iridoids and Disease-Models--Animal

In TgCRND8 (Tg) mice we checked the dose-response effect of diet supplementation with oleuropein aglycone (OLE) at 12.5 or 0.5 mg kg. Four month-old Tg mice were equally divided into four groups and treated for 8 weeks with a modified low fat (5.0%) AIN-76 A diet (10 g day. OLE supplementation at 12.5 mg kg. Our results extend previous data showing that the effects of OLE on behavioural performance and neuropathology are dose-dependent and not closely related to OLE by itself. In fact, diet supplementation with the same dose of a mix of polyphenols found in olive mill waste water resulted in comparable neuroprotection.

Topics: Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Behavior, Animal; Brain; Cognitive Dysfunction; Dietary Supplements; Disease Models, Animal; Dose-Response Relationship, Drug; Iridoid Glucosides; Iridoids; Mice, Transgenic; Olea; Peptide Fragments; Plaque, Amyloid; Polyphenols; Wastewater

Asperuloside (ASP) and geniposide (GP) are iridoids that have shown various biological properties, such as reduction of inflammation, oxidative stress, and neuroprotection. The aim of this study was to investigate the mechanism of action of ASP and GP through the experimental model of pilocarpine-induced seizures. Mice were treated daily with saline, valproic acid (VPA), GP (5, 25, or 50 mg/kg), or ASP (20 or 40 mg/kg) for 8 days. Pilocarpine (PILO) treatment was administered after the last day of treatment, and the epileptic behavior was recorded for 1 h and analyzed by an adapted scale. Afterward, the hippocampus and blood samples were collected for western blot analyses, ELISA and comet assay, and bone marrow to the micronucleus test. We evaluated the expression of the inflammatory marker cyclooxygenase-2 (COX-2), GluN2B, a subunit of the NMDA receptor, pGluR1, an AMPA receptor, and the enzyme GAD-1 by western blot and the cytokine TNF-α by ELISA. The treatments with GP and ASP were capable to decrease the latency to the first seizure, although they did not change the latency to status epilepticus (SE). ASP demonstrated a genotoxic potential analyzed by comet assay; however, the micronuclei frequency was not increased in the bone marrow. The GP and ASP treatments were capable to reduce COX-2 and GluN2B receptor expression after PILO exposure. This study suggests that GP and ASP have a protective effect on PILO-induced seizures, decreasing GluN2B receptor and COX-2 expression.

Topics: Animals; Cyclooxygenase 2; Disease Models, Animal; Hippocampus; Iridoids; Mice; Pilocarpine; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Seizures

Asthma is a chronic airway disorder with a hallmark feature of airflow obstruction that associated with the remodeling and inflammation in the airway wall. Effective therapy for controlling both remodeling and inflammation is still urgently needed. Leonuride is the main pharmacological component identified from Bu-Shen-Yi-Qi-Tang (BSYQT) which has been traditionally used in treatment of lung diseases. However, no pharmacological effects of leonuride in asthma were reported.. Here we aimed to investigated whether leonuride provided a therapeutic efficacy in reversing asthma airway remodeling and inflammation and uncover the underlying mechanisms.. Mouse models of chronic asthma were developed with ovalbumin (OVA) exposure for 8 weeks. Respiratory mechanics, lung histopathology and asthma-related cytokines were examined. Lung tissues were analyzed using RNA sequencing to reveal the transcriptional profiling changes.. After oral administration with leonuride (15 mg/kg or 30 mg/kg), mice exhibited a lower airway hyperresponsiveness in comparison to asthmatic mice. Leonuride suppressed airway inflammation evidenced by the significant reductions in accumulation of inflammatory cells around bronchi and vessels, leukocyte population counts and the abundance of type 2 inflammatory mediators (OVA specific IgE, IL-4, IL-5 and IL-13) in bronchoalveolar lavage fluid (BALF). On the other hand, leonuride slowed down the process of active remodeling as demonstrated by weaker goblet cell metaplasia and subepithelial fibrosis in lung histopathology and lower transforming growth factor (TGF)-β1 levels in serum and BALF in comparison to mice treated with OVA only. Furthermore, we uncovered transcriptional profiling alternations in lung tissue of mice after OVA exposure and leonuride treatment. Gene sets belonging to type-2 cytokine/chemokine activity stood out in leonuride target transcripts. Those upregulated (Bmp10, Ccl12, Ccl22, Ccl8, Ccl9, Cxcl15, Il13, Il33, Tnfrsf9, Il31ra, Il5ra, Il13ra2 and Ccl24) or downregulated (Acvr1c and Il18) genes in asthmatic mice, were all reversely regulated by leonuride treatment.. Our results revealed the therapeutic efficacy of leonuride in experimental chronic asthma for the first time, and implied that its anti-inflammatory and antifibrotic properties might be mediated by regulation of type-2 high cytokine/chemokines responses.

Topics: Animals; Asthma; Bronchoalveolar Lavage Fluid; Chemokines; Cytokines; Disease Models, Animal; Inflammation; Iridoid Glycosides; Iridoids; Lung; Mice; Mice, Inbred BALB C; Ovalbumin; Pyrans

Spinal cord injury (SCI) is a traumatic condition of the central nervous system , which can cause nerve injury and affect nerve regeneration, thus leading to severe dysfunction of motor and sensory pathways, and unfortunately these effects are irreversible. Inflammatory response constitutes one of the important mechanisms of spinal cord secondary injury. Geniposide (Gen) is reported to possess anti-inflammation and neuronal repair capacities.. To investigate the effect and mechanism of Gen on motor function and inflammatory response in SCI rats.. Sprague-Dawley (SD) rats were randomly grouped, and the SCI model was established by Allen's method. The motor function of rats was evaluated by the Basso, Beattie, and Bresnahan (BBB) scale. The protective effect of Gen on the injured spinal cord tissues was evaluated by measuring the water content, myeloperoxidase (MPO) activity, and levels of tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), and IL-6. Moreover, the protein level of the inflammation-related pathway was detected by spectrometry and Western blot assays.. Gen significantly promoted the recovery of SCI rats, decreased the edema of spinal cord tissues, reduced the area of cavity, increased the number of NF-200-positive neurons, as well as increased the number of horseradish peroxidase (HRP) retrograde tracing-positive neurons and regenerated axons with myelin sheath. Additionally, compared with the control group, the neutrophil infiltration, contents of TNF-α, IL-1β, and IL-6, the activity of inhibitor of nuclear factor κB kinase subunit β (IKKβ) kinase, and protein levels of (nuclear factor κB) NF-κB p65 and phosphorylated inhibitor of NF-κB (p-I-κB) in the Gen experimental group were significantly decreased.. Gen effectively alleviated inflammatory response after SCI by inhibiting the IKKs/NF-κB signaling pathway and promoted the recovery of motor function and axon regeneration in rats.. This study can provide novel insights for the early and effective intervention of SCI and confer basic data for the treatment of spinal cord secondary injury.

Topics: Animals; Anti-Inflammatory Agents; Cytokines; Disease Models, Animal; Female; I-kappa B Kinase; Inflammation Mediators; Iridoids; Motor Activity; NF-kappa B; Rats, Sprague-Dawley; Recovery of Function; Signal Transduction; Spinal Cord; Spinal Cord Injuries; Spinal Cord Regeneration

Zhi-zi-Hou-po decoction (ZZHPD) has been used to treat depression in the clinic for thousand years in China. However, the pharmacodynamic substance of ZZHPD is still not totally clear due to its complex components. The objective of this study was to identify the effectual combination ingredients (ECIs) of ZZHPD, which could represent the antidepressant effect of the original formula. Firstly, differential plasma absorbed components with different variable importance in projection (VIP) value in chronic unpredictable mild stress (CUMS)-induced depression and control rat were revealed by untargeted metabolomics-driven strategy based on HPLC-ESI-TOF/MS, XCMS online and SIMCA-p software. Secondly, network topology scores (NTS) of plasma absorbed components were exposed by protein-protein interaction (PPI) network analysis based on components-related genes and depression-related genes, which were performed by network pharmacology tools. Finally, the ECIs were screened by considered of VIP value and NTS. Then the bioactivity was evaluated by cell viability and expression of glial fibrillary acid protein (GFAP), tumor necrosis factor α (TNFα) and interleukin 1β (IL-1β) of a lipopolysaccharide-induced astrocyte depression model. An effective combination composed with 12 components was filtrated as ECIs of ZZHPD, exposed to which the cell viability effect, the expression of GFAP and IL-1β in astrocytes were essentially equivalent with original ZZHPD (p > 0.05), and that both characteristic constituents and trace compounds of ZZHPD might exert synergistic actions through multi-targets. The result of this study provided useful information for the clinical application and modern development of ZZHPD, and the proposed strategy could be regard as an alternative solution for effective combination screening of herbal medicines.

Topics: Animals; Antidepressive Agents; Behavior, Animal; Chromatography, High Pressure Liquid; Disease Models, Animal; Drugs, Chinese Herbal; Iridoids; Male; Mass Spectrometry; Rats; Rats, Sprague-Dawley; Stress, Psychological

Topics: Alzheimer Disease; Animals; Cognitive Dysfunction; Disease Models, Animal; Female; Hippocampus; Iridoids; Mice; Mice, Transgenic; Morris Water Maze Test; Neuroprotective Agents; Proteome

Overexposure to glucocorticoid (GC) produces various clinical complications, including osteoporosis (OP), dyslipidemia, and hypercholesterolemia. Geniposide (GEN) is a natural iridoid compound isolated from Eucommia ulmoides. Our previous study found that GEN could alleviate dexamethasone (DEX)-induced differentiation inhibition of MC3T3-E1 cells. However, whether GEN protected against Dex-induced cholesterol accumulation in osteoblasts was still unclear.. DEX was used to induce rat OP. Micro-CT data was obtained. The ALP activity and mineralization were determined by the staining assays, and the total intracellular cholesterol was determined by the ELISA kits. The protein expression was detected by western blot.. GEN ameliorated Dex-induced micro-structure damages and cell differentiation inhibition in the bone trabecula in rats. In MC3T3-E1 cells, Dex enhanced the total intracellular cholesterol, which reduced the activity of cell proliferation and differentiation. Effectively, GEN decreased DEX-induced cholesterol accumulation, enhanced cell differentiation, and upregulated the expression of the GLP-1R/ABCA1 axis. In addition, inhibition of ABAC1 expression reversed the actions of GEN. Treatment with Exendin9-39, a GLP-1R inhibitor, could abrogate the protective activity of GEN.. GEN ameliorated Dex-induced accumulation of cholesterol and inhibition of cell differentiation by mediating the GLP-1R/ABCA1 axis in MC3T3-E1 cells.

Topics: 3T3 Cells; Animals; ATP Binding Cassette Transporter 1; Cell Differentiation; Cholesterol; Dexamethasone; Disease Models, Animal; Eucommiaceae; Gene Expression Regulation; Glucagon-Like Peptide-1 Receptor; Iridoids; Mice; Osteoblasts; Osteoporosis; Rats; Signal Transduction

Topics: Animals; Disease Models, Animal; Drug Interactions; Hyperalgesia; Iridoids; Male; Mice; Mice, Inbred C57BL; Paclitaxel; Plant Extracts; Vitex

For many centuries, Mexican Valerian (Valeriana edulis ssp. procera) has been an important plant in folk medicine. It has been considered useful to control epilepsy; however, electroencephalographic evidence of its anticonvulsant activity is missing in literature.. In the present study, in situ electroencephalographic (EEG) analysis was performed along with administration of a crude ethanol extract of V. edulis and its valepotriate fraction on the pentylenetetrazole (PTZ)-induced convulsive behavior in rats.. Experiments were performed using male Wistar rats with nail-shaped electrodes implanted in the frontal and parietal cortices for EEG recording. All animals received a single dose of PTZ (35 mg/kg, i.p.) to test the anticonvulsant activity of V. edulis crude extract and valepotriate fraction (100 mg/kg, i.p.) 15 and/or 30 min after administration. EEG recordings were obtained from the cortices and were evaluated to assess ictal behavior over 60-75 min. Chromatographic analysis of the valepotriate fraction and in silico predictions of pharmacodynamic properties were also explored. The latency, frequency and duration of seizures evaluated using EEG recordings from the frontal and parietal cortices of rats showed significant changes demonstrating the inhibition of paroxystic activity.. The spectral analysis confirmed the reduction of excitatory activity induced by V. edulis extract, which was improved in the presence of the valepotriate fraction as compared to that induced by ethosuximide (a reference anticonvulsant drug). The presence of valepotriates such as: isodihydrovaltrate (18.99%), homovaltrate (13.51%), 10-acetoxy-valtrathydrin (4%) and valtrate (1.34%) was identified by chromatographic analysis. Whereas, not only GABA. Our data support the anticonvulsant properties attributed to this plant in folk medicine, due to the presence of valepotriates.

Topics: Animals; Anticonvulsants; Computer Simulation; Disease Models, Animal; Electroencephalography; Ethosuximide; Iridoids; Male; Pentylenetetrazole; Plant Extracts; Plant Roots; Rats; Rats, Wistar; Seizures; Time Factors; Valerian

Type 2 diabetes mellitus (T2DM) has a harmful effect on the stability and osseointegration of dental implants. T2DM induces mitochondrial damage by inhibiting AMPK signaling, resulting in oxidative stress and poor osteogenesis in the peri-implant bone area. Genipin is a major component of gardenia fruits with strong antioxidant, anti-inflammation, and antidiabetic actions, and it also can activate mitochondrial quality control via the AMPK pathway. The purpose of this study was to investigate the effects of genipin and insulin treatment on implant osseointegration in T2DM rats and explore the underlying mechanisms.. Streptozotocin-induced diabetic rats received implant surgery in their femurs and were then assigned to five groups that were subjected to different treatments for three months: control group, T2DM group, insulin-treated T2DM group (10 IU/kg), genipin-treated T2DM group (50 mg/kg), and the genipin and insulin combination-treated T2DM group. Then, we regularly assessed the weight and glucose levels of the animals. Rats were euthanized at 3 months after the implantation procedure, and the femora were harvested for microscopic computerized tomography analysis, biomechanical tests, and different histomorphometric assessment.. The results indicated that the highest blood glucose and oxidative stress levels were measured for the T2DM group, resulting in the poorest osseointegration. The combination-treated T2DM group mitigated hyperglycemia and normalized, reactivated AMPK signaling, and alleviated oxidative stress as well as reversed the negative effect of osseointegration. There were beneficial changes observed in the T2DM-genipin and T2DM-insulin groups, but these were less in comparison to the combination treatment group.. Our study suggests that treatment with genipin in combination with insulin could be an effective method for promoting implant osseointegration in T2DM rats, which may be related to AMPK signaling.

