rosmarinic-acid and Disease-Models--Animal

Both caffeic acid and 3,4-dihydroxyphenyllactic acid (danshensu) are synthesized through two distinct routs of the shikimic acid biosynthesis pathway. In many plants, especially the rosemary and sage family of Lamiaceae, these two compounds are joined through an ester linkage to form rosmarinic acid (RA). A further structural diversity of RA derivatives in some plants such as

Topics: Alkenes; Alzheimer Disease; Amyloid beta-Peptides; Animals; Cell Differentiation; Cinnamates; Dementia, Vascular; Depsides; Disease Models, Animal; Gene Expression Regulation; Humans; Lactates; Neural Stem Cells; Neurons; Neuroprotective Agents; Nootropic Agents; Polyphenols; Rosmarinic Acid; Stroke; tau Proteins

Ocimum sanctum L. or Ocimum tenuiflorum L, commonly known as the Holy Basil in English or Tulsi in the various Indian languages, is a important medicinal plant in the various traditional and folk systems of medicine in Southeast Asia. Scientific studies have shown it to possess antiinflammatory, analgesic, antipyretic, antidiabetic, hepatoprotective, hypolipidemic, antistress, and immunomodulatory activities. Preclinical studies have also shown that Tulsi and some of its phytochemicals eugenol, rosmarinic acid, apigenin, myretenal, luteolin, β-sitosterol, and carnosic acid prevented chemical-induced skin, liver, oral, and lung cancers and to mediate these effects by increasing the antioxidant activity, altering the gene expressions, inducing apoptosis, and inhibiting angiogenesis and metastasis. The aqueous extract of Tulsi and its flavanoids, orintin, and vicenin are shown to protect mice against γ-radiation-induced sickness and mortality and to selectively protect the normal tissues against the tumoricidal effects of radiation. The other important phytochemicals like eugenol, rosmarinic acid, apigenin, and carnosic acid are also shown to prevent radiation-induced DNA damage. This review summarizes the results related to the chemopreventive and radioprotective properties of Tulsi and also emphasizes aspects that warrant future research to establish its activity and utility in cancer prevention and treatment.

Topics: Abietanes; Animals; Apigenin; Cinnamates; Depsides; Disease Models, Animal; Drug Evaluation, Preclinical; Eugenol; Humans; Luteolin; Neoplasms; Ocimum; Phytochemicals; Plant Extracts; Plants, Medicinal; Rosmarinic Acid; Sitosterols

The present study was undertaken to determine whether oral supplementation with rosmarinic acid (RA) is an effective intervention for patients with SAR. In addition, the anti-inflammatory mechanism of RA also estimated in the ear edema models.. Patients were treated daily with RA (200 mg or 50 mg) or placebo for 21 days. Patients recorded symptoms daily and profiles of infiltrating cells and concentration of cytokines were measured in nasal lavage fluid. Compared to placebo, supplementation with RA resulted in a significant decrease in responder rates for each symptom. RA also significantly decreased the numbers of neutrophils and eosinophils in nasal lavage fluid.. Topical application RA showed anti-inflammatory activity 5-hours after 12-tetradecanoylphorbol 13-acetate (TPA) treatment with marked inhibition of neutrophil infiltration. Up regulation of ICAM-1, VCAM-1 cyclooxygenase-2 (COX-2), KC and MIP-2 by TPA were markedly reduced by pre-treatment with extract of perilla (PE) or RA. Reactive oxygen radical production detected as thiobarbituric acid reactive substance (TBARS), lipid peroxide (LPO) and 8-hydroxy-2'deoxyguanosine (8OH-dG), by double treatment of TPA was reduced by pretreatment with PE or RA. RA is an effective intervention for SAR that is mediated by inhibition of PMNL infiltration. This effect of RA is due to two independent mechanisms: inhibition of the inflammatory response and scavenging of ROS.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cinnamates; Depsides; Dietary Supplements; Disease Models, Animal; Double-Blind Method; Histamine H1 Antagonists; Humans; Immunoglobulin E; Leukocyte Count; Phytotherapy; Placebos; Plant Extracts; Rhinitis, Allergic, Seasonal; Rosmarinic Acid

Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide. The main therapeutic approach available nowadays relieves motor symptoms but does not prevent or stop neurodegeneration. Rosmarinic acid (RA), an ester of caffeic and 3,4-dihydroxyphenylacetic acids, is obtained from numerous plant species such as Salvia officinalis L. (sage) and Rosmarinus officinalis (rosemary). This compound has a wide spectrum of biological activities, such as antioxidant and anti-inflammatory, and could be an additional therapy for neurodegenerative disorders. Here we evaluated the potential neuroprotective effects of RA treatment in a murine model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Mice were separated into four groups: CN, Control/saline; RA, Rosmarinic acid/vehicle; MPTP, MPTP/saline; MPTP+RA, MPTP/RA. RA (20 mg/kg, or vehicle) was administered orally by intra-gastric gavage for 14 days, one hour before MPTP or saline injection. MPTP groups received the drug (30 mg/kg, intraperitoneally) once a day for five days (fourth to the eighth day of the experiment). MPTP-treated animals displayed hyperlocomotion behavior, which was significantly prevented by RA treatment. In addition, RA treatment increased dopaminergic signaling in the parkinsonian mice and improved the monoaminergic system in healthy animals. Analysis of alterations in the striatal mRNA expression of dopaminergic system components showed that MAO-A expression was increased in the MPTP+AR group. Overall, this study brings new evidence of the potential neuroprotective properties of RA not only in preventing behavioral features observed in PD, but also by improving neurotransmission in the healthy brain.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Disease Models, Animal; Dopamine; Mice; Mice, Inbred C57BL; Neurodegenerative Diseases; Neuroprotective Agents; Parkinson Disease; Rosmarinic Acid

There is no doubt that Alzheimer's disease (AD) is one of the greatest threats facing mankind today. Within the next few decades, Acetylcholinesterase inhibitors (AChEIs) will be the most widely used treatment for Alzheimer's disease. The withdrawal of the first generation AChEIs drug Tacrine (TAC)/ Cognex from the market as a result of hepatotoxicity has always been an interesting case study. Rosmarinic acid (RA) is a natural compound of phenolic acids that has pharmacological activity for inhibiting Alzheimer's disease, as well as liver protection.. In this study, we determined that RA can reduce the hepatotoxicity of TAC, and both of them act synergistically to inhibit the progression of AD in mice.. In addition to the wild type mice (WT) group, the 6-month-old APP/PS1 (APPswe/PSEN1dE9) double-transgenic (Tg) mice were randomly divided into 6 groups: Tg group, TAC group, RA group, TAC+Silymarin (SIL) group, TAC+RA-L (Rosmarinic Acid Low Dose) goup and TAC+RA-H (Rosmarinic Acid High Dose) group. A series of experiments were carried out, including open field test, Morris water maze test, Hematoxylin - Eosin (HE) staining, Nissl staining, biochemical analysis, immunofluorescence analysis, western blotting analysis and so on.. RA combined with TAC could enter the brain tissue of AD mice, and the combination of drugs could better improve the cognitive behavior and brain pathological damage of AD mice, reduce the expression of A β oligomer, inhibit the deposition of A β, inhibit the activity of AChE and enhance the level of Ach in hippocampus. Both in vivo and in vitro experiments showed that RA could alleviate the hepatotoxicity or liver injury induced by TAC. The Western blot analysis of the liver of AD mice showed that RA combined with TAC might inhibit the apoptosis of Bcl-2/Bax, reduce the programmed apoptosis mediated by caspase-3 and reduce the burden of liver induced by TAC, could inhibit the development of liver apoptosis by alleviating the hepatotoxicity of TAC and inhibiting the phosphorylation of JNK.. The potential drug combination that combines rosmarinic acid with tacrine could reduce tacrine's hepatotoxicity as well as enhance its therapeutic effect on Alzheimer's disease.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Mice; Mice, Transgenic; Rosmarinic Acid; Tacrine

Rosmarinic acid (RA) has been proven to exert antianaphylaxis in atopic dermatitis, asthma, and allergic rhinitis. The aim of this study was to determine the hepatoprotective effects of RA on ovalbumin (OVA) challenge-induced intestinal allergy. The results exhibited that RA could relieve anaphylactic symptoms, decrease diarrhea, and prevent hypothermia in allergic mice. Moreover, the elevation of OVA specific IgE (OVA-sIgE), histamine, and mouse mast cell proteinases (mMCP-1) in the serum of OVA challenged mice were remarkably inhibited by RA. OVA challenge resulted in notable increases in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) activities, liver malondialdehyde (MDA) and nitic oxide (NO) levels, and a remarkable decrease in liver superoxide dismutase (SOD) activity and glutathione (GSH) level. RA treatments succeeded in improving these biochemical parameters and promote the redox homeostasis. Cytokine expression evaluation showed that RA effectively enhanced the expression of anti-inflammatory cytokines (IL-10 and FOXP-3) in the liver of OVA-challenged mice. Meanwhile, the elevation of pro-inflammatory cytokines (TNF-α, IL-4, IL-6, mMCP-1, and iNOS) were remarkably inhibited by RA. These findings suggest that RA possesses hepatoprotective effects on OVA challenge-induced liver injury. The anti-oxidative and anti-inflammatory activities of RA potentially play vital roles in this process.

Topics: Animals; Anti-Inflammatory Agents; Cytokines; Disease Models, Animal; Food Hypersensitivity; Mice; Mice, Inbred BALB C; Ovalbumin; Rosmarinic Acid

Maintaining a steady state of mucus barrier is an important potential target for polyphenol to exert its anticolitis activity. This study elucidates the pivotal role of polyphenol rosmaric acid (RA) in regulating the mucus barrier function and alleviating inflammation by identifying its gut microbiota-derived metabolites and evaluating its inhibitory effect on inflammasomes in colitis mice. Results demonstrated that RA treatment promoted the proliferation of goblet cells and restored the level of mucus secretion, especially Muc2. RA reshaped the microbiota of colitis mice, particularly the boost of core probiotics, such as p.

Topics: Animals; Colitis; Dextran Sulfate; Disease Models, Animal; Gastrointestinal Microbiome; Inflammasomes; Intestinal Mucosa; Mice; Mice, Inbred C57BL; Mucus; Rosmarinic Acid

Asthma is a common chronic inflammatory disease of the airways with no known cure. Lipid mediators (LMs) are a kind of inflammatory signaling molecules which are believed to be involved in the development of asthma.. Anti-inflammatory effect of SXCF and RosA was assessed using OVA-induced asthma model mice by UPLC-MS/MS method.. Overall, RosA played a critical role in anti-asthma treatment. In total, 90% of LMs species that were significantly regulated by SXCF were covered. On the most important LMs associated with asthma, RosA equivalent induced similar effects as SXCF did. It is believed that some constituents in SXCF could neutralize RosA excessive impacts on LMs.

Topics: Animals; Anti-Inflammatory Agents; Asthma; Bronchoalveolar Lavage Fluid; Chromatography, Liquid; Cytokines; Disease Models, Animal; Hyssopus Plant; Lipids; Mice; Mice, Inbred BALB C; Ovalbumin; Rosmarinic Acid; Tandem Mass Spectrometry

Asthma is a highly prevalent and heterogeneous chronic respiratory disease and is often treated with inhaled corticosteroids or in combination with a β

Topics: Adrenergic beta-Agonists; Animals; Anti-Asthmatic Agents; Asthma; Cytokines; Disease Models, Animal; Immunoglobulin E; Lung; Mice; Mice, Inbred BALB C; NF-kappa B; Ovalbumin; Perilla frutescens; Pneumonia; Receptors, Adrenergic, beta; Rosmarinic Acid; Signal Transduction

An abdominal aortic aneurysm is a life-threatening cardiovascular disorder caused by dissection and rupture. No effective medicine is currently available for the > 90% of patients whose aneurysms are below the surgical threshold. The present study investigated the impact of rosmarinic acid, salvianolic acid C, or salvianolic acid B on experimental abdominal aortic aneurysms. Abdominal aortic aneurysms were induced in apolipoprotein E-deficient mice

Topics: Angiotensin II; Animals; Aorta, Abdominal; Aortic Aneurysm; Aortic Aneurysm, Abdominal; Cinnamates; Depsides; Disease Models, Animal; Matrix Metalloproteinase 2; Mice; Mice, Inbred C57BL; Rosmarinic Acid

Cisplatin (CP) is a well-known anticancer drug used to effectively treat various kinds of solid tumors. CP causes acute kidney injury (AKI) and unfortunately, there is no therapeutic approach in hand to prevent AKI. Several signaling pathways are responsible for inducing AKI which leads to inflammation in proximal convoluted tubule cells in the kidney. Furthermore, the nucleotide-binding oligomerization domain (NOD)-like receptor containing pyrin domain 3 (NLRP3) inflammasome is involved in the CP-induced AKI. In this study, we investigated therapeutic effects of rosmarinic acid (RA) against inflammation-induced AKI. RA was orally administered at the dose of 100 mg/kg for two consecutive days after 24 h of a single injection of CP at the dose of 20 mg/kg administered intraperitoneally in Swiss albino male mice. Treatment of RA inhibited the activation of NLRP3 signaling pathway by blocking the activated caspase-1 and downstream signal molecules such as IL-1β and IL18. CP activated HMGB1-TLR4/MyD88 axis was also found to be downregulated with the RA treatment. Activation of nuclear factor-κB and elevated protein expression of cyclooxygenase-2 (COX-2) were also found to be downregulated in RA-treated animals. Alteration of early tubular injury biomarker, kidney injury molecule-1 (KIM-1), was found to be subsided in RA-treated mice. RA has been earlier reported for antioxidant and anti-inflammatory properties. Our findings show that blocking a critical step of inflammasome signaling pathway by RA treatment can be a novel and beneficial approach to prevent the CP-induced AKI.

Topics: Acute Kidney Injury; Administration, Oral; Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Antioxidants; Cinnamates; Cisplatin; Cyclooxygenase 2; Depsides; Disease Models, Animal; Hepatitis A Virus Cellular Receptor 1; Inflammasomes; Kidney Tubules, Proximal; Male; Mice; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Rosmarinic Acid; Signal Transduction; Treatment Outcome

Aiming at assessing the therapeutic effect of ethyl rosmarinate (ER) on ulcerative colitis (UC), the following activities were performed in vitro and in vivo in the present study. Firstly, a lipopolysaccharide (LPS)-induced RAW264.7 cell inflammation model was established to determine the level of inflammatory factors. Then, a UC mice model induced by dextran sodium sulfate (DSS) was established to further investigate the effects of ER on symptoms, inflammatory factors and colon histopathology. Finally, serum and colon metabolomics studies were performed to identify the biomarkers and metabolisms closely related to the protective effect of ER on UC. The results showed that after ER intervention, the levels of inflammatory factors (NO, TNF-α, IL-1β and IL-6) and key enzyme (MPO) in cell supernatant, serum or colon were significantly decreased, and the disease activity index and colon tissue damage in mice were also effectively improved or restored. In addition, 28 biomarkers and 6 metabolisms were found to be re-regulated by ER in the UC model mice. Therefore, it could be concluded that ER could effectively ameliorate the progression of UC and could be used as a new natural agent for the treatment of UC.

