evaluation was carried out when the mice were 4 or 6 months old. The density of neurofibrils decreased with aging in the stratum radiatum of the CA1 region in the hippocampus of SAMP1, not SAMR1. Treatment with magnolol significantly prevented the decrease of neurofibrils in the CA1, when it was administered in 2-month-olds. However, administration at 4 months of age did not result in a preventive effect. These findings suggest that the administration of magnolol before the initiation of neuronal loss may result in a protective effect in the hippocampus.

Topics: Aging; Animals; Biphenyl Compounds; Cell Count; Hippocampus; Lignans; Mice; Mice, Inbred Strains; Nerve Degeneration; Neurites; Neurofibrils; Tissue Embedding

To study the chemical characteristic, to identify the different forms and to establish the new standard for the quality control of Cortex Magnoliae Officinalis.. HPLC method was used with acetonitrile-water (63:37) as the mobile phase at room temperature. The chromatographic column was Lichrospher 100 RP-18e (4.6 mm x 250 mm, 5 microm). The flow rate was 1 mL x min(-1), and the detection wavelength was 294 nm. The chromatograms of 45 individuals from 13 seed resources of Cortex Magnolia Officinalis were recorded. The chemical characteristics analysis and comparability' s calculation of seed resources were made.. It was proposed that the area ratio of peak 5 to 6 (characteristic I) and the area ratio of peak 5 and 6 to the total peak areas (characteristic II) are the identification characteristics for different seed resources of Cortex Magnoliae Officinalis.. This method can be used effectively to identify the high quality seed resource of Cortex Magnoliae Officinalis.

Topics: Biphenyl Compounds; China; Chromatography, High Pressure Liquid; Ecosystem; Lignans; Magnolia; Plant Bark; Plants, Medicinal; Quality Control

Limited evidence is available as to whether Kampo medicine modifies gastrointestinal function in humans. We investigated the effect of a Kampo medicine, Hange-koboku-to (Banxia-houpo-tang, HKT), on patients with functional dyspepsia (FD) and on healthy volunteers with regard to gastric motility. The gastric emptying rate (GER) in FD patients was significantly lower than in the healthy subjects. GER in FD patients and in healthy volunteers showed a significant increase after 2 weeks of medication with HKT. Furthermore, gastrointestinal symptoms improved significantly in the FD patients after the administration of HKT. These results suggest that HKT improves delayed gastric emptying and acts as a prokinetic agent.

Topics: Adult; Biphenyl Compounds; Catechols; Chromatography, High Pressure Liquid; Drugs, Chinese Herbal; Dyspepsia; Fatty Alcohols; Female; Gastric Emptying; Humans; Lignans; Male; Medicine, Kampo; Middle Aged; Phytotherapy; Statistics, Nonparametric; Ultrasonography

The pathological mechanism of percutaneous transluminal coronary angioplasty-induced restenosis has been attributed to outgrowth of vascular smooth muscle cells. Pretreatment with antioxidants has been shown to reduce restenosis. Magnolol, an active compound of Magnolia officinalis, has exhibited approximately 1,000 times more potent antioxidant effects than alpha-tocopherol. In this study, we demonstrate, using cytometric analysis, an approximate 61% reduction of smooth muscle cells progressing to the S-phase by 0.05 mg/ml of magnolol. A BrdU incorporation assay also showed a significant reduction (73%) of DNA synthesis using 0.05 mg/ml of magnolol. The protein level of the proliferating cell nuclear antigen was suppressed by approximately 48% using 0.05 mg/ml of magnolol. This was in agreement with the promoter activity of nuclear factor-kappa B, which was also attenuated by 0.05 mg/ml of magnolol. Since receptor interacting protein and caspase-3 protein expression levels were both increased by magnolol in a dose-dependent manner, the apoptotic pathway may mediate the inhibition of cell growth. Our finding that malondialdehyde formation was significantly inhibited by 0.05 mg/ml of magnolol further supported the antioxidant effect of magnolol. These studies suggest that magnolol might be a potential pharmacological reagent in preventing balloon injury-induced restenosis.

Topics: Angioplasty, Balloon, Coronary; Animals; Antioxidants; Biphenyl Compounds; Blotting, Western; Caspase 3; Caspases; Cell Cycle; Cell Proliferation; Cells, Cultured; Coronary Restenosis; DNA; Dose-Response Relationship, Drug; Lignans; Malondialdehyde; Muscle, Smooth, Vascular; NF-kappa B; Proliferating Cell Nuclear Antigen; Promoter Regions, Genetic; Protein Serine-Threonine Kinases; Rats; Tumor Necrosis Factor Receptor-Associated Peptides and Proteins

The aims of the present study were to examine the effect of magnolol on lipolysis in sterol ester (SE)-loaded 3T3-L1 preadipocytes and to determine the signaling mechanism involved. We demonstrate that magnolol treatment resulted in a decreased number and surface area of lipid droplets, accompanied by release of glycerol. The lipolytic effect of magnolol was not mediated by PKA based on the facts that magnolol did not induce an elevation of intracellular cAMP levels, and protein kinase A (PKA) inhibitor KT5720 did not block magnolol-induced lipolysis. Calcium/calmodulin-dependent protein kinase (CaMK) was involved in this signaling pathway, since magnolol-induced a transient rise of intracellular [Ca(2+)] and Ca(2+) influx across the plasma membrane, and CaMK inhibitor significantly abolished magnolol-induced lipolysis. Moreover, magnolol increased the relative levels of phosphorylated extracellular signal-related kinases (ERK1 and ERK2). In support of the involvement ERK, we demonstrated that magnolol-induced lipolysis was inhibited by PD98059, an inhibitor of mitogen-activated protein kinase kinase (MEK), and PD98059 reversed magnolol-induced ERK phosphorylation. Further, the relationship between CaMK and ERK was connected by the finding that CaMK inhibitor also blocked magnolol-induced ERK phosphorylation. Taken together, these findings suggest that magnolol-induced lipolysis is both CaMK- and ERK-dependent, and this lipolysis signaling pathway is distinct from the traditional PKA pathway. ERK phosphorylation is reported to enhance lipolysis by direct activation of hormone sensitive lipase (HSL), thus magnolol may likely activate HSL through ERK and increase lipolysis of adipocytes.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; 3T3-L1 Cells; Adipocytes; Animals; Benzylamines; Biphenyl Compounds; Calcium; Calcium-Calmodulin-Dependent Protein Kinases; Carbazoles; Cell Survival; Cyclic AMP-Dependent Protein Kinases; Flavonoids; Glycerol; Hydroxycholesterols; Indoles; Lignans; Lipolysis; Mice; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Naphthalenes; Oleic Acid; Phosphorylation; Protein Kinase C; Pyrroles; Signal Transduction; Sulfonamides; Tetradecanoylphorbol Acetate; Vacuoles

We have demonstrated that magnolol suppressed thromboxane B2 (TXB2) and leukotriene B4 (LTB4) formation in A23187-stimulated rat neutrophils. Maximum inhibition was obtained with about 10 microM magnolol. Magnolol was more effective in the inhibition of cyclooxygenase (COX) activity than in the inhibition of 5-lipoxygenase (5-LO) activity as assessed by means of enzyme activity determination in vitro and COX and 5-LO metabolic capacity analyses in vivo. Magnolol alone stimulated cytosolic phospholipase A2 (cPLA2) phosphorylation and the translocation of 5-LO and cPLA2 to the membrane, and evoked arachidonic acid (AA) release. Recruitment of both 5-LO and cPLA2 to the membranes was suppressed by EGTA. Arachidonyl trifluoromethyl ketone (AACOCF3), a PLA2 inhibitor, bromoenol lactone (BEL), a Ca2+-independent PLA2 (iPLA2) inhibitor, and EGTA suppressed the magnolol-induced AA release. However, none of the follows affected magnolol-induced AA-release: 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole (SB203580), a p38 mitogen-activated protein kinase (MAPK) inhibitor, 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene (U0126), a MAPK kinase (MEK) inhibitor, or 2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)-maleimide (GF109203X), a protein kinase C (PKC) inhibitor. In addition, magnolol at 30 microM did not stimulate the p38 MAPK and extracellular signal-regulated kinase 2 (ERK2) enzyme activities. These results indicated that magnolol inhibits the formation of prostaglandins and leukotrienes in A23187-stimulated rat neutrophils, probably through a direct blockade of COX and 5-LO activities. The stimulatory effects of magnolol at high concentration on the membrane association of 5-LO and cPLA2 are attributable to the elevation of [Ca2+]i, and on the AA release is likely via activation of cPLA2 and iPLA2.

Topics: Animals; Arachidonate 5-Lipoxygenase; Arachidonic Acid; Biological Transport; Biphenyl Compounds; Cell Membrane; Egtazic Acid; Eicosanoids; Enzyme Activation; In Vitro Techniques; Lignans; Mitogen-Activated Protein Kinases; Neutrophils; Phospholipases A; Phospholipases A2; Prostaglandin-Endoperoxide Synthases; Rats

High-speed counter-current chromatography was used to isolate and purify honokiol and magnolol from cortex Magnoliae Officinalis (Magnolia officinalis Rehd. et Wils.), a plant used in the traditional Chinese medicine. A crude sample, 150 mg, was successfully separated with a two-phase solvent system composed of n-hexane-ethyl acetate-methanol-water (1:0.4:1:0.4, v/v), and the fractions were analyzed by high-performance liquid chromatography. The separation produced 80 and 45 mg of honokiol and magnolol with purities of 99.2 and 98.2%, respectively, in 2.5 h.

Topics: Biphenyl Compounds; Chromatography, High Pressure Liquid; Countercurrent Distribution; Lignans; Magnetic Resonance Spectroscopy; Magnolia

Honokiol and magnolol, two major phenolic constituents of Magnolia sp., have been known to exhibit antibacterial activities. However, until now, their antibacterial activity against Propionibacterium sp. has not been reported. To this end, the antibacterial activities of honokiol and magnolol were detected using the disk diffusion method and a two-fold serial dilution assay. Honokiol and magnolol showed strong antibacterial activities against both Propionibacterium acnes and Propionibacterium granulosum, which are acne-causing bacteria. The minimum inhibitory concentrations (MIC) of honokiol and magnolol was 3-4 microg/ml (11.3-15 microM) and 9 microg/ml (33.8 microM), respectively. In addition, the killing curve analysis showed that magnolol and honokiol killed P. acnes rapidly, with 10(5) organisms/ml eliminated within 10 min of treatment with either 45 microg (169.2 microM) of magnolol or 20 microg (75.2 microM) of honokiol per ml. The cytotoxic effect of honokiol and magnolol was determined by a colorimetric (3-(4,5-dimetyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide) (MTT) assay using two animal cell lines, human normal fibroblasts and HaCaT. In this experiment, magnolol exhibited lower cytotoxic effects than honokiol at the same concentration, but they showed similar cytotoxicity when triclosan was employed as an acne-mitigating agent. In addition, they reduced secretion of interleukin-8 and tumor necrosis factor alpha (TNF-alpha) induced by P. acnes in THP-1 cells indicating the anti-inflammatory effects of them. When applied topically, neither phenolic compound induced any adverse reactions in a human skin primary irritation test. Therefore, based on these results, we suggest the possibility that magnolol and honokiol may be considered as attractive acne-mitigating candidates for topical application.

Topics: Adult; Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Biphenyl Compounds; Cell Line; Dose-Response Relationship, Drug; Female; Humans; Lignans; Microbial Sensitivity Tests; Propionibacterium; Skin Irritancy Tests

The endotoxin tolerance induced by sublethal hemorrhage (SLH) is associated with an initial surge of proinflammatory cytokines such as TNF-alpha. Magnolol, a potent antioxidative herb, is hypothesized to suppress TNF-alpha production after SLH and to alter or attenuate subsequent endotoxin tolerance. A prospective, randomized experimental study was performed. Male Sprague-Dawley rats were randomly segregated into one of four groups. Rats in the Sham/Veh and Sham/Mag groups received a sham operation for SLH and treatment with vehicle or magnolol, respectively. Rats in the SLH/Veh and SLH/Mag groups received SLH and treatment with vehicle or magnolol, respectively. Animals were subjected to endotoxin challenge (EC) at 12, 24, or 36 h after these procedures. Cytokines (TNF-alpha and IL-10), lipid peroxidation, and superoxide dismutase (SOD) activity were measured in lung tissue following SLH. Plasma cytokines were assessed after SLH or EC at different time points, and survival analyses were performed after EC. Plasma and tissue TNF-alpha increased after SLH; this increase was significantly suppressed by magnolol. Additionally, a significant increase in plasma and tissue IL-10 after SLH was observed in the SLH/Mag group. Lipid peroxidation and SOD activity increased after SLH; magnolol suppressed the lipid peroxidation but not the SOD activity. If EC was performed 12 or 24 h after SLH, greater survival with decreased TNF-alpha and increased IL-10 in plasma was observed in the SLH/Mag group. If EC was performed 24 or 36 h after SLH, greater survival with decreased plasma TNF-alpha was observed in the SLH/Veh group. In conclusion, magnolol induces an antiinflammatory response and provides early protection against EC following SLH; however, magnolol attenuates the protraction of endotoxin tolerance and inhibits late protection against EC following SLH.

Topics: Animals; Antioxidants; Biphenyl Compounds; Endotoxins; Escherichia coli; Immune Tolerance; Interleukin-10; Lignans; Lipid Peroxidation; Lung; Male; Prospective Studies; Random Allocation; Rats; Rats, Sprague-Dawley; Shock, Hemorrhagic; Tumor Necrosis Factor-alpha

To investigate the inhibitory effects of Magnolol and Honokiol on the activity of streptococcal glucosyltransferases (Gtfs).. The effect of Magnolol and Honokiol that inhibits the activities of streptococcal GtfB, GtfC, GtfD and GtfS was explored with standard assays. The results showed that both samples can efficiently inhibit the activity of all Gtfs in solution (66.4-96.3%) and adsorbed on the surface of saliva-coated hydroxyapatite (sHA) beads (65.5-92.7%) at concentrations between 1.25 and 5.0 mg ml(-1). Furthermore, Magnolol had a stronger inhibition of four kinds of Gtfs than Honokiol both in solution and adsorbed on the surface of sHA beads at concentrations between 0.04 and 0.63 mg ml(-1) (P < 0.05).. Magnolol had significant effects on the activities of streptococcal Gtfs.. Magnolol as a natural herb can be developed into a new oral hygiene product to prevent plaque formation.

Topics: Adsorption; Biphenyl Compounds; Enzyme Inhibitors; Glucans; Glucosyltransferases; Lignans; Microspheres; Streptococcus

1 Magnolol, an active component isolated from the root and stem bark of Magnolia officinalis, has been reported to exhibit antitumour effects, but little is known about its molecular mechanisms of action. 2 Magnolol inhibited proliferation of human lung squamous carcinoma CH27 cells at low concentrations (10-40 microM), and induced apoptosis at high concentrations (80-100 microM). 3 Treatment with 80 microM magnolol significantly increased the expression of Bad and Bcl-X(S) proteins, whereas it decreased the expression of Bcl-X(L). Overexpression of Bcl-2 protected CH27 cells against magnolol-triggered apoptosis. 4 Magnolol treatment resulted in accumulation of cytosolic cytochrome c and activation of caspase-9 and downstream caspases (caspase-3 and -6). Pretreatment with z-VAD-fmk markedly inhibited magnolol-induced cell death, but did not prevent cytosolic cytochrome c accumulation. 5 Magnolol induced a modest and persistent JNK activation and ERK inactivation in CH27 cells without evident changes in the protein levels. The responsiveness of JNK and ERK to magnolol suggests the involvement of these kinases in the initiation of the apoptosis process. 6 These results indicate that regulation of the Bcl-2 family, accumulation of cytosolic cytochrome c, and activation of caspase-9 and caspase-3 may be the effector mechanisms of magnolol-induced apoptosis.