Topics: AMP-Activated Protein Kinases; Animals; Anti-Inflammatory Agents; Antioxidants; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Disease Models, Animal; Drug Therapy, Combination; Femur; Hypoglycemic Agents; Insulin; Iridoids; Male; Osseointegration; Oxidative Stress; Phytotherapy; Prostheses and Implants; Rats, Sprague-Dawley; Signal Transduction; Streptozocin

Diabetic nephropathy (DN) is a common pathological feature in patients with diabetes and the leading cause of end-stage renal disease. Although several pharmacological agents have been developed, the management of DN remains challenging. Geniposide, a natural compound has been reported for anti-inflammatory and anti-diabetic effects; however, its role in DN remains poorly understood. This study investigated the protective effects of geniposide on DN and its underlying mechanisms. We used a C57BL/6 mouse model of DN in combination with a high-fat diet and streptozotocin after unilateral nephrectomy and treated with geniposide by oral gavage for 5 weeks. Geniposide effectively improves DN-induced renal structural and functional abnormalities by reducing albuminuria, podocyte loss, glomerular and tubular injury, renal inflammation and interstitial fibrosis. These changes induced by geniposide were associated with an increase of AMPK activity to enhance ULK1-mediated autophagy response and a decrease of AKT activity to block oxidative stress, inflammation and fibrosis in diabetic kidney. In addition, geniposide increased the activities of PKA and GSK3β, possibly modulating AMPK and AKT pathways, efficiently improving renal dysfunction and ameliorating the progression of DN. Conclusively, geniposide enhances ULK1-mediated autophagy and reduces oxidative stress, inflammation and fibrosis, suggesting geniposide as a promising treatment for DN.

Topics: AMP-Activated Protein Kinases; Animals; Anti-Inflammatory Agents; Autophagy; Autophagy-Related Protein-1 Homolog; Cyclic AMP-Dependent Protein Kinases; Diabetes Complications; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Diet, High-Fat; Disease Models, Animal; Fibrosis; Glycogen Synthase Kinase 3 beta; Iridoids; Mice; Mice, Inbred C57BL; Oxidative Stress

Gout is a type of inflammatory arthritis caused by the deposition of monosodium uric acid (MSU) crystals in tissues. The etiology of gout is directly linked to the NLRP3 inflammasome, since MSU crystals are NLRP3 inflammasome activators. Therefore, we decided to search for a small-molecule inhibitor of the NLRP3 inflammasome for the prevention of gout inflammation. We found that loganin suppressed MSU crystals-induced caspase-1 (p20) and interleukin (IL)-1β production and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) specks formation in mouse primary macrophages, showing its ability to inhibit the NLRP3 inflammasome. In an air pouch inflammation model, oral administration of loganin to mice prevented MSU crystals-induced production of mature IL-1β and IL-18 in air pouch exudates, resulting in decreased neutrophil recruitment. Furthermore, oral administration of loganin suppressed MSU crystals-induced gout inflammation in a mouse foot gout model, which was accompanied by the inhibition of the NLRP3 inflammasome. Loganin blocked de novo synthesis of mitochondrial DNA in air pouches and foot tissues injected with MSU crystals. Consistently, loganin prevented MSU crystals-induced mitochondrial damage in macrophages, as it increased mitochondrial membrane potential and decreased the amount of mitochondrial reactive oxygen species. These data demonstrate that loganin suppresses NLRP3 inflammasome activation by inhibiting mitochondrial stress. These results suggest a novel pharmacological strategy to prevent gout inflammation by blocking NLRP3 inflammasome activation and mitochondrial dysfunction.

Topics: Administration, Oral; Animals; Cells, Cultured; Disease Models, Animal; DNA, Mitochondrial; Gout; Inflammasomes; Inflammation; Iridoids; Macrophages; Male; Mice, Inbred C57BL; Mitochondria; NLR Family, Pyrin Domain-Containing 3 Protein; Uric Acid

The growth plate is a cartilage tissue near the ends of children's long bones and is responsible for bone growth. Injury to the growth plate can result in the formation of a 'bony bar' which can span the growth plate and result in bone growth abnormalities in children. Biomaterials such as chitosan microgels could be a potential treatment for growth plate injuries due to their chondrogenic properties, which can be enhanced through loading with biologics. They are commonly fabricated via an emulsion method, which involves solvent rinses that are cytotoxic. Here, we present a high throughput, non-cytotoxic, non-emulsion-based method to fabricate chitosan-genipin microgels. Chitosan was crosslinked with genipin to form a hydrogel network, and then pressed through a syringe filter using mesh with various pore sizes to produce a range of microgel particle sizes. The microgels were then loaded with chemokines and growth factors and their release was studied in vitro. To assess the applicability of the microgels for growth plate cartilage regeneration, they were injected into a rat growth plate injury. They led to increased cartilage repair tissue and were fully degraded by 28 days in vivo. This work demonstrates that chitosan microgels can be fabricated without solvent rinses and demonstrates their potential for the treatment of growth plate injuries.

Topics: Animals; Biocompatible Materials; Cartilage; Chitosan; Disease Models, Animal; Emulsions; Iridoids; Male; Microgels; Rats; Rats, Sprague-Dawley; Regeneration; Salter-Harris Fractures

Sclerosing cholangitis, characterized by biliary inflammation, fibrosis, and stricturing, remains one of the most challenging conditions of clinical hepatology. Geniposide (GE) has anti-inflammatory, hepatoprotective, and cholagogic effects. Whether GE provides inhibition on the development of sclerosing cholangitis is unknown. Here, we investigated the role of GE in a mouse model in which mice were fed with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) for 4 weeks to induce sclerosing cholangitis. The results demonstrated that the increased hepatic gene expressions of pro-inflammatory (IL-6, VCAM-1, MCP-1, and F4/80) and profibrogenic markers (Col1α1, Col1α2, TGF-β, and α-SMA) in DDC feeding mice were reversed after treatment with GE. GE also suppressed expressions of CK19 and Ki67 in DDC-fed mice, suggesting that GE could ameliorate DDC-induced hepatocytes and cholangiocytes proliferation. In addition, GE significantly increased bile acids (BAs) secretion in bile, which correlated with induced expressions of hepatic FXR, BAs secretion transporters (BSEP, MRP2, MDR1, and MDR2), and reduced CYP7A1 mRNA expression. Furthermore, higher expressions of ileal FXR-FGF15 signaling and reduced ASBT were also observed after GE treatment. Taken together, these data showed that GE could modulate inflammation, fibrosis, and BAs homeostasis in DDC-fed mice, which lead to efficiently delay the progression of sclerosing cholangitis.

Topics: Animals; Cholangitis, Sclerosing; Disease Models, Animal; Iridoids; Liver; Mice; Mice, Knockout

Age-related macular degeneration (AMD), mainly wet AMD, is the major reason for nonreversible vision loss worldwide. Choroidal neovascularization (CNV) is a characteristic pathological manifestation of wet AMD. Stress or injury to the retinal pigment epithelium (RPE) induces proangiogenic factors that drive CNV. An iridoid glycoside extracted from the fruit of gardenia, geniposide (GEN) plays an antiangiogenic role. In this study, GEN inhibited the transcription and expression of heparin-binding epidermal growth factor (HB-EGF), a proangiogenic factor, in hypoxic RPE cells and a mouse laser-induced CNV model. Inhibition of glucagon-like peptide-1 receptor (GLP-1R), a GEN receptor blocker, eliminated the protective effect of GEN. Additionally, GEN decreased the transcription and expression of HB-EGF in hypoxia-exposed RPE cells by downregulating the miR-145-5p/NF-κB axis. Therefore, our research provides a promising novel strategy for wet AMD therapy.

Topics: Animals; Cells, Cultured; Choroidal Neovascularization; Disease Models, Animal; Down-Regulation; Gene Expression Regulation; Heparin-binding EGF-like Growth Factor; Iridoids; Male; Mice; MicroRNAs; Retinal Pigment Epithelium

To explore the effects of total iridoids of VJJ extract (TIV) on chronic unpredictable mild stress (CUMS) in mice.. VJJ roots and rhizomes were extracted with 70% ethanol. CUMS rats were treated daily with fluoxetine (2.6 mg/kg, i.g.) or TIV (5.7, 11.4, and 22.8 mg/kg, i.g.) for 14 days. Male Kun Ming mice on normal chow and 0.5% CMC-Na solution were used as a control. Behavioural tests included the tail suspension (TST) and sucrose preference tests (SPT). Evans blue staining was used to evaluate blood-brain barrier (BBB) permeability. Western blotting was used to measure zonula occludens-1 (ZO-1) and occludin expression. 16S rRNA sequencing was used to analyse intestinal flora abundance. Tax4Fun was used to predict KEGG metabolic pathways.. TIV may modulate the intestinal flora, thereby inducing the expression of ZO-1 and occludin, protecting the BBB and exerting an antidepressant effect.

Topics: Animals; Animals, Outbred Strains; Antidepressive Agents; Blood-Brain Barrier; Depression; Disease Models, Animal; Dose-Response Relationship, Drug; Fluoxetine; Gastrointestinal Microbiome; Iridoids; Male; Mice; Occludin; Plant Extracts; Rats; Stress, Psychological; Up-Regulation; Valerian; Zonula Occludens-1 Protein

Corni Fructus (CF), the red fruit of Cornus officinalis Siebold & Zucc, has been used both as food and medicinal herb in traditional Chinese medicine (TCM). Loganin is a major iridoid glycoside and one of the quality control indexes of CF. In TCM clinical practice, prescription containing CF is commonly used to treat osteoarthritis (OA), but the underlying mechanisms of loganin are not yet utterly understood.. The aims of the present study are to confirm the therapeutic effects of loganin in an OA mouse model and to determine the mechanisms involved in the OA protective effects.. The destabilization of the medial meniscus (DMM) procedure was performed on the right knee of 8-week-old C57BL/6 male mice. 30 or 100 μg/ml of loganin was then injected into articular space twice a week for 8 and 12-week. Safranin O/Fast green staining, H&E staining, micro-CT analysis were performed to analyze structural and morphological changes. The protein expression of collagen type II (Col2), metalloproteinase-3 (Mmp3), matrix metalloproteinase 13 (Mmp13) collagen type X (Col10), cryopyrin and caspase-1 were detected by immunochemistry staining. Immuno-fluorescence assay was performed to assess changes in expression of CD31, endomucin, p65 and p-I-κB.. Results of histomorphometry showed that loganin delays the progression of OA in the DMM model. In cartilage, loganin decreased the OARSI score, increasing hyaline cartilage (HC) thickness and decreasing calcified cartilage (CC) thickness. Moreover, loganin inhibited osteophyte formation, reduced the bone volume fraction (BV/TV), lowered trabecular thickness (Tb.Th) and increased trabecular separation (Tb.Sp) in subchondral bone. Mechanistically, loganin increased the expressions of Col2, decreases the expression of Mmp3, Mmp13, Col10, cryopyrin and caspase-1 in cartilage. In parallel, loganin inhibited the expression of CD31 and endomucin in subchondral bone. Furthermore, loganin suppressed nuclear translocation of p65 protein, and decreased the amount of p-I-κB in chondrocytes.. In summary, these results uncovered that loganin inhibits NF-κB signaling and attenuates cartilage matrix catabolism and pyroptosis of chondrocytes in articular cartilage. Loganin may serve as a potential therapeutic agent for OA treatment.

Topics: Animals; Chondrocytes; Collagen Type II; Collagen Type X; Cornus; Disease Models, Animal; Fruit; Humans; Iridoids; Male; Menisci, Tibial; Mice; NF-kappa B; Osteoarthritis, Knee; Pyroptosis; Signal Transduction

Topics: Animals; Antidepressive Agents; Behavior, Animal; Brain; Disease Models, Animal; Gastrointestinal Tract; Hippocampus; Intestines; Iridoids; Mice; Stress, Psychological; Valerian

Genipin has been shown to exert anti-inflammatory effects, but its mechanism in protecting the ethanol-induced acute gastric injuries remains largely unclear. The present study aimed to investigate the effects of genipin on ethanol-induced acute gastric injuries in mice. After intragastrical administration of genipin for 7 consecutive days, acute gastric injuries were induced in the mice by ethanol treatment for 1 h. The expression levels of MDA, MPO, SOD, CAT, and NO in gastric tissues, and the levels of IL-6, TNF-α, MTL, SP, VIP and SS in serum samples were measured by ELISA. In addition, Western blotting was used to determine the expression levels of proteins involved in NLRP3 signaling pathway. The findings revealed that oral administration of genipin significantly ameliorated the pathological injury of gastric mucosa induced by ethanol, decreased the oxidative stress induced by ethanol and suppressed the expression levels of in-flammatory cytokines in gastric tissues and serum samples. In addition, it was observed that oral administration of genipin could remarkably inhibit the expression levels of related proteins in the NLRP3 signaling pathway. In conclusion, these results suggest that genipin may exhibit protective roles in ethanol-induced gastric mucosal injuries by activating antioxidant system and attenuating inflammatory reaction.