Topics: Animals; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Biomarkers; Cinnamates; Colitis, Ulcerative; Colon; Depsides; Dextran Sulfate; Disease Models, Animal; Inflammation; Male; Metabolomics; Mice; Mice, Inbred BALB C; NF-kappa B; Rats; RAW 264.7 Cells; Rosmarinic Acid; Signal Transduction; Tumor Necrosis Factor-alpha

Obstructive sleep apnoea (OSA) causes chronic intermittent hypoxia (CIH), which results in mitochondrial dysfunction and generates reactive oxygen species (ROS) in the heart. Excessive free iron could accelerate oxidative damage, which may be involved in this process. Banxia-Houpu decoction (BHD) was reported to improve the apnoea hypopnoea index in OSA patients, but the specific mechanism was still unclear.. To investigate whether BHD could reduce CIH-induced heart damage by regulating iron metabolism and mitochondrial function.. BHD (7.01 g/kg) significantly improved cardiac dysfunction, pathological change and mitochondrial structure induced by CIH. BHD increased the Bcl-2/Bax ratio (1.4-fold) and inhibited caspase 3 cleavage in CIH mice (0.45-fold). BHD activated mitophagy by upregulating Parkin (1.94-fold) and PINK1 (1.26-fold), inhibiting the PI3K-AKT-mTOR pathway. BHD suppressed ROS generation by decreasing NOX2 (0.59-fold) and 4-HNE (0.83-fold). BHD reduced the total iron in myocardial cells (0.72-fold) and mitochondrial iron by downregulating Mfrn2 (0.81-fold) and MtFt (0.78-fold) proteins, and upregulating ABCB8 protein (1.33-fold). Rosmarinic acid, the main component of Perilla Leaf in BHD, was able to react with Fe. These findings encourage the use of BHD to resist cardiovascular injury and provide the theoretical basis for clinical treatment in OSA patients.

Topics: Animals; Apoptosis; Cinnamates; Depsides; Disease Models, Animal; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Heart Injuries; Hypoxia; Iron; Male; Mice; Mice, Inbred C57BL; Mitochondria; Oxidative Stress; Reactive Oxygen Species; Rosmarinic Acid; Sleep Apnea, Obstructive

Psychiatric disorders and associated cardiac comorbidities have increased the risk of mortality worldwide. Researchers reported that depression increases the possibility of future cardiac abnormalities by approximately 30%. Therefore, there is an unmet need to develop therapeutic interventions to treat depression and associated cardiac abnormalities. The present study was conducted to evaluate the prophylactic effect of rosmarinic acid (RA) against chronic unpredictable stress (CUS)-induced depression associated cardiac abnormalities in Wistar rats. The CUS paradigm, which comprised several stressors, was employed for 40 days to induce depressive-like behavior and associated cardiac abnormalities in rats. Along with CUS, RA at a dose of 25 and 50 mg/kg was administered orally to two groups of animals for 40 days. Behavioral tests (forced swim test and sucrose consumption test) and molecular biomarkers (corticosterone and serotonin) were performed. Electrocardiography was performed before CUS (Day 0), Day 20, and Day 40 to study electrocardiogram parameters. Furthermore, changes in body weight, organ weight, tissue lipid peroxidation, glutathione, catalase, cTn-I, MMP-2, and proinflammatory cytokines (TNF-α and IL-6) were estimated. Our results showed that RA treatment caused a reduction in immobility period, adrenal hyperplasia, corticosterone level, tissue lipid peroxidation, cTn-I, MMP-2, proinflammatory cytokines, and QRS complex duration, while an increase in sucrose consumption, brain serotonin level, T-wave width, glutathione, and catalase activity as compared with the CUS-control group. The results of our study proved that RA administration ameliorates CUS-induced depression-associated cardiac abnormalities in rats via serotonergic, oxidative, and inflammatory pathways.

Topics: Animals; Behavior, Animal; Biomarkers; Catalase; Cinnamates; Copper; Corticosterone; Depression; Depsides; Disease Models, Animal; Diterpenes; Glutathione; Interleukin-6; Matrix Metalloproteinase 2; Oxidative Stress; Rats; Rats, Wistar; Rosmarinic Acid; Serotonin; Sucrose; Tumor Necrosis Factor-alpha

Rosmarinic acid is a polyphenolic compound, abundantly present in herbs of the Lamiaceae family. The aim of the study was to evaluate the immunomodulatory properties of a recently developed phenethyl ester derivative of rosmarinic acid (PERA), with enhanced ability of diffusion through biological membranes, in an animal model of the central nervous system (CNS) autoimmunity. To this end, experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis was used. Daily subcutaneous administration of PERA (30 mg/kg) from day 7 to day 22 after immunization successfully ameliorated EAE induced in Dark Agouti rats, shortening the disease duration and reducing maximal, cumulative and mean clinical score. PERA efficiently reduced production of major encephalitogenic cytokines, interferon (IFN)-γ and interleukin (IL)-17, in immune cells from the CNS or the lymph nodes draining the site of immunization of EAE rats, as well as in CD4

Topics: Animals; Cytokines; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Esters; Mice; Mice, Inbred C57BL; Multiple Sclerosis; Rats; Rosmarinic Acid

This study aims to determine the effects of rosmarinic acid which involved the mechanisms to decrease the postoperative peritoneal adhesion formation in rats. Various incisions and removing a 1 × 1 cm piece of peritoneum was used to induce the peritoneal adhesions. Experimental groups were as follows: 1-Sham group. 2-Control group: Peritoneal adhesions were induced and no treatments were performed. 3-Treatment groups: Following inducing peritoneal adhesions, animals received rosmarinic acid with 50 and 70 mg/kg dosage, respectively. Macroscopic examination of adhesions indicated that adhesion bands were reduced in both treatment groups compared to the control group. Moreover, the adhesion score was decreased in both treatment groups on day 14. Inflammation and fibroblast proliferation were both reduced in the treatment groups on day 14. TGF-β1, TNF-α, and VEGF were all evaluated by western blot and immunohistochemistry on days 3 and 14. Treatment groups reduced inflammatory cytokines on days 3 and 14. The treatment group with a 70 mg/kg dosage decreased TGF-β1 and TNF-α levels more than the other treatment group. The administration of rosmarinic acid significantly reduced MDA and increased CAT levels. In conclusion, the rosmarinic acid was effective to reduce the adhesion bands, inflammatory cytokines, angiogenesis, and oxidative stress.

Topics: Animals; Cytokines; Disease Models, Animal; Peritoneum; Postoperative Complications; Rats; Rosmarinic Acid; Tissue Adhesions; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

Nonalcoholic steatohepatitis (NASH) is considered as a common liver disease. SIRT1, a pivotal sensor, controls activation of metabolic, inflammatory and apoptotic pathways. Rosmarinic acid (RA) has positive effects on the liver injuries; nevertheless, its mechanisms are not completely studied. The aim of this study was to explore the role of rosmarinic acid on the pathways involved by SIRT1 for amelioration of a mouse model of NASH. To do this, C57/BL6 mice were divided into four equal groups (6 in each group). Animals received saline and rosmarinic acid as the control groups. NASH was induced by methionine-choline-deficient (MCD) diet. In the NASH + RA group, Rosmarinic acid was injected daily in mice fed on an MCD diet. Rosmarinic acid decreased plasma triglyceride, cholesterol, liver Steatosis and oxidative stress. Rosmarinic acid administration also increased SIRT1, Nrf2 and PPARα and decreased SREBP1c, FAS, NFκB and caspase3 expressions. Moreover, TNFα, IL6, P53, Bax/Bcl2 ratio and caspase3 expressions decreased. Our study demonstrated that remarkable effects of rosmarinic acid on the mice with NASH might be due to activation of SIRT1/Nrf2, SIRT1/NFκB and SIRT1/PPARα pathways, which alleviate hepatic steatosis, oxidative stress, inflammation and apoptosis.

Topics: Animals; Anti-Inflammatory Agents; Choline; Cinnamates; Depsides; Disease Models, Animal; Liver; Methionine; Mice; Mice, Inbred C57BL; NF-E2-Related Factor 2; NF-kappa B; Non-alcoholic Fatty Liver Disease; PPAR alpha; Rosmarinic Acid; Sirtuin 1

Hyperlipidemia is a potent risk factor for the development of cardiovascular diseases. The reverse cholesterol transport (RCT) process has been shown to alleviate hyperlipidemia and protect against cardiovascular diseases. Recently, rosmarinic acid was reported to exhibit lipid-lowering effects. However, the underlying mechanism is still unclear. This study aims to investigate whether rosmarinic acid lowers lipids by modulating the RCT process in high-fat diet (HFD)-induced hyperlipidemic C57BL/6J mice. Our results indicated that rosmarinic acid treatment significantly decreased body weight, blood glucose, and plasma total cholesterol and triglyceride levels in HFD-fed mice. Rosmarinic acid increased the expression levels of cholesterol uptake-associated receptors in liver tissues, including scavenger receptor B type 1 (SR-B1) and low-density lipoprotein receptor (LDL-R). Furthermore, rosmarinic acid treatment notably increased the expression of cholesterol excretion molecules, ATP-binding cassette G5 (ABCG5) and G8 (ABCG8) transporters, and cholesterol 7 alpha-hydroxylase A1 (CYP7A1) as well as markedly reduced cholesterol and triglyceride levels in liver tissues. In addition, rosmarinic acid facilitated fatty acid oxidation through AMP-activated protein kinase (AMPK)-mediated carnitine palmitoyltransferase 1A (CPT1A) induction. In conclusion, rosmarinic acid exhibited a lipid-lowering effect by modulating the expression of RCT-related proteins and lipid metabolism-associated molecules, confirming its potential for the prevention or treatment of hyperlipidemia-derived diseases.

Topics: AMP-Activated Protein Kinase Kinases; Animals; ATP Binding Cassette Transporter, Subfamily G, Member 5; ATP Binding Cassette Transporter, Subfamily G, Member 8; Cardiovascular Diseases; Carnitine O-Palmitoyltransferase; Cholesterol; Cholesterol 7-alpha-Hydroxylase; Cinnamates; Depsides; Diet, High-Fat; Disease Models, Animal; Gene Expression Regulation; Humans; Hyperlipidemias; Lipid Metabolism; Lipoproteins; Liver; Male; Mice; Receptors, LDL; Rosmarinic Acid; Scavenger Receptors, Class B

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Brain; Cinnamates; Cytokines; Depsides; Disease Models, Animal; Ferns; Inflammation; Plant Extracts; Rosmarinic Acid; Zebrafish

Rosmarinic acid (RA) is a water-soluble phenolic compound extracted from Boraginaceae and Lamiaceae. This study was designed to investigate the role and mechanism of action of RA in improving nonalcoholic fatty liver disease (NAFLD). Male SD rats maintained on a high fat diet and L02 cells stimulated with oleic acid were treated with RA. Our results showed that RA significantly reduced total cholesterol, triglycerides, low-density lipoprotein cholesterol, alanine aminotransferase, aspartate aminotransferase, and malondialdehyde levels and increased high-density lipoprotein cholesterol, superoxide dismutase and adenosine triphosphate levels both in vivo and in vitro. Hematoxylin and eosin staining and oil red O staining showed that RA had a good lipid-lowering effect and substantial protective effects on liver injury. Transmission electron microscopy and JC-1 fluorescence results showed that RA could improve mitochondrial damage in hepatocytes. Additionally, flow cytometry results indicated that RA inhibited ROS generation and apoptosis in L02 cells. The impaired hepatocytes were restored by using RA in NAFLD models characterized by down-regulating YAP1 and TAZ, meanwhile up-regulating PPARγ and PGC-1α. When YAP1 was over-expressed, RA reduced the expression of YAP1; however, the action of RA was significantly blocked by silencing YAP1. The experimental results indicated that RA markedly alleviated NAFLD by repairing mitochondrial damage and regulating the YAP1/TAZ-PPARγ/PGC-1α signaling pathway.

Topics: Animals; Cinnamates; Depsides; Disease Models, Animal; Male; Non-alcoholic Fatty Liver Disease; PPAR gamma; Rats; Rats, Sprague-Dawley; Rosmarinic Acid; Signal Transduction; Transfection

Ulcerative colitis (UC), one of the two main types of inflammatory bowel disease, has no effective treatment. Rosmarinic acid (RA) is a polyphenol that, when administered orally, is metabolised in the small intestine, compromising its beneficial effects. We used chitosan/nutriose-coated niosomes loaded with RA to protect RA from gastric degradation and target the colon and evaluated their effect on acute colitis induced by 4% dextran sodium sulphate (DSS) for seven days in mice. RA-loaded nanovesicles (5, 10 and 20 mg/kg) or free RA (20 mg/kg) were orally administered from three days prior to colitis induction and during days 1, 3, 5 and 7 of DSS administration. RA-loaded nanovesicles improved body weight loss and disease activity index as well as increased mucus production and decreased myeloperoxidase activity and TNF-α production. Moreover, RA-loaded nanovesicles downregulated protein expression of inflammasome components such as NLR family pyrin domain-containing 3 (NLRP3), adaptor protein (ASC) and caspase-1, and the consequent reduction of IL-1β levels. Furthermore, nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) protein expression increased after the RA-loaded nanovesicles treatment However, these mechanistic changes were not detected with the RA-free treatment. Our findings suggest that the use of chitosan/nutriose-coated niosomes to increase RA local bioavailability could be a promising nutraceutical strategy for oral colon-targeted UC therapy.

Topics: Animals; Cinnamates; Colitis; Depsides; Disease Models, Animal; Heme Oxygenase-1; In Vitro Techniques; Inflammasomes; Inflammation; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Nanomedicine; Nanoparticles; NF-E2-Related Factor 2; NLR Family, Pyrin Domain-Containing 3 Protein; Oxidative Stress; Peroxidase; Rosmarinic Acid; Signal Transduction; Tumor Necrosis Factor-alpha

Rosmarinus officinalis, commonly known as rosemary, is a medicinal herb that presents significant biological properties such as antimicrobial, antioxidant, anti-inflammatory, anti-diabetic and anti-depressant activities. Recent findings correlate impaired adult neurogenesis, which is crucial for the maintenance of synaptic plasticity and hippocampal functioning, synaptic regulation with the pathological hallmarks of Alzheimer's disease (AD). These observations call for the need to developing compounds that promote neurogenesis and alleviates deficits in cognition and synaptic regulation.. The present study was conducted to determine the proneurogenic effects of R. officinalis and its active compounds (ursolic acid and rosmarinic acid) in comparison to Donepezil in an Aβ. BALB/c mice were divided into ten groups. Half were injected with Aβ. The results show a protective effect by rosmarinic acid and ursolic acid in reversing the deficits in spatial and recognition memory as well as changes in anxiety induced by Aβ. Our findings indicate the potential of R. officinalis and its active compounds as therapeutic agents against Aβ

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cinnamates; Cognition; Depsides; Disease Models, Animal; Doublecortin Protein; Gene Expression Regulation; Hippocampus; Male; Maze Learning; Mice, Inbred BALB C; Neurogenesis; Neurons; Neuroprotective Agents; Peptide Fragments; Rosmarinic Acid; Rosmarinus; Triterpenes; Ursolic Acid

IL-23/Th17 (IL-17) axis plays a critical role in psoriasis. Rosmarinic acid (RA) was proved the inhibitory effect of T cell infiltration in the skin. However, whether and how RA has beneficial effects on psoriasis did not really know yet. So lipopolysaccharide (LPS)-induced abnormal proliferation Hacat cell line and Imiquimod (IMQ)-induced psoriasis-like mouse dermatitis were used to assess the pharmacological effects and mechanisms of RA by Psoriasis Area Severity Index (PASI) score, histopathology, flow cytometry, reverse transcription-polymerase chain reaction (RT-PCR) and western blotting. The results showed that RA inhibited LPS-induced aberrant expression of Hacat cell line, and significantly alleviated IMQ-induced skin inflammation. Although RA had no obviously effect on the ratio of epidermal Langerhans cell (LC) and LC migration from the skin to the skin draining lymph nodes, RA inhibited the expression of IL-23 in skin lesions, as well as reduced the differentiation of Th17 cells and producing of IL-17A by down regulating the transcriptor factor RORγt and JAK2/Stat3 signal pathway, comparing to IMQ treated group. The findings suggest that RA inhibits psoriasis-like skin inflammation in vivo and in vitro by reducing the expression of IL-23, inhibiting Th17 dominated inflammation and down regulating the Jak2/Stat3 signal pathway.