Topics: Apoptosis; Biphenyl Compounds; Carcinoma, Squamous Cell; Cell Line; Cell Survival; Gene Expression Regulation; Humans; Lignans; Lung Neoplasms; Magnolia; MAP Kinase Signaling System; Plant Bark; Plant Extracts; Tumor Cells, Cultured

The aim of this study was to investigate the protective effect of honokiol and magnolol on hepatocyte injury induced by either tertiary butyl hydroperoxide (tBH)- or D-galactosamine (GalN). The cellular leakage of LDH and AST, and cell death by treatment with 1.5 mM tBH for 1 h, were significantly inhibited by treatment with honokiol (40 and 20 microM) or magnolol (40 microM). Treatment with honokiol or magnolol significantly inhibited lipid peroxidation in both cells and media, the generation of intracellular reactive oxygen species (ROIs), and intracellular glutathione (GSH) depletion induced by tBH. The cellular leakage of LDH and AST, and cell death, by 24-hour treatment with 30 mM GalN were significantly inhibited by treatment with honokiol (20, 5 and 1 microM) or magnolol (20, 5 and 1 microM). Treatment with honokiol (20, 5 and 1 microM) or magnolol (20 and 5 microM) significantly inhibited the intracellular GSH depletion induced by GalN. The hepatoprotective effects of honokiol and magnolol on oxidative stress induced by tBH were probably the result of their antioxidant activity. Honokiol and magnolol also had a protective effect against GalN-induced hepatotoxicity, which was used as an alternate model to oxidative stress, acting by inhibiting intracellular GSH depletion.

Topics: Animals; Biphenyl Compounds; Cells, Cultured; Galactosamine; Hepatocytes; Lignans; Liver; Male; Protective Agents; Rats; Rats, Sprague-Dawley; tert-Butylhydroperoxide

Magnolol, isolated from the stem bark of Magnolia officnalis, was found to inhibit proliferation of human HL-60 cells and Jurkat T leukemia cells via inducing apoptosis in a dose- and time-dependent manner. By contrast, magnolol did not cause apoptosis in neutrophils and peripheral blood mononuclear cells of healthy donors. Apoptosis was determined by detection of DNA fragmentation in gel electrophoresis, morphological alternations by flow cytometry, quantification of phosphatidylserine externalization by Annexin V labeling and oligonucleosomal DNA content by TUNEL labeling. Activation of caspase-9, -3 and -2, and the proteolytic cleavage of poly(ADP-ribose) polymerase were found during apoptosis induced by magnolol. In addition, both pan-caspase and selective caspase-9 inhibitor blocked magnolol-induced apoptosis. The apoptosis could also be partially attenuated by caspase-3 and -2 inhibitors. Magnolol induced the reduction of mitochondrial transmembrane potential and the release of cytochrome c into cytoplasm. In conclusion, our findings indicate that magnolol-induced apoptotic signaling is carried out through mitochondria alternations to caspase-9 and that then the downstream effector caspases are activated sequentially. Magnolol could be a potentially effective drug for leukemia with low toxicity to normal blood cells and it merits further investigation.

Topics: Antineoplastic Agents; Apoptosis; Biphenyl Compounds; Caspases; Cytochromes c; DNA Fragmentation; Dose-Response Relationship, Drug; Electrophoresis, Agar Gel; Enzyme Activation; Flow Cytometry; HL-60 Cells; Humans; In Situ Nick-End Labeling; Inhibitory Concentration 50; Jurkat Cells; Lignans; Magnolia; Membrane Potentials; Mitochondria; Poly(ADP-ribose) Polymerases; Time Factors

Cell apoptosis following warm ischemia-reperfusion injury is a major concern in clinical issues such as organ transplantation, trauma, and cardiogenic shock. The purpose of this study was to evaluate the possible role of magnolol, a Chinese herb drug, in apoptotic injury and the kinetic expression of apoptotic-related genes in rat livers subjected to warm ischemia-reperfusion (WI/R).. Three weeks prior to the experiment 10 rats underwent a portosystemic shunt operation according to Bengmerk's method. The rats were divided into three groups. Group 1 (GI) was the control group, Group 2 (GII) and Group 3 (GIII) the magnolol-treated groups. GI and GII were subjected to 2 h and GIII to 3 h of WI/R by clamping the portal vein and hepatic artery under ether anesthesia.. Results show that all the control rats died after 2 h WI/R. Apoptotic cells were detected under microscopy as well as by DNA assay. Magnolol-treated groups tolerated warm ischemia-reperfusion for 2 h and significantly less apoptotic cells were observed (198 +/- 22 vs 42.6 +/- 28). But magnolol-treated rats could not tolerate 3 h warm ischemia-reperfusion. RT-PCR of liver tissue shows that there is an upregulated expression of the anti-apoptotic Bcl-xL gene and suppression of the Bcl-xS gene in GII.. Magnolol has an anti-apoptotic effect and protects the liver against WI/R for 2 h but not for 3 h through upregulation of the anti-apoptotic Bcl-XL gene and suppression of the Bcl-xS gene.

Topics: Animals; Apoptosis; bcl-X Protein; Biphenyl Compounds; Drugs, Chinese Herbal; Enzyme Inhibitors; Gene Expression Regulation; Lignans; Liver; Models, Animal; Nitric Oxide Synthase; Proto-Oncogene Proteins c-bcl-2; Rats; Reperfusion Injury

The interaction of magnolol with bovine serum albumin(BSA) was studied using fluorescence spectroscopy under physiological conditions. The binding constants, K, and the ratio of quantum yields of protein fluorescence for complex and free protein, f, at 298 K, 304 K, and 310 K were obtained; the values were 6.799x10(5) L mol(-1), 5.541x10(5) L mol(-1), and 4.344x10(5) L mol(-1) and 0.17, 0.30, and 0.34, respectively. The standard enthalpy change (delta H degrees ) and the standard entropy change (delta S degrees ) were calculated to be -28.53 kJ mol(-1) and 15.88 J mol(-1) K(-1), which indicated that hydrophobic forces played major role in the interaction of magnolol and BSA. The binding average distance between magnolol and BSA (4.32 nm) was obtained on the basis of the theory of Förster energy transfer.

Topics: Animals; Biphenyl Compounds; Cattle; Fluorescence; Lignans; Molecular Structure; Serum Albumin, Bovine; Spectrometry, Fluorescence; Thermodynamics; Ultraviolet Rays

Magnolol and honokiol are the two major phenolic constituents of the plant medicine "Houpo" ( Magnolia obovata), which is used in the treatment of chest tightness and asthma. The aim of this study was to investigate the influence of magnolol and honokiol on smooth muscle tone in porcine trachea. Magnolol and honokiol (0.1 - 100 microM) inhibited carbachol- and high K +-induced muscle contractions in a concentration-dependent fashion, but did not affect basal muscle tension. After washout of these pretreatments, carbachol- and high K +-evoked muscle contractions were still abolished, suggesting that the inhibition was irreversible. Magnolol and honokiol also concentration-dependently decreased the Ca 2+-dependent muscle contraction induced by high K + depolarization. Ca 2+ channel antagonists attenuated carbachol-induced muscular response by approximately 30 %, but did not further potentiate the inhibitory actions of magnolol and honokiol on muscle contraction. However, the inhibitory effects of magnolol and honokiol on carbachol-evoked muscular contractile response were partially reversed after removal of Ca 2+ channel antagonist pretreatment. Alternatively, caffeine-elicited muscle contractions were not altered by magnolol, honokiol, and verapamil. In conclusion, the relaxant effects of magnolol and honokiol on porcine tracheal smooth muscle suggest an association with the blockade of Ca 2+ influx through voltage-operated Ca 2+ channels instead of Ca 2+ release from intracellular Ca 2+ stores. The magnolol- and honokiol-induced inhibitions on tracheal smooth muscle contraction may be relevant to the claimed therapeutic effects of the extract from magnolia bark and contribute to their pharmacological effects by acting as anti-asthmatic agents.

Topics: Animals; Asthma; Biphenyl Compounds; Bronchodilator Agents; Calcium; Carbachol; Dose-Response Relationship, Drug; Lignans; Magnolia; Male; Muscle Contraction; Muscle, Smooth; Phytotherapy; Potassium Chloride; Swine; Trachea; Verapamil

Magnolol, an active component extracted from Magnolia officinalis, has various pharmacological effects, including potent antioxidant activity. In the present study, we investigated the effect of magnolol on apoptosis in rat vascular smooth muscle cells (VSMCs), using terminal-deoxynucleotidyl-transferase-mediated deoxyuridine triphosphate nick end labelling (TUNEL) and flow cytometric analysis. Magnolol (5-20 micro M) concentration-dependently induced significant VSMC apoptosis, this effect being blocked by the caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (z-VAD-fmk, 50 micro M). To study the molecular mechanism, the mitochondrial death pathway was examined. Magnolol increased caspase-3 and caspase-9 activities significantly and reduced the mitochondrial potential (Deltapsi(m)). The levels of B-cell leukaemia/lymphoma-2 (Bcl-2), but not those of Bcl-2-associated X protein (Bax) or Bcl-x(L), were down-regulated concentration dependently by magnolol. In an animal model, balloon angioplasty-induced neointima formation was inhibited significantly by magnolol and Bcl-2 protein levels were reduced. Taken together, these results show that magnolol induces apoptosis in VSMCs via the mitochondrial death pathway. This effect is mediated through down-regulation of Bcl-2 protein levels, both in vivo and in vitro. Magnolol thus shows potential as a novel therapeutic agent for the treatment of atherosclerosis and re-stenosis.

Topics: Angioplasty, Balloon; Animals; Antioxidants; Apoptosis; bcl-2-Associated X Protein; bcl-X Protein; Biphenyl Compounds; Carotid Artery Diseases; Caspase 3; Caspase 9; Caspases; Cells, Cultured; Constriction, Pathologic; Down-Regulation; Enzyme Activation; Lignans; Male; Membrane Potentials; Mitochondria, Muscle; Muscle, Smooth, Vascular; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley

We reported the discovery of potent antioxidants based on magnolol, a naturally occurring biphenolic obtained from the bark of Magnolia officinalis. The allylmagnolols 3a,b were synthesized via O-alkylation of the biphenols followed by Claisen rearrangement. In-vitro using enhanced chemiluminescence (CL) and flow cytometric assays in whole cells revealed that both 3a and 3b displayed promising free radical scavenging effects in PMA- and LPS-stimulated models as compared with magnolol. Further DNA labeling analysis for cytotoxicity indicated that these analogues show no cytotoxic effects for the scavenging of the oxygen-derived free radicals under PMA-stimulated concentrations. The results from 3,3'-bisallylmagnolol (3b) suggested that the naturally occurring constituent was suitable to be a lead compound for the development of potential antioxidants for certain diseases.

Topics: Animals; Antioxidants; Biphenyl Compounds; Hydrogen Peroxide; Lignans; Luminescent Measurements; Neutrophils

We examined the intracellular Ca(2+) response in primary cultured rat cortical neurons and human neuroblastoma SH-SY5Y cells by Fluo 3 fluorescence imaging analysis. In these two kinds of neuronal cells, honokiol and magnolol increased cytoplasmic free Ca(2+) with a characteristic lag phase. The cytoplasmic free Ca(2+) increase was independent of extracellular Ca(2+), but dependent on activation of phospholipase C and inositol 1,4,5-triphosphate (IP(3)) receptors. These results suggest that honokiol and magnolol increase cytoplasmic free Ca(2+) through a phospholipase C-mediated pathway, and that the release of Ca(2+) from intracellular stores mainly contributes to the increase in cytoplasmic free Ca(2+). Thus, honokiol and magnolol may be involved in a new activation mechanism closely associated with intracellular Ca(2+) mobilization.

Topics: Animals; Biphenyl Compounds; Calcium; Cell Line, Tumor; Cells, Cultured; Cerebral Cortex; Female; Humans; Lignans; Neuroblastoma; Neurons; Pregnancy; Rats; Rats, Sprague-Dawley

Magnolol is a Chinese herb that has potent antioxidant effects. This study evaluated the effect of magnolol in the treatment of severe injury using a two-hit model in Sprague-Dawley rats. Hemorrhagic shock followed by resuscitation was performed. Intra-abdominal sepsis was induced by cecal ligation puncture. The rats were randomly segregated into the following three groups: group 1 (sham group) rats were sham-operated; group 2 (untreated group) rats received hemorrhagic shock and resuscitation and cecal ligation puncture 24 h later; and group 3 (treated group) rats were treated with magnolol and subjected to the same procedures as group 2. Plasma cytokine levels and tissue cytokine contents of lung, including tumor necrosis factor alpha (TNFalpha) and interleukin (IL)-10 were assayed after hemorrhagic shock and sepsis. Pulmonary injury study was performed using Evans blue dye and survival analysis was performed after development of sepsis. Plasma and tissue TNFalpha levels increased after hemorrhagic shock. Magnolol treatment blunted the TNFalpha levels in plasma and tissue. The plasma IL-10 level increased after hemorrhagic shock, whereas the tissue level of IL-10 did not change. Magnolol treatment did not alter the plasma level of IL-10 but did increase tissue level. After sepsis, TNFalpha levels in both plasma and tissue of magnolol-treated animals were significantly lower than those in untreated animals, whereas plasma and tissue IL-10 levels were not significantly different between treated and untreated groups. Pulmonary injury study showed that magnolol-treated rats had decreased pulmonary permeability after the onset of sepsis. Survival analysis showed that survival rate was significantly higher in the treated group. In conclusion, magnolol modifies the cytokine response after hemorrhagic shock and resuscitation; the proinflammatory cytokine response is suppressed. The modified cytokines response induced by magnolol may result in decreased tissue injury and increased survival in subsequent intra-abdominal sepsis.

Topics: Animals; Biphenyl Compounds; Cytokines; Interleukin-10; Lignans; Lung Injury; Male; Rats; Rats, Sprague-Dawley; Sepsis; Shock, Hemorrhagic; Time Factors; Tumor Necrosis Factor-alpha

The effects of honokiol and magnolol extracted from the Magnolia officinalis on muscular contractile responses and intracellular Ca(2+) mobilization were investigated in the non-pregnant rat uterus. Honokiol and magnolol (1-100 micromol/l) were observed to inhibit spontaneous and uterotonic agonists (carbachol, PGF(2alpha), and oxytocin)-, high K(+)-, and Ca(2+) channel activator (Bay K 8644)-induced uterine contractions in a concentration-dependent manner. The inhibition rate of honokiol on spontaneous contractions appeared to be slower than that of magnolol-induced response. The time periods that were required for honokiol and magnolol, at 100 micromol/l, to abolish 50% spontaneous contractions were approximately 6 min. Furthermore, honokiol and magnolol at 10 micromol/l also blocked the Ca(2+)-dependent oscillatory contractions. Consistently, the increases in intracellular Ca(2+) concentrations ([Ca(2+)](i)) induced by PGF(2alpha) and high K(+) were suppressed by both honokiol and magnolol at 10 micromol/l. After washout of these treatments, the rise in [Ca(2+)](i) induced by PGF(2alpha) and high K(+) was still partially abolished. In conclusion, the inhibitory effects of honokiol and magnolol on uterine contraction may be mediated by blockade of external Ca(2+) influx, leading to a decrease in [Ca(2+)](i). Honokiol and magnolol may be considered as putative Ca(2+) channel blockers and be of potential value in the treatment of gynecological dysfunctions associated with uterine muscular spasm and dysmenorrhea.