Topics: Acute Disease; Animals; Anti-Inflammatory Agents; Disease Models, Animal; Ethanol; Gastric Mucosa; Humans; Inflammasomes; Iridoids; Male; Mice; NLR Family, Pyrin Domain-Containing 3 Protein; Oxidative Stress; Signal Transduction; Stomach Ulcer

The aim of this study is to investigate the protective effects as well as the underlying molecular mechanisms of geniposide in APP/PS1 transgenic mice.. APP/PS1 mice were subjected to intragastric administration of geniposide (50 mg/kg/d) for 8 weeks (including a 2-week behavior test). The novel object recognition (NOR) and the Morris water maze (MWM) tests were used for behavioral assessments. Aβ1-40 plaques in mice cortices and hippocampi are visualized with immunohistochemistical staining. ELISA was used to quantify the levels of soluble Aβ1-40 and Aβ1-42 in the hippocampus. Western blot was used to detect p-Akt/Akt, p-mTOR/mTOR and p-4E-BP1/4E-BP1 levels. The relative mRNA levels of Akt, mTOR and 4E-BP1 were quantified using real-time PCR (RT-PCR).. Geniposide alleviated cognitive impairment by improving the ability of novel object exploration, spatial memory, and reduced the level of Aβ in the brain of APP/PS1 mice. Geniposide possibly regulates mTOR-related proteins through modification of phosphorylation. Geniposide markedly lowered p-mTOR and p-Akt expressions while elevating p-4E-BP1 expression. Geniposide obviously reduced the relative mRNA levels of Akt and mTOR and increased the relative mRNA level of 4E-BP1.. Geniposide is able to alleviate cognitive impairments and cerebral damage in APP/PS1 mice, with its neuroprotective effects likely mediated via modulation of the mTOR signaling pathway.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cerebral Cortex; Cognitive Dysfunction; Disease Models, Animal; Hippocampus; Iridoids; Male; Mice, Inbred C57BL; Mice, Transgenic; Neuroprotective Agents; Peptide Fragments; Plaque, Amyloid; Signal Transduction; TOR Serine-Threonine Kinases

Bone allografts are the preferred method for bone augmentation in over 500,000 orthopedic surgical procedures in the US. Sterilization by ionizing radiation is the most effective method of minimizing the bioburden of bone allografts; however, radiation causes chain scission of collagen, resulting in the reduction of the allografts' mechanical strength. In this study, we doped bone allografts with vitamin E as radioprotectant using a novel two-step process to protect the collagen architecture against radiation damage and to preserve the mechanical strength of the construct. In addition, combining the radioprotectant with a cross-linking agent further minimized collagen degradation and further preserved the mechanical strength of the allografts. Both vitamin E and combined vitamin E/genipin-treated allograft were less cytotoxic to both osteoblasts and osteoclasts when compared to irradiated-only allografts. Host bone-allograft unionization was faster in a rat calvaria defect model with vitamin E-treated and combined vitamin E and genipin-treated allograft when compare to irradiated-only allografts. This method can enable the efficient and uniform radioprotective treatment of bone allograft of desired shapes for sterilization with improved mechanical strength and biointegration.

Topics: Allografts; Animals; Bone and Bones; Bone Transplantation; Collagen; Cross-Linking Reagents; Disease Models, Animal; Humans; Iridoids; Mechanical Phenomena; Osteoblasts; Osteoclasts; Radiation-Protective Agents; Skull; Sterilization; Vitamin E

Morroniside and loganin are iridoid glycosides extracted from Cornus officinalis, a plant species widely used in traditional Chinese medicine. However, the anti-inflammatory effects of morroniside and loganin in colitis are barely understood. The aim of the present study was to explore the effects of morroniside and loganin on the dextran sodium sulfate (DSS)-induced murine model of colitis and an LPS-induced colorectal cancer (CRC) cell inflammation model, and to clarify the underlying mechanisms. We found that morroniside and loganin were able to ameliorate clinical features, including disease activity index (DAI), histological inflammation score and periodic acid-Schiff staining (PAS). In the mouse model, morroniside and loganin treatment increased expression of tight junction proteins (TJs) and decreased pro-inflammatory cytokine production. Moreover, our findings showed that the expression of p-STAT3 and p-p65 were suppressed compared to the disease group. In in vitro experiments, treatment with morroniside and loganin had no obvious effects on proliferative activity in HCT116 cells and HIEC-6 cells. Expression of pro-inflammatory cytokines was inhibited by morroniside and loganin treatment in comparison with the LPS-treated group. Taken together, morroniside and loganin have beneficial effects on colitis in vivo and are anti-inflammatory in vitro. Possible mechanisms of the anti-inflammatory response may include blockade of the STAT3/NF-κB pathway.

Topics: Animals; Anti-Inflammatory Agents; Cell Line; Colitis; Colitis, Ulcerative; Cornus; Dextran Sulfate; Disease Models, Animal; Glycosides; Humans; Iridoid Glycosides; Iridoids; Male; Medicine, Chinese Traditional; Mice; Mice, Inbred C57BL; NF-kappa B; Phosphorylation; Signal Transduction; STAT3 Transcription Factor

Depression is still one of challenging, and widely encountered disorders with complex etiology. The role of healthy diet and olive oil in ameliorating depression has been claimed. This study was designed to explore the effects of oleuropein; the main constituent of olive oil; on depression-like behaviors that are induced by repeated administration of corticosterone (40 mg/kg, i.p.), once a day for 21 days, in mice. Oleuropein (8, 16, and 32 mg/kg, i.p.) or fluoxetine (20 mg/kg, positive control, i.p.1) was administered 30 minutes prior to corticosterone injection. Sucrose consumption test, open-field test (OFT), tail suspension test (TST), and forced swimming test (FST) were performed. Reduced Glutathione (GSH), lipid peroxidation, and biogenic amines; serotonin, dopamine, and nor-epinephrine; levels were also analyzed in brain homogenates. Corticosterone treatment induced depression-like behaviors, it increased immobility time in the TST, OFT, and FST, decreased the number of movements in OFT, and decreased sucrose consumption. Corticosterone effect was associated with depletion of reduced glutathione and increase of lipid peroxidation, in addition to modification of biogenic amines; decreased serotonin and dopamine. Oleuropein or fluoxetine administration counteracted corticosterone-induced changes. In conclusion, oleuropein showed a promising antidepressant activity, that is evident by improving corticosterone-induced depression-like behaviors, and normalizing levels of biogenic amines.

Topics: Anhedonia; Animals; Behavior, Animal; Biogenic Amines; Brain; Corticosterone; Depression; Disease Models, Animal; Hindlimb Suspension; Immobilization; Iridoid Glucosides; Iridoids; Male; Mice; Movement; Neurotransmitter Agents; Oxidative Stress; Sucrose; Swimming

High myopia can lead to blindness. Genipin is a collagen cross-linking agent that may be used to treat myopia. However, the mechanism of action of genipin for the treatment of myopia is unclear. This study investigated the effect of genipin on the scleral expression of the miR-29 cluster, matrix metalloproteinase 2 (MMP2), and collagen alpha1 chain of type I (COL1A1) in a guinea pig model of myopia.. The model of myopia was established by treating guinea pigs with a - 8D lens on both eyes for 21 days, and eyes with a refractive error of - 6D or greater were included. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) and western blot were used to examine the mRNA and protein expression, respectively. A dual-luciferase assay was used to determine the direct targeting of the miR-29 cluster on the 3'-untranslated region (UTR) of the COL1A1 gene.. The scleral expression of miR-29a, miR-29b, and miR-29c as well as MMP2 was significantly increased, and the scleral expression of COL1A1 was significantly decreased in the myopia group. Genipin treatment reversed these effects in myopic eyes. The dual-luciferase assay showed that the luciferase activities were significantly decreased in human embryonic kidney (HEK) cells transfected with miR-29a and miR-29b, but not miR-29c, compared with those transfected with control miRNAs.. Genipin inhibits the scleral expression of the miR-29 cluster and MMP2 and promotes COL1A1 expression in a guinea pig model of myopia. Thus, genipin may promote COL1A1 expression by reducing the expression of the miR-29 cluster.

Topics: Animals; Blotting, Western; Cells, Cultured; Cholagogues and Choleretics; Collagen Type I; Collagen Type I, alpha 1 Chain; Disease Models, Animal; Female; Gene Expression Regulation; Guinea Pigs; HEK293 Cells; Humans; Iridoids; Male; Matrix Metalloproteinase 2; MicroRNAs; Myopia; Real-Time Polymerase Chain Reaction; RNA, Messenger; Sclera

Inflammation and oxidative stress pathways have emerged as novel targets in the management of inflammatory bowel diseases (IBD). Targeting the drug to the inflamed colon remains a challenge. Nanostructured lipid carriers (NLCs) have been reported to accumulate in inflamed colonic mucosa. The antioxidant/antiinflamatory polyphenol oleuropein (OLE) was loaded in NLCs (NLC-OLE). NLC-OLE showed to be more effective in decreasing the TNF-α secretion and intracellular reactive oxygen species (ROS) by activated macrophages (J774) compared to the conventional form of OLE. OLE efficacy was preserved within NLC-OLE ameliorating inflammation in a murine model of acute colitis: reduced levels of TNF-α and IL-6, decreased neutrophil infiltration and improved histopathology of the colon were reported. In addition, NLC-OLE enhanced the ROS scavenging activity of OLE in the colon after oral administration. These data suggest that the proposed NLC-OLE could be a promising drug delivery system for OLE in IBD treatment.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents; Antioxidants; Cell Line; Colitis; Disease Models, Animal; Drug Carriers; Drug Delivery Systems; Inflammation; Iridoid Glucosides; Iridoids; Lipids; Macrophages; Male; Mice; Mice, Inbred C57BL; Nanostructures; Oxidative Stress; Reactive Oxygen Species

Although cisplatin is a common drug in the treatment of malignant tumors, its clinical application is limited due to various side effects, especially acute kidney injury (AKI). Till now, few effective pharmacological strategies can be applied to inhibit cisplatin-induced AKI. Here, we aimed to investigate the protective effects and possible mechanisms of monotropein on cisplatin-induced AKI. In this study, an AKI model was established in cisplatin-treated mice, and serum level of inflammatory cytokines, protein expressions of biochemical indicators and renal pathology were analyzed. Our results showed that our results showed that monotropein could significantly attenuate cisplatin-induced nephrotoxicity and reduce the levels of blood urea nitrogen (BUN) and serum creatinine (CRE). Furthermore, monotropein inhibited cisplatin-induced oxidative stress by reducing MDA level and increasing the activities of GSH, SOD and CAT. The underlying mechanisms of monotropein on alleviating cisplatin-induced AKI were associated with the activation of Nrf2/HO-1 pathway against oxidative stress and the inhibition on NF-κB signaling to suppress inflammation as well as the regulation on the expressions of proteins in apoptosis pathway in this renal injury model. This study firstly provided the evidence that monotropein could significantly attenuate cisplatin-induced AKI and suggested that monotropein might be used as a potential agent to alleviate side effects of cisplatin.

Topics: Acute Kidney Injury; Animals; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Apoptosis Regulatory Proteins; Cisplatin; Disease Models, Animal; Heme Oxygenase-1; Inflammation Mediators; Iridoids; Kidney; Membrane Proteins; Mice, Inbred BALB C; NF-E2-Related Factor 2; NF-kappa B; Oxidative Stress; Signal Transduction

To investigate the effects and the mechanism of geniposide on the neuroinflammation occured in the neurodegeneration course of a chronic cerebral hypoperfusion rat model.. Permanent bilateral common carotid arteries occlusions was performed to induce gradient cognitive deficit in rats. The sham group was used as control group. Then 18 rats that met the Screening Criteria were randomly selected 8 weeks post surgery, and were randomly divided into three groups, the 2-VO rats with saline solution group (2-VO+saline group), 2-VO rats with 50 mg/kg per day geniposide group (2-VO+G50) and 2-VO rats with 100 mg/kg per day geniposide group (2-VO+G100). All intervention groups were daily administered with geniposide or saline for 4 weeks. The sham-operated rats were administrated with saline. Then the rats were tested for Morris water maze to evaluate the memory and learning ability. Rats were sacrificed to obtain cortex and hippocampus tissues for HE staining and to detect expression level of glial fibrillary acidic protein (GFAP), inducible nitric oxide synthase (iNOS) and nuclear factor-kappa B (NF-κB), and the level of inflammatory factors tumor necrosis factor-α (TNF-α) and interleukin (IL)-6.. These findings demonstrated that geniposide significantly prevented cognition deterioration induced by chronic cerebral hypoperfusion in rats. Geniposide inhibited neuroinflammation occurred in the process of chronic cerebral ischemia probably via reducing iNOS and NF-κB expression and suppressing the release of inflammatory factor TNF-α and IL-6.

Topics: Animals; Anti-Inflammatory Agents; Brain Ischemia; Cognition Disorders; Disease Models, Animal; Hippocampus; Iridoids; Maze Learning; Random Allocation; Rats

Recently, it has reported that many inflammatory bowel disease (IBD) patients were contracted secondary liver injury. Monotropein (MON), an iridoid glycoside, is demonstrated to possess protective effects on acute colitis mice due to its anti-inflammatory activities. However, it was remained unknown whether MON could inhibit secondary liver injury caused by IBD. The aim of the present study was to investigate the protective roles and mechanisms of MON on secondary liver injury in chronic colitis mice model. In this study, 2% Dextran sodium sulfate (DSS) was used to induce mice model of chronic colitis. The results showed that MON attenuated DSS-induced hepatic pathological damage, liver parameters, infiltration of macrophages and cytokines levels. Furthermore, we found that MON attenuated liver injury through suppressing the activation of the toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) signaling pathway and down-regulating the activity of NLRP3 (NOD-, LRR- and pyrin domain-containing 3) inflammasome. All the data indicated that MON may be an effective therapeutic reagent to attenuate secondary liver injury induced by chronic colitis.