Topics: Animals; Cinnamates; Cytokines; Depsides; Disease Models, Animal; HaCaT Cells; Humans; Imiquimod; Interleukin-23; Janus Kinase 2; Mice; Mice, Inbred BALB C; Psoriasis; Rosmarinic Acid; Signal Transduction; Skin; STAT3 Transcription Factor; Th17 Cells

Previously, we found that rosmarinic acid (RA) exerted anti-inflammatory activities in a dextran sulfate sodium (DSS)-induced colitis model. Here, we investigated the anti-tumor effects of RA on colitis-associated colon cancer (CAC) and the underlying molecular mechanisms. We established an azoxymethane (AOM)/DSS-induced CAC murine model for in vivo studies and used a conditioned media (CM) culture system in vitro. H&E staining, immunohistochemistry, western blot assay, enzyme-linked immunosorbent assay, molecular docking, co-immunoprecipitation, and immunofluorescence assay were utilized to investigate how RA prevented colorectal cancer. In the AOM/DSS-induced CAC murine model, RA significantly reduced colitis severity, inflammation-related protein expression, tumor incidence, and colorectal adenoma development. It significantly modulated toll-like receptor-4 (TLR4)-mediated nuclear factor-kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) activation, thus attenuating the expression of anti-apoptotic factors, which mediate transcription factor-dependent tumor growth. In vitro, RA inhibited CM-induced TLR4 overexpression and competitively inhibited TLR4-myeloid differentiation factor 2 complex in an inflammatory microenvironment. Thus, RA suppressed NF-κB and STAT3 activation in colon cancer cells in an inflammatory microenvironment. Therefore, RA suppressed colitis-associated tumorigenesis in the AOM/DSS-induced CAC murine model and abrogated human colon cancer progression in an inflammatory microenvironment by propitiating TLR4-mediated NF-κB and STAT3 activation, pleiotropically.

Topics: Animals; Biomarkers; Cell Line, Tumor; Cinnamates; Colitis-Associated Neoplasms; Colonic Neoplasms; Depsides; Disease Models, Animal; Humans; Immunohistochemistry; Male; Mice; Models, Molecular; NF-kappa B; Rosmarinic Acid; Signal Transduction; STAT3 Transcription Factor; Structure-Activity Relationship; Toll-Like Receptor 4; Xenograft Model Antitumor Assays

Nonalcoholic fatty liver disease (NAFLD) ranges in severity from hepatic steatosis to cirrhosis. Lemon balm and its major constituent, rosmarinic acid (RA), effectively improve the liver injury and obesity; however, their therapeutic effects on nonalcoholic steatohepatitis (NASH) are unknown. In this study, we investigated the effects of RA and a lemon balm extract (LBE) on NAFLD and liver fibrosis and elucidated their mechanisms. Palmitic acid (PA)-exposed HepG2 cells and db/db mice fed a methionine- and choline-deficient (MCD) diet were utilized to exhibit symptoms of human NASH. LBE and RA treatments alleviated the oxidative stress by increasing antioxidant enzymes and modulated lipid metabolism-related gene expression by the activation of adenosine monophosphate-activated protein kinase (AMPK) in vitro and in vivo. LBE and RA treatments inhibited the expression of genes involved in hepatic fibrosis and inflammation in vitro and in vivo. Together, LBE and RA could improve liver damage by non-alcoholic lipid accumulation and may be promising medications to treat NASH.

Topics: AMP-Activated Protein Kinases; Animals; Cells, Cultured; Cinnamates; Depsides; Disease Models, Animal; Gene Expression; Hep G2 Cells; Humans; Lipid Metabolism; Liver; Male; Melissa; Mice, Inbred Strains; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Phytotherapy; Rosmarinic Acid

Enterovirus A71 (EV-A71), a positive-stranded RNA virus of the Picornaviridae family, may cause neurological complications or fatality in children. We examined specific factors responsible for this virulence using a chemical genetics approach. Known compounds from an anti-EV-A71 herbal medicine,

Topics: Animals; Antiviral Agents; Capsid Proteins; Cell Line; Cinnamates; Depsides; Disease Models, Animal; Drug Evaluation, Preclinical; Enterovirus A, Human; Enterovirus Infections; Heparitin Sulfate; Humans; Jurkat Cells; Membrane Glycoproteins; Mice; Mutation; Plant Extracts; Protein Binding; Rosmarinic Acid; Salvia miltiorrhiza; Static Electricity; Virulence Factors

During an acute stroke, reactive oxygen species are overproduced and the endogenous antioxidative defense systems are disrupted. Therefore, antioxidative therapy can be a promising scheme to reduce the severity of stroke. Neumentix is a novel antioxidative supplement produced from a patented mint line and contains a high content of rosmarinic acid (RA). Although Neumentix has proven diverse efficacy and safety in clinical trials, its effect on strokes is unclear.. Mice that were treated with Neumentix or vehicle for 14 days underwent transient middle cerebral artery occlusion (tMCAO) for 60 min. Mice were sacrificed 5 days after tMCAO.. Neumentix preserved body weight after tMCAO, showed a high antioxidative effect in serum, and reduced infarction volume compared to the vehicle. The expression of 4-hydroxy-2-nonenal, Nε-(carboxymethyl) lysine, and 8-hydroxy-2'-deoxyguanosine was reduced in Neumentix-treated mice.. The antioxidative effect of Neumentix was confirmed. This is the first report to demonstrate the antioxidative effect of Neumentix on strokes.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aldehydes; Animals; Antioxidants; Brain; Cinnamates; Depsides; Dietary Supplements; Disease Models, Animal; Infarction, Middle Cerebral Artery; Lysine; Male; Mice, Inbred C57BL; Neuroprotective Agents; Oxidative Stress; Reactive Oxygen Species; Rosmarinic Acid

Rosmarinic acid (RA), one of the most important polyphenol-based antioxidants, has received growing interest because of its bioactive properties, including anti-inflammatory, anticancer, and antibacterial activities. Despite the high therapeutic potential of RA, its intrinsic properties of poor water solubility and low bioavailability have limited its translation into the clinic. Here, we report on the synthesis and preparation of PEGylated RA-derived nanoparticles (RANPs) and their use as a therapeutic nanomedicine for treatment of inflammatory bowel disease (IBD) in a dextran sulfate sodium (DSS)-induced acute colitis mouse model. PEGylated RA, synthesized

Topics: Animals; Antioxidants; Cinnamates; Colitis; Colon; Depsides; Dextran Sulfate; Disease Models, Animal; Hydrogen Peroxide; Inflammatory Bowel Diseases; Mice; Mice, Inbred C57BL; Nanoparticles; Rosmarinic Acid

DEHP (di-2-ethylhexyl phthalate), an environmental endocrine disruptor, is widely used in industrial products, particularly as plasticizers and softeners which could disrupt the function of the hypothalamic-pituitary-thyroid (HPT) axis. Rosmarinic acid (RA) possesses potential antioxidant and anti-inflammatory capacities in disease models. Nevertheless, evidence on the association between DEHP-induced thyroid dysfunction and inflammation, as well as the molecular mechanism underlying the protective effects of RA-mitigated DEHP-induced thyroid injury remains inconclusive. Male Sprague Dawley (SD) rats were intragastrically administered DEHP (150 mg/kg, 300 mg/kg, 600 mg/kg) once a day for 90 consecutive days. Also, FRTL-5 cells were treated with a wide range of DEHP concentrations (10

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Boraginaceae; Cell Death; Cells, Cultured; Cinnamates; Cytokines; Depsides; Diethylhexyl Phthalate; Disease Models, Animal; Dose-Response Relationship, Drug; Endocrine Disruptors; Hypothyroidism; Inflammasomes; Inflammation Mediators; Male; Phytotherapy; Rats, Sprague-Dawley; Rosmarinic Acid; Thyroid Epithelial Cells

The aim of this study was to investigate the protective effect of rosmarinic acid (RA) in a premature ovarian failure (POF) mouse model and the potential mechanisms. The POF model was induced by a single intraperitoneal injection of 120 mg/kg cyclophosphamide (CP). Additionally, 40 mg/kg RA was administered for 7 days before CP injection. The concentration of sex hormones was determined by fluorescence immunohistochemistry. Histological analysis was performed after ovarian tissue sections were stained with hematoxylin and eosin. The expression of the NLRP3 inflammasome was examined by western blot analysis and polymerase chain reaction. The expression of apoptosis markers of cytochrome c and caspase-3 was also detected by western blot analysis and immunohistochemistry. The results showed that RA not only decreased the ovarian index in POF mice but also improved the abnormal secretion of reproductive hormones associated with POF. Treatment with RA suppressed the ovarian expression of the NLRP3 inflammasome and regulated the ovarian expression of apoptosis-related proteins. The results suggested that RA exhibited a protective effect against CP-induced POF potentially by suppressing apoptosis and the NLRP3 inflammasome.

Topics: Animals; Apoptosis; Body Weight; Cinnamates; Cyclophosphamide; Depsides; Disease Models, Animal; Female; Humans; Injections, Intraperitoneal; Mice; Organ Size; Primary Ovarian Insufficiency; Rosmarinic Acid

Serum amyloid A (SAA) is one of the most important precursor amyloid proteins and plays a vital step in AA amyloidosis, although the underlying aggregation mechanism has not been elucidated. Since SAA aggregation is a key step in this pathogenesis, inhibitors are useful to prevent and treat AA amyloidosis, serving as tools to investigate the pathogenic mechanism. In this study, we showed that rosmarinic acid (RA), which is a well-known inhibitor of the aggregation of amyloid β (Aβ), displayed inhibitory activity against SAA aggregation in vitro using a microliter-scale high-throughput screening (MSHTS) system with quantum-dot nanoprobes. Therefore, we evaluated the amyloid aggregation inhibitory activity of blood and the deposition of SAA in organs by feeding mice with

Topics: Amyloid beta-Peptides; Amyloidosis; Animals; Cinnamates; Depsides; Dietary Supplements; Disease Models, Animal; Female; High-Throughput Screening Assays; Interleukin 1 Receptor Antagonist Protein; Male; Melissa; Mice, Knockout; Molecular Imaging; Plant Extracts; Quantum Dots; Rosmarinic Acid; Serum Amyloid A Protein

Rosmarinic acid (RA) is extensively utilized in herbal medicine in China. The AMP-activated protein kinase (AMPK) signaling can be activated by RA and inhibited by the synthetic, reversible AMP-competitive inhibitor, Compound C (CC). The objective of this study was to investigate the role of AMPK signaling involving the protective effects of RA on concanavalin A (Con A)-induced autoimmune hepatitis (AIH) in mice. BALB/c mice were treated with RA, with or without CC, followed by the pretreatment with Con A. Analysis of serum aminotransferases and cytokines were conducted and liver tissue histology was performed to evaluate hepatic injury. Cytokine levels in serum and hepatic tissue were respectively measured by enzyme-linked immunoassay (ELISA) and used quantitative (q)PCR. Levels of phosphorylated acetyl CoA carboxylase in the liver, representing AMPK activation, were detected by Western blotting. Compared with the Con A group, serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in RA group (100 and 150 mg/kg/d) were significantly reduced. RA also reduced hepatocyte swelling, cell death, and infiltration of leukocytes in the liver of Con A-treated mice. Serum levels of cytokines, such as interferon-γ (IFN-γ), interleukin-2 (IL-2) and interleukin-1β (IL-1β), were reduced by RA pretreatment, while the levels of serum interleukin-10 (IL-10), an anti-inflammatory cytokine, was elevated. These protective effects were reversed by treatment with CC. RA treatment reduced the hepatic damage via the activation of AMPK in the mice of Con A-induced. So RA acts as a potential part in the therapy of autoimmune hepatitis.

Topics: Alanine Transaminase; AMP-Activated Protein Kinases; Animals; Aspartate Aminotransferases; Cinnamates; Concanavalin A; Depsides; Disease Models, Animal; Drug Evaluation, Preclinical; Hepatitis, Autoimmune; Humans; Liver; Male; Mice; Mice, Inbred BALB C; Protective Agents; Pyrazoles; Pyrimidines; Rosmarinic Acid; Signal Transduction

Atherosclerosis is widely known to be a chronic inflammatory disease. C-reactive protein (CRP), an important inflammatory factor, plays an essential role in the pathogenesis of atherosclerosis. Nicotine, the main addictive component of cigarette, has been shown to induce the production of CRP. The aim of this study was to investigate the effect of rosmarinic acid (RA), a polyphenol with antiinflammatory activity, on nicotine-induced elevation of CRP in vascular smooth muscle cells (VSMCs). We found that pretreatment of VSMCs with RA attenuated nicotine-induced expression of CRP in a time- and dose-dependant manner. In addition, RA also inhibited the activation of NLR family pyrin domain containing 3 (NLRP3) inflammasome and reactive oxygen species (ROS) production resulting from nicotine treatment in VSMCs. To confirm these findings in vivo, we constructed a nicotine-induced atherosclerosis rat model. RA did not significantly reduce the serum nicotine level of the rats, whereas it significantly decreased the levels of serum lipids, including concentrations of cholesterol, triglycerides, and low-density lipoprotein cholesterol, and the serum level of CRP. RA also led to diminished nicotine-induced activation of NLRP3 inflammasome and elevation in the CRP level in the aortic tissue of the model rats. The results of this study suggested a protective role of RA in nicotine-induced atherosclerosis by inhibiting the ROS-NLRP3 inflammasome-CRP axial, and RA therefore represented a potential effective therapeutic approach to atherosclerosis, in particular for those who smoke.

Topics: Animals; Anti-Inflammatory Agents; Atherosclerosis; C-Reactive Protein; Cells, Cultured; Cinnamates; Depsides; Disease Models, Animal; Inflammasomes; Inflammation; Lipids; Male; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Nicotine; NLR Family, Pyrin Domain-Containing 3 Protein; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Rosmarinic Acid; Signal Transduction

Studies have indicated that epilepsy, an important neurological disease, can generate oxidative stress and mitochondrial dysfunction, among other damages to the brain. In this context, the use of antioxidant compounds could provide neuroprotection and help to reduce the damage caused by epileptic seizures and thereby the use of anticonvulsant drugs. Rosmarinic acid (RA) is an ester of caffeic acid and 3,4-dihydroxyphenylactic acid that prevents cell damage caused by free radicals, acting as an antioxidant. It also presents anti-inflammatory, antimutagenic, and antiapoptotic properties. In this work, we used two models of acute seizure, 4-aminopyridine (4-AP) and picrotoxin (PTX)-induced seizures in mice, to investigate the anticonvulsant, antioxidant, and neuroprotective profile of RA. Diazepam and valproic acid, antiepileptic drugs already used in the treatment of epilepsy, were used as positive controls. Although RA could not prevent seizures in the models used in this study, neither enhance the latency time to first seizure at the tested doses, it exhibited an antioxidant and neuroprotective effect. RA (8 and 16 mg/kg) decreased reactive oxygen species production, superoxide dismutase activity, and DNA damage, measured in hippocampus, after seizures induced by PTX and 4-AP. Catalase activity was decreased by RA only after seizures induced by 4-AP. The activity of the mitochondrial complex II was increased by RA in hippocampus samples after both seizure models. The results obtained in this study suggest that RA is able to reduce cell damage generated by the 4-AP and PTX seizures and therefore could represent a potential candidate in reducing pathophysiological processes involved in epilepsy.