Topics: Animals; Biphenyl Compounds; Calcium; Carbachol; Central Nervous System Depressants; Dinoprost; Female; Fluorescent Dyes; Fura-2; In Vitro Techniques; Lignans; Muscarinic Agonists; Myometrium; Oxytocics; Oxytocin; Potassium Chloride; Rats; Uterine Contraction; Uterus

ICI-182,780 is known to be a selective inhibitor of the intracellular estrogen receptors. The effect of ICI-182,780 on ion currents was studied in cultured endothelial cells of human coronary artery. In whole-cell current recordings, ICI-182,780 reversibly decreased the amplitude of K(+) outward currents. The decrease in outward current caused by ICI-182,780 could be counteracted by further application of magnolol or nordihydroguaiaretic acid, yet not by 17beta-estradiol. Under current-clamp condition, ICI-182,780 (3microM) depolarized the membrane potentials of the cells, and magnolol (10 microM) or nordihydroguaiaretic acid (10 microM) reversed ICI-182,780-induced depolarization. In inside-out patches, ICI-182,780 added to the bath did not alter single-channel conductance of large-conductance Ca(2+)-activated K(+) channels (BK(Ca) channels), but decreased their open probability. ICI-182,780 reduced channel activity in a concentration-dependent manner with an IC(50) value of 3 microM. After BK(Ca) channel activity was suppressed by 2-methoxyestradiol (3 microM), subsequent application of ICI-182,780 (3 microM) did not further reduce the channel activity. The application of ICI-182,780 shifted the activation curve of BK(Ca) channels to positive potentials. Its decrease in the open probability primarily involved a reduction in channel open duration. ICI-182,780 also suppressed the proliferation of these endothelial cells with an IC(50) value of 2 microM. However, in coronary smooth muscle cells, a bell-shaped concentration-response curve for the ICI-182,780 effect on BK(Ca) channel activity was observed. This study provides evidence that ICI-182,780 can inhibit BK(Ca) channels in vascular endothelial cells in a mechanism unlikely to be linked to its anti-estrogen activity. The inhibitory effects on these channels may partly contribute to the underlying mechanisms by which ICI-182,780 affects endothelial function.

Topics: 2-Methoxyestradiol; Biphenyl Compounds; Cell Division; Cells, Cultured; Coronary Vessels; Drug Interactions; Endothelium, Vascular; Estradiol; Fulvestrant; Humans; Kinetics; Lignans; Masoprocol; Membrane Potentials; Potassium Channel Blockers; Potassium Channels, Calcium-Activated; Receptors, Estrogen

Topics: Animals; Anti-Arrhythmia Agents; Biphenyl Compounds; Intestinal Mucosa; Intestine, Small; Lignans; Microcirculation; Rats; Reperfusion Injury

To study the HPLC-FPS of Cortex Magnoliae Officinalis, the substitute species and counterfeits from different habitats, and to obtain the sameness and differences.. HPLC-FPS was used.. There were sameness and differences between two certified Cortex Magnoliae Officinalis, which were easily distinguished from their substitute species and counterfeits.. The HPLC-FPS can provide the useful information for the quality estimation and plant source of Cortex Magnoliae Officinalis.

Topics: Biphenyl Compounds; Chromatography, High Pressure Liquid; Drugs, Chinese Herbal; Lignans; Magnoliaceae; Quality Control

We previously found that multiple intraperitoneal administration of magnolol from Magnolia obovata inhibited tumor metastasis and growth in vivo, and that the anti-metastatic effect of magnolol was due to the inhibition of the tumor cell invasion. The purpose of this study was to clarify the inhibitory mechanism of magnolol on the growth of tumor cells, and we expect that magnolol may have the ability to induce apoptosis in tumor cells. In an in vitro proliferation assay, 100 microM of magnolol inhibited the proliferation of B16-BL6, THP-1, BAE and HT-1080 cells, but 30 microM of magnolol did not affected cells proliferation. In addition, 100 microM of magnolol induced apoptotic cell death within 24 h in three tumor cell lines, B16-BL6, THP-1 and HT-1080, not BAE cells, and then up-regulated the activity of caspase-3 and caspase-8. The up-regulation of caspases activity by 100 microM of magnolol was suppressed by the inhibitor of all caspases, z-VAD-fmk. These data suggest that magnolol possesses ability to inhibit tumor growth, and the ability is due to the induction of apoptosis with the activation of caspases.

Topics: Apoptosis; Biphenyl Compounds; Caspases; DNA Fragmentation; Humans; Lignans; Tumor Cells, Cultured

We have investigated the developdment of potential antioxidants based on magnolol, a naturally occurring biphenolic obtained from the bark of Magnolia officinalis. A series of aminomethylated derivatives of magnolol were synthesized under the aromatic Mannich reaction. In-vitro testing for diphenyl-p-picrylhydrazyl (DPPH) scavenging and chemiluminescence assays in whole cell models revealed that the pyrrolidyl-containing magnolols (2b (5,5'-diallyl-3-(pyrrolidin-1-ylmethyl)-biphenyl-2,2'-diol), 3a (5,5'-diallyl-3,3'-bis-(pyrrolidin-1-ylmethyl)-biphenyl-2,2'-diol) and 4c (5,5'-diallyl-3-(morphorin-4-ylmethyl)-3'-(pyrrolidin-1-ylmethyl)-biphenyl-2,2'-diol)) displayed promising free radical scavenging effects as compared with magnolol. The results from compound 4c indicated that the naturally occurring component was suitable to be a lead compound toward promising antioxidants.

Topics: Biphenyl Compounds; Free Radical Scavengers; Hydrazines; Lignans; Luminescent Measurements; Magnolia; Picrates; Plant Bark; Plant Oils

To lay a theoretical foundation for studies on strategies for improvement of Magnolia officinalis and select superior gemplasm resources to meet the demand for modernization, industrialization and internationalization of Chinese medicine.. Seeds of Magnolia officinalis from 13 main habitats of 7 provinces were collected and strewn in a place of Jingning County, Zhejiang. At the age of seven, 195 samples were collected from the same height of the trunk of 15 individual trees of each provenance, and assayed for effective ingredients with HPLC.. Differences in the content of phenols were significant among the seed sources and even greater among individuals within a seed source.. 3 seed sources viz. Wufeng, Hefeng and Enshi of Hubei were obviously superior to other seed sources on account of high contents of magnolol, honokoiol and total phenols. Extension and application of these 3 seed sources is an effective path leading to quality improvement of Magnolia officinalis. With great differences in the content of phenols existing among individuals within each source, there is a big gap between production of medicinal materials by merely using superior seed sources of Magnolia officinalis and the demand of stable and controllable quality for modernization and internationalization of Chinese medicine. But the great difference has laid a material foundation and brought about a great potential for genetic improvement of Magnolia officinalis. Therefore, the superior individuals within a superior seed source are an excellent material for the breeding of Magnolia officinalis.

Topics: Biphenyl Compounds; China; Drugs, Chinese Herbal; Ecosystem; Lignans; Magnolia; Phenols; Plant Bark; Plants, Medicinal; Quality Control; Seeds; Species Specificity

1. In a previous study, we showed that magnolol, a potent antioxidant derived from a Chinese herb, attenuates monocyte chemotactic protein-1 (MCP-1) expression and intimal hyperplasia in the balloon-injured aorta of cholesterol-fed rabbits. Expression of cell adhesion molecules by the arterial endothelium and the attachment of leukocytes to the endothelium may play a major role in atherosclerosis. In the present study, the effects of magnolol on the expression of endothelial-leukocyte adhesion molecules and the activation of nuclear factor kappa B (NF-kappa B) in tumour necrosis factor-alpha (TNF-alpha)-treated human aortic endothelial cells (HAECs) were investigated. 2. Pretreatment of HAECs with magnolol (5 microM) significantly suppressed the TNF-alpha-induced expression of vascular cell adhesion molecule-1 (VCAM-1) (64.8+/-1.9%), but had no effect on the expression of intercellular cell adhesion molecule-1 and endothelial cell selectin. 3. Magnolol (5 and 10 microM) significantly reduced the binding of the human monocytic cell line, U937, to TNF-alpha-stimulated HAECs (58.4 and 56.4% inhibition, respectively). Gel shift assays using the (32)P-labelled NF-kappa B consensus sequence as probe showed that magnolol pretreatment reduced the density of the shifted bands seen after TNF-alpha-induced activation. Immunoblot analysis and immunofluorescence staining of nuclear extracts demonstrated a 58% reduction in the amount of NF-kappa B p65 in the nuclei in magnolol-treated HAECs. Magnolol also attenuated intracellular H(2)O(2) generation in both control and TNF-alpha treated HAECs. 4. Furthermore, in vivo, magnolol attenuates the intimal thickening and TNF-alpha and VCAM-1 protein expression seen in the thoracic aortas of cholesterol-fed rabbits. 5. Taken together, these data demonstrate that magnolol inhibits TNF-alpha-induced nuclear translocation of NF-kappa B p65 and thereby suppresses expression of VCAM-1, resulting in reduced adhesion of leukocytes. These results suggest that magnolol has anti-inflammatory properties and may play important roles in the prevention of atherosclerosis and inflammatory responses in vivo.

Topics: Animals; Aorta, Thoracic; Biphenyl Compounds; Cell Adhesion; Cell Survival; Cells, Cultured; Cholesterol; Diet; Drugs, Chinese Herbal; E-Selectin; Endothelium, Vascular; Gene Expression Regulation; Humans; Hydrogen Peroxide; Intercellular Adhesion Molecule-1; Leukocytes; Lignans; Male; NF-kappa B; Platelet Aggregation Inhibitors; Rabbits; Transcription Factor RelA; Tumor Necrosis Factor-alpha; U937 Cells; Vascular Cell Adhesion Molecule-1

Magnolol, a compound isolated from the cortex of Magnolia officinalis, has been found to possess anti-allergic and anti-asthmatic activity.. The effect of magnolol on ionic currents was studied in cultured smooth muscle cells of human trachea with the aid of the patch clamp technique.. In whole cell current recordings magnolol reversibly increased the amplitude of K+ outward currents. The increase in outward current caused by magnolol was sensitive to inhibition by iberiotoxin (200 nM) or paxilline (1 microM) but not by glibenclamide (10 microM). In inside out patches, magnolol added to the bath did not modify single channel conductance but effectively enhanced the activity of large conductance Ca2+ activated K+ (BK(Ca)) channels. Magnolol increased the probability of these channel openings in a concentration dependent manner with an EC50 value of 1.5 microM. The magnolol stimulated increase in the probability of channels opening was independent of internal Ca2+. The application of magnolol also shifted the activation curve of BK(Ca) channels to less positive membrane potentials. The change in the kinetic behaviour of BK(Ca) channels caused by magnolol in these cells is the result of an increase in dissociation and gating constants.. These results provide evidence that, in addition to the presence of antioxidative activity, magnolol is potent in stimulating BK(Ca) channel activity in tracheal smooth muscle cells. The direct stimulation of these BK(Ca) channels by magnolol may contribute to the underlying mechanism by which it acts as an anti-asthmatic compound.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Biphenyl Compounds; Calcium; Calcium Channel Blockers; Cells, Cultured; Evans Blue; Flavanones; Flavonoids; Glycyrrhetinic Acid; Humans; Large-Conductance Calcium-Activated Potassium Channels; Lignans; Membrane Potentials; Muscle, Smooth; Niflumic Acid; Potassium; Potassium Channels; Potassium Channels, Calcium-Activated; Trachea

Magnolol, a hydroxylated biphenyl compound isolated from the Chinese herb Hou p'u of Magnolia officinalis, has been reported to have anti-cancer activity. In the present study, magnolol at very low concentrations of 3-10 microM inhibited DNA synthesis and decreased cell number in cultured human cancer cells (COLO-205 and Hep-G2) in a dose-dependent manner, but not in human untransformed cells such as keratinocytes, fibroblasts, and human umbilical vein endothelial cells (HUVEC). Magnolol was not cytotoxic at these concentrations and this indicates that it may have an inhibitory effect on cell proliferation in the subcultured cancer cell lines. [(3)H] thymidine incorporation and flow cytometry analyses revealed that magnolol treatment decreased DNA synthesis and arrested the cells at the G0/G1 phase of the cell cycle. Moreover, the magnolol-induced cell cycle arrest occurred when the cyclin-CDK system was inhibited, just as p21 protein expression was augmented. When magnolol concentration was increased to 100 microM, apoptosis was observed in COLO-205 and Hep-G2 cells, but not in cultured human fibroblasts and HUVEC. COLO-205 cells implanted subcutaneously in nude mice formed solid tumors; subsequent daily i.p.-injections of magnolol led to profound regression of these tumors of up to 85%. In these tumors, an increase in the expression of p21 protein level and the occurrence of apoptosis were observed. These findings demonstrate for the first time that magnolol can inhibit the proliferation of tumor cells in vitro and in vivo.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Biphenyl Compounds; Calcium; Cell Cycle; Cell Cycle Proteins; Cell Division; Cell Nucleus; Cells, Cultured; Colonic Neoplasms; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; DNA; DNA Fragmentation; Humans; Kinetics; Lignans; Liver Neoplasms; Thymidine; Tumor Cells, Cultured

To find out the optimal extraction process for magnoliae cortex, the extraction process was studied by orthogonal design with yield of the extracta sicca from magnoliae cortex and magnolol content as indexes. Four factors were chosen in this experiment, including alcohol consistence, the alcohol consumption, duration of extraction and times of extraction. The results showed that the optimal extraction process was 65% alcohol consumpted 8 times the amount of magnoliae cortex, refluxing for 3 times, each time 120 min.

Topics: Alcohols; Biphenyl Compounds; Chemical Fractionation; Lignans; Magnolia; Plant Bark

The antimicrobial activity of honokiol and magnolol, the main constituents of Magnolia officinalis was investigated. The antimicrobial activity was assayed by the agar dilution method using brain heart infusion medium and the minimum inhibitory concentration (MIC) were determined for each compound using a twofold serial dilution assay. The results showed that honokiol and magnolol have a marked antimicrobial effect (MIC = 25 microg/mL) against Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis, Prevotella intermedia, Micrococcus luteus and Bacillus subtilis, but did not show antimicrobial activity (MIC > or = 100 microg/mL) for Shigella flexneii, Staphylococcus epidermidis, Enterobacter aerogenes, Proteus vulgaris, Escherichia coli and Pseudomonas aeruginosa. Our results indicate that honokiol and magnolol, although less potent than tetracycline, show a significant antimicrobial activity for periodontal pathogens. Hence we suggest that honokiol and magnolol might have the potential to be an adjunct in the treatment of periodontitis.