Topics: Animals; Anti-Inflammatory Agents; Chronic Disease; Colitis; Dextran Sulfate; Disease Models, Animal; Inflammasomes; Iridoids; Liver; Liver Diseases; Macrophages; Male; Mice; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Signal Transduction; Toll-Like Receptor 4

To investigate the effects of geniposide in an iridoid found in Gardenia jasminoides var. radicans Makino (GJRM) in spontaneous hypertensive rat (SHR) and explore the possible mechanisms.. In this study, we detected the content of geniposide in GJRM by high-performance liquid chromatography (HPLC). Then, we used acute diuretic experiments to determine whether geniposide has diuretic effect. Moreover, we carried out experiments on SHR to further study the mechanism of hypertension, while real-time PCR, Western blot and immunohistochemistry were used for the experiments in vivo test. Hypotonic model was used for in vitro test.. Our data showed that the content of geniposide in the extract of GJRM is 27.54%. Meanwhile, 50 mg/kg geniposide showed the strongest effect on promoting urine volume. Further study indicated that the extract of GJRM and geniposide could significantly reduce blood pressure and promote the excretion of urine and Na. Collectively, we would suggest that geniposide may potentially be utilized as an adjunct to existing thiazide and thiazide-like diuretics to control hypertension, mainly through inhibiting the activation of the WNK signalling pathway mediated by the estrogen receptor.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Cell Line; Disease Models, Animal; Diuresis; Diuretics; Estrogen Receptor alpha; Estrogen Receptor beta; Gardenia; Hypertension; Iridoids; Kidney Tubules, Proximal; Male; Plant Extracts; Protein Serine-Threonine Kinases; Rats, Inbred SHR; Rats, Inbred WKY; Signal Transduction

Rotavirus is the leading cause of acute gastroenteritis among young children worldwide. However, agents specifically designed to treat rotavirus infection have not been developed yet. In this study, the anti-rotavirus and anti-inflammatory effects of genipin, a chemical compound found in the fruit of Gardenia jasminoides, were evaluated. Genipin had an antiviral effect against the human rotavirus Wa and SA-11 strains in vitro, and it inhibited two distinct stages of the viral replication cycle: attachment and penetration (early stage) in pre-treatment and assembly and release (late stage) in post-treatment. Additionally, genipin downregulated nitric oxide synthase and pro-inflammatory cytokines in lipopolysaccharide-stimulated RAW264.7 cells and rotavirus-infected Caco-2 cells. Oral administration of genipin before and after viral infection with the murine rotavirus epidemic diarrhea of infant mice strain led to a reduced duration of diarrhea and faecal viral shedding and to decreased destruction of the enteric epithelium. Genipin could have potential as a natural compound with preventive and therapeutic effects against infection and colitis caused by rotavirus.

Topics: Animals; Animals, Newborn; Anti-Inflammatory Agents; Antiviral Agents; Caco-2 Cells; Cytokines; Diarrhea; Disease Models, Animal; Humans; Inflammation; Iridoids; Mice; Nitric Oxide Synthase; RAW 264.7 Cells; Rotavirus; Rotavirus Infections; Virus Replication; Virus Shedding

Ulcerative colitis is a chronic and recurrent inflammatory bowel disease mediated by immune response. Geniposide is the main active ingredient extracted from Gardenia jasminoides, which has been suggested to exert excellent efficacy on inflammatory disease. Herein, in this study, we aimed to uncover the systematic understanding of the mechanism and effects of geniposide in ameliorating inflammatory responses in colitis. In brief, the TCMSP server and GEO DataSets were used to analyze the systematic understanding of the mechanism and effects of geniposide in ameliorating inflammatory responses in colitis. Dextran Sulfate Sodium (DSS)-induced acute colitis of mice were administered with 25-100[Formula: see text]mg/kg of geniposide for 7 days by gavage. Lipopolysaccharide (LPS)-induced Bone Marrow Derived Macrophage (BMDM) cell or RAW264.7 cell models were treated with 20, 50 and 100[Formula: see text][Formula: see text]M of geniposide for 4[Formula: see text]h. Myeloperoxidase (MPO) activity and Interleukin-1[Formula: see text] (IL-1[Formula: see text] levels were measured using MPO activity kits and IL-1[Formula: see text] levels enzyme-linked immunosorbent assay (ELISA) kits, respectively. Additionally, Western blot was used to determine the relevant protein expression. As a result, Geniposide could ameliorate inflammatory responses and prevent colitis in DSS-induced acute colitis of mice by activating AMP-activated protein kinase (AMPK)/Transcription 1 (Sirt1) dependent signaling via the suppression of nod-like receptor protein 3 (NLRP3) inflammasome. Geniposide attenuated macrophage differentiation in DSS-induced acute colitis of mice. Geniposide suppressed NLRP3 inflammasome and induced AMPK/Sirt1 signaling in LPS-induced BMDM cell or RAW264.7 cell models. In mechanism studies, the inhibition of AMPK/Sirt1 attenuated the anti-inflammatory effects of geniposide in colitis. The activation of NLRP3 attenuated the anti-inflammatory effects of geniposide in colitis. Taken together, our results demonstrated that geniposide ameliorated inflammatory responses in colitis vai the suppression of NLRP3 inflammasome in macrophages by AMPK/Sirt1-dependent signaling.

Topics: AMP-Activated Protein Kinases; Animals; Cells, Cultured; Colitis; Disease Models, Animal; Inflammasomes; Inflammation; Iridoids; Macrophages; Mice; Mice, Inbred C57BL; NLR Family, Pyrin Domain-Containing 3 Protein; Phytotherapy; RAW 264.7 Cells; Signal Transduction; Sirtuin 1

Breast cancer is one of the most common cancers in women and is associated with a high mortality rate. The majority of deaths resulting from breast cancer are attributable to metastatic growth; in addition, chemoresistance is a major concern in the treatment of patients with breast cancer. However, limited drugs are available for the treatment of metastatic breast cancer. In this study, the chemoadjuvant effects of a methanolic extract from the leaves of Pseudolysimachion rotundum var. subintegrum (NC13) and an active component isolated from the plant, verminoside (Vms), were evaluated. Furthermore, their potent anti-metastatic activities were validated in vitro and in vivo in animal models. The anti-metastatic and chemosensitizing activities of NC13 and Vms on cisplatin treatment were found to be partly mediated by suppression of the epithelial-mesenchymal transition of cancer cells. Collectively, our results implied that NC13 and its bioactive component Vms could be developed as effective chemoadjuvants in combination with conventional therapeutics.

Topics: Adjuvants, Pharmaceutic; Allografts; Animals; Antineoplastic Agents; Breast Neoplasms; Cell Survival; Cisplatin; Diet; Disease Models, Animal; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; Female; Humans; Iridoids; Male; MCF-7 Cells; Mice; Mice, Inbred BALB C; Neoplasm Metastasis; Phytotherapy; Plant Extracts; Plant Leaves; Veronica

Osteoporosis is a common disease caused by an imbalance of processes between bone resorption by osteoclasts and bone formation by osteoblasts in postmenopausal women. The roots of

Topics: Administration, Oral; Animals; Carbon-13 Magnetic Resonance Spectroscopy; Cell Differentiation; Cell Line; Cells, Cultured; Disease Models, Animal; Gentiana; Iridoids; Mice; Osteoblasts; Osteoclasts; Osteoporosis; Ovariectomy; Plant Extracts; Plant Roots; Protective Agents; Proton Magnetic Resonance Spectroscopy

Alzheimer's disease (AD), also defined as a tauopathology, is a common neurodegenerative disease. Hyper-phosphorylation, cleavage or truncation, and aggregation of tau contribute to AD. Thus, targeting the post-translational modifications on tau may be a therapeutic strategy to treat AD. This study understood how cornel iridoid glycoside (CIG) affects tau post-translational modifications and synaptic abnormalities. The 10-month old P301S tau transgenic mice were given CIG at 100 and 200 mg/kg every day orally for 1 month. Hyperphosphorylated and truncated tau, synapse-associated proteins and glutamatergic receptors were all detected using Western blotting. The interactions between Morroniside (MOR) or Loganin (LOG) and tau were detected using Autodock and Surface Plasmon Resonance (SPR). The effects of CIG on the aggregation of tau were investigated using a cell-free system. CIG attenuated tau hyperphosphorylation at Thr205, Ser212, Ser262, Thr231 and Ser235 (AT180), but had no effect on tau truncation in the brains of 10-month old P301S mice. Binding free energies and interactions revealed that MOR and LOG bound with tau. We also found that CIG upregulated synapse-associated proteins such as PSD-95, syntaxin1A and synaptotagmin. In addition, CIG restored N-methyl-D-aspartic acid receptor and glutamate receptor levels. CIG improves post-translational modification of tau as well as synaptic abnormalities. The data presented here reveal that CIG may be used in the treatment of AD.

Topics: Administration, Oral; Animals; Brain; Cell-Free System; Disease Models, Animal; Female; Glycosides; Humans; Iridoids; Male; Mice; Mice, Transgenic; Models, Molecular; Molecular Docking Simulation; Mutation; Phenotype; Protein Binding; Receptors, Glutamate; Receptors, N-Methyl-D-Aspartate; tau Proteins; Tauopathies; Treatment Outcome

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disorder associated with features of metabolic syndrome and oxidative stress. We examined the mechanism by which the combined extracts of

Topics: AMP-Activated Protein Kinases; Animals; Antioxidants; Diet, High-Fat; Disease Models, Animal; Endoplasmic Reticulum Stress; Eucommiaceae; Fatty Liver; Iridoid Glucosides; Iridoids; Lipid Peroxidation; Male; Oxidative Stress; Phytotherapy; Plant Extracts; Rats, Sprague-Dawley; Reactive Oxygen Species

Topics: Animals; Dietary Supplements; Disease Models, Animal; Heme Oxygenase-1; Inflammasomes; Iridoid Glucosides; Iridoids; Janus Kinases; Kidney; Lupus Nephritis; MAP Kinase Signaling System; Matrix Metalloproteinase 3; Membrane Proteins; Mice, Inbred BALB C; NF-kappa B; Nitric Oxide Synthase Type II; NLR Family, Pyrin Domain-Containing 3 Protein; STAT Transcription Factors; Terpenes

Topics: Animals; Chromatography, High Pressure Liquid; Depression; Disaccharides; Disease Models, Animal; Drug Synergism; Drugs, Chinese Herbal; Flavanones; Hesperidin; Intestinal Absorption; Iridoids; Male; Rats; Rats, Sprague-Dawley

Monotropein, astragalin, and spiraeoside (MAS) are active compounds extracted from medicinal herbs; monotropein from Morinda officinalis How (Rubiaceae), astragalin (kaempferol 3-O-glucoside) from Cuscuta chinensis Lamark (Convolvulaceae) and spiraeoside from the outer scales of Allium cepa L. (Liliceae) in a ratio of 6.69:0.41:3.61. Monotropein, astragalin, and spiraeoside are well-known antioxidants, anti-inflammatory, and antinociceptive agents. The current investigation aims to study the molecular mechanism of varicocele-induced male infertility and the underlying pharmacological mechanisms of MAS.. Four groups were included: control (CTR), MAS 200 group (MAS 200 mg/kg), varicocele group (VC), and VC + MAS 200 group (MAS 200 mg/kg). Sprague-Dawley (SD) rats were treated with 200 mg/kg MAS or vehicle once daily for 28 days. The possible signaling mechanism and effects of MAS were measured via histological staining, immunohistochemistry, western blot, and biochemical assays.. Parameters such as sperm motility and count, Johnsen's scores, spermatogenic cell density, serum testosterone, testicular superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx) and expression of the steroidogenic acute regulatory protein (StAR) improved significantly in the VC + MAS 200 group compared with the VC group. MAS treatment of varicocele-induced group significantly decreased the levels of serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH), as well as testicular interleukin-6 (IL6), tumor necrosis factor-α (TNF-α), ROS/RNS, and malondialdehyde (MDA). It also decreased the apoptotic index and reduced the expression of endoplasmic reticulum (ER) protein levels (Grp78, p-IRE1α, and p-JNK) and apoptotic markers such as cleaved caspase-3 and Bax/Bcl2 ratio.. This study suggests that the crosstalk between oxidative stress, ER stress, and mitochondrial pathway mediates varicocele-induced testicular germ cell apoptosis. MAS promotes spermatogenesis in varicocele-induced SD rat, probably by decreasing cytokines (IL-6, TNF-α) levels, regulating abnormal sex hormones, and decreasing oxidative stress, ER stress, and apoptosis.

Topics: Animals; Antioxidants; Body Weight; Disease Models, Animal; Endoplasmic Reticulum Stress; Iridoids; Kaempferols; Male; Mitochondria; Organ Size; Oxidative Stress; Quercetin; Rats; Rats, Sprague-Dawley; Signal Transduction; Testis; Varicocele

Genipin, as the most effective ingredient of various traditional medications, encompasses antioxidative, anti-inflammatory, and antibacterial capacities. More recently, it is suggested that genipin protects against septic liver damage by restoring autophagy. The purpose of the current study was to explore the protective effect of genipin against carbon tetrachloride- (CCl

Topics: Animals; Autophagy; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Inflammation; Iridoids; Liver; Male; Medicine, Traditional; Mice; Rubiaceae

Bronchopulmonary dysplasia is the most common chronic lung disease of infancy and is associated with pulmonary hypertension (PH). Inhibition of glycogen synthase kinase (GSK)-3 β has been shown to attenuate lung injury and PH in hyperoxia-exposed newborn rats. Genipin has been widely used for the treatment of inflammatory diseases. The aim of this study was to show that genipin decreased the expression of GSK-3 β in lung tissues of hyperoxia-exposed rat pups.. We established models of hyperoxia-exposed rat pups, evaluated lung injury and pulmonary hypertension and detected the mRNA and protein expression of key molecules.. Hyperoxia resulted in the reduction of survival rate and histologic injury of lung tissues; an increase of the messenger RNA (mRNA) expression of transforming growth factor-β1, extracellular matrix proteins collagen-I and fibronectin, and α-smooth muscle actin; an increase of right ventricular (RV) systolic pressure and the weight ratio of RV to left ventriclar (LV) plus septum (S) (RV/LV + S) were inhibited by genipin. Genipin also decreased the levels of tumor necrosis factor-α, interleukin-1 β, and interleukin-6 in both bronchoalveolar lavage fluid and lung tissues after hyperoxia exposure. In addition, genipin inhibited p65 nuclear factor-κB nuclear translocation and matrix metalloproteinase-2 and -9 expression. Moreover, hyperoxia resulted in an increase of methane dicarboxylic aldehyde content and a decrease of superoxide dismutase activity, catalytic subunit of glutamate-cysteine ligase, modified subunit of glutamate-cysteine ligase, and nuclear factor erythroid 2-related factor 2 expression were inhibited by genipin. All these effects induced by genipin were blocked by upregulation of GSK-3 β. Genipin downregulated GSK-3 β expression, decreased nuclear factor-κB translocation, increased nuclear factor erythroid 2-related factor 2 expression, attenuated inflammation and oxidative stress, leading to amelioration of lung injury and PH in hyperoxia-exposed rat pups.. Overall, genipin may provide a novel therapeutic option for preventing and treating infants with bronchopulmonary dysplasia.