Topics: 4-Aminopyridine; Animals; Anticonvulsants; Antioxidants; Behavior, Animal; Cinnamates; Depsides; Disease Models, Animal; DNA Damage; Electron Transport Complex II; Hippocampus; Mice; Mitochondria; Neuroprotective Agents; Oxidative Stress; Picrotoxin; Rosmarinic Acid; Seizures

Cataracts are the major cause of blindness and are associated with oxidative damage of the lens. In the present study, the aim was to evaluate the protective effects of rosmarinic acid on selenite-induced cataractogenesis in Sprague-Dawley rat pups. The animals were randomly divided into five groups, each of which consisted of 10 rat pups. Group I served as normal control (vehicle administration). For testing cataract induction, animals of Groups II, III, IV, and V were administered a single subcutaneous injection of sodium selenite (2.46 mg/kg body weight) on postpartum day 12. After sodium selenite intoxication, Group II served as control selenite. From the 11th day through the 17th day, Groups III-V received rosmarinic acid intraperitoneally at doses of 5, 10, and 50 mg/kg, respectively. On postpartum day 24, the rat pups were examined for cataract formation, and the lenses were isolated for further analysis of proteins and oxidative damage indicators. Selenite caused significant (

Topics: Animals; Antioxidants; Catalase; Cataract; Cinnamates; Depsides; Disease Models, Animal; Gene Expression; Humans; Lipid Peroxidation; Oxidative Stress; Plant Extracts; Rats; Rosmarinic Acid; Selenious Acid; Superoxide Dismutase

Rosmarinic acid (RA) as an active component of several medicinal plants, has shown anti-inflammatory and anti-oxidant effects. In this study, the effect of RA on tracheal responsiveness (TR), lung inflammatory cells, oxidant biomarkers in sensitized rats were evaluated.. TR to methacholine and ovalbumin (OVA) as well as total and differential white blood cell (WBC) count and levels of nitrogen dioxide, nitrate, malondialdehyde, thiol, superoxide dismutase, and catalase in bronchoalveolar lavage fluid were measured in control (group C) rats, sensitized animals to OVA and given drinking water alone (group S), S groups receiving drinking water containing three concentrations of RA (0.125, 0.250 and 0.500 mg/mL) and dexamethasone (1.25 μg/mL), (n = 6 in each group).. Increased TR to methacholine and OVA, total WBC count, percentages of eosinophils, monocytes, neutrophils and levels of oxidant biomarkers but decreased other measured parameters were observed in group S compared to group C. Percentages of lymphocytes and antioxidant biomarkers were significantly increased but other measured parameters were significantly decreased in S group treated with dexamethasone and in rats treated with the two higher concentrations of RA compared to S group. The effect of RA medium concentration on percentage of eosinophils and RA high concentration on total WBC count and percentages of eosinophils and lymphocytes, were significantly higher than those of dexamethasone.. These results showed the concentration-dependent effect of RA on tracheal responses, lung inflammatory cells and oxidant-antioxidant parameters which was comparable to that of dexamethasone at used concentrations in sensitized rats.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Biomarkers; Bronchoalveolar Lavage Fluid; Cinnamates; Depsides; Dexamethasone; Disease Models, Animal; Dose-Response Relationship, Drug; Leukocytes; Methacholine Chloride; Muscle Contraction; Muscle, Smooth; Ovalbumin; Oxidative Stress; Rats, Wistar; Respiratory Hypersensitivity; Rosmarinic Acid; Trachea

Trans-tympanic Rosmarinic Acid (RA), as compared with the systemic administration, protects against noise-induced auditory hair cell and hearing losses in rats in vivo.. ROS production, lipoperoxidative damage, and an imbalance of antioxidant defences play a significant role in noise-induced hearing loss. Several molecules with antioxidant properties have been tested to restore redox homeostasis; however, drug delivery system represents a challenge for their effectiveness. In our model, acute and intense noise exposure induces hearing loss, hair cell death, and oxidative stress, with an increase in superoxide production and over-expression of lipid peroxidation in cochlear structures.. RA was administrated in male Wistar rats by trans-tympanic (20 μl) and systemic (10 mg/kg) modality. In systemic administration, RA was injected 1 hour before noise exposure and once daily for the following 3 days. ABRs were measured before and at days 1, 3, 7, and 30 after noise exposure. Rhodamine-phalloidin staining, dihydroethidium and 8-isoprostane immunostainings were performed to assess and quantify outer hair cells loss, superoxide production, and lipid peroxidation in the different experimental groups.. Systemic RA administration significantly decreased noise-induced hearing loss and the improvement of auditory function was paralleled by a significant reduction in cochlear oxidative stress. The trans-tympanic modality of drug administration showed a similar degree of protection both at the functional and morphological levels.. The effectiveness of RA given via trans-tympanic injection could be interesting for the future application of this minimally-invasive procedure in the treatment of ROS-induced hearing loss.

Topics: Animals; Antioxidants; Cinnamates; Depsides; Disease Models, Animal; Hair Cells, Auditory; Hearing; Hearing Loss, Noise-Induced; Male; Oxidative Stress; Rats; Rats, Wistar; Rosmarinic Acid

We aimed to investigate the potential prophylactic and curative effects of rosmarinic acid, one of the main constituents of rosemary, on the neuropathic pain induced by chronic constriction injury (CCI) in rats.. CCI was used to induce peripheral neuropathic pain. In prophylactic groups, rosmarinic acid (10, 20, and 40 mg/kg, i.p.) was administered from the day of surgery (day 0) for 14 days. In treatment group, rosmarinic acid (40 mg/kg) was given from day 5 (after the pain was established), for 7 days. The degree of mechanical allodynia, cold allodynia, and heat hyperalgesia were measured on days 0, 3, 5, 7, 10 and 14 post-surgery. The open field test was carried out to assess locomotor activity of animals. Lumbar spinal cord levels of astroglia activation marker, glial fibrillary acidic protein (GFAP), microglial activation marker, ionized calcium-binding adapter molecule 1 (Iba-1), toll-like receptor 4 (TLR-4), tumor necrosis factor alpha (TNF-α), inducible isoform of nitric oxide synthase enzyme (iNOS) and apoptotic factors were quantified via western blot on days 7 and 14.. CCI rats showed a significant mechanical allodynia, cold allodynia and thermal hyperalgesia, compared to sham ones on day 3, persisted up to day 14 post-CCI. Rosmarinic acid was able to prevent and also attenuate CCI-induced behavioral features in prophylactic as well as treatment groups, respectively. A significant increase in the levels of TNF-α, iNOS, apoptotic factors (Bax, caspases 3, 9), Iba-1, TLR-4, and GFAP was observed on both days 7 and 14, which was suppressed by 14 days administration of rosmarinic acid.. These findings further support the use of rosemary in traditional medicine to alleviate pain. Rosmarinic acid could be a promising compound in prophylaxis and treatment of neuropathic pain. Anti-apoptotic and anti-inflammatory effects of rosmarinic acid may have important roles in the observed antinociceptive properties.

Topics: Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Biomarkers; Cinnamates; Depsides; Disease Models, Animal; Hyperalgesia; Male; Neuralgia; Nitric Oxide Synthase Type II; Rats, Sprague-Dawley; Rats, Wistar; Rosmarinic Acid; Spinal Cord; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

Ulcerative colitis (UC), a type of inflammatory bowel disease (IBD), is a chronic inflammatory disorder of the colon. Although UC is generally treated with anti-inflammatory drugs or immunosuppressants, most of these treatments often prove to be inadequate. Rosmarinic acid (RA) is a phenolic ester included in various medicinal herbs such as Salvia miltiorrhiz and Perilla frutescens. Although RA has many biological and pharmacological activities, the anti-inflammatory effect of RA in colonic tissue remains unclear. In this study, we investigated the anti-inflammatory effects and underlying molecular mechanism of RA in mice with dextran sulphate sodium (DSS)-induced colitis. In the DSS-induced colitis model, RA significantly reduced the severity of colitis, as assessed by disease activity index (DAI) scores, colonic damage, and colon length. In addition, RA resulted in the reduction of the inflammatory-related cytokines, such as IL-6, IL-1β, and IL-22, and protein levels of COX-2 and iNOS in mice with DSS-induced colitis. Furthermore, RA effectively and pleiotropically inhibited nuclear factor-kappa B and signal transducer and activator of transcription 3 activation, and subsequently reduced the activity of pro-survival genes that depend on these transcription factors. These results demonstrate that RA has an ameliorative effect on colonic inflammation and thus a potential therapeutic role in colitis.

Topics: Animals; Cinnamates; Colitis; Colon; Cyclooxygenase 2; Cytokines; Depsides; Dextran Sulfate; Disease Models, Animal; Disease Progression; Gene Expression Regulation; Inflammation; Inflammation Mediators; Male; Mice, Inbred ICR; NF-kappa B; Nitric Oxide Synthase Type II; Peroxidase; Rosmarinic Acid; Spleen; STAT3 Transcription Factor

Rosmarinic acid-4-O-β-D-glucoside (RAG) is a dicaffeoyl phenolic compound isolated from Sarcandra glabra (Thunb.) Nakai. Preliminary studies show that RAG has significant anti-inflammatory properties and can alleviate ear swelling in mice and the paw swelling in rats. Here, the anti-influenza effects of RAG were investigated in mice infected with A/FM/1/47 H1N1 virus. The survival rate and body weight were observed, the lung edema, virus copies, inflammatory cytokines (including IL-4, IL-5, TNF-α and IFN-γ) and oxidative damage indexes (including SOD, MDA, NO, and CAT) were measured. Moreover, immune cell recruitment in alveoli was measured with white blood cells and differential counts. Therapeutic RAG concentrations substantially improve the symptoms, mitigate body weight loss and alleviate lung edema induced by virus, thus improve survival protection effects. Furthermore, RAG was shown to regulate influenza virus-induced inflammatory cytokine expression, specifically by downregulating the Th1 cell cytokines IFN-γ, TNF-α and upregulating the Th2 cell cytokines IL-4, IL-5. Cell migration and infiltration were also diminished after RAG administration.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents, Non-Steroidal; Body Weight; Cinnamates; Cytokines; Depsides; Disease Models, Animal; Glucosides; Lung; Mice; Orthomyxoviridae Infections; Rosmarinic Acid; Survival Analysis; Viral Load

Pathophysiology of spinal cord injury (SCI) causes primary and secondary effects leading to loss of neuronal function. The aim of the present study was to investigate the role of rosmarinic acid (RA) in protection against SCI.. The experimental study was carried out in male wistar rats categorized into three groups. Group I - sham operated rats; Group II - SCI; Group III - SCI followed by RA treatment (10 mg/kg). The spinal tissues after treatment schedule were analyzed for oxidative stress status through determination of reactive oxygen species (ROS), lipid peroxidation, protein damage (carbonyl and sulfhydryl contents), and antioxidant enzyme activities. The expression of oxidative stress factors NF-κB and Nrf-2 was determined by Western blot analysis. Further pro-inflammatory cytokines (TNF-α, IL-6, MCP-1, and IL-1β) were measured by enzyme-linked immunosorbent assay (ELISA).. The results show that treatment with RA significantly enhances the antioxidant status and decrease the oxidative stress in wistar rats post-SCI. RA effectively ameliorated inflammatory mechanisms by downregulation of NF-κB and pro-inflammatory cytokines post-SCI.. The study demonstrates for the first time on the role of RA in protecting the spinal cord from injury and demonstrates its neuroprotection in wistar rats.

Topics: Active Transport, Cell Nucleus; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Apoptosis; Biomarkers; Cinnamates; Depsides; Disease Models, Animal; Injections, Intraperitoneal; Lipid Peroxidation; Male; Motor Neurons; Nerve Tissue Proteins; Neuroprotective Agents; NF-kappa B; Oxidative Stress; Protein Carbonylation; Rats, Wistar; Reactive Oxygen Species; Rosmarinic Acid; Spinal Cord; Spinal Cord Injuries

Cerebral ischemia/reperfusion injury can result in neuronal death, which further results in brain damage and can even lead to death. Although recent studies showed that rosmarinic acid (RA) exerts neuroprotective effects and attenuates ischemia-induced brain injury and neuronal cell death, little is known about the precise mechanisms that occur during cerebral ischemia/reperfusion (I/R). Therefore, the aim of this study was to examine the underlying mechanism of the neuroprotective effects of RA against ischemic brain injury induced by cerebral I/R. Transient global brain ischemia was induced by 4-vessel occlusion in adult male Sprague-Dawley rats. We randomly divided rats into five groups: sham, I/R, I/R+RA, I/R+Vehicle and I/R+RA+LY. Open-field, closed-field and Morris water maze tests were carried our separately to examine the anxiety and cognitive behavior of each group. Cresyl violet staining was used to examine the survival of hippocampal CA1 pyramidal neurons. The levels of p-Akt, p-JNK3 and cleaved caspase-3 in the hippocampus were also examined by Western blotting. Our results showed that administration of RA protected locomotive ability, relieved anxiety behavior and protected cognitive ability in cerebral I/R-injured rats. Additionally, RA significantly protected neurons in the hippocampal CA1 region against cerebral I/R-induced damage. Furthermore, RA increased the phosphorylation of Akt1, downregulated the phosphorylation of JNK3 and reduced the expression of cleaved caspase-3. Finally, the Akt inhibitor LY294002 reversed all the protective effects of RA, indicating that RA protects neurons in the hippocampal CA1 region from ischemic damage through the Akt/JNK3/caspase-3 signaling pathway.

Topics: Animals; Anxiety; Apoptosis; Brain Ischemia; CA1 Region, Hippocampal; Caspase 3; Cell Survival; Cinnamates; Cognition Disorders; Depsides; Disease Models, Animal; Male; Maze Learning; Mitogen-Activated Protein Kinase 10; Neurons; Neuroprotective Agents; Phosphorylation; Proto-Oncogene Proteins c-akt; Random Allocation; Rats, Sprague-Dawley; Reperfusion Injury; Rosmarinic Acid

Polyphenols have neuroprotective effects after brain ischemia. It has been demonstrated that rosmarinic acid (RA), a natural phenolic compound, possesses antioxidant and anti-inflammatory properties. To evaluate the effectiveness of RA against memory deficits induced by permanent middle cerebral artery occlusion (pMCAO) mice were treated with RA (0.1, 1, and 20mg/kg/day, i.p. before ischemia and during 5 days). Animals were evaluated for locomotor activity and working memory 72 h after pMCAO, and spatial and recognition memories 96 h after pMCAO. In addition, in another set of experiments brain infarction, neurological deficit score and myeloperoxidase (MPO) activity were evaluates 24h after the pMCAO. Finally, immunohistochemistry, and western blot, and ELISA assay were used to analyze glial fibrillary acidic protein (GFAP), and synaptophysin (SYP) expression, and BDNF level, respectively. The working, spatial, and recognition memory deficits were significantly improved with RA treatment (20mg/kg). RA reduced infarct size and neurological deficits caused by acute ischemia. The mechanism for RA neuroprotection involved, neuronal loss suppression, and increase of synaptophysin expression, and increase of BDNF. Furthermore, the increase of MPO activity and GFAP immunireactivity were prevented in MCAO group treated with RA. These results suggest that RA exerts memory protective effects probably due to synaptogenic activity and anti-inflammatory action.

Topics: Animals; Astrocytes; Brain; Brain Ischemia; Brain-Derived Neurotrophic Factor; Cinnamates; Depsides; Disease Models, Animal; Dose-Response Relationship, Drug; Gliosis; Infarction, Middle Cerebral Artery; Male; Memory Disorders; Memory, Short-Term; Mice; Motor Activity; Neuroprotective Agents; Peroxidase; Recognition, Psychology; Rosmarinic Acid; Spatial Memory; Synapses

Stress is an important risk factor of Alzheimer's disease (AD). It has been evidenced that stress could induce tau phosphorylation and increase tau insolubility in brain; however, little is known about the interactional effect of stress with aging on tauopathy. Therefore, we explored the effects of aging on stress-induced tauopathy and the potential mechanism in mouse model of chronic restraint stress (CRS). Here we found that in general, the level of phosphorylated tau (P-tau) was higher in brain of middle-aged mice than that in adult mice under physiological conditions. CRS-induced tau phosphorylation and its insolubility were more prominent in middle-aged mice. The increase of AT8-labeled insoluble P-tau was dramatic in middle-aged mice, which was highly ubiquitinated but did not form PHF structures. The levels of chaperones were relatively lower in middle-aged mice brain; CRS further reduced the expression, especially for HDJ2/HSP40. CRS also suppressed the expression of Pin1, the peptidylprolyl cis/trans isomerase, in middle-aged mice but not in adult mice. Downregulation of HSP40 or Pin1 caused an increase of transfected extraneous tau in 293 cells. Rosmarinic acid (RA) could effectively suppress the elevation of P-tau and insoluble P-tau formation induced by CRS, and reversed the abnormal changes of chaperones and Pin1 particularly in middle-aged mice. Taken together, our findings provided evidence that aging could be a promoting factor in stress-induced tauopathy, which was relevant with malregulation of chaperones and Pin1, and RA might be a promising beneficial agent for stress-induced tauopathy.