Topics: Actinobacillus; Anti-Bacterial Agents; Bacillus; Bacteria; Biphenyl Compounds; Drugs, Chinese Herbal; Humans; Lignans; Magnoliopsida; Microbial Sensitivity Tests; Micrococcus; Periodontal Diseases; Plants, Medicinal; Porphyromonas; Prevotella

Magnolol is an 11beta-hydroxysteroid dehydrogenase (11beta-HSD) inhibitor contained in Magnolia officinalis which is used in Chinese remedies. We have reported that glycyrrhetinic acid, a strong 11beta-HSD inhibitor isolated from licorice, induces apoptosis of murine thymocytes via accumulation of corticosterone. In this paper, we report that magnolol inhibited 11beta-HSD without increases in the blood concentration of corticosterone and in thymocyte apoptosis in mice. Oxidative activities of the enzyme (from corticosterone to 11-dehydrocorticosterone) in liver, kidney and thymus in vitro were examined 24 h after a single administration of magnolol. Magnolol inhibited the enzyme activity in kidney (P < 0.0001) and thymus (P < 0.002), while the activity in liver was not affected. Blood concentrations of corticosterone in the magnolol-treated mice were unexpectedly lower than those in the control animals (P < 0.002). This means that the inhibition of 11beta-HSD by magnolol did not increase the systemic level of corticosterone which is relevant to thymocyte apoptosis. Accordingly, our flow cytometric analysis of thymocytes after magnolol treatment showed no change in the number of apoptotic cells. We concluded that unlike glycyrrhetinic acid, magnolol selectively inhibited 11beta-HSD in kidney and thymus but not in liver, so that the blood concentrations of corticosterone could not exceed the control level.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; Animals; Apoptosis; Biphenyl Compounds; Corticosterone; Enzyme Inhibitors; Hydroxysteroid Dehydrogenases; Lignans; Magnoliopsida; Male; Mice; Mice, Inbred C57BL; Thymus Gland

Honokiol and magnolol have been identified as modulators of the GABAA receptors in vitro. Our previous study suggested a possible selectivity of honokiol and magnolol on GABAA receptor subtypes. This possibility was examined in the current study by 3H-muscimol and 3H-flunitrazepam binding assays on various rat brain membrane preparations and human recombinant GABA(A) receptor subunit combinations expressed by the Sf-9/baculovirus system. Generally, honokiol and magnolol have a similar enhancing effect on (3)H-muscimol binding to various membrane preparations in nonsaturation binding assays. Honokiol and magnolol preferentially increased (3)H-muscimol binding to hippocampus compared to cortex and cerebellum (with a maximum enhancement of 400% of control). As for subunit combinations, honokiol and magnolol have a more potent enhancing effect on alpha2 subunit containing combinations (with a maximum enhancement of 400-450% of control). This action was independent of the gamma subunit. In saturation binding assays, magnolol affected either the number of binding sites (ca. 4-fold on alpha2 containing combinations) or the binding affinity (on alpha1 containing combinations) of (3)H-muscimol binding to various GABAA receptor subunit combinations. In contrast, honokiol increased only binding sites on alpha2beta3gamma2s and alpha2beta3 combinations, but both the number of binding sites and the binding affinity on alpha1beta2gamma2S and alpha(1)beta2 combinations. These results indicate that honokiol and magnolol have some selectivity on different GABAA receptor subtypes. The property of interacting with GABAA receptors and their selectivity could be responsible for the reported in vivo effects of these two compounds.

Topics: Animals; Biphenyl Compounds; Cell Line; Cerebellum; Drugs, Chinese Herbal; Flunitrazepam; GABA Agonists; GABA Modulators; Hippocampus; Humans; Insecta; Lignans; Male; Muscimol; Nitric Oxide Synthase; Protein Subunits; Rats; Rats, Wistar; Receptors, GABA-A; Recombinant Proteins; Tritium

The accumulation of oxygen-free radicals and activation of neutrophils are strongly implicated as important pathophysiological mechanisms mediating myocardial ischemia/reperfusion injury. It has been proven that various antioxidants have cardioprotective effects. Magnolol, an active component extracted from the Chinese medicinal herb Magnolia officinalis, possesses potent antioxidant and free radical scavenging activities. In this study, the cardioprotective activity of magnolol was evaluated in an open-chest anesthetized rat model of myocardial ischemia/reperfusion injury. The results demonstrated that pretreatment with magnolol (0.2 and 0.5 microg/kg, i.v. bolus) at 10 min before 45 min of left coronary artery occlusion, significantly suppressed the incidence of ventricular fibrillation and mortality when compared with the control group. Magnolol (0.2 and 0.5 microg/kg) also significantly reduced the total duration of ventricular tachycardia and ventricular fibrillation. After 1 h of reperfusion, pretreatment with magnolol (0.2 and 0.5 microg/kg) caused a significant reduction in infarct size. In addition, magnolol (0.2 microg/kg) significantly reduced superoxide anion production and myeloperoxidase activity, an index of neutrophil infiltration in the ischemic myocardium. In addition, pretreatment with magnolol (0.2 and 0.5 microg/kg) suppressed ventricular arrhythmias elicited by reperfusion following 5 min of ischemia. In vitro studies of magnolol (5, 20 and 50 microM) significantly suppressed N-formylmethionyl-leucyl-phenylalanine (fMLP; 25 nM)-activated human neutrophil migration in a concentration-dependent manner. It is concluded that magnolol suppresses ischemia- and reperfusion-induced ventricular arrhythmias and reduces the size of the infarct resulting from ischemia/reperfusion injury. This pronounced cardioprotective activity of magnolol may be mediated by its antioxidant activity and by its capacity for neutrophil inhibition in myocardial ischemia/reperfusion.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Biphenyl Compounds; Chemotaxis, Leukocyte; Dose-Response Relationship, Drug; Female; Hemodynamics; Lignans; Male; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Neutrophils; Peroxidase; Rats; Rats, Sprague-Dawley; Superoxides

Restenosis is a common complication after balloon angioplasty. A number of cytokines, chemotactic factors and growth factors may be involved. Several antioxidants have been shown to inhibit intimal thickening after balloon injury in hyperlipidemic animals.. The effects of magnolol on the expression of monocyte chemotactic protein-1 (MCP-1) and intimal response in balloon injured aorta of cholesterol-fed rabbits were investigated.. Male New Zealand white rabbits were fed a 2% high cholesterol (HC) diet together with daily intramuscular injection of either 1 microg/kg B.W. of magnolol (HC-M, n = 10) or vehicle (propylene glycol) as a control (HC-C, n = 10) for a total of 6 weeks. Another 10 rabbits fed a regular diet also served as a control (C) group. A balloon denudation of abdominal aorta was performed in each group at the end of the third week. The aortas were harvested at the end of 6 weeks.. Magnolol treatment significantly inhibited Cu2+-induced LDL oxidation in cholesterol-fed rabbits and reduced atheroma formation [atheroma area ratio: 0.10 +/- 0.03 (HC-M) versus 0.33 +/- 0.07 (HC-C), p < 0.05] in thoracic aortas without lowering serum cholesterol. The intimal response was significantly attenuated in the HC-M rabbits when compared to those of the HC-C group [intimal thickness: 88.95 +/- 14.91 microm (HC-M) versus 198.02 +/- 20.35 microm (HC-C), p < 0.05; intimal area: 278.21 +/- 43.16 x 10(3) microm2 (HC-M) versus 642.70 +/- 65.01 x 10(3) microm2 (HC-C), p < 0.05]. The MCP-1 mRNA and protein expression were reduced in the HC-M group compared to the HC-C and C groups.. The inhibitory effects on intimal hyperplasia and MCP-1 expression might be attributed to the antioxidant capacity of magnolol instead of lowering serum cholesterol. Magnolol may offer some protection against postangioplasty restenosis.

Topics: Angioplasty, Balloon; Animals; Antioxidants; Aorta; Arteriosclerosis; Biphenyl Compounds; Chemokine CCL2; Cholesterol; Cholesterol, Dietary; Cholesterol, LDL; Lignans; Male; Oxidation-Reduction; Rabbits; RNA, Messenger; Triglycerides; Tunica Intima; Wounds and Injuries

We investigated the inhibitory effect of Magnolia obovata Thunb. bark ethanol extracts on human fibrosarcoma HT-1080 cells invasion in a reconstituted basement membrane [Matrigel (MG)]. We found that the effective components of the bark ethanol extracts were magnolol and honokiol, two biphenyl compounds. The extracts, magnolol and honokiol, did not affect HT-1080 cells adhesion to MG, but did inhibit HT-1080 cells migration at a high concentration (100 microM). HT-1080 cells secrete matrix metalloproteinase (MMP)-9, which degrades the extracellular matrix as a part of the invasive process. Magnolol and honokiol inhibited the activity of MMP-9, which may have been responsible, in part, for the inhibition of tumor cell invasiveness.

Topics: Antineoplastic Agents, Phytogenic; Biphenyl Compounds; Fibrosarcoma; Humans; Lignans; Magnoliaceae; Matrix Metalloproteinase Inhibitors; Neoplasm Invasiveness; Phytotherapy; Plant Bark; Tumor Cells, Cultured

We have previously reported that saiboku-to, an Oriental herbal remedy composed of a mixture of 10 different herbal extracts, possesses anti-histamine release effect on mast cells in rats. This effect may be due mainly to the extract of the bark of Magnolia obovata (M. obovata), a constituent herb of saiboku-to. In the present study, it was demonstrated that the bark extract inhibited compound 48/80 (C48/80)-induced histamine release from mast cells in a concentration-dependent manner (50 % inhibitory concentration, IC(50) = 56.98 microg/ml). Furthermore, the inhibitory activity was found in the methanol fraction, but not in water and 50 % aqueous methanol fractions derived from the bark extract. Magnolol and honokiol isolated from the methanol fraction inhibited C48/80-induced histamine release from mast cells. The potency of magnolol (IC(50) = 1.04 microg/ml) was greater than that of honokiol (IC(50) = 2.77 microg/ml). Furthermore, the actual amount of magnolol (49.76 +/- 1.14 mg) contained in the bark of M. obovata (5 g) was greater than that (8.58 +/- 0.19 mg) of honokiol. Taken together, the present results suggest that magnolol may be responsible for the biological efficacy of the bark extract of M. obovata.

Topics: Animals; Biphenyl Compounds; Drugs, Chinese Herbal; Histamine H1 Antagonists; Histamine Release; Lignans; Magnoliaceae; Mast Cells; Medicine, Kampo; p-Methoxy-N-methylphenethylamine; Peritoneal Cavity; Plant Bark; Plant Extracts; Rats

Magnolol has been reported to have anticancer activity. In this study we found that treatment with 100 microm magnolol induced apoptosis in cultured human hepatoma (Hep G2) and colon cancer (COLO 205) cell lines but not in human untransformed gingival fibroblasts and human umbilical vein endothelial cells. Our investigation of apoptosis in Hep G2 cells showed a sequence of associated intracellular events that included (a) increased cytosolic free Ca(2+); (b) increased translocation of cytochrome c (Cyto c) from mitochondria to cytosol; (c) activation of caspase 3, caspase 8, and caspase 9; and (d) downregulation of bcl-2 protein. Pretreatment of the cells with the phospholipase C inhibitor 1-[6-[[(17 beta)-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1 H-pyrrole-2,5-dione (U73122) or the intracellular chelator of Ca(2+) 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester (BAPTA/AM) inhibited the subsequent magnolol augmentation of [Ca(2+)](i) and also the activation of caspase-8 and caspase-9, so that the occurrence of apoptosis in those cells was greatly reduced. Pretreatment of the cells with ZB4 (which disrupts the Fas response mechanism) also decreased the subsequent magnolol-induced caspase-8 activation and reduced the occurrence of apoptosis. We interpreted these findings to indicate that the above-listed sequence of intracellular events led to the apoptosis seen in Hep G2 cells and that [Ca(2+)](i), Cyto c, and Fas function as intracellular signals to coordinate those events.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Biphenyl Compounds; Calcium; Caspases; Colonic Neoplasms; Cytochrome c Group; Endothelium, Vascular; fas Receptor; Fibroblasts; Humans; Lignans; Liver Neoplasms; Signal Transduction; Tumor Cells, Cultured

To understand the main factors influencing the bark quality of Magnolia officinalis so as to theoretically establish a basis for quality assessment, genetic improvement and layout of bark producing areas.. Eighty-two samples from the main bark producing areas(11 counties of 7 provinces such as Zhejiang, Fujian, Sichuan, Hunan, Guangxi, Jiangxi and Hubei) were collected. Totally there were 121 samples, including 39 from the trial stand located in Jingning of Zhejiang the obtained out of the seeds from the bark producing areas mentioned above. HPLC was used in the analysis of phenols contained in the bark of Magnolia officinalis.. The main factors influencing the bark quality have been made clear.. The quality is affected by provenance, leaf shape, DBH, tree height, crown size, age, bark thickness color of bark powder, oiliness, grounding nature, bark type, position of sampling, etc., of which provenance, leaf shape, powder color, bark thickness and DBH are the most influential factors. These factors should be fully considered when making quality assessment and genetic improvement of the bark of Magnolia officinalis.

Topics: Biphenyl Compounds; Lignans; Magnolia; Plant Bark; Plants, Medicinal; Quality Control

A reversed-phase high performance liquid chromatographic method for simultaneous determination of magnolol and honokiol in serum and urine of rat has been established. Two drugs were determined within 15 minutes by the method on the column with spherisorb C18, by using a mobile phase consisted of methanol-water-glacial acetic acid (70:30:1, V/V) at 1 mL/min, monitored at 294 nm and with a sensitivity of 0.005 AUFS. After 0.25, 1 and 8 hour of administration of the drugs, protein in serum and urine of Wistar rat was precipitated by methanol and magnolol and honokiol in acidified body fluid were determined after being extracted by a mixture of ethyl acetate and ether. Good linear relationship between concentration in serum and urine and peak area in the ranges of 0.05-2 mg/L for magnolol and 0.025-1 mg/L for honokiol was obtained. Good precision and reproducibility were found too. The average recoveries of the two drugs were 95.6% (RSD = 3.85%), 93.8% (RSD = 3.95%) in serum and 96.0% (RSD = 3.83%), 94.9% (RSD = 3.54%) for urine respectively. The lower limit of the method was 0.02 mg/L of magnolol and 0.04 mg/L of honokiol respectively. The results showed that this method is suitable for the determination of magnolol and honokiol in body fluids.

Topics: Animals; Biphenyl Compounds; Chromatography, High Pressure Liquid; Drugs, Chinese Herbal; Lignans; Magnolia; Male; Platelet Aggregation Inhibitors; Rats; Rats, Wistar

It's found that a significant correlation between the samples of Magnoliae officinalis from the provenance in phenols content and varieties or forms. The total content of magnolol and honokiol in its bark is usually used as an index to measure the quality. Therefore, Cortex Magnoliae officinalis produced in Sichuan and Hubei being considered genuinenss and good in quality, should be actually referred to local varieties. This conclusion can also reveals the nature and scientific connotation of genuineness on Cortex Magnoliae Officinalis.

Topics: Biphenyl Compounds; Chromatography, High Pressure Liquid; Drugs, Chinese Herbal; Lignans; Magnolia; Plant Leaves; Plants, Medicinal; Quality Control

Reactive oxygen species and peroxidative damage are implicated in the pathophysiology of sepsis. Magnolol is a compound extracted from the Chinese medicinal herb Magnolia officinalis and has multiple pharmacological effects, notably antioxidant functions. To determine whether magnolol can modulate the course of sepsis, survival rate and biochemical parameters were analyzed in rats with sepsis with various treatment protocols. Magnolol at doses ranging from 10(-9) g/kg to 10(-5) g/kg was administered either before or after induction of sepsis by cecal ligation and puncture. Magnolol did not modulate the course of sepsis induced by two cecal punctures. When one cecal puncture was performed, a moderately evolving type of sepsis was induced, and the survival rate of affected rats was significantly improved by pretreatment with 10(-7) g/kg magnolol. The beneficial effect was partially retained if magnolol was administered 6 hours after onset of sepsis when a higher dose (10(-5) g/kg) was used. The intensity of lipid peroxidation in plasma, liver, and lung of septic rats was also attenuated in a treatment-dependent manner. Magnolol at this dose range exerted these beneficial effects probably through its antioxidant efficacy. These significant results may suggest magnolol as a candidate agent for the treatment of sepsis.

Topics: Animals; Anti-Infective Agents; Biphenyl Compounds; Cecum; Dose-Response Relationship, Drug; Drug Administration Schedule; Drugs, Chinese Herbal; Lignans; Lipid Peroxidation; Liver; Lung; Male; Punctures; Rats; Rats, Sprague-Dawley; Sepsis; Survival Rate

Two neolignan compounds, magnolol (5,5'-diallyl-2,2'-dihydroxybiphenyl, 1) and honokiol (5,5'-diallyl-2,4'-dihydroxybiphenyl, 2), were isolated from the stem bark of Magnolia obovata and evaluated for antifungal activity against various human pathogenic fungi. Compound 1 and 2 showed significant inhibitory activities against Trichophyton mentagrophytes, Microsporium gypseum, Epidermophyton floccosum, Aspergillus niger, Cryptococcus neoformans, and Candida albicans with minimum inhibitory concentrations (MIC) in a range of 25-100 microg/ml. Therefore, compound 1 and 2 could be used as lead compounds for the development of novel antifungal agents.