Topics: Animals; Animals, Newborn; Anti-Inflammatory Agents; Antioxidants; Bronchopulmonary Dysplasia; Disease Models, Animal; Gardenia; Glycogen Synthase Kinase 3 beta; Humans; Hyperoxia; Hypertension, Pulmonary; Infant, Newborn; Interleukins; Iridoids; Lung; Lung Injury; NF-E2-Related Factor 2; NF-kappa B; Oxygen; Phytotherapy; Plant Extracts; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

Topics: Animals; Biomarkers; Chemical and Drug Induced Liver Injury; Chromatography, High Pressure Liquid; Computational Biology; Disease Models, Animal; Drugs, Chinese Herbal; Iridoids; Liver; Metabolic Networks and Pathways; Metabolome; Metabolomics; Rats; Reproducibility of Results; Tandem Mass Spectrometry; Tissue Distribution

This study aims to develop and evaluate oleuropein loaded surface functionalized folate-targeted - PEG liposomes for the effective management of prostate cancer in an animal model.. Film hydration-cum-extrusion technique was used to produce liposomes. Particle size, entrapment efficiency, drug loading, electron microscopy, and drug release study were performed for the characterization. Cell viability and various in vitro studies (phosphatidylserine internalization, TUNEL assay, measurement of mitochondrial membrane potential and caspase-3 assay) were performed to compare the anticancer and apoptotic effects of developed liposomes against the plain oleuropein. Comparative pharmacokinetic profiling and anticancer efficacy studies including a change in tumor volume, body weight, and survival analysis were performed in mice model.. The developed liposomes (OL-FML) showed the particle size of 184.2 ± 9.16 nm, the zeta potential of 1.41 ± 0.24 mV, entrapment efficiency of 63.52 ± 4.15% and drug loading of 21.31 ± 2.37%. OL-FML showed higher in vitro anti-proliferative effect and apoptosis on 22Rv1 cells. In vivo pharmacokinetic study revealed a nearly 6 fold increase in the bioavailability of OL-FML (AUC. The study provides conclusive evidence for the utilization of combining passive and active targeting strategy to enhance the anticancer effect of OL.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Survival; Disease Models, Animal; Drug Liberation; Folic Acid; Humans; Iridoid Glucosides; Iridoids; Liposomes; Male; Mice; Mice, Inbred BALB C; Particle Size; Prostatic Neoplasms

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

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

We address the hypothesis that uncoupling protein 2 (UCP2), a cellular glucose regulator, delays physiologic retinal vascular development (PRVD) by interfering with glucose uptake through glucose transporter 1 (Glut1).. In the rat 50/10 oxygen-induced retinopathy (OIR) model, retinal Glut1 and UCP2 were measured and compared to room air (RA)-raised pups at postnatal day 14 (p14). Pups in OIR and RA received intraperitoneal genipin, an UCP2 inhibitor, or control every other day from p3 until p13. Analyses at p14 included avascular/total retinal area (AVA), Western blots of retinal UCP2 and Glut1, and immunostaining of Glut1 in retinal cryosections. Intravitreal neovascular/total retinal area (IVNV) was analyzed at p18, and electroretinograms were performed at p26. Glut1 and phosphorylated VEGFR2 (p-VEGFR2), glucose uptake, adenosine triphosphate (ATP) production, and cell proliferation were measured in human retinal microvascular endothelial cells (hRMVECs) pretreated with genipin or transfected with UCP2siRNA, Glut1siRNA, or control siRNA when incubated with VEGF or PBS.. At p14, OIR pups had increased AVA with decreased Glut1 and increased UCP2 in the retina compared to RA retinas. Intraperitoneal genipin increased retinal Glut1 and reduced AVA. Compared to control, treatment with genipin or knockdown of UCP2 significantly increased Glut1, glucose uptake, ATP production, VEGF-induced p-VEGFR2 and cell proliferation in hRMVECs. Knockdown of Glut1 inhibited VEGF-induced p-VEGFR2. Genipin-treated OIR pups with decreased AVA at p14 had reduced IVNV at p18 and increased amplitudes in a- and b-waves at p26.. Extending PRVD by increasing retinal endothelial glucose uptake may represent a strategy to prevent severe retinopathy of prematurity and vision loss.

Topics: Adenosine Triphosphate; Animals; Animals, Newborn; Blotting, Western; Cholagogues and Choleretics; Diabetic Retinopathy; Disease Models, Animal; Electroretinography; Endothelium, Vascular; Female; Gene Silencing; Glucose; Glucose Transporter Type 1; Glycolysis; Injections, Intraperitoneal; Iridoids; Male; Oxygen; Pregnancy; Rats; Rats, Sprague-Dawley; Retinal Vessels; Transfection; Uncoupling Protein 2; Vascular Endothelial Growth Factor Receptor-2

Epilepsy is a prevalent neurological disorder that was reported to affect about 56 million people in the world. Approximately one-third of the epileptic patients that suffer from seizures do not receive effective medical treatment. The aim of this study was to determine the potential anticonvulsant activities of Baldrinal (BAL) with a mouse model of pilocarpine (PILO)-induced epilepsy. The mice were treated with different doses of BAL or sodium valproate prior to PILO injection. Spontaneous and evoked seizures were evaluated from EEG recordings, and their severity was tested by the Racine scale. In addition, the brain tissues were analyzed for histological changes, and the in situ levels of glutamic acid (Glu) and gamma-aminobutyric acid (GABA) were also measured. Activation of astrocytes in the hippocampus was measured. PILO-treated mice showed a significant increase in Glu levels, which was restored by BAL. In addition, BAL treatment also reduced the rate of seizures in the epileptic mice, and ameliorated the increased levels of NMDAR

Topics: Animals; Anticonvulsants; Brain; Disease Models, Animal; Epilepsy; gamma-Aminobutyric Acid; Glutamic Acid; Humans; Iridoids; Mice; Pilocarpine; Seizures

Back pain commonly arises from intervertebral disc (IVD) damage including annulus fibrosus (AF) defects and nucleus pulposus (NP) loss. Poor IVD healing motivates developing tissue engineering repair strategies. This study evaluated a composite injectable IVD biomaterial repair strategy using carboxymethylcellulose-methylcellulose (CMC-MC) and genipin-crosslinked fibrin (FibGen) that mimic NP and AF properties, respectively. Bovine ex vivo caudal IVDs were evaluated in cyclic compression-tension, torsion, and compression-to-failure tests to determine IVD biomechanical properties, height loss, and herniation risk following experimentally-induced severe herniation injury and discectomy (4 mm biopsy defect with 20% NP removed). FibGen with and without CMC-MC had failure strength similar to discectomy injury suggesting no increased risk compared to surgical procedures, yet no biomaterials improved axial or torsional biomechanical properties suggesting they were incapable of adequately restoring AF tension. FibGen had the largest failure strength and was further evaluated in additional discectomy injury models with varying AF defect types (2 mm biopsy, 4 mm cruciate, 4 mm biopsy) and NP removal volume (0%, 20%). All simulated discectomy defects significantly compromised failure strength and biomechanical properties. The 0% NP removal group had mean values of axial biomechanical properties closer to intact levels than defects with 20% NP removed but they were not statistically different and 0% NP removal also decreased failure strength. FibGen with and without CMC-MC failed at super-physiological stress levels above simulated discectomy suggesting repair with these tissue engineered biomaterials may perform better than discectomy alone, although restored biomechanical function may require additional healing with the potential application of these biomaterials as sealants and cell/drug delivery carriers.

Topics: Animals; Annulus Fibrosus; Biocompatible Materials; Biomechanical Phenomena; Carboxymethylcellulose Sodium; Cattle; Cross-Linking Reagents; Disease Models, Animal; Diskectomy; Fibrin; Hydrogels; In Vitro Techniques; Injections, Spinal; Intervertebral Disc Displacement; Iridoids; Materials Testing; Methylcellulose; Nucleus Pulposus

Post-traumatic stress disorder (PTSD) is a condition that develops after an individual has experienced a major trauma. This psychopathological response to traumatic stressors induces learning and memory deficits in rats. Oleuropein (OLE), a major compound in olive leaves, has been reported to possess several pharmacological properties, including anti-cancer, anti-diabetic, anti-atherosclerotic and neuroprotective activities. However, the cognitive effects of OLE and its mechanism of action have remained unclear in PTSD. In this study, we examined whether OLE improved spatial cognitive impairment induced in rats following single prolonged stress (SPS), an animal model of PTSD. Male rats were treated intraperitoneally (i.p.) with vehicle or various doses of OLE for 14 consecutive days after the SPS procedure. The SPS procedure resulted in cognitive impairment in the object recognition task and the Morris water maze test, which was reversed by OLE (100 mg/kg, i.p). Additionally, as assessed by immunohistochemistry and reverse transcription-polymerase chain reaction analysis, the administration of OLE significantly alleviated memory-associated decreases in the levels of brain-derived neurotrophic factor and cAMP response element-binding protein and mRNA in the hippocampus. Together, these findings suggest that OLE attenuated SPS-induced cognitive impairment significantly by inhibiting the expression of pro-inflammatory mediators in the rat brain. Thus, OLE reversed several behavioral impairments triggered by the traumatic stress of SPS and might be a potential useful therapeutic intervention for PTSD.

Topics: Animals; Brain-Derived Neurotrophic Factor; Cognition; Cytokines; Disease Models, Animal; Hippocampus; Iridoid Glucosides; Iridoids; Male; Rats; Rats, Sprague-Dawley; Stress Disorders, Post-Traumatic; Vasodilator Agents

Topics: Animals; Biomarkers; Carbon Tetrachloride; Discriminant Analysis; Disease Models, Animal; Drugs, Chinese Herbal; Gas Chromatography-Mass Spectrometry; Humans; Iridoids; Liver; Liver Cirrhosis; Male; Medicine, Chinese Traditional; Metabolic Networks and Pathways; Metabolome; Metabolomics; Mice; Mice, Inbred C57BL; Principal Component Analysis; Protective Agents; Tandem Mass Spectrometry

Geniposide, an active component of Gardenia, has been reported to protect against cerebral ischemia in animals. Ginsenoside Rg1, a component of Panax notoginseng, is usually administered in combination with Gardenia for the treatment of acute ischemic stroke; however, there are unknown effects of ginsenoside Rg1 that require further investigation. In the present study, the effects of geniposide and ginsensoide Rg1 combination treatment on focal cerebral ischemic stroke were investigated. For in vivo analysis, male rats were separated into three groups, including the (control), model and geniposide + ginsenoside Rg1 groups (n=8 per group). A middle cerebral artery occlusion model was established as the model group. The treatment group was treated with geniposide (30 mg/kg, tail vein injection) + ginsenoside Rg1 (6 mg/kg, tail vein injection), and the model group received saline instead. Neurobehavioral deficits, infarct volume, brain edema, and the expression of microRNA (miR)‑155‑5p and CD11b by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and immunohistochemistry, were assessed following 24 h of ischemia. For in vitro analysis, BV2 mouse microglial cells were cultured and exposed to geniposide (40 µg/ml) + ginsenoside Rg1 (8 µg/ml) during various durations of oxygen‑glucose deprivation (OGD). The expression levels of miR‑155‑5p, pri‑miR‑155 and pre‑miR‑155 were detected by RT‑qPCR. The results demonstrated that increases in brain infarct volume, edema volume, CD11b‑positive cells and miR‑155‑5p levels were alleviated following geniposide + ginsenoside administration in rats exposed to ischemia. Furthermore, geniposide + ginsenoside Rg1 treatment suppressed the miR‑155‑5p, pri‑miR‑155 and pre‑miR‑155 expression levels in OGD‑injured BV2 microglial cells. The results of the present study demonstrated that tail vein administration of geniposide in combination with ginsenoside Rg1 protected against focal cerebral ischemia in rats through inhibition of microglial miR‑155‑5p following ischemic injury, which may serve as a novel therapeutic agent for the treatment of strokes.

Topics: Animals; Brain; Brain Ischemia; CD11b Antigen; Cell Hypoxia; Cells, Cultured; Disease Models, Animal; Ginsenosides; Glucose; Infarction, Middle Cerebral Artery; Iridoids; Male; Microglia; MicroRNAs; Neuroprotective Agents; Panax notoginseng; Rats; Rats, Sprague-Dawley

Both baicalin (BA) and jasminoidin (JA) are active ingredients in Chinese herb medicine Scutellaria baicalensis and Fructus gardeniae, respectively. They have been shown to exert additive neuroprotective action in ischemic stroke models. In this study we used transcriptome analysis to explore the pure therapeutic mechanisms of BA, JA and their combination (BJ) contributing to phenotype variation and reversal of pathological processes. Mice with middle cerebral artery obstruction were treated with BA, JA, their combination (BJ), or concha margaritifera (CM). Cerebral infarct volume was examined to determine the effect of these compounds on phenotype. Using the hippocampus microarray and ingenuity pathway analysis (IPA) software, we exacted the differentially expressed genes, networks, pathways, and functions in positive-phenotype groups (BA, JA and BJ) by comparing with the negative-phenotype group (CM). In the BA, JA, and BJ groups, a total of 7, 4, and 11 specific target molecules, 1, 1, and 4 networks, 51, 59, and 18 canonical pathways and 70, 53, and 64 biological functions, respectively, were identified. Pure therapeutic mechanisms of BA and JA were mainly overlapped in specific target molecules, functions and pathways, which were related to the nervous system, inflammation and immune response. The specific mechanisms of BA and JA were associated with apoptosis and cancer-related signaling and endocrine and hormone regulation, respectively. In the BJ group, novel target profiles distinct from mono-therapies were revealed, including 11 specific target molecules, 10 functions, and 10 pathways, the majority of which were related to a virus-mediated immune response. The pure additive effects between BA and JA were based on enhanced action in virus-mediated immune response. This pure mechanistic analysis may provide a clearer outline of the target profiles of multi-target compounds and combination therapies.