Topics: Aging; Animals; Antioxidants; Brain; Cinnamates; Corticotropin-Releasing Hormone; Depsides; Disease Models, Animal; HEK293 Cells; HSP90 Heat-Shock Proteins; Humans; Male; Mice; Mice, Inbred C57BL; Microscopy, Immunoelectron; NIMA-Interacting Peptidylprolyl Isomerase; Peptidylprolyl Isomerase; Phosphorylation; Precipitating Factors; Receptors, Corticotropin; Restraint, Physical; Rosmarinic Acid; Stress, Psychological; tau Proteins; Transfection

Rosmarinic acid (RA) has numerous pharmacologic effects, including anti-oxidant, anti-inflammatory, and analgesic effects. This study aimed to evaluate the preventive activity of RA in a murine model of asthma and to investigate its possible molecular mechanisms. Female BALB/c mice sensitized and challenged with ovalbumin (Ova) were pretreated with RA (5, 10 or 20 mg/kg) at 1 h before Ova challenge. The results demonstrated that RA markedly inhibited increases in inflammatory cells and Th2 cytokines in the bronchoalveolar lavage fluid (BALF), significantly reduced the total IgE and Ova-specific IgE concentrations, and greatly ameliorated airway hyperresponsiveness (AHR) compared with the control Ova-induced mice. Histological analyses showed that RA substantially decreased the number of inflammatory cells and mucus hypersecretion in the airway. In addition, our results suggested that the protective effects of RA might be mediated by the suppression of ERK, JNK and p38 phosphorylation and activation of nuclear factor-κB (NF-κB). Furthermore, RA pretreatment resulted in a noticeable reduction in AMCase, CCL11, CCR3, Ym2 and E-selectin mRNA expression in lung tissues. These findings suggest that RA may effectively delay the progression of airway inflammation.

Topics: Analgesics; Animals; Antioxidants; Asthma; Bronchoalveolar Lavage Fluid; Cinnamates; Depsides; Disease Models, Animal; Female; Humans; Inflammation; Lung; Mice; Rosmarinic Acid

The goal of this study was to investigate the effects of rosmarinic acid (RA) and caffeic acid (CA) in the acute pentylenetetrazole (PTZ) and pilocarpine (PIL) seizure models. We also evaluated the effect of RA and CA on the diazepam (DZP)-induced sleeping time test and its possible neuroprotective effect against the genotoxic damage induced by PTZ and PIL. Mice were treated intraperitoneally (i.p.) with saline, RA (2 or 4 mg/kg), or CA (4 or 8 mg/kg) alone or associated to low-dose DZP. After, mice received a single dose of PTZ (88 mg/kg) or PIL (250 mg/kg) and were monitored for the percentage of seizures and the latency to first seizure (LFS) >3 s. Vigabatrin and DZP were used as positive controls. In the DZP-induced sleeping time test, mice were treated with RA and CA and 30 min after receiving DZP (25 mg/kg, i.p.). The alkaline comet assay was performed after acute seizure tests to evaluate the antigenotoxic profiles of RA and CA. The doses of RA and CA tested alone did not reduce the occurrence of seizures induced by PTZ or PIL. The association of 4 mg/kg RA + low-dose DZP was shown to increase LFS in the PTZ model, compared to the group that received only the DZP. In the DZP-induced sleeping time test, the latency to sleep was reduced by 4 mg/kg RA and 8 mg/kg CA. The PTZ-induced genotoxic damage was not prevented by RA or CA, but the PIL-induced genotoxic damage was decreased by pretreatment with 4 mg/kg RA (in cortex) and 4 mg/kg CA (in hippocampus). In conclusion, RA and CA presented neuroprotective effect against PIL-induced genotoxic damage and reduced the latency to DZP-induced sleep. Of the rosmarinic acid, 4 mg/kg enhanced the DZP effect in the increase of latency to clonic PTZ-induced seizures.

Topics: Animals; Anticonvulsants; Behavior, Animal; Brain; Caffeic Acids; Cinnamates; Comet Assay; Depsides; Diazepam; Disease Models, Animal; DNA Damage; Dose-Response Relationship, Drug; Male; Mice; Neuroprotective Agents; Pentylenetetrazole; Pilocarpine; Reaction Time; Rosmarinic Acid; Seizures; Sleep; Time Factors

Rosmarinic acid (RA) is an active component of a traditional Chinese herbal medicine. Previously, we reported that RA exerted a strong anti-inflammatory effect in a mouse acute lung injury model. Therefore, we hypothesized that RA might also have potential therapeutic effects in a murine model of asthma. In this study, we aimed to evaluate the anti-asthmatic activity of RA and explored its possible molecular mechanisms of action. Female BALB/c mice that had been sensitized to and challenged with ovalbumin (Ova) were treated with RA (20mg/kg) 1h after challenge. The results showed that RA greatly diminished the number of inflammatory cells and the production of Th2 cytokines in the bronchoalveolar lavage fluid (BALF); significantly reduced the secretion of total IgE, Ova-specific IgE, and eotaxin; and markedly ameliorated airway hyperresponsiveness (AHR) compared with Ova-induced mice. Histological studies further revealed that RA substantially decreased inflammatory cells infiltration and mucus hypersecretion compared with Ova-induced mice. Moreover, our results suggested that the protective effects of RA were mediated by the inhibition of JNK and p38 MAPK phosphorylation and nuclear factor-κB (NF-κB) activation. Furthermore, RA treatment resulted in a significant reduction in the mRNA expression of AMCase, CCL11, CCR3, Ym2 and E-selectin in lung tissue. These findings suggest that RA may effectively delay the development of airway inflammation and could thus be used as a therapy for allergic asthma.

Topics: Allergens; Animals; Anti-Asthmatic Agents; Asthma; Bronchoalveolar Lavage Fluid; Chemokine CCL11; Cinnamates; Cytokines; Depsides; Disease Models, Animal; Female; Immunoglobulin E; Lung; Mice, Inbred BALB C; Mitogen-Activated Protein Kinases; NF-kappa B; Ovalbumin; Receptors, CCR3; Respiratory Hypersensitivity; RNA, Messenger; Rosmarinic Acid

Colon cancer is one of the most common cancers in both men and women. The present study is an effort to unravel the anticarcinogenic effects of rosmarinic acid (RA) in 1,2-dimethylhydrazine (DMH)-induced rat colon carcinogenesis. Administration of DMH induces multiple tumors in the rat colon, which mimics human colon cancer.. Male Wistar rats were divided into six groups and fed a high-fat diet. Group 1 served as control, group 2 rats were given RA [5 mg/kg body weight (b.w.)] orally every day for a total period of 30 weeks, and groups 3-6 were given weekly injections of DMH (20 mg/kg b.w. subcutaneous) once a week in the groin for the first 15 weeks. In addition to DMH, groups 4-6 received RA at a dose of 5 mg/kg b.w. during the initiation and postinitiation stages, and also throughout the entire study period. Colon tissues were examined histologically; further, the extent of oxidative stress was assessed by measuring lipid peroxidation and antioxidant levels in the colonic mucosa of rats.. Macroscopic and microscopic tumors were identified in all the groups that received DMH. The results revealed that supplementation with RA significantly inhibited the tumor formation and tumor multiplicity in DMH-treated rats. RA supplementation to DMH-administered rats significantly reduced the cell proliferation markers, namely, argyrophilic nucleolar organizing regions as well as proliferative cell nuclear antigen labeling index. In addition, RA supplementation reduces the expressions of tumor necrosis factor-α, interlukin-6, and cyclooxygenase-2, and modulates the expression of p65.. The above findings clearly underline the chemopreventive efficacy of RA against DMH-induced colon carcinogenesis.

Topics: 1,2-Dimethylhydrazine; Animals; Anticarcinogenic Agents; Antioxidants; Cell Proliferation; Cinnamates; Colonic Neoplasms; Depsides; Disease Models, Animal; Gene Expression Regulation, Neoplastic; Lipid Peroxidation; Male; Oxidative Stress; Rats; Rats, Wistar; Rosmarinic Acid

Rosmarinic acid is a polyphenolic compound and main constituent of Rosmarinus officinalis and has been shown to possess antioxidant and anti-inflammatory properties. We aimed to evaluate the anti-inflammatory properties of rosmarinic acid and of an extract of R. officinalis in local inflammation (carrageenin-induced paw oedema model in the rat), and further evaluate the protective effect of rosmarinic acid in rat models of systemic inflammation: liver ischaemia-reperfusion (I/R) and thermal injury models. In the local inflammation model, rosmarinic acid was administered at 10, 25 and 50 mg/kg (p.o.), and the extract was administered at 10 and 25 mg/kg (equivalent doses to rosmarinic acid groups) to male Wistar rats. Administration of rosmarinic acid and extract at the dose of 25 mg/kg reduced paw oedema at 6 hr by over 60%, exhibiting a dose-response effect, suggesting that rosmarinic was the main contributor to the anti-inflammatory effect. In the liver I/R model, rosmarinic acid was administered at 25 mg/kg (i.v.) 30 min. prior to the induction of ischaemia and led to the significant reduction in the serum concentration of transaminases (AST and ALT) and LDH. In the thermal injury model, rosmarinic acid was administered at 25 mg/kg (i.v.) 5 min. prior to the induction of injury and significantly reduced multi-organ dysfunction markers (liver, kidney, lung) by modulating NF-κB and metalloproteinase-9. For the first time, the anti-inflammatory potential of rosmarinic acid has been identified, as it causes a substantial reduction in inflammation, and we speculate that it might be useful in the pharmacological modulation of injuries associated to inflammation.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Biomarkers; Bronchoalveolar Lavage Fluid; Carrageenan; Cinnamates; Depsides; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Inflammation; Inflammation Mediators; Lung; Male; Neutrophils; Oxidative Stress; Phytotherapy; Plant Extracts; Plants, Medicinal; Rats, Wistar; Reperfusion Injury; Respiratory Burst; Rosmarinic Acid; Rosmarinus; Time Factors

Bone homeostasis is ensured by the balance between bone formation and resorption. Thus, control of the recruitment, proliferation, and differentiation of bone cells is essential to maintain bone mass. The aim of this study was to elucidate the effects of rosmarinic acid as a potential therapeutic agent on bone metabolism using bone cells and a mouse model.. Rosmarinic acid increased alkaline phosphatase activity and induced mineralization in osteoblasts. Addition of rosmarinic acid to cultures of calvarial osteoblastic cells prepared from T-cell factor/β-catenin TOP-GAL mutant mice strongly induced the expression of LacZ and promoted stabilization of β-catenin in the cytoplasm of ST2 cells, suggesting that rosmarinic acid affects the canonical Wnt signaling pathway. Moreover, rosmarinic acid inhibited not only osteoclast formation in cocultures of mouse bone marrow cells and osteoblasts, but also receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclastic differentiation in bone marrow-derived macrophages. RANKL-induced p38 mitogen-activated protein kinase and the expression of nuclear factor of activated T cell, c-Jun, and c-Fos were inhibited by rosmarinic acid in bone marrow macrophages. Finally, we confirmed that rosmarinic acid improved bone mass in a soluble RANKL-induced bone loss mouse model.. Rosmarinic acid has dual regulatory effects on bone metabolism and may control the bone functions by controlling osteoblastic and osteoclastic differentiation.

Topics: Animals; beta Catenin; Bone Density; Bone Marrow Cells; Bone Resorption; Cell Differentiation; Cells, Cultured; Cinnamates; Coculture Techniques; Depsides; Disease Models, Animal; Male; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Transgenic; Osteoblasts; Osteoclasts; RANK Ligand; Rosmarinic Acid; Wnt3A Protein

Excessive subconjunctival scarring is associated with increased angiogenesis and leads to filtration failure in glaucoma surgery. In this study, we describe that rosmarinic acid (RA) has anti-angiogenic activity during wound healing in a rabbit model of glaucoma surgery.. Forty New Zealand rabbits underwent an experimental trabeculectomy and were randomly allocated into two treatment groups: RA group - treated with subconjunctival injections of 0.1 ml RA (15 mg/ml; n = 20) - and control group - treated with subconjunctival injections of 0.1 ml balanced salt solution (n = 20). The in vivo effect of RA was investigated after 5 and 15 d by measuring the intraocular pressure (IOP; with Tonopen) and bleb area and vascularity (using the Moorfields Bleb Grading System). Vascularization was also studied by counting histological blood vessels and by immunohistochemistry of vascular endothelial growth factor (VEGF) at the surgical site and by quantification of vessels in chicken's chorioallantoic membrane (CAM), treated with AR 500 μg/ml for 48 h.. On the fifth day, eyes of RA group displayed higher bleb area (3.6 ± 0.2 versus 1.8 ± 0.2; p = 0.004) and lower vascularity (3.0 ± 0.5 versus 4.0 ± 0.4; p = 0.009) than controls; however, difference in IOP reduction was not significant (-1.4 ± 0.3 versus -0.8 ± 0.3 mmHg; p = 0.226). Proportion of vessels/field (4.6 ± 0.5 versus 10.4 ± 0.9; p = 0.008) and VEGF immunostaining (15,347 ± 3788 versus 31,043 ± 3230; p = 0.019) also declined with RA treatment. However, at the 15th day, none of the parameters were different between the groups, except for vessels/field proportion (5.4 ± 1.0 versus 10.6 ± 1.6; p = 0.035). CAM exposed to AR inhibited vascularization (-45.67 ± 4.74%; p < 0.001).. These data indicate RA has a short-term anti-angiogenic effect and could be a potential modulator of neovascularization during subconjunctival healing at glaucoma filtration surgical sites.

Topics: Angiogenesis Inhibitors; Animals; Antioxidants; Chick Embryo; Chorioallantoic Membrane; Cinnamates; Conjunctiva; Depsides; Disease Models, Animal; Female; Glaucoma; Immunohistochemistry; Injections, Intraocular; Intraocular Pressure; Neovascularization, Pathologic; Rabbits; Rosmarinic Acid; Trabeculectomy; Vascular Endothelial Growth Factor A

Temporal lobe epilepsy (TLE) is an intractable neurological disorder. Rosmarinic acid (RA) is a natural polyphenol with antioxidant, anti-apoptotic, and anti-inflammatory properties.. This study evaluates beneficial effect of RA in intrahippocampal kainate-induced model of TLE.. Rats were divided into sham, RA-pretreated sham, kainate, and sodium valproate (VA) or RA-pretreated kainate groups. Rats received RA or VA p.o. at doses of 10 or 300 mg/kg/d, respectively, starting 1 week before the surgery. After 6 weeks, seizure intensity, apoptosis, and oxidative stress markers were evaluated in addition to determination of Timm index as an indicator of mossy fiber sprouting (MFS) and the number of Nissl-stained neurons.. All rats in the kainate group had seizure and 24.3% of rats in the kainate + VA group and 36.7% of rats in the kainate + RA group showed seizure. The kainate group had a significant elevation of malondialdehyde (MDA) (p < 0.05) and nitrite (p < 0.01) and reduction of glutathione (GSH) and catalase activity (p < 0.05) and pretreatment of kainate-lesioned rats with RA or VA significantly lowered MDA and nitrite content (p < 0.05) and raised activity of catalase (p < 0.05). The kainate group also had a significant reduction of neurons in CA1 and CA3 regions and an elevation of Timm index (p < 0.05-0.001) and RA or VA significantly (p < 0.05-0.01) prevented these changes.. RA could attenuate seizure, mitigates oxidative stress, augments the activity of defensive systems, and prevent hippocampal neuronal loss and MFS in the kainate model of TLE.