Topics: Antifungal Agents; Biphenyl Compounds; Humans; Lignans; Microbial Sensitivity Tests

The crude extract of magnolia bark, an herbal drug, inhibited the secretion of catecholamines from bovine adrenal chromaffin cells stimulated by acetylcholine (ACh) in a concentration-dependent manner (200-900 microg/mL). The extract also diminished the secretion induced by high K(+), which is a stimulus directly depolarizing the plasma membranes, but its inhibition was weaker than that of ACh-evoked secretion. beta-Eudesmol, honokiol, magnolol, and bornyl acetate, but not alpha- and beta-pinenes, all of which are ingredients of magnolia bark, greatly reduced ACh-evoked secretion. beta-Eudesmol and magnolol also inhibited high K(+)-induced secretion to an extent similar to that of ACh-evoked secretion. However, honokiol and bornyl acetate inhibited the secretion induced by high K(+) much less than the secretion evoked by ACh. ACh-induced Na(+) influx and ACh- or high K(+)-induced Ca(2+) influx into the cells were diminished by beta-eudesmol or honokiol. These results indicate that magnolia bark contains some effective components inhibiting the secretion of catecholamines from bovine adrenal chromaffin cells stimulated by ACh due to the antagonism of Na(+) and Ca(2+) influxes into the cells. However, inhibition by the extract of magnolia bark seems to be attributable to honokiol and bornyl acetate. Furthermore, the results indicate that the inhibitory effect of magnolia bark may be associated with its pharmacological effect on activities of the nervous system.

Topics: Acetylcholine; Adrenal Glands; Animals; Biphenyl Compounds; Calcium; Camphanes; Catecholamines; Cattle; Chromaffin Cells; In Vitro Techniques; Lignans; Magnoliopsida; Plant Extracts; Potassium; Sesquiterpenes, Eudesmane; Sodium; Terpenes

Nitric oxide (NO) and tumor necrosis factor-alpha (TNF-alpha) are the major mediators produced in activated macrophages which contribute to the circulatory failure associated with septic shock. An activity-guided fractionation of an MeOH extract of stem bark of Magnolia obovata afforded two inhibitors of NO production in lipopolysaccharides (LPS)-activated macrophages by the suppression of i-NOS expression. Their structures were elucidated by spectroscopic methods to be magnolol and honokiol with IC50 values of 16.8 and 6.4 microM, respectively. They also inhibited the production of TNF-alpha in LPS-activated macrophages. Thus, these compounds may be possible candidates for the development of new drugs to treat endotoxemia accompanied by the overproduction of NO and TNF-alpha.

Topics: Animals; Biphenyl Compounds; Blotting, Western; Cell Line; Enzyme Inhibitors; Lignans; Lipopolysaccharides; Macrophage Activation; Macrophages; Magnetic Resonance Spectroscopy; Magnoliopsida; Mice; Nitric Oxide; Nitric Oxide Synthase; Tumor Necrosis Factor-alpha

Magnolol is an active component purified from Magnolia officinalis that has been reported to protect the myocardium against infarction and reperfusion injury. The purpose of this study was to investigate the effect of magnolol on the coronary circulation and to determine whether a change in coronary vascular resistance could be the mechanism underlying its myocardial protective effect.. Male New Zealand white rabbits were anesthetized. A 3-mm suction-type pulsed Doppler velocimetry probe was applied to the proximal part of the left anterior descending coronary artery after median sternotomy. The 39 rabbits received intravenous injection of either vehicle (n = 5), magnolol (10(-6) g/kg, n = 6; 10(-5) g/kg, n = 5; 10(-4) g/kg, n = 5), or nitroglycerin (10(-5) g/kg, n = 6; 10(-4) g/kg, n = 6; 10(-3) g/kg, n = 6). The effects of magnolol and nitroglycerin on coronary vascular resistance were compared.. Magnolol did not change blood pressure or coronary blood flow velocity. However, at a dose of 10(-4) g/kg, it decreased coronary vascular resistance significantly more than vehicle (88 +/- 1% vs 95 +/- 1% of baseline coronary vascular resistance, p < 0.001). Nitroglycerin increased coronary blood flow velocity and decreased coronary vascular resistance in a dose-dependent manner (p < 0.01).. Magnolol reduced coronary vascular resistance in anesthetized, open-chest rabbits only at a high concentration. Its effect was modest compared with that of nitroglycerin. Since magnolol protects the myocardium at relatively low doses, coronary vasodilatation is unlikely to be the underlying mechanism responsible for its myocardial protective effects.

Topics: Animals; Anti-Arrhythmia Agents; Biphenyl Compounds; Blood Pressure; Coronary Circulation; Coronary Vessels; Heart Rate; Laser-Doppler Flowmetry; Lignans; Male; Nitroglycerin; Rabbits; Vascular Resistance

Magnolol, an antioxidant, has been reported to possess various protective effects on the cardiovascular system. However, its effect on myocardial stunning has not been elucidated. The purpose of this study was to investigate the antistunning effect of magnolol by evaluating the recovery of regional myocardial function after 10-minute coronary artery occlusion in anesthetized, open-chest rabbits. There was no significant hemodynamic change after intravenous infusion of magnolol. Systolic wall thickening fraction (WThF) measured with an epicardial Doppler sensor in animals pretreated with normal saline and vehicle solution remained significantly depressed (60 +/- 7% and 77 +/- 4% of baseline WThF, respectively) 3 hours after coronary artery reperfusion (CAR). Pretreatment with magnolol (10(-7) and 10(-6) g/kg, intravenous infusion) significantly enhanced the recovery of systolic wall thickening fraction (98 +/- 1 and 99 +/- 1% of baseline WThF, respectively) 60 minutes after CAR. This study demonstrated that intravenous pretreatment with magnolol protected myocardium against stunning.

Topics: Animals; Anti-Arrhythmia Agents; Antioxidants; Arrhythmias, Cardiac; Biphenyl Compounds; Heart; Infusions, Intravenous; Lignans; Male; Myocardial Stunning; Rabbits

Our previous studies demonstrated that magnolol protects neurons against chemical hypoxia by KCN in cortical neuron-astrocyte mixed cultures (14). In the present study, we examined whether the neuroprotective effect of magnolol involve modulating inflammatory mediators, prostaglandin E2 (PGE2) and nitric oxide (NO), induced by KCN (hypoxia) or KCN plus lipopolysaccharide (LPS). In glucose-absent (hypoglycemia) media, KCN or KCN plus LPS induced increases in lactate dehydrogenase (LDH) activity by 32% and 34%, and PGE2 production by 12% and 32%, respectively. Both LDH and PGE2 increases were suppressed by 100 microM magnolol. In addition, although KCN or LPS alone did not increase NO generation, KCN plus LPS increased NO generation. This increase was reduced by 100 microM magnolol or 10 microM L-NAME, but the LDH increase and PGE2 production were not reduced by L-NAME. These findings suggest that the protective effects of magnolol against brain damage by KCN or KCN plus LPS in hypoglycemic media may involve inhibition of PGE2 production, but inhibition of NO generation may not be important.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Biphenyl Compounds; Cell Hypoxia; Cells, Cultured; Cerebral Cortex; Culture Media; Dinoprostone; Enzyme Inhibitors; Hypoglycemia; L-Lactate Dehydrogenase; Lignans; Lipopolysaccharides; Neurons; Neuroprotective Agents; NG-Nitroarginine Methyl Ester; Nitric Oxide; Potassium Cyanide; Rats; Rats, Sprague-Dawley

1. This study investigated the effect of magnolol, a compound purified from Magnolia officinalis, on glucocorticoid production by primary adrenal cell culture. 2. Magnolol increased corticosterone secretion in a dose-dependent manner, this effect being maximal at 40 microM. A similar effect was seen in a minced adrenal gland system. 3. In magnolol-treated cells, the number and total area of cytoplasmic lipid droplets were reduced, suggesting a high utilization rate of cholesterol esters stored in lipid droplets. In control cells, the capsule of the lipid droplet was clearly delineated by immunostaining with antibody A2, whereas capsular staining was discontinuous or undetectable following magnolol treatment. The percentage of decapsulated cells increased significantly from 20% in the control group to 80% in the magnolol-treated group. 4. Magnolol-induced steroidogenesis was not mediated either via the traditional ACTH-cyclic AMP-protein kinase A pathway or by protein kinase C, since the intracellular cyclic AMP level did not change and inhibition of protein kinase A or C did not block the action of magnolol. Furthermore, calcium/calmodulin-dependent protein kinase II was not involved in magnolol-induced steroidogenesis. 5. The stimulatory effect of magnolol on steroidogenesis apparently requires new protein synthesis, since cycloheximide inhibited magnolol-induced corticosterone production by 50%. 6. Although other studies have shown that high concentrations of magnolol inhibit acyl-CoA: cholesterol acyltransferase and 11 beta-hydroxysteroid dehydrogenase in a cell-free system, our data show that, in adrenal cell cultures, low concentrations of magnolol have a stimulatory effect on steroidogenesis, and the glucocorticoid produced may explain the effective control of asthma by Magnolia officinalis.

Topics: Adrenal Glands; Animals; Anti-Inflammatory Agents, Non-Steroidal; Biphenyl Compounds; Cells, Cultured; Corticosterone; Cycloheximide; Dose-Response Relationship, Drug; Female; Lignans; Lipid Metabolism; Protein Synthesis Inhibitors; Rats; Rats, Wistar; Signal Transduction

Honokiol and magnolol, phenolic compounds isolated from the stem bark of Magnolia officinalis, have been demonstrated to increase choline acetyltransferase activity, inhibit acetylcholinesterase, promote potassium-induced acetylcholine release and exhibit neurotrophic function in in vitro studies. The objective of the present study was to determine the effect of these compounds on hippocampal acetylcholine release in conscious, freely-moving rats. 10(-4) M-10(-6) M of honokiol or magnolol was perfused into rat hippocampus via a dialysis probe. The results showed that at 10(-4) M concentration, honokiol and magnolol markedly increased extracellular acetylcholine release to 165.5+/-5.78% and 237.83+/-9.47% of the basal level, respectively. However, lower concentrations of either compounds failed to elicit significant acetylcholine release. This result suggests that a high dose of honokiol or magnolol may enhance in vivo hippocampal acetylcholine release.

Topics: Acetylcholine; Animals; Biphenyl Compounds; Drugs, Chinese Herbal; Hippocampus; Lignans; Male; Rats; Rats, Sprague-Dawley

To build up the quality criteria for Wushicha capsules.. Rhizoma Atractylodis, Cortex Magnoliae Officinalis, Rhizoma Chuanxiong, Herba Pogostemonis in Wushicha capsules were identified by TLC. The contents of magnolol in the preparation were determined by GC.. These methods are simple and accurate.. These methods can be used for the quantitative analysis of Wushicha capsules.

Topics: Asteraceae; Biphenyl Compounds; Capsules; Chromatography, Gas; Chromatography, Thin Layer; Densitometry; Drug Combinations; Drugs, Chinese Herbal; Lamiaceae; Lignans; Ligusticum; Magnoliaceae; Plant Preparations; Plants, Medicinal; Quality Control

Contents of magnolol and honokiol in 76 samples of Magnolia officinalis collected from 11 counties in Zhejiang, Fujian, Sichuan, Guangxi, Hunan, Jiangxi and Hubei are analyzed by means of HPLC. A study on the effect of tree age on effective ingredients in Magnolia offcinalis shows that the influence of tree age on the content of magnolol and honokiol is correlated with the varieties under cultivation, but a small effect on the content of the phenols with an indent at the tip of leaves. The content of magnolol in other types of leaves increases rapidly with increase in age, diameter of the trunk and thickness of the bark, with not many changes found at the age of 12 or up. Increase in age may be favorable to the full expression of oily characteristic. These results provide a scientific base for the determination of optimal time for harvesting bark from artificially established Magnolia officinalis stands.

Topics: Age Factors; Biphenyl Compounds; China; Chromatography, High Pressure Liquid; Lignans; Magnolia; Plant Bark; Plant Leaves; Plants, Medicinal

A mechanism suggested to cause injury to preserved organs is the generation of oxygen free radicals. Lipid peroxidation is one of the biological damages caused by oxygen free radicals. It is our aim to investigate whether magnolol, a strong antioxidant, suppresses the generation of oxygen free radicals and improves the viability of cold-preserved warm-reperfused rat livers.. In vitro lipid peroxidation was induced in rat hepatic mitochondria with ADP and FeSO4. The inhibitory effect of magnolol on lipid peroxidation was measured with oxygen consumption and malondialdehyde (MDA) formation. Subsequently, we preserved and reperfused rat livers in preservation solutions that contained magnolol. The hepatic enzymes and liver MDA were measured to assess the protective effect of magnolol on isolated rat livers.. In rat hepatic mitochondria, magnolol was 470 times more potent than alpha-tocopherol in inhibiting oxygen consumption and 340 times more potent than alpha-tocopherol in inhibiting MDA formation. Addition of magnolol to Ringer's lactate solution had a protective effect, in terms of MDA formation and leakage of hepatic enzymes, on warm-reperfused but not cold-stored liver tissue. Addition of magnolol to University of Wisconsin (UW) solution, a widely used preservation solution, did not modify the effect of this solution on isolated liver tissues.. We conclude that magnolol is an effective antioxidant and suppresses lipid peroxidation in rat liver mitochondria and can be used as a rinsing solution in protecting transplanted organs from lipid peroxidation during reperfusion, especially for those organs not preserved with UW solution.

Topics: Animals; Antioxidants; Biphenyl Compounds; Cold Temperature; In Vitro Techniques; Lignans; Lipid Peroxidation; Liver; Male; Malondialdehyde; Mitochondria, Liver; Organ Preservation; Oxygen Consumption; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Vitamin E

We have observed an inhibitory action of magnolol on the production of leukotriene (LT) C4 and LTB4, important lipid mediators in allergy and inflammation. IgE- and A23187-stimulated production of LTC4 and LTB4 was measured by radio-immunoassay (RIA) in the absence or presence of various concentrations of magnolol in intact rat basophilic leukemia (RBL)-2H3 cells. Magnolol dose-dependently inhibited synthesis of LTC4 and LTB4. Magnolol inhibited the IgE-mediated increase of intracellular calcium ion concentration, resulting in the inhibition of cytosolic phospholipase A2 (cPLA2) and possibly 5-lipoxygenase (5-LO), both calcium ion-dependent enzymes. In cell-free studies magnolol inhibited LTC4 synthase activity. LTA4 hydrolase activity was only inhibited at the higher concentration (2.5 x 10(-5)M). These results indicate that magnolol inhibits production of LTs by inhibiting PLA2, 5-LO, LTC4 synthase and LTA4 hydrolase which are essential for LT-synthesis. Magnolol may have anti-allergic effect by blocking LT-synthesis.