Topics: Animals; Apoptosis; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Flavonoids; Gene Expression Profiling; Gene Expression Regulation; Gene Regulatory Networks; Hippocampus; Immunity, Innate; Infarction, Middle Cerebral Artery; Iridoids; Male; Mice; Neuroprotective Agents; Oligonucleotide Array Sequence Analysis; Phenotype; RNA, Messenger; Signal Transduction; Systems Biology; Transcriptome

Genipin is the major active component of Gardeniae fructus and has been shown to ameliorate diabetes and insulin resistance in rat models. In this study, we first investigated the effect of genipin on obesity and the related lipid metabolism mechanisms in diet-induced obese rats. Our results showed that genipin reduced body weight, food intake, and visceral fat mass; ameliorated dyslipidemia, glucose intolerance, insulin intolerance, adipocyte hypertrophy, and hepatic steatosis; and reduced serum tumor necrosis factor-α level in diet-induced obese rats. Quantitative real-time reverse-transcription polymerase chain reaction results further illustrated that genipin promoted lipolysis and β-oxidation of fatty acid by upregulating gene expressions of hormone-sensitive lipase and adipose triglyceride lipase in white adipose tissue (WAT) and peroxisome proliferator-activated receptor-α and carnitine palmitoyltransferase 1α in hepatic tissue. Moreover, genipin promoted browning of WAT by upregulating the mRNA and protein levels of uncoupling protein 1 and PRD1-BF1-RIZ1 homologous domain containing 16 in WAT. Additionally, genipin inhibited gene expressions of activin receptor-like kinase 7, tumor necrosis factor-α, and interlukin-6 in WAT. These results indicated that genipin had a potential therapeutic role in obesity, in which regulation of lipid mobilization and browning of WAT were involved.

Topics: Adipose Tissue, White; Animals; Diet; Disease Models, Animal; Iridoids; Lipid Mobilization; Male; Obesity; Rats

Pterocephalus hookeri (C.B. Clarke) Höeck, one of the most popular Tibetan herbs, has been widely applied in Tibetan medicine prescriptions. Chemical investigations have led to the isolation of many bis-iridoids. However, the pharmacological activities of bis-iridoid constituents of this plant have never been reported before.. This study evaluated the anti-inflammatory and analgesic activities of afraction of bis-iridoid constituents of P. hookeri (BCPH) in order to provide experimental evidence for its traditional use, such as for cold, flu, and rheumatoid arthritis.. The analgesic effects of BCPH were investigated using the hot-plate test and acetic acid-induced writhing test. The anti-inflammatory activities were observed using the following models: carrageenin-induced edema of the hind paw of rats and xylene-induced ear edema in mice. The effects of dexamethasone administration were also studied.. BCPH significantly increased the hot-platepain threshold and reduced acetic acid-induced writhing response in mice. Moreover, BCPH remarkably inhibited xylene-induced ear edema and reduced the carrageenin-induced rat paw edema perimeter.. The results reveal that BCPH has central, peripheral analgesic activities as well as anti-inflammatory effects, supporting the traditional application of this herb in treating various diseases associated with inflammation and pain.

Topics: Acetic Acid; Analgesics; Animals; Anti-Inflammatory Agents; Caprifoliaceae; Carrageenan; Dexamethasone; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Female; Hot Temperature; Iridoids; Male; Mice, Inbred ICR; Nociceptive Pain; Phytotherapy; Plant Extracts; Plants, Medicinal; Rats, Sprague-Dawley; Xylenes

Altered proteostasis induced by amyloid peptide aggregation and hyperphosphorylation of tau protein, is a prominent feature of Alzheimer's disease, which highlights the occurrence of endoplasmic reticulum stress and triggers the activation of the unfolded protein response (UPR), a signaling pathway that enforces adaptive programs to sustain proteostasis. In this study, we investigated the role of geniposide in the activation of UPR induced by high glucose in primary cortical neurons. We found that high glucose induced a significant activation of UPR, and geniposide enhanced the effect of high glucose on the phosphorylation of IRE1α, the most conserved UPR signaling branch. We observed that geniposide induced the expression of HRD1, an ubiquitin-ligase E3 in a time dependent manner, and amplified the expression of HRD1 induced by high glucose in primary cortical neurons. Suppression of IRE1α activity with STF-083010, an inhibitor of IRE1 phosphorylation, prevented the roles of geniposide on the expression of HRD1 and APP degradation in high glucose-treated cortical neurons. In addition, the results from RNA interfere on HRD1 revealed that HRD1 was involved in geniposide regulating APP degradation in cortical neurons. These data suggest that geniposide might be benefit to re-establish proteostasis by enhancing the UPR to decrease the load of APP in neurons challenged by high glucose.

Topics: Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Disease Models, Animal; Endoplasmic Reticulum Stress; Iridoids; Neurons; Rats, Sprague-Dawley; Signal Transduction; Ubiquitin-Protein Ligases; Unfolded Protein Response

Synthetic antidepressants in current use for the complex etiopathogeneses of depression have slow response and remission as well as various unpleasant side effects. As a result, it is imperative to develop new antidepressants with more effectiveness and less severe side effects. Recent studies demonstrated that genipin, the aglycon of geniposide, extracted from Gardenia jasminoides Ellis has antidepressive effects. However, knowledge regarding the molecular mechanisms of its antidepressant effects remains limited. Employing a depression-like mouse model, we confirmed that genipin is capable of correcting depressions-like behaviors induced by prenatal stress in offspring from prenatally stressed dams (defined as PRS mice). In further experiments, we found that the effect of genipin on PRS mice occurs through DNA demethylation by inhibiting DNA methyltransferase 1 (DNMT1), normalizing the expression of reduced brain-derived neurotrophic factor (BDNF) in the hippocampus.

Topics: Animals; Antidepressive Agents; Brain-Derived Neurotrophic Factor; Depression; Disease Models, Animal; DNA (Cytosine-5-)-Methyltransferase 1; DNA Methylation; Female; Gardenia; Gene Expression Regulation; Hippocampus; Humans; Iridoids; Mice; Pregnancy; Prenatal Exposure Delayed Effects; Stress, Psychological

Myopia progression is thought to involve biomechanical weakening of the sclera, which leads to irreversible deformations and axial elongation of the eye. Scleral crosslinking has been proposed as a potential treatment option for myopia control by strengthening the mechanically weakened sclera. The biomechanical mechanism by which the sclera weakens during myopia and strengthens after crosslinking is not fully understood. Here, we assess the effect of lens-induced myopia and exogenous crosslinking using genipin on the inelastic mechanical properties of the tree shrew sclera measured by cyclic tensile tests.. Cyclic tensile tests were performed on 2-mm wide scleral strips at physiological loading conditions (50 cycles, 0-3.3 g, 30 s cycle. -5D lens treatment significantly increased the cyclic softening response of the sclera when compared to contralateral control eyes (0.10% ± 0.029%, mean ± standard error, P = 0.037). Exogenous crosslinking of the lens treated sclera significantly decreased the cyclic softening response (-0.12% ± 0.014%, P = 2.2 × 10. Results indicated that cyclic tensile loading leads to an inelastic, cyclic softening of the juvenile tree shrew sclera. The softening rate increased during lens-induced myopia and was diminished after genipin crosslinking. This finding suggests that axial elongation in myopia may involve a biomechanical weakening mechanism that increased the cyclic softening response of the sclera, which was inhibited by scleral crosslinking using genipin.

Topics: Adhesives; Animals; Biomechanical Phenomena; Cross-Linking Reagents; Disease Models, Animal; Disease Progression; Iridoids; Myopia; Refraction, Ocular; Sclera; Tensile Strength; Tupaiidae

Topics: Animals; Anti-Inflammatory Agents; Arthritis, Experimental; Chromatography, High Pressure Liquid; Dialysis Solutions; Dinoprostone; Disease Models, Animal; Iridoids; Knee Joint; Male; Microdialysis; Rats; Tandem Mass Spectrometry; Treatment Outcome

Hepatotoxicity induced by cyclophosphamide (Cyclo) is a major concern in clinical practice. This study was designed to investigate the possible cytoprotective effect of natural antioxidants as oleuropein and quercetin against Cyclo induced hepatotoxicity via the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway. Male Wistar rats were randomly divided into six groups and treated for 10 days as follow: Group I (Normal control) received saline, group II (Oleu control): received orally oleuropein 30 mg/kg/day, group III (Quer control): administered orally quercetin 50 mg/kg/day, group IV (Cyclo): received saline and injected with single intraperitoneal (i.p) dose of Cyclo 200 mg/kg at day 5, group V (Oleu ttt): treated with oleuropein plus Cyclo i.p. injection at day 5, and group VI (Quer ttt): treated with quercetin plus Cyclo i.p. injection at day 5. Injection of Cyclo showed marked increase in serum transaminases and alkaline phosphatase, hepatic malondialdehyde (MDA) and tumor necrosis factor-alpha (TNF-⍺) levels along with significant reduction in hepatic reduced glutathione (GSH), superoxide dismutase (SOD), and catalase levels in addition to downregulation of hepatic Nrf2 and HO-1 expressions and reduction in hepatic nuclear Nrf2 binding activity when compared with normal group. Histopathological examination of Cyclo treated rats revealed hepatic damage. Both oleuropein and quercetin exhibited an improvement in the biochemical and histopathological findings. In conclusion, the natural antioxidants oleuropein and quercetin counteract the Cyclo induced hepatotoxicity through activation of Nrf2/HO-1 signaling pathway with subsequent suppression of oxidative stress and inflammation.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Biological Products; Chemical and Drug Induced Liver Injury; Cyclophosphamide; Disease Models, Animal; Heme Oxygenase-1; Humans; Iridoid Glucosides; Iridoids; Liver; Male; NF-E2-Related Factor 2; Oxidative Stress; Quercetin; Rats; Rats, Wistar; Signal Transduction

Recent evidence demonstrates that a double dose of Jasminoidin (2·JA) is more effective than Jasminoidin (JA) in cerebral ischemia therapy, but its dosage-effect mechanisms are unclear. In this study, the software GeneGo MetaCore was used to perform pathway analysis of the differentially expressed genes obtained in microarrays of mice belonging to four groups (Sham, Vehicle, JA, and 2·JA), aiming to elucidate differences in JA and 2·JA's dose-dependent pharmacological mechanism from a system's perspective. The top 10 enriched pathways in the 2·JA condition were mainly involved in neuroprotection (70% of the pathways), apoptosis and survival (40%), and anti-inflammation (20%), while JA induced pathways were mainly involved in apoptosis and survival (60%), anti-inflammation (20%), and lipid metabolism (20%). Regarding shared pathways and processes, 3, 1, and 3 pathways overlapped between the Vehicle and JA, Vehicle and 2·JA, and JA and 2·JA conditions, respectively; for the top ten overlapped processes these numbers were 3, 0, and 4, respectively. The common pathways and processes in the 2·JA condition included differentially expressed genes significantly different from those in JA. Seven representative pathways were only activated by 2·JA, such as

Topics: Animals; Cerebrovascular Disorders; Disease Models, Animal; Dose-Response Relationship, Drug; Gene Expression Profiling; Gene Expression Regulation; Humans; Iridoids; Male; Mice; Reperfusion Injury

BACKGROUND In this study, we investigated the potential neuroprotective effect of oleuropein (OLE) on apoptotic changes via modulating Akt/glycogen synthase kinase 3 beta (Akt/GSK-3b) signaling in a rat model of cerebral ischemia/reperfusion injury (IRI). MATERIAL AND METHODS Sprague-Dawley male rats (12 weeks, n=200) were randomly assigned to 5 groups: sham group, vehicle (IRI+ vehicle) group, OLE (IRI+OLE) group, OLE+LY294002 (IRI+OLE+LY294002) group, and LY294002(IRI+LY294002) group. The rats were subjected to cerebral ischemia/reperfusion injury (IRI) model and treated once daily for 5 days with vehicle and OLE (100 mg/kg via intraperitoneal injection) after IRI injury. LY294002 (0.3 mg/kg) was intraperitoneally injected once at 30 min after IRI injury. Brain edema, neurological deficit, rotarod latencies, and Morris water maze (MWM) performance were evaluated after IRI. The number of dead cells were assayed by TUNEL staining. Western blot was used to detect the expression of Bcl-2, Bax, cleaved caspase-3 (CC3), neurotrophic factors, and the phosphorylation levels of Akt and GSK-3β. RESULTS Compared with the vehicle group, brain water content, neurological deficits, rotarod latencies, and escape latency following IRI were reduced in the OLE group. Cell apoptosis and reduced neurotrophic factor caused by IRI was also attenuated by OLE. Furthermore, increased p-Akt and decreased p-GSK-3β were caused by OLE, which were associated with decrease of Bax/Bcl-2 ratio and the suppression of Caspase-3 activity after IRI. Importantly, all the beneficial effects of OLE in the vehicle group were abrogated by PI3K inhibitor LY294002. CONCLUSIONS Cerebral ischemia was protected by OLE via suppressing apoptosis through the Akt/GSK-3β pathway and upregulating neurotrophic factor after IRI.

Topics: Animals; Apoptosis; Brain; Brain Ischemia; Disease Models, Animal; Glycogen Synthase Kinase 3 beta; Infarction, Middle Cerebral Artery; Iridoid Glucosides; Iridoids; Male; Neurons; Neuroprotective Agents; Oncogene Protein v-akt; Phosphatidylinositol 3-Kinases; Phosphorylation; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Signal Transduction

Aging represents a major risk factor for developing neurodegenerative diseases such as Alzheimer's disease (AD). As components of the Mediterranean diet, olive polyphenols may play a crucial role in the prevention of AD. Since mitochondrial dysfunction acts as a final pathway in both brain aging and AD, respectively, the effects of a mixture of highly purified olive secoiridoids were tested on cognition and ATP levels in a commonly used mouse model for brain aging. Over 6 months, female NMRI mice (12 months of age) were fed with a blend containing highly purified olive secoiridoids (POS) including oleuropein, hydroxytyrosol and oleurosid standardized for 50 mg oleuropein/kg diet (equivalent to 13.75 mg POS/kg b.w.) or the study diet without POS as control. Mice aged 3 months served as young controls. Behavioral tests showed deficits in cognition in aged mice. Levels of ATP and mRNA levels of NADH-reductase, cytochrome-c-oxidase, and citrate synthase were significantly reduced in the brains of aged mice indicating mitochondrial dysfunction. Moreover, gene expression of Sirt1, CREB, Gap43, and GPx-1 was significantly reduced in the brain tissue of aged mice. POS-fed mice showed improved spatial working memory. Furthermore, POS restored brain ATP levels in aged mice which were significantly increased. Our results show that a diet rich in purified olive polyphenols has positive long-term effects on cognition and energy metabolism in the brain of aged mice.