Topics: Animals; Antioxidants; Cinnamates; Depsides; Disease Models, Animal; Epilepsy, Temporal Lobe; Kainic Acid; Male; Neuroprotective Agents; Rats; Rats, Wistar; Rosmarinic Acid

Salviaolate is a group of depside salts isolated from Danshen (a traditional Chinese herbal medicine), with ≥ 85 % of magnesium lithospermate B. This study aims to investigate whether salviaolate is able to protect the rat brain from ischemia/reperfusion injury and the underlying mechanisms. Rats were subjected to 2 h of cerebral ischemia and 24 h of reperfusion to establish an ischemia/reperfusion injury model. The neuroprotective effects of salviaolate at different dosages were evaluated. A dosage (25 mg/kg) was chosen to explore the neuroprotective mechanisms of salviaolate. Neurological function, infarct volume, cellular apoptosis, nicotinamide adenine dinucleotide phosphate-oxidase activity, and H2O2 content were measured. In a nerve cell model of hypoxia/reoxygenation injury, magnesium lithospermate B was applied. Cellular apoptosis, lactate dehydrogenase, nicotinamide adenine dinucleotide phosphate-oxidase activity, and H2O2 content were examined. Ischemia/reperfusion treatment significantly increased the neurological deficit score, infarct volume, and cellular apoptosis accompanied by the elevated nicotinamide adenine dinucleotide phosphate-oxidase activity and H2O2 content in the rat brains. Administration of salviaolate reduced ischemia/reperfusion-induced cerebral injury in a dose-dependent manner concomitant with a decrease in nicotinamide adenine dinucleotide phosphate-oxidase activity and H2O2 production. Magnesium lithospermate B (20 mg/kg) and edaravone (6 mg/kg, the positive control) achieved the same beneficial effects as salviaolate did. In the cell experiments, the injury (indicated by apoptosis ratio and lactate dehydrogenase release), nicotinamide adenine dinucleotide phosphate-oxidase activity and H2O2 content were dramatically increased following hypoxia/reoxygenation, which were attenuated in the presence of magnesium lithospermate B (10(-5) M), VAS2870 (nicotinamide adenine dinucleotide phosphate-oxidase inhibitor), or edaravone (10(-5) M). The results suggest that salviaolate is able to protect the brain from ischemia/reperfusion oxidative injury, which is related to the inhibition of nicotinamide adenine dinucleotide phosphate-oxidase and a reduction of reactive oxygen species production.

Topics: Animals; Antioxidants; Benzofurans; Benzoxazoles; Brain; Brain Ischemia; Cells, Cultured; China; Cinnamates; Depsides; Disease Models, Animal; Drugs, Chinese Herbal; Male; NADPH Oxidases; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Rosmarinic Acid; Salvia miltiorrhiza; Triazoles

Animal models designed to mimic certain features of Alzheimer's disease (AD) can help us to increase our understanding of the underlying mechanisms of disease. Previous studies have revealed that long-term D-galactose injection combined with ovariectomy results in pathophysiologic alterations associated with AD. Thus, the aim of the present study was to investigate the effects of rosmarinic acid (RA) administration on pathological changes associated with ovariectomy and D-galactose injection, which serve as a two-insult model for AD.. One hundred female Wistar rats were divided into five equal groups: control (C), Sham (Sh), rosmarinic acid treated (R), ovariectomized rats treated with D-galactose (OD), ovariectomized rats treated with D-galactose and rosmarinic acid (ODR) groups. D-galactose (80 mg/kg/day) was administered by i.p. injection and RA (50 mg/kg/day) was given via gavage for 60 days. Open field and Y-maze tests were used to assess locomotor activity and short-term spatial memory, respectively. Biochemical and histopathological analyses of the brain tissue were performed.. Open field testing showed that the locomotor activity and exploratory behavior of rats were prominently impaired in the OD group as compared to the other studied groups. Similarly, Y-maze test results revealed a decrease of short-term spatial memory in the OD rats. A concomitant treatment with RA significantly restored altered locomotor activity and cognitive functions in the ODR group. Lipid peroxidation levels, cyclooxygenase-2 expression and prostaglandin E2 levels in the brain tissue were higher in the OD group and RA treatment inhibited these changes. AD-like histopathological alterations and amyloid b peptide (Ab) depositions were observed in the OD group. Normal cell structure and lower Ab depositions were observed in the ODR group compared with the OD group.. RA could have the potential to prevent some psychological and biochemical alterations of brain tissue found in a rat model of AD probably by attenuating lipid peroxidation and inflammatory response.

Topics: Alzheimer Disease; Animals; Brain; Cinnamates; Cognition; Depsides; Disease Models, Animal; Female; Galactose; Humans; Lipid Peroxidation; Memory, Short-Term; Motor Activity; Ovariectomy; Rats; Rats, Wistar; Rosmarinic Acid

CONTEXT. Antivenom is expensive and not always available, so alternative treatments are being investigated. OBJECTIVE. The efficacy of trypsin or rosmarinic acid (RA) in treating Micrurus fulvius in a murine model is determined. MATERIALS AND METHODS.. randomized controlled blinded study.. Fifty mice (20-30 g). Study groups: Intraperitoneal injections of: 1) 2 mg/kg M. fulvius venom (approximately twice the LD50 for mice; n = 10); 2) 2 mg/kg M. fulvius venom incubated in vitro for 1 h prior to injection with RA at a 1:10 ratio (n = 17); 3) 2 mg/kg M. fulvius venom incubated in vitro for 1 h prior to injection with 1 mg of trypsin (n = 17); 4)1 mg trypsin IP without venom (n = 3); and 5) RA IP without venom (n = 3).. time to toxicity (respiratory distress (< 25 breaths/min.), loss of spontaneous locomotor activity, or inability to upright self).. Time to toxicity using Tukey-Kramer HSD; Survival to 4, 6, and 12 h using Chi-square analysis. RESULTS. Onset of toxicity: venom + saline, 120.3 + 64.4 min; venom + rosmarinic acid, 238.1 ± 139.2 min (p = 0.15 relative to venom + saline); venom + trypsin, 319.7 + 201.0 min (p = 0.007 relative to venom + saline). Venom + trypsin but not venom + RA survival to 4 h was significant compared to venom + saline (p = 0.023). Two mice in the venom + trypsin group and one mouse in the venom + RA group survived to 12 h. Mice receiving trypsin without venom or RA without venom survived to 12 h without toxicity. Discussion. This work suggests that trypsin and RA may have efficacy in treatment M. fulvius envenomation. CONCLUSION. In vitro neutralization of M. Fulvius venom by trypsin justifies progressing to an in vivo model in future studies.

Topics: Animals; Antivenins; Cinnamates; Depsides; Disease Models, Animal; Elapid Venoms; Elapidae; Injections, Intraperitoneal; Lethal Dose 50; Mice; Random Allocation; Rosmarinic Acid; Snake Bites; Trypsin

Rosmarinic acid (RA) is an important component of Chinese herbal medicine treatments and has been demonstrated to exert therapeutic effects in mood disorders. The present study was designed to assess the effects of RA on post-traumatic stress disorder (PTSD)-like symptoms, hippocampal cell proliferation and phosphorylation extracellular regulated protein kinases (pERK1/2) expression. We found that administration of RA (10mg/kg) alleviated PTSD-like symptoms in rats exposed to an enhanced single prolonged stress (ESPS) paradigm and restored hippocampal proliferation and pERK1/2 expression. Interestingly, the effects of RA were inhibited by the blockage of the ERK signaling. These data support the use of RA for treating PTSD and indicate that the ERK1/2 signaling cascade may play a critical role in the therapeutic efficacy of RA in treating such conditions.

Topics: Analysis of Variance; Animals; Anti-Inflammatory Agents, Non-Steroidal; Bromodeoxyuridine; Butadienes; Cell Proliferation; Cell Survival; Cells, Cultured; Cinnamates; Depsides; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors; Freezing Reaction, Cataleptic; Hippocampus; Male; MAP Kinase Signaling System; Maze Learning; Motor Activity; Neural Stem Cells; Nitriles; Rats; Rats, Sprague-Dawley; Rosmarinic Acid; Stress Disorders, Post-Traumatic

Diabetic neuropathic (DN) pain is one of the diabetes complications. Rosmarinic acid (RA), a natural phenol antioxidant, shows some biological activities, including anti-inflammatory, analgesic, and anti-diabetic effects.. We investigated the efficacy of RA administration (10 and 30 mg/kg) on streptozotocin (STZ)-induced neuropathy in rats.. The animals received saline or RA (10 and 30 mg/kg, p.o.; once daily) for 8 weeks. DN was evaluated by the tail flick (TF) method, formalin test, and tactile allodynia. At the end, all rats were weighed and underwent plasma glucose measurement.. There was an increase in licking time during both formalin test phases in diabetic animals (138.5 ± 10.7 and 448.7 ± 2.6 s) that was decreased by RA10 mg/kg (103.5 ± 7.5 and 284.4 ± 19 s) and RA 30 mg/kg (81.8 ± 11 and 192.7 ± 14 s). RA 30 mg/kg caused anti-nociception during the early phase in treated controls (52.1 ± 6 s) than untreated controls (99.4 ± 5.9 s). The TF latency in diabetics (2.9 ± 0.1 s) was increased in RA10 and 30 mg/kg treated diabetics (5.3 ± 0.4 and 6 ± 0.86 s). The paw withdrawal threshold (PWT) of the diabetics (3.6 ± 0.7 g) was increased after RA 10 and 30 mg/kg (13.8 ± 0.3 and 14 ± 0.4 g) treatment. RA did not induce a significant change in body weight and plasma glucose of rats.. RA showed efficacy in amelioration of some aspects of DN. Therefore, RA makes a good candidate for DN treatment in clinical studies.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Glucose; Cinnamates; Depsides; Diabetic Neuropathies; Disease Models, Animal; Male; Pain; Pain Measurement; Rats; Rats, Wistar; Rosmarinic Acid; Treatment Outcome

Despite several pharmacological applications of Rosmarinus officinalis L. (Lamiaceae), studies on its analgesic and anti-inflammatory properties have been scarce.. The aim of this work was to use in vivo models to evaluate the analgesic and anti-inflammatory activities of the aqueous extracts obtained from leaves (AEL) and stems (AES) of Rosmarinus officinalis, as well as its isolated compound--rosmarinic acid (RA). We also prepared and assessed the acetyl ester derivative of RA.. The analgesic activity was evaluated using abdominal constriction and formalin tests. For the evaluation of the anti-inflammatory effects, carrageenin-induced paw edema in rats were used. The extracts were used at doses of 100, 200 and 400 mg kg⁻¹ compounds were tested at 10, 20 and 40 mg kg⁻¹.. Orally administered AEL, AES and RA were not significantly active at any of the doses tested during the abdominal constriction test; the acetyl ester derivative of RA displayed significant analgesic activity. In the carrageenin-induced paw edema assay, the acetyl derivative of RA at all the tested doses produced significant anti-inflammatory effects and reduced the number of paw licks in the second phase of the formalin test.. The results suggest that the analgesic effects of the acetyl derivative of RA operate via a peripheral-mediated mechanism. The acetyl ester derivative of RA is potentially applicable as a new lead compound for the management of pain and inflammation.

Topics: Acetylation; Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Behavior, Animal; Brazil; Cinnamates; Depsides; Disease Models, Animal; Dose-Response Relationship, Drug; Ethnopharmacology; Male; Medicine, Traditional; Mice; Neuralgia; Neurogenic Inflammation; Plant Extracts; Plant Leaves; Plant Stems; Rats; Rats, Wistar; Rosmarinic Acid; Rosmarinus

The endothelial protein C receptor (EPCR) plays pivotal roles in coagulation and inflammation, however, its activity is markedly changed by ectodomain cleavage and release as the soluble protein (sEPCR). According to previous studies, there are approximately 100ng/ml sEPCR in human plasma and the levels increase in inflammatory diseases. EPCR can be shed from the cell surface, and this is mediated by tumor necrosis factor-α converting enzyme (TACE). We recently reported on the anti-inflammatory and barrier protective activities of rosmarinic acid (RA), an important component of the leaves of Perilla frutescens. However, little is known about the effects of RA on EPCR shedding. Here, we investigated this issue by monitoring the effects of RA on phorbol-12-myristate 13-acetate (PMA), tumor necrosis factor (TNF)-α, and interleukin (IL)-1β, and on cecal ligation and puncture (CLP)-mediated EPCR shedding and underlying mechanisms. Data showed that treatment with RA resulted in potent inhibition of PMA, TNF-α, IL-induced EPCR shedding by suppression of TACE expression. In addition, RA reduced PMA-stimulated phosphorylation of p38, extracellular regulated kinases (ERK) 1/2, and c-Jun N-terminal kinase (JNK). These results suggest the potential for use of RA as an anti-sEPCR shedding reagent against PMA, TNF-α, IL-1β and CLP-mediated EPCR shedding.

Topics: ADAM Proteins; ADAM17 Protein; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antigens, CD; Cells, Cultured; Cinnamates; Depsides; Disease Models, Animal; Down-Regulation; Endothelial Protein C Receptor; Endothelium, Vascular; Human Umbilical Vein Endothelial Cells; Humans; Male; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Peptide Fragments; Phosphorylation; Protein Processing, Post-Translational; Proteolysis; Receptors, Cell Surface; Rosmarinic Acid; Sepsis; Solubility

Renal fibrosis characterized by accumulation of extracellular matrix protein results in chronic renal diseases including diabetic nephropathy. Transforming growth factor β1 (TGF-β1) signaling pathway plays a key role in mediating renal fibrosis. Hence, agents that antagonize TGF-β signaling could be candidate for kidney disease therapy.. We established renal fibrosis model both in vitro with fibroblast cells treated with rhTGF-β1 and streptozocin(STZ)-induced diabetic nephropathy rats model in vivo and evaluated the effect of the aqueous extract of Lycopus lucidus Turcz, the blood-circulation-promoting Chinese herb, on diabetic nephropathy and investigated the mechanism of action.. We found that Lycopus suppressed rhTGF-β1-induced Smad2 and ERK1/2 activation, down-regulated the expression of TGF-βRI, TGF-βRII, Smad4 and Smad7 in SV40 MES13 cells without inhibiting cell viability. In vivo, lycopus inhibited Smad2 phosphorylation, reduced mRNA level of TGF-β1, ameliorated expansion of the mesangial area in glomerular tissue and reduced the levels of Scr and BUN of serum and total-SOD (superoxide dismutase) activity in STZ-induced diabetic rats.. Lycopus is a novel inhibitor of renal fibrosis by blocking TGF-β signaling pathway and possess a protective effect on renal damage of STZ-induced diabetic nephropathy in rats.