Topics: Animals; Biphenyl Compounds; Enzyme Inhibitors; Epoxide Hydrolases; Glutathione Transferase; Leukemia, Basophilic, Acute; Leukotriene B4; Leukotriene C4; Lignans; Lipoxygenase Inhibitors; Rats; Tumor Cells, Cultured

The influence of the plant product magnolol on neutrophil superoxide anion (O2-*) generation has been investigated in the rat. Intraperitoneal injection of magnolol (30mg kg(-1)) significantly inhibited the formylmethionyl-leucyl-phenylalanine (fMLP)-induced respiratory burst in rat whole blood ex-vivo. Magnolol also inhibited the 02-* generation with an IC50 (concentration resulting in 50% inhibition) of 15.4+/-1.6 microM and O2 consumption in rat neutrophils in-vitro. Magnolol weakly inhibited the O2-* generation in the xanthine-xanthine oxidase system, decreased cellular cyclic AMP level and had no effect on cyclic GMP levels. It weakly inhibited neutrophil cytosolic protein kinase C activity but did not alter porcine heart protein kinase A activity. Magnolol attenuated fMLP-induced protein tyrosine phosphorylation with an IC50 of 24.0+/-1.9 microM and the phosphorylation of mitogen-activated protein kinase p42/44 with an IC50 of 28.5+/-4.5 microM. However, magnolol alone activated neutrophil phospholipase D activity as determined by the formation of phosphatidic acid and phosphatidyl-ethanol in the presence of ethanol. In the presence of NADPH, the arachidonate-activated NADPH oxidase activity in a cell-free system was weakly suppressed by magnolol. These results suggest that the inhibition of respiratory burst in fMLP-activated neutrophils by magnolol is probably attributable mainly to the attenuation of protein tyrosine phosphorylation and p42/44 mitogen-activated protein kinase activation, and partly to the suppression of protein kinase C and NADPH oxidase activities.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Biphenyl Compounds; Blotting, Western; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclic GMP; Drug Interactions; Lignans; Luminescent Measurements; Mitogens; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Oxygen; Phospholipase D; Phosphorylation; Protein Kinase C; Rats; Respiratory Burst; Superoxides; Xanthine Oxidase

This study was designed to evaluate the in vivo effect of magnolol and honokiol on the acute phase of coronary ligation in the presence of nitric oxide inhibitor (L-NAME) or cyclooxygenase inhibitor (aspirin). After Sprague-Dawley rats were anesthetized with urethane, the changes of ventricular arrhythmia induced by coronary ligation for 30 min were determined with or without pretreatment with study medications. The incidence and duration of ventricular arrhythmia were significantly reduced after intravenous pretreatment (15 min before coronary ligation) with 10(-7) g/kg magnolol or 10(-7) g/kg honokiol. However, the antiarrhythmic effect of magnolol or honokiol could be abolished with the pretreatment of 1 mg/kg L-NAME, but not with pretreatment of 100 mg/kg aspirin. The abolishment of the myocardial beneficial effect of magnolol and honokiol by L-NAME, instead of aspirin, suggests an involvement of an increased nitric oxide synthesis in the protection offered by magnolol and honokiol against arrhythmia during myocardial ischemia.

Topics: Anesthesia; Animals; Anti-Arrhythmia Agents; Anti-Inflammatory Agents, Non-Steroidal; Arrhythmias, Cardiac; Aspirin; Biphenyl Compounds; Blood Pressure; Coronary Disease; Enzyme Inhibitors; Lignans; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Rats; Rats, Sprague-Dawley

1. The bark of the root and stem of various Magnolia species has been used in Traditional Chinese Medicine to treat a variety of disorders including anxiety and nervous disturbances. The biphenolic compounds honokiol (H) and magnolol (M), the main components of the Chinese medicinal plant Magnolia officinalis, interact with GABA(A) receptors in rat brain in vitro. We compared the effects of H and M on [3H]muscimol (MUS) and [3H]flunitrazepam (FNM) binding using EDTA/water dialyzed rat brain membranes in a buffer containing 150 mM NaCl plus 5 mM Tris-HCl, pH 7.5 as well as [35S]t-butylbicyclophosphorothionate (TBPS) in 200 mM KBr plus 5 mM Tris-HCl, pH 7.5. H and M had similar enhancing effects on [3H]MUS as well as on [3H]FNM binding to rat brain membrane preparations, but H was 2.5 to 5.2 times more potent than M. 2. [3H]FNM binding. GABA alone almost doubled [3H]FNM binding with EC50 = 450 nM and 200 nM using forebrain and cerebellar membranes, respectively. In the presence of 5 microM H or M the EC50 values for GABA were decreased to 79 and 89 nM, respectively, using forebrain, and 39 and 78 nM, using cerebellar membranes. H and M potently enhanced the potentiating effect of 200 nM GABA on [3H]FNM binding with EC50 values of 0.61 microM and 1.6 microM using forebrain membranes, with maximal enhancements of 33 and 47%, respectively. Using cerebellar membranes, the corresponding values were 0.25 and 1.1 microM, and 22 and 34%. 3. [3H]MUS binding. H and M increased [3H]MUS binding to whole forebrain membranes about 3-fold with EC50 values of 6.0 and 15 microM. Using cerebellar membranes, H and M increased [3H]MUS binding approximately 68% with EC50 values of 2.3 and 12 microM, respectively. Scatchard analysis revealed that the enhancements of [3H]MUS binding were due primarily to increases in the number of binding sites (Bmax values) with no effect on the high affinity binding constants (Kd values). The enhancing effect of H and M were not additive. 4. [35S]TBPS binding. H and M displaced [35S]TBPS binding from sites on whole rat forebrain membranes with IC50 values of 7.8 and 6.0 microM, respectively. Using cerebellar membranes, the corresponding IC50 values were 5.3 and 4.8 microM. These inhibitory effects were reversed by the potent GABA(A) receptor blocker R5135 (10 nM), suggesting that H and M allosterically increase the affinity of GABA(A) receptors for GABA and MUS by binding to sites in GABA(A) receptor complexes. 5. Two monophenols, the anestheti

Topics: Allosteric Regulation; Androstanes; Animals; Azasteroids; Binding Sites; Biphenyl Compounds; Cell Membrane; Central Nervous System Depressants; Cerebellum; Diflunisal; Drugs, Chinese Herbal; Flunitrazepam; GABA Antagonists; gamma-Aminobutyric Acid; Kinetics; Lignans; Muscimol; Picrotoxin; Propofol; Prosencephalon; Rats; Receptors, GABA-A; Tritium

An analysis of effective ingredients in 20 to 29 year old Magnolia officinalis of three different leaf types coming from various sources shows that the content of phenols differ extremely significantly in various leaf types which are a key to determination of quality of Magnolia officinalis also varies significantly among different sources which only have a significant effect on the content of magnolol. Varieties and types cultivated in different places are responsible for the variation in content of magnolol. The conclusions obtained from this study coincide with the traditional insight into quality of Magnolia officinalis.

Topics: Biphenyl Compounds; China; Chromatography, High Pressure Liquid; Lignans; Magnolia; Plant Leaves; Plants, Medicinal; Quality Control; Species Specificity

The principal active anxiolytic components in Saiboku-to, an Oriental herbal medicine, have been isolated and identified as magnolol (5,5'-di-2-propenyl-1,1'-biphenyl-2,2'-diol) and honokiol (3',5-di-2-propenyl-1,1'-biphenyl-2,4'-diol). Evaluation by means of an elevated plus-maze test showed that honokiol was at least 5000 times more potent than Saiboku-to when mice were treated orally for 7 days.

Topics: Animals; Anti-Anxiety Agents; Anxiety; Biphenyl Compounds; Drugs, Chinese Herbal; Lignans; Male; Medicine, Kampo; Mice; Mice, Inbred Strains; Plant Extracts

Magnolol, a phenolic compound isolated from a Chinese herbal drug, Magnolia officinalis, has been shown to protect rat heart from ischemia/reperfusion injury. Neutrophil adhesion plays a crucial process during this inflammatory response. To evaluate whether magnolol prevents ischemia/reperfusion injury by inhibiting neutrophil adhesion, we determined whether magnolol can inhibit adhesion of phorbol-12-myristate-13-acetate (PMA)-activated human neutrophils to a fibrinogen-coated surface in a dose-dependent manner. Using flow cytometric analysis, we observed that magnolol pretreatment (10 min at 37 degrees C) diminished PMA (100 ng/ml)-induced Mac-1 upregulation. PMA also induced rapid intracellular accumulation of superoxide (O2-.) and hydrogen peroxide (H2O2) in neutrophils; magnolol pretreatment attenuated the accumulation of these two substances. Inhibition of reactive oxygen species by superoxide dismutase and/or catalase, which decompose O2-. and H2O2, respectively, also abolished Mac-1 upregulation and neutrophil adhesion. We conclude that magnolol inhibits neutrophil adhesion and that this can account for its anti-ischemia/reperfusion injury effect. We propose that the inhibitory effect of magnolol on neutrophil adhesion to the extracellular matrix is mediated, at least in part, by inhibition of the accumulation of reactive oxygen species, which in turn suppresses the upregulation of Mac-1 that is essential for neutrophil adhesion.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Biphenyl Compounds; Cell Adhesion; Female; Fibrinogen; Humans; Hydrogen Peroxide; Lignans; Macrophage-1 Antigen; Male; Neutrophils; Superoxides

Magnolol (1) and honokiol (2), main compounds from the stem bark of Magnolia obovata Thunb., were evaluated for an antimicrobial activity against periodontopathic microorganisms, Porphyromonas gingivalis, Prevotella gingivalis, Actinobacillus actinomycetemcomitans, Capnocytophaga gingivalis, and Veillonella disper, and a cytotoxicity against human gingival fibroblasts and epithelial cells. Our results indicate that magnolol and honokiol, although less potent than chlorhexidine, show a significant antimicrobial activity against these microorganisms, and a relatively low cytotoxic effect on human gingival cells. Thus, it is suggested that magnolol and honokiol may have a potential therapeutic use as a safe oral antiseptic for the prevention and the treatment of periodontal disease.

Topics: Aggregatibacter actinomycetemcomitans; Anti-Bacterial Agents; Biphenyl Compounds; Capnocytophaga; Cells, Cultured; Epithelial Cells; Fibroblasts; Gingiva; Humans; Lignans; Porphyromonas gingivalis; Prevotella; Veillonella

In the present study, we describe the role of inositol trisphosphate in the signalling pathway that leads to the elevation of cytosolic-free Ca2+ in rat neutrophils stimulated with magnolol, a compound isolated from the cortex of Magnolia officinalis. Magnolol increased [Ca2+]i, by stimulating Ca2+ release from internal stores and Ca2+ influx across the plasma membrane, in a concentration-dependent manner. Ni2+ and [6-[[(17beta)-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H -pyrrole-2,5-dione (U73122), but not pertussis toxin, inhibited the magnolol-induced Ca2+ influx. Measurement of cellular levels of inositol trisphosphate showed a clear increase upon exposure to magnolol. U73122 but not ryanodine suppressed the Ca2+ release from internal stores caused by magnolol. Pretreatment of cells with formyl-Met-Leu-Phe (fMLP) or cyclopiazonic acid greatly reduced the [Ca2+]i changes caused by the subsequent addition of magnolol. Collectively, these findings suggest that a pertussis toxin-insensitive inositol trisphosphate signalling pathway is involved in the magnolol-induced [Ca2+]i elevation in rat neutrophils.

Topics: Animals; Biphenyl Compounds; Calcium; Cytosol; Estrenes; In Vitro Techniques; Indoles; Inositol 1,4,5-Trisphosphate; Lignans; Manganese; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Pyrrolidinones; Rats; Ryanodine; Signal Transduction

1. The effects of magnolol, isolated and purified from the cortex of Magnolia officinalis Rehd. et Wils, on thermoregulation and hypothalamic release of 5-hydroxytryptamine (5-HT) by in vivo microdialysis were assessed in normothermic rats and in febrile rats treated with interleukin-1 beta. 2. Intraperitoneal administration of magnolol (25-100 mg/kg) produced a decrease in colon temperature, an increase in foot skin temperature, a decrease in metabolic rate and a decrease in the endogenous release of 5-HT in the rat hypothalamus. 3. Depletion of rat brain 5-HT, produced by intracerebroventricular pretreatment with 5,7-dihydroxytryptamine, attenuated the magnolol-induced hypothermia, cutaneous vasodilation and decreased metabolism. 4. Intracerebroventricular administration of (+/-)-2,5-dimethoxy-4-iodoamphetamine (a 5-HT2 receptor agonist; 5-10 micrograms/5 microL) increased basal colon temperature and reversed the magnolol-induced hypothermia. 5. The increases in both colon temperature and hypothalamic 5-HT release produced by interleukin-1 beta injection were attenuated by treatment with magnolol. 6. The data suggest that magnolol decreases body temperature (due to increased heat loss and decreased heat production) by reducing 5-HT release in rat hypothalamus.

Topics: Animals; Biphenyl Compounds; Body Temperature Regulation; Central Nervous System Depressants; Colon; Down-Regulation; Hypothalamus; Interleukin-1; Lignans; Male; Plants, Medicinal; Rats; Rats, Sprague-Dawley; Serotonin; Serotonin Antagonists; Skin

The influence of the plant product magnolol on neutrophil aggregation has been investigated in the rat. Magnolol inhibited phorbol 12-myristate 13-acetate (PMA)-activated rat neutrophil aggregation in a concentration-dependent manner with an IC50 (concentration resulting in 50% inhibition) of 24.2 +/- 1.7 microM. Magnolol suppressed the enzyme activity of neutrophil cytosolic and rat brain protein kinase C (PKC) over the same range of concentrations at which it inhibited the aggregation. Magnolol did not affect PMA-induced cytosolic PKC-alpha and -delta membrane translocation or trypsin-treated rat-brain PKC activity, but attenuated [3H]phorbol 12,13-dibutyrate binding to neutrophil cytosolic PKC. These results suggest that the inhibition of PMA-induced rat neutrophil aggregation by magnolol is probably attributable, at least in part, to the direct suppression of PKC activity through blockade of the regulatory region of PKC.

Topics: Animals; Biological Transport; Biphenyl Compounds; Enzyme Inhibitors; In Vitro Techniques; Lignans; Neutrophils; Platelet Aggregation Inhibitors; Protein Kinase C; Rats; Tetradecanoylphorbol Acetate; Tritium; Trypsin

The protective effect of magnolol, a component of Magnolia officinalis, against hypoxia-induced cell injury in cortical neuron-astrocyte mixed cultures was examined. Exposure of the cells to chemical hypoxia (0.5 mM KCN) produced morphological changes in neurons but not in astrocytes. KCN induced dose- and time-dependent increases in release of LDH and decreases in viable cell number. Treatment with magnolol (10 and 100 microM) significantly reduced the KCN-induced LDH release in a concentration-dependent manner. A higher concentration (750 microM) magnolol was toxic. Nuclear condensation was not observed in KCN-treated cells, suggesting that chemical hypoxia-induced cell death was via necrosis, rather than via apoptosis. This is the first report demonstrating that magnolol protects neurons against chemical hypoxic damage or necrotic cell death in cortical neuron-astrocyte mixed cultures.

Topics: Animals; Astrocytes; Biphenyl Compounds; Cell Death; Cell Hypoxia; Cell Survival; Cells, Cultured; Central Nervous System Depressants; Fluorescent Dyes; Hypoglycemia; Indoles; L-Lactate Dehydrogenase; Lignans; Neurons; Neurotoxins; Potassium Cyanide; Rats; Rats, Sprague-Dawley

Intraperitoneal administration of magnolol (25-100 mg/kg) produced a dose-related fall in rats' colonic temperature. The magnolol-induced hypothermia was attenuated by pretreatment with intracerebroventricular 6-hydroxydopamine (200 microg/rat). The L-DOPA (200 mg/kg, i.p.) plus benserazide (50 mg/kg, i.p.)-induced hyperthermia was attenuated by magnolol. On the other hand, the alpha-methyltyrosine (100 mg/kg, i.p.)-induced hypothermia was potentiated by magnolol. Furthermore, magnolol (50 mg/kg, i.p.) decreased the dopamine and norepinephrine release in the hypothalamus, but did not change the concentrations for their metabolites (3,4-dihydroxyphenylacetic acid and homovanillic acid). The data suggest that magnolol decreases colonic temperature by reducing catecholaminergic activity in rat hypothalamus.