Topics: Adenosine Triphosphate; Aging; Animals; Brain; Cognition; Disease Models, Animal; Female; Humans; Iridoids; Mice; Neuroblastoma; Olea; Tumor Cells, Cultured

Oleuropein mediates most of the beneficial effects of olive products. This study examined the role of oxidative stress in the effects of oleuropein on lipid profile and blood glucose in rats with simultaneous renovascular hypertension and type 2 diabetes. Eight groups (n = 7-9 each) of male Sprague-Dawley rats including a control, a type 2 diabetic, a renovascular hypertensive, a sham, a simultaneously hypertensive diabetic receiving vehicle, and 3 simultaneously hypertensive-diabetic receiving 20, 40, or 60 mg/kg/day oleuropein were used. Four weeks after treatment, blood glucose, lipid profile, and biomarkers of oxidative stress were measured, and glucose tolerance test (GTT) was performed. Simultaneously hypertensive diabetic rats had significantly higher blood pressure, blood glucose, and serum total cholesterol, low-density lipoprotein cholesterol (LDL-C), triglyceride and malondialdehyde. They also had lower serum high-density lipoprotein cholesterol, erythrocyte superoxide dismutase, and impaired glucose tolerance. Oleuropein significantly reduced blood pressure, blood glucose, and serum total cholesterol, LDL-C, triglyceride and malondoaldehyde. It also increased serum high-density lipoprotein cholesterol, erythrocyte superoxide dismutase, and improved glucose tolerance. The findings show that the model is associated with impaired glucose tolerance, and adverse lipid profile. They also show that oleuropein, partly by an antioxidant mechanism, improves glucose tolerance and changed lipid profile favorably.

Topics: Animals; Antioxidants; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Disease Models, Animal; Glucose Tolerance Test; Hypertension, Renal; Hypertension, Renovascular; Iridoid Glucosides; Iridoids; Lipids; Male; Malondialdehyde; Molecular Structure; Oxidative Stress; Rats; Rats, Sprague-Dawley; Streptozocin; Superoxide Dismutase

Beneficial effects of the Chinese herbal medicine Qushi Huayu Decoction (QHD) were observed with non-alcoholic fatty liver disease (NAFLD) patients and animal models. The impact of QHD or its active components (geniposide and chlorogenic acid, GC) on NAFLD liver transcriptome and gut microbiota was examined with NAFLD rats. Increased expression for genes required for glutathione production and decreased expression for genes required for lipid synthesis was observed in NAFLD livers treated with QHD and GC. GC treatment decreased serum LPS, which could be explained by reduced mucosal damage in the colon of GC-treated rats. Further, our data suggest an increased abundance of Treg-inducing bacteria that stimulated the Treg activity in GC treated colon, which in turn down-regulated inflammatory signals, improved gut barrier function and consequently reduced hepatic exposure to microbial products. Our study suggests that QHD simultaneously enhanced the hepatic anti-oxidative mechanism, decreased hepatic lipid synthesis, and promoted the regulatory T cell inducing microbiota in the gut.

Topics: Animals; Chlorogenic Acid; Colon; Disease Models, Animal; Down-Regulation; Drugs, Chinese Herbal; Gastrointestinal Microbiome; Glutathione; Humans; Intestinal Mucosa; Iridoids; Lipid Metabolism; Lipopolysaccharides; Liver; Male; Mice; Mice, Inbred C57BL; Molecular Targeted Therapy; Non-alcoholic Fatty Liver Disease; Rats; Rats, Sprague-Dawley; Signal Transduction; T-Lymphocytes, Regulatory; Transcriptome

This study aimed to investigate the pure pharmacological mechanisms of baicalin/baicalein (BA) in the targeted network of mouse cerebral ischemia using a poly-dimensional network comparative analysis.. Eighty mice with induced focal cerebral ischemia were randomly divided into four groups: BA, Concha Margaritifera (CM), vehicle and sham group. A poly-dimensional comparative analysis of the expression levels of 374 stroke-related genes in each of the four groups was performed using MetaCore.. BA significantly reduced the ischemic infarct volume (P<0.05), whereas CM was ineffective. Two processes and 10 network nodes were shared between "BA vs CM" and vehicle, but there were no overlapping pathways. Two pathways, three processes and 12 network nodes overlapped in "BA vs CM" and BA. The pure pharmacological mechanism of BA resulted in targeting of pathways related to development, G-protein signaling, apoptosis, signal transduction and immunity. The biological processes affected by BA were primarily found to correlate with apoptotic, anti-apoptotic and neurophysiological processes. Three network nodes changed from up-regulation to down-regulation, while mitogen-activated protein kinase kinase 6 (MAP2K6, also known as MEK6) changed from down-regulation to up-regulation in "BA vs CM" and vehicle. The changed nodes were all related to cell death and development.. The pure pharmacological mechanism of BA is related to immunity, apoptosis, development, cytoskeletal remodeling, transduction and neurophysiology, as ascertained using a poly-dimensional network comparative analysis.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cerebral Infarction; Disease Models, Animal; Down-Regulation; Drugs, Chinese Herbal; Flavonoids; Gene Expression Profiling; Iridoids; Mice; Reperfusion Injury; Signal Transduction

Oleuropein (OLE) is a natural secoiridoid that is derived from Olea europaea. OLE possesses cardioprotective effects in experimental models of hypertension, myocardial infarction, atherosclerosis and hyperlipidaemia. In the present study, the effects of OLE on experimental autoimmune myocarditis (EAM) were evaluated. EAM in rats were induced by subcutaneous injections of porcine cardiac myosin. Cardiac function parameters, myocardial pathology, myocardial inflammatory cell infiltration and nuclear factor kappa-B (NF-κB) expression were measured. Our data showed that the postmyocarditis rats exhibited increased left ventricular end systolic diameters, left ventricular end diastolic diameters, left ventricular end-diastolic pressures (LVEDP), and decreased ejection fractions. However, OLE significantly suppressed these changes in EAM rats. Histological analysis revealed that myosin induced miliary foci of discolouration on endocardial surfaces and extensive myocardial injuries with inflammatory cell infiltration were significantly improved by OLE therapy. A definitive positive correlation between the histological scores and LVEDP was observed. Moreover, OLE inhibited CD4

Topics: Animals; Autoimmune Diseases; Cardiac Myosins; Cardiotonic Agents; Cytokines; Disease Models, Animal; Iridoid Glucosides; Iridoids; Male; Mitogen-Activated Protein Kinases; Myocarditis; Myocardium; NF-kappa B; Rats, Inbred Lew; Signal Transduction; T-Lymphocytes; Ventricular Function, Left

Ulcerative colitis (UC), an idiopathic inflammatory bowel disease, not only affects millions of patients worldwide, but also increases the risk of colon cancer. Geniposide is an iridoid glycoside and has many biological activities such as anti-inflammatory and antioxidant. However, its protective efficacy and mechanism of action against UC are still unclear. In this study, we aimed to investigate the protective effects and mechanisms of geniposide on dextran sulfate sodium (DSS)-induced experimental colitis in mice. The results revealed that geniposide alleviated body weight loss, disease activity index, colon length shortening and colonic pathological damage induced by DSS. Geniposide significantly suppressed pro-inflammatory cytokines by regulating NF-κB and PPARγ pathways in vivo and in vitro. Furthermore, geniposide also significantly regulated the expressions of ZO-1 and occludin in DSS-induced experimental colitis in mice and lipopolysaccharide (LPS)-triggered inflammation in Caco-2 cells. These findings indicated that geniposide may be a new natural chemopreventive agent to combat UC.

Topics: Animals; Anti-Inflammatory Agents; Caco-2 Cells; Colitis; Colitis, Ulcerative; Colon; Cytokines; Dextran Sulfate; Disease Models, Animal; Humans; Inflammation; Inflammation Mediators; Intestinal Mucosa; Iridoids; Male; Mice; Mice, Inbred C57BL; NF-kappa B; PPAR gamma; Signal Transduction

Fructus Gardenia (FG), containing the major active constituent Geniposide, is widely used in China for medicinal purposes. Currently, clinical reports of FG toxicity have not been published, however, animal studies have shown FG or Geniposide can cause hepatotoxicity in rats. We investigated Geniposide-induced hepatic injury in male Sprague-Dawley rats after 3-day intragastric administration of 100 mg/kg or 300 mg/kg Geniposide. Changes in hepatic histomorphology, serum liver enzyme, serum and hepatic bile acid profiles, and hepatic bile acid synthesis and transportation gene expression were measured. The 300 mg/kg Geniposide caused liver injury evidenced by pathological changes and increases in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and γ-glutamytransferase (γ-GT). While liver, but not sera, total bile acids (TBAs) were increased 75% by this dose, dominated by increases in taurine-conjugated bile acids (t-CBAs). The 300 mg/kg Geniposide also down-regulated expression of Farnesoid X receptor (FXR), small heterodimer partner (SHP) and bile salt export pump (BSEP). In conclusion, 300 mg/kg Geniposide can induce liver injury with associated changes in bile acid regulating genes, leading to an accumulation of taurine conjugates in the rat liver. Taurocholic acid (TCA), taurochenodeoxycholic acid (TCDCA) as well as tauro-α-muricholic acid (T-α-MCA) are potential markers for Geniposide-induced hepatic damage.

Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Aspartate Aminotransferases; ATP Binding Cassette Transporter, Subfamily B, Member 11; Bile Acids and Salts; Biomarkers; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Early Diagnosis; gamma-Glutamyltransferase; Gene Expression Regulation; Iridoids; Male; Rats; Rats, Sprague-Dawley; Receptors, Cytoplasmic and Nuclear

The purpose of this study was the evaluation of the antioxidant activity of natural and semisynthetic polyphenol derivatives from Olea europea L., by assessing malondialdehyde (MDA), an important marker of oxidative stress.. Polyphenol as hydroxytyrosol, oleuropein, oleuropein aglycone as mix of four tautomeric forms and their respective acetyl-derivatives were obtained from olive leaves using semisynthetic protocols. These compounds were administered intraperitoneally to Wistar rats treated with paraquat, an herbicide which is able to cause oxidative stress after central administration. Malondialdehyde was derivatized with 2,4-dinitrophenylhydrazine to produce hydrazone that was purified by solid-phase extraction. Using high-performance liquid chromatography coupled with a diode array, free and total MDA was measured on homogenate rat brain as marker of lipid peroxidation. The analytical method was fully validated and showed linearity in the tested concentration range, with detection limit of 5 ng/ml. Recovery ranged from 94.1 to 105.8%.. Both natural and semisynthetic polyphenol derivatives from a natural source as olive leaves were able to reduce MDA detection. The more lipophilic acetyl-derivatives showed an antioxidant activity greater than parent compounds. This potency seems to put in evidence a strict correlation between lipophilicity and bioavailability.

Topics: Animals; Antioxidants; Brain; Chromatography, High Pressure Liquid; Disease Models, Animal; Iridoid Glucosides; Iridoids; Limit of Detection; Lipid Peroxidation; Male; Malondialdehyde; Olea; Oxidative Stress; Plant Extracts; Plant Leaves; Polyphenols; Rats; Rats, Wistar

Genipin is a natural compound isolated from the fruit of Gardenia jasminoides with various pharmacological effects. In this study, we investigated whether genipin effectively alleviates allergic responses in a murine model of ovalbumin (OVA)-induced asthma. The mice were administered an intraperitoneal injection of OVA on day 0 and 14 to boost the immune response; genipin was then administered from day 18 to 23 by oral gavage. On days 21 to 23, mice were OVA-challenged using am ultrasonic nebulizer, and airway hyperresponsiveness (AHR) was determined on day 24 by plethysmography. Genipin significantly reduced the inflammatory cell count in bronchoalveolar lavage fluids (BALF) and AHR, which were accompanied by lower interleukin-5 (IL-5), IL-13 and OVA-specific immunoglobulin (Ig) E levels in the BALF or serum from OVA-induced asthmatic mice. In histology, genipin significantly decreased airway inflammation and mucus hypersecretion in OVA-induced asthmatic mice. Additionally, genipin inhibited OVA-induced increases in the expression of inducible nitric oxide synthase and cyclooxygenase-2 proteins. Further, genipin reduced the activity and protein levels of matrix metalloproteinase-9 in lung tissue from OVA induced asthmatic mice. Overall, genipin effectively alleviated the asthmatic inflammatory response in an OVA-induced asthmatic model. Therefore, our results suggest that genipin has therapeutic potential for treating asthma.

Topics: Animals; Anti-Inflammatory Agents; Asthma; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Female; Gardenia; Hypersensitivity; Immunoglobulin E; Inflammation; Interleukin-13; Interleukin-5; Iridoids; Lung; Matrix Metalloproteinase 9; Mice; Mice, Inbred BALB C; Nitric Oxide Synthase Type II; Ovalbumin

Intracerebral haemorrhage (ICH) as a devastating form of stroke has remained a public health threat due to lack of FDA-approved therapy. Oxidative stress originated from blood cell degradation products plays a crucial role in the ICH pathogenesis. In this study we evaluated oleuropein, a potent natural antioxidant from olive, in a well-established rat ICH model from overall symptoms to detailed molecular mechanism.. ICH model was established by collagenase injection to the brain of rats, which were randomly divided into groups with vehicle mock treatment, followed by treatment with different doses of oleuropein via daily intraperitoneal injection post-ICH for 3days. The overall neurological deficit, brain edema level and blood-brain barrier (BBB) integrity were then measured in different treatment groups. To understand the protection mechanism of oleuropein in ICH, BBB structural components ZO-1 and occludin, oxidative stress and MAPK signalling pathways were also examined.. Oleuropein treatment showed overall alleviation of ICH-associated neurological deficit and brain edema in a dose dependent manner. Consistently, it could preserve the BBB structure and attenuate oxidative stress as well as ICH-induced MAPK activation in brain tissue.. Our study suggests oleuropein could be used as a promising therapeutic agent for ICH.