Topics: Animals; Caffeic Acids; Cell Line; Cinnamates; Depsides; Diabetic Nephropathies; Disease Models, Animal; Fibrosis; Gene Expression Regulation; Glucosides; Humans; Luteolin; Lycopus; Male; Mice; Phosphorylation; Plant Extracts; Plants, Medicinal; Rats; Rats, Sprague-Dawley; Rosmarinic Acid; Signal Transduction; Streptozocin; Transforming Growth Factor beta1

Rosmarinus officinalis, also named rosemary, is a native plant from the Mediterranean region that is useful for the treatment of inflammatory diseases. Studies using experimental models and/or in vitro tests have shown the important biological effects of rosemary. In this context, the mechanism of the anti-inflammatory activity of rosemary must be investigated to support the discovery of new substances with anti-inflammatory effects. The aim of the present study was to investigate the anti-inflammatory effects of crude extract oil free obtained from the leaves of rosemary in an animal model of inflammation, thus evaluating its medicinal use for the treatment of inflammatory conditions. Also its ethanol, hexane, and ethyl acetate fractions, as well as its isolated compounds carnosol and rosmarinic acid were analyzed. Swiss mice were used for the in vivo experiments. The effect of this herb on the inhibition of the leukocytes, exudation, myeloperoxidase, and adenosine-deaminase activities, nitrite/nitrate, interleukin 17A, and interleukin 10 levels and mRNA expression was determined. The crude extract and its derived fractions, in addition to its isolated compounds, inhibited leukocytes and decreased exudation and myeloperoxidase and adenosine-deaminase activities, as well as nitrite/nitrate and interleukin 17A levels and mRNA expression, besides increasing interleukin 10 levels and mRNA expression. Rosemary showed important anti-inflammatory activity by inhibiting leukocytes and decreasing exudation. These effects were associated with a decrease in the proinflammatory parameters (myeloperoxidase, adenosine-deaminase, nitrite/nitrate, and interleukin 17A) and an increase in the anti-inflammatory cytokine (interleukin 10). This study confirms the anti-inflammatory properties of rosemary and validates its use in folk medicine to treat inflammatory diseases such as rheumatism and asthma.

Topics: Abietanes; Adenosine Deaminase; Animals; Anti-Inflammatory Agents; Carrageenan; Cinnamates; Cytokines; Depsides; Disease Models, Animal; Inflammation; Inflammation Mediators; Leukocytes; Mice; Mice, Inbred Strains; Nitrates; Nitrites; Peroxidase; Phytotherapy; Plant Extracts; Plant Leaves; Pleurisy; RNA, Messenger; Rosmarinic Acid; Rosmarinus

This study was carried out to investigate the chemopreventive potential of rosmarinic acid (RA) against 1,2-dimethylhydrazine (DMH) induced rat colon carcinogenesis by evaluating the effect of RA on tumour formation, antioxidant enzymes, cytochrome P450 content, p-nitrophenol hydroxylase and GST activities. Rats were divided into six groups and fed modified pellet diet for the entire experimental period. Group 1 served as control, group 2 received RA (10 mg/kgb.w.). Groups 3-6 were induced colon cancer by injecting DMH (20 mg/kgb.w.) subcutaneously once a week for the first four weeks (groups 3-6). In addition, RA was administered at the doses of 2.5, 5 and 10 mg/kgb.w. to groups 4-6 respectively. DMH treated rats showed large number of colonic tumours; decreased lipid peroxidation; decreased antioxidant status; elevated CYP450 content and PNPH activities; and decreased GST activity in the liver and colon. Supplementation with RA (5 mgkg/b.w.) to DMH treated rats significantly decreased the number of polyps (50%); reversed the markers of oxidative stress (21.0%); antioxidant status (38.55%); CYP450 content (29.41%); and PNPH activities (21.9%). RA at the dose of 5 mg/kgb.w. showed a most pronounced effect and could be used as a possible chemopreventive agent against colon cancer.

Topics: 1,2-Dimethylhydrazine; Animals; Antineoplastic Agents; Antioxidants; Carcinogens; Cinnamates; Colonic Neoplasms; Depsides; Dietary Supplements; Disease Models, Animal; Male; Oxidative Stress; Rats; Rats, Wistar; Rosmarinic Acid

Rosmarinus officinalis (R. officinalis), a culinary aromatic and medicinal plant, is very rich in polyphenols and flavonoids with high antioxidant properties. This plant was reported to exert multiple benefits for neuronal system and alleviate mood disorder. In our previous study, we demonstrated that R. officinalis and its active compounds, luteolin (Lut), carnosic acid (CA), and rosmarinic acid (RA), exhibited neurotrophic effects and improved cholinergic functions in PC12 cells in correlation with mitogen-activated protein kinase (MAPK), ERK1/2 signaling pathway. The current study was conducted to evaluate and understand the anti-depressant effect of R. officinalis using tail suspension test (TST) in ICR mice and PC12 cells as in vitro neuronal model. Proteomics analysis of PC12 cells treated with R. officinalis polyphenols (ROP) Lut, CA, and RA revealed a significant upregulation of tyrosine hydroxylase (TH) and pyruvate carboxylase (PC) two major genes involved in dopaminergic, serotonergic and GABAergic pathway regulations. Moreover, ROP were demonstrated to protect neuronal cells against corticosterone-induced toxicity. These results were concordant with decreasing immobility time in TST and regulation of several neurotransmitters (dopamine, norepinephrine, serotonin and acetylcholine) and gene expression in mice brain like TH, PC and MAPK phosphatase (MKP-1). To the best of our knowledge this is the first evidence to contribute to the understanding of molecular mechanism behind the anti-depressant effect of R. officinalis and its major active compounds.

Topics: Abietanes; Animals; Antidepressive Agents; Cinnamates; Depressive Disorder; Depsides; Disease Models, Animal; Mice; Neurons; PC12 Cells; Phytotherapy; Plant Extracts; Pyruvate Carboxylase; Rats; Rosmarinic Acid; Rosmarinus; Tyrosine 3-Monooxygenase; Up-Regulation

Hepatic stellate cells (HSCs) undergo myofibroblastic transdifferentiation (activation) to participate in liver fibrosis and identification of molecular targets for this cell fate regulation is essential for development of efficacious therapeutic modalities for the disease. Peroxisomal proliferator-activated receptor γ (PPARγ) is required for differentiation of HSCs and its epigenetic repression underlies HSC activation. The herbal prescription Yang-Gan-Wan (YGW) prevents liver fibrosis, but its active ingredients and molecular mechanisms are unknown. Here we demonstrate YGW prevents and reverses HSC activation by way of epigenetic derepression of Pparγ involving reductions in MeCP2 expression and its recruitment to Pparγ promoter, suppressed expression of PRC2 methyltransferase EZH2, and consequent reduction of H2K27di-methylation at the 3' exon. High-performance liquid chromatography / mass spectrometry (HPLC/MS) and nuclear magnetic resonance (NMR) analyses identify polyphenolic rosmarinic acid (RA) and baicalin (BC) as active phytocompounds. RA and BC suppress the expression and signaling by canonical Wnts, which are implicated in the aforementioned Pparγ epigenetic repression. RA treatment in mice with existing cholestatic liver fibrosis inhibits HSC activation and progression of liver fibrosis.. These results demonstrate a therapeutic potential of YGW and its active component RA and BC for liver fibrosis by way of Pparγ derepression mediated by suppression of canonical Wnt signaling in HSCs.

Topics: Animals; Cell Differentiation; Cells, Cultured; Cinnamates; Depsides; Disease Models, Animal; Drugs, Chinese Herbal; Epigenesis, Genetic; Flavonoids; Gene Expression Regulation; Hepatic Stellate Cells; Liver Cirrhosis; Male; Mice; Mice, Inbred C57BL; NF-kappa B; PPAR gamma; Rats; Rats, Wistar; Rosmarinic Acid; Signal Transduction; Wnt Proteins

Rosmarinic acid (RA) is a naturally occurring polyphenolic compound. It has been reported that RA possessed antioxidant and anti-inflammatory properties. Our previous study showed that RA could protect MES23.5 dopaminergic cells against 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in vitro. The purpose of this study was to explore the neuroreparative (neurorescue) effect of RA on 6-OHDA-lesioned rat model of Parkinson's disease (PD) in vivo. In this study, the rats were given RA orally after intrastriatal 6-OHDA lesion. Results showed that the dopamine content in the striatum decreased and the numbers of tyrosine hydroxylase-immunoreactive neurons reduced after 6-OHDA treatment. RA treatment after 6-OHDA administration could restore these changes. Further studies demonstrated that 6-OHDA treatment increased the iron-staining positive cells, which were markedly decreased by RA treatment. Moreover, RA suppressed the increased ratio of Bax/Bcl-2 at gene level induced by 6-OHDA. This indicates that the neurorescue effects of RA against 6-ODHA-induced degeneration of the nigrostriatal dopaminergic system were achieved by decreasing nigral iron levels and regulating the ratio of Bcl-2/Bax gene expression.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cinnamates; Depsides; Disease Models, Animal; Female; Neuroprotective Agents; Oxidopamine; Parkinsonian Disorders; Rats; Rats, Wistar; Rosmarinic Acid; Substantia Nigra; Sympatholytics

Rosmarinic acid (RA), a polyphenolic phytochemical, is a natural prolyl oligopeptidase inhibitor. In the present study, we found that RA exerted potent anti-inflammatory effects in in vivo models of acute lung injury (ALI) induced by lipopolysaccharide (LPS). Mice were pretreated with RA one hour before challenge with a dose of 0.5 mg/kg LPS. Twenty-four hours after LPS was given, bronchoalveolar lavage fluid (BALF) was obtained to measure pro-inflammatory mediator and total cell counts. RA significantly decreased the production of LPS-induced TNF-a, IL-6, and IL-1β compare with the LPS group. When pretreated with RA (5, 10, or 20 mg/kg) the lung wet-to-dry weight (W/D) ratio of the lung tissue and the number of total cells, neutrophils and macrophages in the BALF were decreased significantly. Furthermore, RA may enhance oxidase dimutase (SOD) activity during the inflammatory response to LPS-induced ALI. And we further demonstrated that RA exerts anti-inflammation effect in vivo models of ALI through suppresses ERK/MAPK signaling in a dose dependent manner. These studies have important implications for RA administration as a potential treatment for ALI.

Topics: Acute Lung Injury; Animals; Blotting, Western; Cinnamates; Depsides; Disease Models, Animal; Enzyme Inhibitors; Lipopolysaccharides; Male; Mice; Mice, Inbred BALB C; Prolyl Oligopeptidases; Protease Inhibitors; Rosmarinic Acid; Serine Endopeptidases

Allergic asthma has emerged as an important public health problem of urban populations in developed countries. Very often herbal medicine is used to treat this widespread disease, due to the lack of efficacy and the important side effects related to the classical drugs in use. Along this line, Ocimum gratissimum (Og) is a plant widely used in Brazilian folk medicine to treat inflammatory disorders, such as asthma. In the present study we evaluated the immunomodulatory effects of Og and rosmarinic acid (RA, a polyphenolic compound) in a murine model of respiratory allergy induced by the Blomia tropicalis (Bt) mite. The respiratory allergy was induced in A/J mice by administration of Bt extract and the treatment was done using 25, 50 or 100mg/kg of an Og methanolic extract or using 2, 20 or 200mg/kg of RA. We then evaluated the changes induced by these drugs on immunological parameters related to the allergic process, which are up-regulated in this allergic model. The treatment of animals with 100mg/Kg Og and 200mg/Kg RA led to a significant reduction in the numbers of leukocytes/eosinophils in bronchoalveolar lavage (BAL); eosinophil peroxidase activity in BAL; presence of mucus in respiratory tract, histopathological changes in the lung, and IL-4 in BAL. These results suggest that the methanolic extract of Og and the polyphenol RA have therapeutic potential in this murine model of respiratory allergy to a clinically relevant human sensitizer allergen.

Topics: Animals; Bronchoalveolar Lavage Fluid; Cinnamates; Depsides; Disease Models, Animal; Eosinophil Peroxidase; Eosinophils; Immunologic Factors; Interleukin-4; Lung; Male; Mice; Mice, Inbred Strains; Ocimum; Plant Extracts; Respiratory Hypersensitivity; Respiratory Mucosa; Rosmarinic Acid; Sarcoptidae

Rosmarinic acid (RA), a constituent of culinary herbs is considered to possess cancer chemopreventive properties. It has been shown to inhibit the development of cancer in preclinical models but data are conflicting and whether it can protect against gastrointestinal malignancies in vivo has not been examined. This study aimed to investigate the effect of RA on the development of intestinal adenomas in the Apc(Min) mouse model of colorectal carcinogenesis, and to correlate efficacy with levels of RA achieved in the plasma and gastrointestinal tract.. RA inhibited the growth of APC10.1 cells derived from Apc(Min) mouse adenomas, with an IC₅₀ of 43 μM. Consumption of dietary RA (0.3%) by Apc(Min) mice for 8 weeks post weaning decreased adenoma burden by ∼35%, but the difference from controls was not significant. Although RA significantly decreased the frequency of large adenomas, the number of small ones increased. Using a novel validated HPLC assay, average levels of RA in the plasma and intestinal mucosa of these mice were found to be 1.1 μM and 38 nmol/g, respectively.. Chronic consumption of RA furnished quantifiable levels of parent compound in the plasma and intestinal tract of Apc(Min) mice and may slow adenoma development.

Topics: Adenoma; Animals; Anticarcinogenic Agents; Calibration; Chromatography, High Pressure Liquid; Cinnamates; Colorectal Neoplasms; Depsides; Dietary Supplements; Disease Models, Animal; Drug Screening Assays, Antitumor; Genes, APC; Intestinal Mucosa; Intestinal Neoplasms; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Reproducibility of Results; Rosmarinic Acid; Sensitivity and Specificity; Tumor Cells, Cultured

Allergy is characterized by an overreaction of the immune system. Perilla frutescens leaf extract has been reported to exhibit antiallergic inflammatory activity. To investigate precisely the effect and mechanism of 30% ethanol extract powder of P. frutescens var. acuta Kudo (EPPF) and rosmarinic acid (RA), a component of EPPF in allergic rhinitis and rhinoconjunctivitis, the antiallergic effects of EPPF and RA were analyzed using in vivo and in vitro models. Cytokine production was analyzed by means of an enzyme-linked immunosorbent assay. Cytokine expression was analyzed via reverse transcription-polymerase chain reaction and Western blotting. Transcription factor and caspase-1 activity were analyzed by a luciferase assay and caspase-1 assay, respectively. The number of nasal, ear and eye rubs after an ovalbumin (OVA) challenge in OVA-sensitized mice was significantly higher than that in OVA-unsensitized mice. Increased number of rubs was inhibited by administration of EPPF or RA. Increased levels of IgE in the serum, spleen and nasal mucosa of OVA-sensitized mice were reduced by EPPF or RA administration. The histamine level was also reduced by EPPF or RA administration in the serum of OVA-sensitized mice. Protein levels and mRNA expressions of interleukin (IL)-1β, IL-6 and tumor necrosis factor-α were inhibited by EPPF or RA administration in the nasal mucosa tissue or spleen of OVA-sensitized mice. In EPPF or RA-administered mice, the mast cell and eosinophil infiltration increase as caused by OVA-sensitization was decreased. In addition, EPPF or RA inhibited both cyclooxygenase-2 protein expression and caspase-1 activity in the same nasal mucosa tissue. In activated human mast cells, nuclear factor-kappa B (NF-κB)/Rel A and caspase-1 activation increased, whereas NF-κB/Rel A and caspase-1 activation was inhibited after a treatment of EPPF or RA. These results indicate that EPPF and RA ameliorate allergic inflammatory reactions such as allergic rhinitis and allergic rhinoconjunctivitis.