Topics: 3,4-Dihydroxyphenylacetic Acid; Adrenergic Agents; alpha-Methyltyrosine; Animals; Anti-Anxiety Agents; Biphenyl Compounds; Body Temperature; Catecholamines; Colon; Dopamine; Dopamine Agents; Dose-Response Relationship, Drug; Enzyme Inhibitors; Epinephrine; Homovanillic Acid; Hypothalamus; Hypothermia, Induced; Injections, Intraperitoneal; Injections, Intraventricular; Levodopa; Lignans; Male; Norepinephrine; Oxidopamine; Rats; Rats, Sprague-Dawley

The Rhizoma Atractylodis, Cortex Magnoliae Officinalis and Pericarpium Citri Reticulatae in Huoxiang-zhengqi Liquid were identified by TLC. The total contents of magnolol and honokiol were determined by HPLC to be no less than 1.9 mg/ml, with an average recovery of 104.4% and 103.3%, RSD 1.23% and 0.91% respectively.

Topics: Asteraceae; Biphenyl Compounds; Chromatography, High Pressure Liquid; Chromatography, Thin Layer; Citrus; Drug Combinations; Drugs, Chinese Herbal; Lignans; Magnoliopsida; Quality Control

Honokiol and magnolol, neolignans in Magnolia obovata, have been evaluated as antioxidants. Microsomal lipid peroxidation induced by Fe(III)-ADP/NADPH and mitochondrial lipid peroxidation induced by Fe(III)-ADP/NADH were inhibited by these compounds. These neolignans protected mitochondrial respiratory chain enzyme activity against NADPH-induced peroxidative stress and protected red cells against oxidative haemolysis. The anti-oxidative activity of honokiol was more potent than that of magnolol. Neolignans in M. obovata were shown to be effective in protecting biological systems and functions against oxidative stress.

Topics: Animals; Antioxidants; Biphenyl Compounds; Drugs, Chinese Herbal; Erythrocytes; Hemolysis; Lignans; Lipid Peroxidation; Male; Microsomes, Liver; Mitochondria, Liver; Rats; Rats, Wistar; Trees

The pharmacokinetics of magnolol in rats was studied after 2, 5, or 10 mg/kg-1 intravenous bolus injection. Plasma concentration-time profiles of magnolol were fitted by a two-compartment open model. There were no significant differences in the elimination half-life, the total body clearance, steady-state volume of distribution, or mean residence time. The area under the plasma-time curve and area under the moment-time curve of magnolol appears to increase proportionally from a dose of 2 to 10 mg/kg-1. These results suggest that magnolol possess linear pharmacokinetics. Notwithstanding, brain concentration of magnolol showed no significant difference among various regions (cerebral cortex, olfactory bulb, hippocampus, striatum, cerebellum, brain stem and rest of brain) after 10 min of magnolol (5 mg/kg-1, i.v.) administration, the mean brain drug concentration was approximately fourfold that of magnolol in plasma.

Topics: Animals; Biphenyl Compounds; Brain; Central Nervous System Depressants; Chromatography, High Pressure Liquid; Injections, Intravenous; Lignans; Male; Rats; Rats, Sprague-Dawley; Reproducibility of Results; Software; Statistics as Topic; Tissue Distribution

1. Magnolol is an active component of Magnolia officinalis. It is 1000-times more potent than alpha-tocopherol in inhibiting lipid peroxidation in rat heart mitochondria. In the present study, the in vivo antiarrhythmic and anti-ischaemic effects of magnolol in coronary ligated rats were investigated. 2. Male Sprague-Dawley rats were anaesthetized with urethane. Magnolol, at dosages of 10(-7), 10(-8) and 10(-9) g/kg, was administered intravenously 15 min before ligation of the coronary artery. 3. The incidence and duration of ventricular tachycardia and ventricular fibrillation during 30 min coronary ligation were significantly reduced by magnolol. Ventricular arrhythmias during 10 min reperfusion after the relief of coronary ligation were also reduced. 4. In rats subjected to 4 h coronary ligation, 10(-7) and 10(-8) g/kg magnolol significantly reduced infarct size. 5. We conclude that magnolol may protect the myocardium against ischaemic injury and suppress ventricular arrhythmia during ischaemia and reperfusion.

Topics: Analysis of Variance; Animals; Arrhythmias, Cardiac; Biphenyl Compounds; Ligation; Lignans; Male; Myocardial Ischemia; Platelet Aggregation Inhibitors; Rats; Rats, Sprague-Dawley

To study the possible mechanism through which honokiol and magnolol elicit their central depressant effects, we examined the influence of these two phenolic compounds on 25 mM K(+)-stimulated release of [3H]acetylcholine (ACh) from the rat's hippocampal slices. Honokiol, but not magnolol, elicited a concentration-dependent enhancement of K+-evoked ACh release. Addition of either tetrodotoxin, pilocarpine, or methoctramine had no effect on honokiol-enhanced ACh release. These results suggest that honokiol enhanced K(+)-evoked ACh release directly on hippocampal cholinergic terminals via receptors other than the M2 cholinergic subtypes.

Topics: Acetylcholine; Animals; Biphenyl Compounds; Central Nervous System Depressants; Hippocampus; In Vitro Techniques; Lignans; Rats; Rats, Sprague-Dawley

Topics: Animals; Biphenyl Compounds; Chromatography, High Pressure Liquid; Drugs, Chinese Herbal; Glucuronidase; Lignans; Male; Rats; Rats, Sprague-Dawley; Spectrometry, Fluorescence

Topics: Animals; Biphenyl Compounds; Blood Platelets; Chromatography, High Pressure Liquid; Collagen; Depression, Chemical; Hydroxyindoleacetic Acid; Lignans; Molecular Structure; Platelet Activation; Rabbits; Serotonin

Fluorescence assay was applied to the determination of magnolol in rabbit blood, and the best way to administer the bark of official magnolia per rectal was established by orthogonal test. Then the two routes of administration were compared by AUC of magnolol and per rectal was found better than P.O. In addition, the modified isolated rectum-bag method was applied successfully to the research on rectal administration of bark of official magnolia.

Topics: Administration, Rectal; Animals; Biological Availability; Biphenyl Compounds; Drugs, Chinese Herbal; Female; Lignans; Male; Rabbits; Rats; Rats, Wistar; Spectrometry, Fluorescence

Topics: Animals; Biphenyl Compounds; Drug Combinations; Drugs, Chinese Herbal; Glycyrrhetinic Acid; Glycyrrhizic Acid; Humans; Lignans; Pyrazines; Rats; Rats, Wistar

Magnolol, a phenolic constituent of magnolia bark, is a known central nervous system depressant. To examine the possibility that magnolol may elicit its depressant effect by modulating central serotonergic activity, its effect on 35 mM K(+)-stimulated 5-[3H]HT release from rat hippocampal and frontal cortical slices were examined. Inclusion of magnolol (1-100 microM) had no effect on 5-HT release in hippocampal slices but elicited a dose-related inhibition on 5-HT release from cortical slices. The inhibitory effect of magnolol on K(+)-stimulated 5-HT release from the cortex was not affected by either antagonists (metergoline, propranolol, and cyproheptadine) (0.01-10 microM) of various 5-HT receptor subtypes or the voltage-dependent sodium channel blocker tetrodotoxin (1 microM). It is concluded that the suppression of brain 5-HT release by magnolol is site-specific, and the suppression of cortical 5-HT release by magnolol is not via the 5-HT autoreceptors at the 5-HT terminals.

Topics: Animals; Antineoplastic Agents, Phytogenic; Biphenyl Compounds; Cerebral Cortex; Hippocampus; In Vitro Techniques; Lignans; Male; Potassium; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Serotonin; Serotonin Antagonists

In the present study, A23187-induced pleurisy in mice was used to investigate the anti-inflammatory effect of magnolol, a phenolic compound isolated from Chinese medicine Hou p'u (cortex of Magnolia officinalis). A23187-induced protein leakage was reduced by magnolol (10 mg kg-1, i.p.), indomethacin (10 mg kg-1, i.p.) and BW755C (30 mg kg-1, i.p.). A23187-induced polymorphonuclear (PMN) leucocyte infiltration in the pleural cavity was suppressed by magnolol and BW755C, while enhanced by indomethacin. Like BW755C, magnolol reduced both prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) levels in the pleural fluid of A23187-induced pleurisy, while indomethacin reduced PGE2 but increased LTB4 formation. In the rat isolated peripheral neutrophil suspension, magnolol (3.7 microM) and BW755C (10 microM) also suppressed the A23187-induced thromboxane B2 (TXB2) and LTB4 formation. These results suggest that magnolol, like BW755C, might be a dual cyclo-oxygenase and lipoxygenase inhibitor. The inhibitory effect of magnolol on the A23187-induced pleurisy is proposed to be, at least partly, dependent on the reduction of the formation of eicosanoids mediators in the inflammatory site.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acid; Biphenyl Compounds; Body Fluids; Calcimycin; Dinoprostone; Disease Models, Animal; Leukotriene B4; Lignans; Mice; Mice, Inbred ICR; Plant Extracts; Pleura; Pleurisy; Proteins; Rats; Rats, Sprague-Dawley

A HPLC method for the determination of magnolol and honokiol in Baoji Pill has been established. The method can be used to control the quality of Boji Pill.

Topics: Biphenyl Compounds; Chromatography, High Pressure Liquid; Drug Combinations; Drugs, Chinese Herbal; Gastrointestinal Agents; Lignans; Quality Control

To identify the inhibitor of prednisolone metabolism contained in Saiboku-To, we conducted in-vitro experiments of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD), using rat liver homogenate and cortisol as a typical substrate. We studied the effects of ten herbal constituents on 11 beta-HSD. Five herbal extracts showed inhibitory activity with Glycyrrhiza glabra > Perillae frutescens > Zizyphus vulgaris > Magnolia officinalis > Scutellaria baicalensis. This suggests that unknown 11 beta-HSD inhibitors are contained in four herbs other than G. glabra which contains a known inhibitor, glycyrrhizin (and glycyrrhetinic acid). Seven chemical constituents which have been identified as the major urinary products of Saiboku-To in healthy and asthmatic subjects were studied; magnolol derived from M. officinalis showed the most potent inhibition of the enzyme (IC50, 1.8 x 10(-4) M). Although this activity was less than that of glycyrrhizin, the inhibition mechanism (non-competitive) was different from a known competitive mechanism. These results suggest that magnolol might contribute to the inhibitory effects of Saiboku-To on prednisolone metabolism through inhibition of 11 beta-HSD.

Topics: 11-beta-Hydroxysteroid Dehydrogenases; Animals; Antineoplastic Agents, Phytogenic; Asthma; Biphenyl Compounds; Chromatography, High Pressure Liquid; Cortisone; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Glucocorticoids; Glycyrrhetinic Acid; Glycyrrhizic Acid; Hydrocortisone; Hydroxysteroid Dehydrogenases; Immunosuppressive Agents; Lignans; Liver; Male; Medicine, Kampo; Rats; Rats, Wistar

In isolated rat heart mitochondria lipid peroxidation was induced with ADP and ferrous sulfate (FeSO4). Oxygen consumption and malondialdehyde (MDA) production were measured to quantitate lipid peroxidation. The antioxidant effects of magnolol and honokiol purified from Magnolia officinalis were 1000 times higher than that of alpha-tocopherol. The IC50 values of magnolol and honokiol for inhibition of oxygen consumption were 8.0 x 10(-8) M and 1.0 x 10(-7) M, respectively, while that of alpha-tocopherol was 1.0 x 10(-4) M. Magnolol at 0.5 microM inhibited 71.4 +/- 9.4% of oxygen consumption and 59.3 +/- 4.6% MDA production. At the same concentration, honokiol inhibited 78.1 +/- 4.7% of oxygen consumption and 86.9 +/- 4.0% of MDA production. Of conjugated diene formation 48.4 +/- 4.6% and 53.1 +/- 3.4% were inhibited by 0.5 microM magnolol and honokiol, respectively. Also both magnolol and honokiol exhibited free radical scavenging activities as shown by the diphenyl-p-picrylhydrazyl assay, but they were less potent than alpha-tocopherol.

Topics: Animals; Antioxidants; Biphenyl Compounds; Lignans; Lipid Peroxidation; Male; Malondialdehyde; Mitochondria, Heart; Oxygen Consumption; Phytotherapy; Plants, Medicinal; Rats; Rats, Sprague-Dawley; Vitamin E

Magnolol and honokiol, biphenyl compounds, were isolated as anti-emetic principles from the methanolic extract of Magnolia obovata bark. [6]-, [8]-, and [10]-shogaols and [6]-, [8]-, and [10]-gingerols were isolated from the methanolic extract of Zingiber officinale rhizome as anti-emetic principles. Some phenyl-propanoids with allyl side-chains were found to show the same activity. They inhibited the emetic action induced by the oral administration of copper sulfate pentahydrate to leopard and ranid frogs.

Topics: Animals; Antiemetics; Anura; Biphenyl Compounds; Catechols; Fatty Alcohols; Female; Lignans; Male; Plants, Medicinal

A method was developed for determining the activity of acetyl-CoA:1-alkyl-sn-glycero-3-phosphocholine acetyltransferase (EC 2.3.1.67), a key enzyme in the biosynthesis of platelet-activating factor (PAF, 1-alkyl-2-acetyl-sn-glycero-3-phosphocholine). The assay involves measurement of the radioactivity in the trichloroacetic acid (TCA)-precipitated complex of radioactive product and albumin after incubation of 1-alkyl-sn-glycero-3-phosphocholine and [3H]acetyl-CoA with rat spleen microsomes or membrane fractions of human polymorphonuclear leukocytes (PMNs). The radioactive product associated with the precipitate was identified as PAF using an ultrahigh-sensitivity TV camera system after extraction and separation by TLC. This TCA method was then used to screen the components of crude preparations that inhibited acetyltransferase activity. Major components from the cortex of Magnoliae (magnolol and honokiol), which have anti-inflammatory and anti-bacterial actions, inhibited the acetyltransferase activity in rat spleen microsomes (IC50, 150 and 150 microM, respectively) and membrane fractions of human PMNs (IC50, 70 and 60 microM, respectively). The inhibitory action of magnolol and honokiol was reversible, and similar to or higher than that of nordihydroguaiaretic acid. PAF production in human PMNs stimulated by the ionophore A23187 was also suppressed dose dependently by magnolol and honokiol. These activities may be relevant to the claimed therapeutic effects of the extract from Magnoliae cortex.

Topics: Acetyltransferases; Animals; Biphenyl Compounds; Humans; In Vitro Techniques; Lignans; Male; Plant Extracts; Rats; Rats, Wistar; Reproducibility of Results

Saiboku-To is an anti-asthmatic herbal remedy which consists of ten herbal extracts. To investigate the clinical relationship between the effects and chemical components of Saiboku-To, a simple and sensitive high-performance liquid chromatographic method (HPLC) for determination of magnolol, one of the major urinary products, was developed. Organic solvent extraction of urinary magnolol was conducted by diatomaceous earth column rapid-flow fractionation using ethanol/dichloromethane (8/92, v/v). Recovery rates of magnolol were more than 99% with coefficient of variations less than 6% in the concentration range 9.7-970 ng mL-1. Subsequent HPLC determination of magnolol was achieved using a conventional silica-gel column, a mobile phase mixture of acetic acid/diethyl ether/n-hexane (0.2/17.0/82.8, v/v), and a UV-absorption detector set at 290 nm. Calibration was on the basis of peak height ratio between magnolol and flavone as an internal standard. The method was used to demonstrate excretion profiles of magnolol in healthy and asthmatic subjects following single administration of Saiboku-To.

Topics: Adult; Aged; Asthma; Biphenyl Compounds; Chromatography, High Pressure Liquid; Drugs, Chinese Herbal; Histamine H1 Antagonists; Humans; Lignans; Male; Medicine, Kampo; Middle Aged

Saiboku-To, a mixture of ten different herbal extracts, has been used in Japan and Czechoslovakia for corticosteroid-dependent severe asthma to reduce the maintenance doses of corticosteroid. Magnolol has been considered to be an active component of Saiboku-To as an inhibitor of 11 beta-hydroxysteroid dehydrogenase and T-lymphocyte proliferation resulting in corticosteroid-sparing. To investigate the relationship between magnolol and the clinical effects of Saiboku-To, urinary magnolol excretion was compared in responders and non-responders under long-term Saiboku-To treatment. The clinical outcome of the Saiboku-To treatment was evaluated in nine asthmatic patients at 52 weeks after the onset of the treatment, using individual fluctuation of asthmatic points obtained from the patients' diary cards. Three patients whose clinical conditions were improved by the treatment were termed responders and six others were termed non-responders. The difference in the amounts of the total magnolol excreted were not significant; however, free (or non-conjugated) amounts of magnolol excreted in the responders were 7 times those in the non-responders (P < 0.05). These results suggest that the magnolol might be responsible for the therapeutic effect of Saiboku-To, indicating practical bioavailability in the responders.

Topics: Adult; Aged; Asthma; Biological Availability; Biphenyl Compounds; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Female; Histamine H1 Antagonists; Humans; Lignans; Male; Medicine, Kampo; Middle Aged

In the present study, we demonstrated the inhibitory effect of magnolol on the plasma leakage in passive cutaneous anaphylactic (PCA) reaction, neurogenic inflammation, dorsal skin and ear edema in mice. Hind-paw skin plasma extravasation caused by antidromic stimulation of the saphenous nerve was reduced in mice pretreated with magnolol, diphenydramine or methysergide, but not with indomethacin. Ear edema formation in the PCA reaction was reduced by magnolol in dose-dependent manner. In addition, histamine-, serotonin-, compound 48/80-, bradykinin- and substance P-induced ear edema in mice was also suppressed by magnolol. A dose- and time-dependency of the inhibitory effect of magnolol was demonstrated in histamine- and compound 48/80-induced dorsal skin edema. The maximal inhibitory effect produced by a single dose of magnolol (10 mg/kg) persisted for 1 h, and significant suppression lasted for at least 3 h. In compound 48/80-pretreated mice, the histamine content of the ear was greatly reduced. Bradykinin- and substance P-induced ear edema in compound 48/80-pretreated mice was less severe than that seen in normal mice, but was still significantly reduced by magnolol pretreatment. Moreover, the inhibitory effect of magnolol was more marked than that of diphenhydramine combined with methysergide. These results suggest that the inhibitory effect of magnolol on local edema formation probably occurs through a nonselective inhibition on vascular tissue to prevent the permeability change caused by various mediators.

Topics: Adrenalectomy; Animals; Antineoplastic Agents, Phytogenic; Biphenyl Compounds; Capillary Permeability; Edema; Electric Stimulation; Exudates and Transudates; Histamine; Inflammation; Lignans; Mast Cells; Mice; Mice, Inbred ICR; Neurons, Afferent; p-Methoxy-N-methylphenethylamine; Passive Cutaneous Anaphylaxis; Regional Blood Flow; Serotonin Antagonists; Skin; Skin Absorption

A simple method using ion-pair high-performance liquid chromatography was established for the rapid and precise determination of honokiol(3',5-di-2-propenyl-1,1'-biphenyl-2,4'-diol) and magnolol(5,5'-di-2-propenyl-1,1'-biphenyl-2,2'-diol) in eighteen species of oriental pharmaceutical decoctions containing Magnolia bark. An ODS column and a mixed solvent system of water involving 10 mM tetra-n-amyl-ammonium bromide (TAA) and acetonitrile (4:6) as a mobile phase were used for the separation. Honokiol and magnolol were eluted without interference of other coexisting components within 12 min.

Topics: Biphenyl Compounds; Chromatography, High Pressure Liquid; Drugs, Chinese Herbal; Lignans

A simple method using ion-pair high-performance liquid chromatography was established for the rapid and precise simultaneous determination of honokiol (3', 5-di-2-propenyl-1, 1'-biphenyl-2,4'-diol) and magnolol (5,5'-di-2-propenyl-1,1'-biphenyl-2,2'-diol) in oriental pharmaceutical decoctions containing Magnolia bark. An ODS column and a mixture of water involving 10 mM tetra-n-amylammonium bromide (TAA) and acetonitrile (4:6) as a mobile phase were used for the separation. Honokiol and magnolol were eluted without interference of other co-existing components within 12 min.

Topics: Biphenyl Compounds; Chromatography, High Pressure Liquid; Drugs, Chinese Herbal; Lignans

Magnolol, isolated from Magnolia officinalis, inhibited mouse hind-paw edema induced by carrageenan, compound 48/80, polymyxin B and reversed passive Arthus reaction. Acetic acid-induced writhing response was depressed by magnolol, indomethacin and ibuprofen. The lethality of endotoxin challenge was reduced by pretreatment with magnolol, indomethacin and BW755C, a dual cyclo-oxygenase/lipoxygenase inhibitor. The recovered myeloperoxidase activity in edematous paw was significantly decreased in mice pretreated with magnolol and BW755C. Suppression of edema was demonstrated not only in normal mice but also in adrenalectomized animals. Magnolol was less potent on reducing PGD2 formation in rat mast cell than that of indomethacin. Unlike dexamethasone, magnolol did not increase liver glycogen level. The results suggest that the anti-inflammatory effect of magnolol was neither mediated by glucocorticoid activity nor through releasing steroid hormones from adrenal gland. The action of magnolol is proposed to be dependent on reducing the level of eicosanoid mediators.

Topics: Adrenalectomy; Animals; Antineoplastic Agents, Phytogenic; Biphenyl Compounds; Dexamethasone; Edema; Female; Indomethacin; Lignans; Liver; Mice; Mice, Inbred ICR; Peroxidase; Polymyxin B; Prostaglandin D2; Rats; Rats, Wistar

HPLC was applied to determine and compare 17 samples of Houpo processed in different ways: sauted with ginger juice, dipped with ginger juice, boiled with ginger juice, and so on. The results provide a scientific basis for screening the best processing technology of Houpo.

Topics: Biphenyl Compounds; Chromatography, High Pressure Liquid; Drugs, Chinese Herbal; Hot Temperature; Lignans; Technology, Pharmaceutical

Based on the method of assessing the growing age of trees by "annual ring in the bark", the active ingredients magnolol and honokiol in 3 species Houpo (Magnolia officinalis, M. biloba, M. rostrata) of different ages, were determined by HPLC. The results present a reference for defining the reasonable period of collection and quality evaluation of Houpo.

Topics: Biphenyl Compounds; Chromatography, High Pressure Liquid; Drugs, Chinese Herbal; Lignans; Plants, Medicinal; Quality Control; Species Specificity; Time Factors

This paper adds TLC identification of binglang and other three cruds drugs to the quality control of kakxiong shunqi pills incorporated in Chinese Pharmacopoeia. The contents of magnolol and honokinol were determined by TLC scanning. The method is simple, rapid accurate, and useful in controlling the quality of kaixiong shunqi pills.

Topics: Biphenyl Compounds; Chromatography, Thin Layer; Densitometry; Drug Combinations; Drugs, Chinese Herbal; Lignans; Quality Control

The experimental result of the quantitative determination of magnolol in Cortex Magnoliae Officinalis and its processed samples by HPLC has shown that the stir-fried sample has the highest content of magnolol among all sample and so does the ginger-fried sample among all ginger-processed samples. As a condiment, ginger can increase the content of magnolol to a certain extent, but the quantity used in processing does not affect the content significantly.

Topics: Biphenyl Compounds; Chromatography, High Pressure Liquid; Drugs, Chinese Herbal; Hot Temperature; Lignans

Fluorescent determination of magnolol has been effected employing the sensitivity- and stability-enhancing action of the non-ionic surfaceactive emulsifier OP. As a result the accuracy of determination is raised by 2 orders of magnitude as compared to that of ultraviolet spectrophotometry.

Topics: Biphenyl Compounds; Drugs, Chinese Herbal; Lignans; Spectrometry, Fluorescence; Surface-Active Agents

Magnolol is an antiplatelet agent isolated from Chinese herb Magnolia officinalis. It inhibited norepinephrine (NE, 3 microM)-induced phasic and tonic contractions in rat thoracic aorta. At the plateau of the NE-induced tonic contraction, addition of magnolol caused two phases (fast and slow) of relaxation. These two relaxations were concentration-dependent (10-100 micrograms/ml), and were not inhibited by indomethacin (20 microM). The fast relaxation was completely antagonized by hemoglobin (10 microM) and methylene blue (50 microM), and disappeared in de-endothelialized aorta while the slow relaxation was not affected by the above treatments. Magnolol also inhibited high potassium (60 mM)-induced, calcium-dependent (0.03 to 3 mM) contraction of rat aorta in a concentration-dependent manner. 45Ca(+)+ influx induced by high potassium or NE was markedly inhibited by magnolol. Cyclic GMP, but not PGI2, was increased by magnolol in intact, but not in de-endothelialized aorta. It is concluded that magnolol relaxed vascular smooth muscle by releasing endothelium-derived relaxing factor (EDRF) and by inhibiting calcium influx through voltage-gated calcium channels.

Topics: Animals; Aorta; Biphenyl Compounds; Calcium; Calcium Channels; Cyclic GMP; Drugs, Chinese Herbal; Endothelium, Vascular; Epoprostenol; Female; Hemoglobins; In Vitro Techniques; Lignans; Male; Methylene Blue; Nitric Oxide; Norepinephrine; Platelet Aggregation Inhibitors; Rats; Rats, Inbred Strains; Vasoconstriction

Data from a survey of the drug market and investigation of the original plant of "Tu-hou-po", after careful botanical examinations, showed that the drugs were derived from 5 species of the genus Manglietia of Magnoliaceae, viz. Manglietia chingii Dandy, M. insignis (Wall.) Bl., M. duclouxii Finet et Gagnep., M. yuyuanensis Law and M. szechuanica Hu. Comparisons of the main characteristics of the plants, Tu-hou-po and Hou-po crude drugs and chemical components showed that Manglietia is taxonomically the closest to Magnolia and contained similar components (tab 1-2 and fig 1). The results of HPLC analysis demonstrated that they contained magnolol, honokiol, magnocurine and salicifoline, in different quantities. However, no magnosprengerine was detected. Besides, it was also found that the percentage of magnolol and honokiol contents were higher, while that of magnocurine was lower in Hou-po. On the contrary, the content of magnocurine was higher, while that of magnolol and honokiol were lower in Tu-hou-po. Manglietia chingii (Tu-hou-po) is being used as the Chinese traditional drug "Hou-po" in the clinic in Guangxi. Therefore, M. chingii is noteworthily exploited as a new resource of Hou-po for further research.

Topics: Biphenyl Compounds; Drugs, Chinese Herbal; Isoquinolines; Lignans; Neuromuscular Nondepolarizing Agents; Plants, Medicinal

This study reports on the connexion of the content of the efficacious constituents, magnolol and honokiol of Magnolia officinalis var. biloba with age, diameter of the trunk and various parts of the tree, thus presenting a basis for its collection, quality control and clinical applications.

Topics: Biphenyl Compounds; Lignans; Plants, Medicinal; Quality Control; Time Factors

Magnolol and honokiol are two position isomers isolated from the bark of Magnolia officinalis. Both inhibited the aggregation and ATP release of rabbit platelet-rich plasma induced by collagen and arachidonic acid without affecting that induced by ADP, PAF or thrombin. Aggregation of washed platelets was more markedly inhibited than that of platelet-rich plasma, while the aggregation of whole blood was least affected by both inhibitors. Thromboxane B2 formation caused by collagen, arachidonic acid or thrombin was in each case inhibited by magnolol and honokiol. The rise of intracellular calcium caused by arachidonic acid or collagen was also suppressed by both agents. Collagen-induced intracellular calcium increase in the presence of indomethacin was suppressed by magnolol. It is concluded that the antiplatelet effect of magnolol and honokiol is due to an inhibitory effect on thromboxane formation and also an inhibition of intracellular calcium mobilization.

Topics: Animals; Biphenyl Compounds; Calcium; In Vitro Techniques; Lignans; Medicine, Chinese Traditional; Platelet Aggregation Inhibitors; Platelet Function Tests; Rabbits; Thromboxane B2

Topics: Administration, Oral; Animals; Biotransformation; Biphenyl Compounds; Feces; Female; Injections, Intraperitoneal; Intestinal Absorption; Lignans; Male; Medicine, Chinese Traditional; Rats; Rats, Inbred Strains

Topics: Animals; Aorta, Thoracic; Biphenyl Compounds; Calcium Channel Blockers; In Vitro Techniques; Lignans; Male; Medicine, Chinese Traditional; Medicine, East Asian Traditional; Muscle Contraction; Muscle, Smooth, Vascular; Plants, Medicinal; Rats; Rats, Inbred Strains

Topics: Biphenyl Compounds; Hot Temperature; Lignans; Medicine, Chinese Traditional; Medicine, East Asian Traditional; Plants, Medicinal; Tissue Distribution

Topics: Biphenyl Compounds; Isoquinolines; Lignans; Medicine, Chinese Traditional; Medicine, East Asian Traditional; Plants, Medicinal

Topics: Biphenyl Compounds; China; Lignans; Plants, Medicinal

Topics: Animals; Biotransformation; Biphenyl Compounds; Chromatography, Liquid; Feces; Lignans; Male; Mass Spectrometry; Rats; Rats, Inbred Strains

Topics: Animals; Biphenyl Compounds; Central Nervous System Depressants; Chickens; Lignans; Male; Mice; Rats; Rats, Inbred Strains

Effects of some diphenyl and monophenyl compounds on grip strength in mice and spinal reflexes in young chicks were investigated in order to study structure-activity relationships between muscle relaxant activity and neolignane compounds, magnolol and honokiol extracted from Magnolia officinalis THUNB. Diphenyl produced a long-lasting suppression in the spinal reflex and relatively weak inhibition in the grip strength. An introduction of a hydroxyl into 2-position of diphenyl, o-phenylphenol, increased the muscle relaxant activity and accelerated the onset, although the duration was still long. In the spinal reflex preparation the duration of action became short. The introduction of two hydroxyls into 2- and 2'-position of diphenyl, 2,2'-dihydroxydiphenyl, further strengthened the activity and shortened the duration of the inhibitory effect on the grip strength and the spinal reflex. When two allyls are introduced into 5,5'-position of 2,2'-dihydroxydiphenyl, it corresponds to magnolol. Magnolol, 5,5'-diallyl-2,2'-dihydroxydiphenyl, produced potent inhibitory effects of gradual onset and of long duration on the two test preparations. Position of allyls and hydroxyls in honokiol, 5,3'-diallyl-2,4'-dihydroxydiphenyl, is different from magnolol, although the pharmacological characteristics are quite similar to magnolol. These results suggest that a hydroxyl accelerates the onset and shortens the muscle relaxant activity of diphenyl and an allyl influences the activity in the opposite direction. Both radicals appear to intensify the activity.

Topics: Animals; Biphenyl Compounds; Chemical Phenomena; Chemistry; Chickens; Eugenol; Lignans; Male; Mephenesin; Mice; Muscle Contraction; Muscle Relaxants, Central; Reflex; Spinal Cord; Structure-Activity Relationship

Topics: Biphenyl Compounds; China; Lignans; Plants, Medicinal

Topics: Allyl Compounds; Biphenyl Compounds; Lignans; Plant Extracts; Plants