Topics: Animals; Blotting, Western; Cell Line; Cinnamates; Conjunctivitis, Allergic; Cyclooxygenase 2; Cytokines; Depsides; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Female; Histamine; Humans; Immunoglobulin E; Mast Cells; Mice; Mice, Inbred BALB C; Nasal Mucosa; NF-kappa B; Perilla frutescens; Phytotherapy; Plant Extracts; Plant Leaves; Respiratory Hypersensitivity; Reverse Transcriptase Polymerase Chain Reaction; Rosmarinic Acid

Plectranthus amboinicus has been known to treat inflammatory diseases or swelling symptoms. We investigated whether P. amboinicus exhibited an inhibitory effect on osteoclastogenesis in vitro and inflammatory bone erosion in collagen-induced arthritis (CIA) mice, an animal model of rheumatoid arthritis. We attempted to identify the active component of P. amboinicus involved in regulation of osteoclastogenesis.. We treated M-CSF- and RANKL-stimulated murine bone marrow-derived macrophages (BMM) and RANKL-induced RAW264.7 cells with different concentrations of P. amboinicus or rosmarinic acid, a phytopolyphenol purified from P. amboinicus, to monitor osteoclast formation by TRAP staining. The mechanism of the inhibition was studied by biochemical analysis such as RT-PCR and immunoblotting. CIA mice were administered gavages of P. amboinicus (375 mg/kg) or placebo. Then clinical, histological, and biochemical measures were assessed to determine the effects of P. amboinicus on synovial inflammation and bone erosion by H&E staining of the inflamed joints and ELISA.. Rosmarinic acid strongly inhibited RANKL-induced NF-κB activation and nuclear factor of activated T cells c1 (NFATc1) nuclear translocation in BMM, and also inhibited RANKL-induced formation of TRAP-positive multinucleated cells. A pit formation assay and the CIA animal model showed that P. amboinicus significantly inhibited the bone-resorbing activity of mature osteoclasts.. We postulated that rosmarinic acid conferred the inhibitory activity on P. amboinicus for inhibition of osteoclastogenesis via downregulation of RANKL-induced NFATc1 expression. Our results indicated the possibility of P. amboinicus as a new remedy against inflammatory bone destruction.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Bone Density Conservation Agents; Cell Line; Cinnamates; Depsides; Disease Models, Animal; Down-Regulation; Male; Mice; Mice, Inbred DBA; NFATC Transcription Factors; Osteitis; Plant Extracts; Plectranthus; Primary Cell Culture; RANK Ligand; Rosmarinic Acid

Oral cancer accounts for 40%-50% of all cancers in India. Tobacco and alcohol are the major etiological factors contributing to its pathogenesis. The aim of the present study was to explore the key mechanism behind the inhibitory effects of rosmarinic acid against 7,12-dimethylbenz(a)anthracene (DMBA)-induced oral carcinogenesis by evaluating the status of biochemical markers (lipid peroxidation, antioxidants, and detoxification enzymes) and immunoexpression patterns of p53 and bcl-2 proteins. Oral tumors were developed by painting the buccal pouches of golden Syrian hamsters with 0.5% DMBA in liquid paraffin 3 times a week for 14 weeks. We noticed 100% tumor formation in hamsters treated with DMBA alone, and the tumors were histopathologically confirmed as well-differentiated squamous cell carcinoma. Oral administration of rosmarinic acid (100 mg/kg body wt) to DMBA-treated hamsters completely prevented the tumor formation. In addition, rosmarinic acid significantly returned the status of biochemical and molecular markers to near normal range in DMBA-treated hamsters. The results of the present study suggest that rosmarinic acid suppresses oral carcinogenesis by stimulating the activities of detoxification enzymes, improves the status of lipid peroxidation and antioxidants, and downregulates the expression of p53 and bcl-2 during DMBA-induced oral carcinogenesis.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Antineoplastic Agents; Carcinogens; Carcinoma, Squamous Cell; Cinnamates; Cricetinae; Cytochrome P-450 Enzyme System; Cytochromes b5; Depsides; Disease Models, Animal; Glutathione; Glutathione Peroxidase; Lipid Peroxidation; Male; Mesocricetus; Mouth Mucosa; Mouth Neoplasms; Proto-Oncogene Proteins c-bcl-2; Rosmarinic Acid; Thiobarbituric Acid Reactive Substances; Tumor Suppressor Protein p53

Oral use of Luromarin, extracted from sea algae Zostera asiatica, was efficient in protection of mice from lethal infection induced by highly pathogenic strain of TBE virus, by extending their average lifespan. Luromarin demonstrated potentiating action in combination with ribavirin and cycloferon.

Topics: Acridines; Animals; Antiviral Agents; Caffeic Acids; Disease Models, Animal; Drug Therapy, Combination; Encephalitis Viruses, Tick-Borne; Encephalitis, Tick-Borne; Luteolin; Mice; Ribavirin; Rosmarinic Acid; Virus Replication; Zosteraceae

This study was carried out to investigate whether rosmarinic acid (RA) has antifibrotic effect on experimental liver fibrosis in vitro and in vivo and its possible mechanism. Culture of hepatic stellate cells (HSCs) determine proliferation and expression of transforming growth factor-beta1 (TGF-beta1), connective transforming growth factor (CTGF) and alpha-smooth muscle actin (alpha-SMA). In carbon tetrachloride (CCL(4))-induced rat liver fibrosis model, determined biochemical indicator, liver fibrosis grade and histopathological changes, immunohistochemical detected liver TGF-beta1 and CTGF expression. The results indicated that RA could inhibit HSCs proliferation, inhibit TGF-beta1, CTGF and alpha-SMA expression in cultured HSCs. It has marked evident in reducing fibrosis grade, ameliorating biochemical indicator and histopathological morphology, reducing liver TGF-beta1 and CTGF expression in CCL(4)-induced liver fibrosis. These findings suggest that RA has potentially conferring antifibrogenic effects.

Topics: Actins; Animals; Antioxidants; Carbon Tetrachloride Poisoning; Cell Proliferation; Cells, Cultured; Cinnamates; Connective Tissue Growth Factor; Depsides; Disease Models, Animal; Hepatic Stellate Cells; Liver; Liver Cirrhosis; Male; Phytotherapy; Plant Extracts; Rats; Rats, Sprague-Dawley; Rosmarinic Acid; Transforming Growth Factor beta1

Amyotrophic lateral sclerosis (ALS) is a late-onset progressive neurodegenerative disease affecting motor neurons. About 2% of patients with the disease are associated with mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1). The purpose of this study is to assess the effect of rosemary extract and its major constituents, rosmarinic acid (RA) and carnosic acid (CA), in human SOD1 G93A transgenic mice, which are well-established mouse models for ALS. The present study demonstrates that intraperitoneal administration of rosemary extract or RA from the presymptomatic stage significantly delayed motor dysfunction in paw grip endurance tests, attenuated the degeneration of motor neurons, and extended the life span of ALS model mice. In addition, RA administration significantly improved the clinical score and suppressed body weight loss compared with a vehicle-treated group. In conclusion, this study provides the first report that rosemary extract and, especially, RA have preventive effects in the mouse model of ALS.

Topics: Aging; Amyotrophic Lateral Sclerosis; Animals; Antioxidants; Body Weight; Cinnamates; Depsides; Disease Models, Animal; Humans; Longevity; Mice; Mice, Transgenic; Motor Activity; Motor Neurons; Movement Disorders; Mutation; Phytotherapy; Psychomotor Performance; Rosmarinic Acid; Rosmarinus; Spinal Cord; Superoxide Dismutase

The present study was to investigate the effects of rosmarinic acid (RA) in cultured RAW264.7 cells and experimental model of sepsis induced by cecal ligation and puncture in rats and the potential mechanism. Results showed that RA concentration dependently down-regulated the levels of TNF-alpha, IL-6, and high-mobility group box 1 protein in LPS-induced RAW264.7 cells, inhibited the IkappaB kinase pathway, and modulated nuclear factor-kappaB. Intravenous injection of RA alone or in combination with imipenem reduced cecal ligation and puncture-induced lethality in rats. In addition, serum levels of TNF-alpha, IL-6, high-mobility group box 1 protein, triggering receptor expressed on myeloid cells, and endotoxin were down-regulated; in contrast, serum level of IL-10 was up-regulated. Amelioration of hemodynamics and decrease in serum enzyme activities and myeloperoxidase in lung, liver, and small intestine were also observed after RA injection. These data indicate that the antisepsis effect of RA was mediated by decreasing local and systemic levels of a wide spectrum of inflammatory mediators. This article provides the first evidence that RA has the capacity to inactivate inflammatory response in sepsis. The anti-inflammatory mechanism of RA may inhibit activation of the nuclear factor- kappaB pathway by inhibiting IkappaB kinase activity.

Topics: Animals; Anti-Bacterial Agents; Cinnamates; Depsides; Disease Models, Animal; Endotoxins; Gene Expression Regulation; Hemodynamics; Humans; Imipenem; Inflammation; Male; Mice; Myeloid Cells; Rats; Rats, Sprague-Dawley; Rosmarinic Acid; Sepsis; Tretinoin

Pathological angiogenesis is the most common cause of blindness at all ages including retinopathy of prematurity, diabetic retinopathy, and age-related macular degeneration. Despite advances in therapy, retinopathy of prematurity remains the most sight-threatening vaso-proliferative retinopathy in children. Herein, we demonstrated that rosmarinic acid has an anti-angiogenic activity to retinal neovascularization in a mouse model of retinopathy of prematurity, which is related to cell cycle arrest with increase of p21(WAF1). Rosmarinic acid significantly inhibited the proliferation of retinal endothelial cells in a dose-dependent manner, and inhibited in vitro angiogenesis of tube formation. Interestingly, the anti-proliferative activity of rosmarinic acid on retinal endothelial cells was related to G2/M phase cell cycle arrest in a dose-dependent manner. With treatment of rosmarinic acid, retinal endothelial cells in G2/M phase increased whereas those in G0/G1 and S phases decreased, which was accompanied by increase of p21(WAF1) expression in a dose-dependent manner. Moreover, rosmarinic acid effectively suppressed retinal neovascularization in a mouse model of retinopathy of prematurity, and showed no retinal toxicity. These data suggest rosmarinic acid could be a potent inhibitor of retinal neovascularization and may be applied in the treatment of other vasoproliferative retinopathies.

Topics: Angiogenesis Inhibitors; Animals; Cell Cycle; Cell Proliferation; Cells, Cultured; Cinnamates; Cyclin-Dependent Kinase Inhibitor p21; Depsides; Disease Models, Animal; Dose-Response Relationship, Drug; Humans; Infant, Newborn; Mice; Mice, Inbred C57BL; Retinal Neovascularization; Retinopathy of Prematurity; Rosmarinic Acid

Inhibition of amyloid-beta (Abeta) aggregation is an attractive therapeutic strategy for Alzheimer's disease (AD). Certain phenolic compounds have been reported to have anti-Abeta aggregation effects in vitro. This study systematically investigated the effects of phenolic compounds on AD model transgenic mice (Tg2576). Mice were fed five phenolic compounds (curcumin, ferulic acid, myricetin, nordihydroguaiaretic acid (NDGA), and rosmarinic acid (RA)) for 10 months from the age of 5 months. Immunohistochemically, in both the NDGA- and RA-treated groups, Abeta deposition was significantly decreased in the brain (P < 0.05). In the RA-treated group, the level of Tris-buffered saline (TBS)-soluble Abeta monomers was increased (P < 0.01), whereas that of oligomers, as probed with the A11 antibody (A11-positive oligomers), was decreased (P < 0.001). However, in the NDGA-treated group, the abundance of A11-positive oligomers was increased (P < 0.05) without any change in the levels of TBS-soluble or TBS-insoluble Abeta. In the curcumin- and myricetin-treated groups, changes in the Abeta profile were similar to those in the RA-treated group, but Abeta plaque deposition was not significantly decreased. In the ferulic acid-treated group, there was no significant difference in the Abeta profile. These results showed that oral administration of phenolic compounds prevented the development of AD pathology by affecting different Abeta aggregation pathways in vivo. Clinical trials with these compounds are necessary to confirm the anti-AD effects and safety in humans.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Cinnamates; Coumaric Acids; Curcumin; Depsides; Disease Models, Animal; Female; Flavonoids; Humans; Immunohistochemistry; Masoprocol; Mice; Mice, Transgenic; Phenols; Rosmarinic Acid; Signal Transduction

Perilla frutescens (perilla) is a herbal medicine used in Japanese traditional Kampo medicine. The present study was conducted to evaluate the anti-nephritic effects of perilla in HIGA mice that spontaneously develop high levels of serum immunoglobulin A (IgA) along with mesangial IgA deposition.. A perilla decoction and its major active constituent, rosmarinic acid (RsA), were orally administrated to 10-week-old HIGA mice for 16 weeks. At study completion, we measured proteinuria and serum IgA levels and generated histological scores from kidney specimens. In addition, we measured concentrations of IgA in culture media of intestinal Peyer's patch cells and spleen cells obtained from the HIGA mice.. Perilla suppressed proteinuria, proliferation of glomerular cells, serum levels of IgA, glomerular IgA and IgG depositions in HIGA mice. Cultured Peyer's patch cells and spleen cells from perilla-treated mice produced significantly less IgA than controls. Rosmarinic acid, by itself, suppressed serum IgA levels and glomerular IgA deposition in HIGA mice. Cultured spleen cells from RsA-treated mice produced less IgA than controls.. The perilla decoction may suppress IgA nephropathy, in part, through modulation of the intestinal mucosal immune system. These effects were caused by RsA acting synergistically with other constituents.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cinnamates; Depsides; Digestive System; Disease Models, Animal; Female; Glomerulonephritis, IGA; Immunoglobulin A; Mice; Perilla frutescens; Phytotherapy; Plant Extracts; Plant Leaves; Random Allocation; Rosmarinic Acid

To assess the therapeutic potential of rosmarinic acid (RosA) in an inflammatory autoimmune arthritis model.. Collagen induced arthritis is established in male DBA/1 mice. Mice were administered daily with 50 mg/kg/day of RosA for 15 days from Day 21 post-immunization and inspected daily to determine the progression of arthritis. After termination of injection, affected hindpaws were subjected to histopathological analyses and immunohistochemical assays for cyclooxygenase-2 (COX-2) expression.. Repeated administration of RosA dramatically reduced the arthritic index and number of affected paws. Histopathologic observations closely paralleled clinical data, showing that RosA treated mice retained nearly normal architecture of synovial tissues, whereas control mice exhibited severe synovitis. Synovial tissues from RosA treated mice exhibited remarkably reduced frequency of COX-2-expressing cells, compared to those from untreated mice.. RosA suppressed synovitis in a murine collagen induced arthritis model; this effect may be beneficial for treatment of rheumatoid arthritis in clinical settings.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Cinnamates; Cyclooxygenase 2; Depsides; Disease Models, Animal; Disease Progression; Isoenzymes; Joints; Male; Mice; Mice, Inbred DBA; Prostaglandin-Endoperoxide Synthases; Rosmarinic Acid

Rosmarinic acid is known to be a natural phenolic compound widely distributed in Labiatae herbs such as rosemary, sweet basil, and perilla. In the present study, we evaluated the suppressive effects of rosmarinic acid on mesangioproliferative glomerulonephritis in vivo, which was induced by intravenous injection of rabbit anti-rat thymocyte serum (ATS) to rats.. Rosmarinic acid was orally administered to the rats at a dose of 100 mg/kg/day from the day of ATS injection (day 0) to day 8 when rats were sacrificed. The degree of mesangial cell proliferation and matrix accumulation were evaluated by trichrome staining and by immunostaining for proliferating cell nuclear antigen (PCNA), fibronectin, type IV collagen and fibrin. Superoxide dismutase (SOD)-activity in the homogenate of renal cortex was also evaluated.. The number of PCNA-positive cells, staining areas of trichrome, fibronectin, collagen IV and fibrin in the glomerulus were significantly decreased, and SOD-activity of renal cortex homogenate was significantly augmented in rosmarinic acid-treated group.. Rosmarinic acid would suppress the proliferation of mesangial cells and glomerular matrix expansion in vivo by its fibrinolytic and anti-oxidative activity.

Topics: Albumins; Animals; Antibodies; Antineoplastic Agents, Hormonal; Antioxidants; Cell Division; Cinnamates; Depsides; Disease Models, Animal; Extracellular Matrix Proteins; Fibronectins; Glomerulonephritis, Membranoproliferative; Male; Molecular Structure; Perilla frutescens; Phytotherapy; Plant Extracts; Prednisolone; Proliferating Cell Nuclear Antigen; Rabbits; Rats; Rats, Wistar; Rosmarinic Acid; Superoxide Dismutase