Topics: Animals; Antioxidants; Blood-Brain Barrier; Brain Edema; Cerebral Hemorrhage; Disease Models, Animal; Dose-Response Relationship, Drug; Injections, Intraperitoneal; Iridoid Glucosides; Iridoids; Male; MAP Kinase Signaling System; Oxidative Stress; Rats; Rats, Sprague-Dawley; Stroke

Herbal extracts have been extensively used worldwide for their application on memory improvement, especially among aged and memory-deficit populations. In the present study, the memory loss induced by human Abeta protein over-expression in fruitfly Alzheimer's disease (AD) model was rescued by multiple extracts from Gardenia jasminoides. Three extracts that rich with gardenia yellow, geniposide, and gardenoside components showed distinct rescue effect on memory loss. Further investigation on adding gardenoside into a formula of Ganoderma lucidum, Panax notoginseng and Panax ginseng (GPP) also support its therapeutic effects on memory improvement. Interestingly, the application of GPP and gardenoside did not alter the accumulation of Abeta proteins but suppressed the expression of immune-related genes in the brain. These results revealed the importance and relevancy of anti-inflammation process and the underlying mechanisms on rescuing memory deficits, suggesting the potential therapeutic use of the improved GPP formulation in improving cognition in defined population in the future.

Topics: Alzheimer Disease; Animals; Antimicrobial Cationic Peptides; Brain; Cognition; Disease Models, Animal; Drosophila; Drosophila Proteins; Gardenia; Gene Expression Regulation; Immunity, Innate; Iridoids; Plant Extracts; Polymerase Chain Reaction

Amarogentin has been reported to have a preventive effect on liver cancer via inducing cancer cell apoptosis. We attempted to elucidate the roles of p53-associated apoptosis pathways in the chemopreventive mechanism of amarogentin. The findings of this study will facilitate the development of a novel supplementary strategy for the treatment of liver cancer.. The purity of amarogentin was assessed by high-performance liquid chromatography. The inhibitory ratios of the liver cell lines were determined using a Cell Counting Kit-8 following treatment with a gradient concentration of amarogentin. Cell apoptosis was detected by flow cytometry using annexin V-fluorescein isothiocyanate/propidium iodide kits. The gene and protein expression of p53-associated molecules, such as Akt, human telomerase reverse transcriptase, RelA, and p38, was detected by real-time quantitative polymerase chain reaction, Western blotting, and immunohistochemical staining in liver cancer cells and mouse tumor tissues after treatment with amarogentin.. The inhibitory effect of amarogentin on cell proliferation was more obvious in liver cancer cells, and amarogentin was more likely to induce the apoptosis of liver cancer cells than that of normal liver cells. The gene and protein expression levels of Akt, RelA, and human telomerase reverse transcriptase were markedly higher in the control group than in the preventive group and treatment groups. Only the expression of human telomerase reverse transcriptase was downregulated, accompanied by the upregulation of p53.. The results of our study suggest that amarogentin promotes apoptosis of liver cancer cells by the upregulation of p53 and downregulation of human telomerase reverse transcriptase and prevents the malignant transformation of these cells.

Topics: Animals; Apoptosis; Cell Line, Tumor; Cell Movement; Cell Proliferation; Disease Models, Animal; Gene Expression Regulation, Neoplastic; Humans; Iridoids; Liver Neoplasms; Male; Mice; Signal Transduction; Telomerase; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays

The therapeutic effect on HCl/ethanol induced gastric injury of Gardenia jasminoides (JXGJ-1 and JXGJ-2) were determined by a animal model. JXGJ-2 group reduced area of its gastric injury as compared to the control group, JXGJ-2 also helped in decreasing the gastric secretion volume results raised in pH value. The NO contents in serum, heart, liver, kidney and stomach of JXGJ-2 group were more than JXGJ-1 and control groups. JXGJ-2 reduce cytokine levels as compared to JXGJ-1 and control group. The serum and gastric tissue SOD, GSH-Px, GSH levels in JXGJ-2 treated mice were higher than JXGJ-1 treated and control mice, but the MDA, PC levels showed the crosscurrents, these levels were close to normal mice. Gardenia jasminoides could increase the occludin, EGF, EGFR, VEGF, IκB-α, nNOS, eNOS, Cu/Zn-SOD, Mn-SOD, CAT, GSH-Px (GSH1) mRNA and protein expressions and decrease the p38MAPK (p38), NF-κB, Bcl-2, COX-2, iNOS expressions in gastric tissues unlike to the control mice, JXGJ-2 had much better effect than JXGJ-1. JXGJ-1contained the higher genipin gentiobioside and gardenoside, they might be the key components of gastric injury inhibition. Gardenia jasminoides had a remarkable effect on gastric injury, and they were derived from two important components of genipin gentiobioside and gardenoside.

Topics: Animals; Antioxidants; Disease Models, Animal; Drugs, Chinese Herbal; Ethanol; Gardenia; Hydrochloric Acid; Iridoids; Male; Mice; Stomach; Stomach Diseases

Much of the beneficial effects of olive products have been attributed to oleuropein. This study examined the effects of oleuropein in rats with heart failure induced by permanent ligation of left coronary arteries. Twenty-four hours after the operation, the rats were assigned to five groups including a sham assigned to receive vehicle (1 ml/day) and four coronary ligated groups assigned to receive vehicle or oleuropein at 5, 10, or 20 mg/kg/day. Five weeks later, echocardiographic and hemodynamic parameters, serum concentrations of oxidative stress, and inflammatory markers were determined. Myocardial infarction group receiving vehicle showed impaired hemodynamic and echocardiographic parameters as evidenced by decreased left ventricular systolic pressure, rate of rise and decrease of left ventricular pressure, stroke volume, ejection fraction, and cardiac output. In addition, significant reduction in superoxide dismutase and glutathione reductase was observed. Oleuropein treatment prevented the reduction of these variables. Moreover, the group had a significantly higher infarct size and serum malondialdehyde, interleukin-1β, and tumor necrosis factor-α than those of the sham group. Treatment with oleuropein prevented the increase of these variables. The results show that oleuropein attenuates the progression of heart failure, possibly by antioxidative and antiinflammatory effects.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Biomarkers; Disease Models, Animal; Disease Progression; Glutathione Reductase; Heart Failure; Hemodynamics; Inflammation Mediators; Interleukin-1beta; Iridoid Glucosides; Iridoids; Male; Malondialdehyde; Myocardial Infarction; Oxidative Stress; Rats, Sprague-Dawley; Superoxide Dismutase; Tumor Necrosis Factor-alpha; Ventricular Function, Left

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory deficits and cognitive decline. Amyloid-β (Aβ) deposition and cholinergic defect are widely thought to be the underlying mechanism of learning and memory impairment. Geniposide, which is the main active component of the traditional Chinese herbal Gardenia jasminoides Ellis, elicits neuroprotective effects by alleviating inflammation responses and oxidative damages. In this study, we investigated the protective effect of geniposide on levels of cholinergic markers, RAGE, RAGE-dependent signalling pathways and amyloid accumulation in the APPswe/PS1dE9 AD model mouse. Geniposide suppressed MAPK signaling over-activation mediated by Aβ-RAGE interaction, resulting in reduced Aβ accumulation and amelioration of cholinergic deficits in the cerebral hippocampus. Furthermore, geniposide inhibited the toxic effect of oligomeric Aβ

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloidosis; Animals; Brain; Cognition Disorders; Disease Models, Animal; Dose-Response Relationship, Drug; Iridoids; Male; MAP Kinase Signaling System; Memory Disorders; Mice, Inbred C57BL; Mice, Transgenic; Neurons; Neuroprotective Agents; Nootropic Agents; Peptide Fragments; Receptor for Advanced Glycation End Products

Degenerative disc disease, associated with discrete structural changes in the peripheral annulus and vertebral endplate, is one of the most common pathological triggers of acute and chronic low back pain, significantly depreciating an individual's quality of life and instigating huge socioeconomic costs. Novel emerging therapeutic techniques are hence of great interest to both research and clinical communities alike. Exogenous crosslinking, such as Genipin, and platelet-rich plasma therapies have been recently demonstrated encouraging results for the repair and regeneration of degenerated discs, but there remains a knowledge gap regarding the quantitative degree of effectiveness and particular influence on the mechanical properties of the disc. This study aimed to investigate and quantify the material properties of intact (N = 8), trypsin-denatured (N = 8), Genipin-treated (N = 8), and platelet-rich plasma-treated (N = 8) discs in 32 porcine thoracic motion segments. A poroelastic finite element model was used to describe the mechanical properties during different treatments, while a meta-model analytical approach was used in combination with ex vivo experiments to extract the poroelastic material properties. The results revealed that both Genipin and platelet-rich plasma are able to recover the mechanical properties of denatured discs, thereby affording promising therapeutic modalities. However, platelet-rich plasma-treated discs fared slightly, but not significantly, better than Genipin in terms of recovering the glycosaminoglycans content, an essential building block for healthy discs. In addition to investigating these particular degenerative disc disease therapies, this study provides a systematic methodology for quantifying the detailed poroelastic mechanical properties of intervertebral disc.

Topics: Animals; Biomechanical Phenomena; Computer Simulation; Cross-Linking Reagents; Disease Models, Animal; Elasticity; Finite Element Analysis; Humans; In Vitro Techniques; Intervertebral Disc Degeneration; Iridoids; Models, Biological; Platelet-Rich Plasma; Regenerative Medicine; Sus scrofa

Oleuropein, a well-known olive polyphenol, has been shown to mediate neuroprotection in Alzheimer's disease and cerebral ischemia. We investigated the effects of oleuropein on pentylenetetrazole (PTZ)-induced seizures in male NMRI mice, with diazepam as the standard drug. We also examined the possible involvement of opioidergic/nitrergic pathways in the probable effects of oleuropein. Intraperitoneal (i.p.) administration of different doses of oleuropein (10, 20 and 30 mg/kg) significantly increased the seizure threshold 60 min prior to induction of seizure, in a dose-dependent manner. Administration of naltrexone (10 mg/kg, i.p.), an opioid receptor antagonist, completely reversed the anticonvulsant effects of oleuropein (10 mg/kg). On the other hand, the anticonvulsant effect of oleuropein (10 mg/kg) was blocked by a non-effective dose of nonspecific inhibitor of nitric oxide synthase (NOS), L-NAME (1 and 10 mg/kg, i.p) and a selective inhibitor of neuronal NOS, 7-nitroindazole (30 mg/kg, i.p.). However, the nitric oxide precursor, L-arginine (30 and 60 mg/kg, i.p.) potentiated the anticonvulsant activity of oleuropein (10 mg/kg). A selective inducible NOS inhibitor, aminoguanidine (100 mg/kg, i.p.) did not change the anticonvulsant activity of oleuropein. It seems that the opioidergic system and constitutive neuronal NOS may be involved in the anticonvulsant properties of oleuropein.

Topics: Animals; Biological Products; Disease Models, Animal; Dose-Response Relationship, Drug; Iridoid Glucosides; Iridoids; Male; Mice; Olea; Pentylenetetrazole; Seizures

Stimulating fibroblast-like synoviocyte (FLS) apoptosis in rheumatoid arthritis (RA) is a promising strategy for clinical treatment. Previous studies have confirmed that geniposide shows a certain anti-arthritic effect in vivo. However, whether geniposide can induce RA FLS apoptosis and the underlying mechanisms has not been elucidated. Herein, adjuvant-induced arthritis (AIA) in rat was induced and FLS was isolated from synovial tissues by tissue explant cultivation method. MTT assay, Hoechst staining, and flow cytometric apoptosis assay were applied to evaluate apoptotic effect of geniposide on AIA FLS. Bcl-2, Bax, and caspase 3 messenger RNA (mRNA) levels, and extracellular-signal-regulated kinases (ERKs) and phosphorylated ERK protein levels were examined by real-time PCR and western blot, respectively. We found that geniposide dose-dependently inhibited AIA FLS proliferation in vitro. AIA FLS treated with geniposide displayed typical apoptotic morphological characteristics including nuclear shrinkage and chromatin condensation. Flow cytometric apoptosis assay indicated that geniposide significantly increased the apoptosis rate of AIA FLS. Additionally, geniposide treatment on AIA FLS decreased Bcl-2 mRNA level and increased Bax and caspase 3 mRNA levels, accompanied by reduced protein levels of phosphorylated-ERK1/2, without affecting total ERK1/2. In conclusion, geniposide effectively induces AIA FLS apoptosis through regulating the apoptosis-related gene expressions and inhibiting ERK signal pathway.

Topics: Animals; Apoptosis; Arthritis, Experimental; Arthritis, Rheumatoid; bcl-2-Associated X Protein; Caspase 3; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Fibroblasts; Flow Cytometry; Iridoids; Male; Phosphorylation; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; RNA, Messenger; Synovial Membrane

Our previous studies have shown that geniposide plays an essential role in glucose-stimulated insulin secretion from pancreatic β cells and also regulates the metabolism of Aβ and its deposition in neurons. In this study, we reported that insulin deficiency induced significant increase of tau phosphorylation. Administration of geniposide for 4 weeks significantly decreased the phosphorylated level of tau and the acceleration of GSK-3β phosphorylation in the brain of APP/PS1 transgenic mice induced by insulin deficiency. We also observed that geniposide decreased the phosphorylation of tau protein directly and increased the phosphorylation of Akt in primary cultured cortical neurons. Furthermore, geniposide enhanced the role of insulin on the phosphorylation of Akt, GSK-3β, and tau in primary cultured cortical neurons. And these effects of geniposide in cortical neurons could be prevented by preincubation with LY294002, an inhibitor of PI3K. Taken together, our findings provide a mechanistic and perhaps a foundational link between diabetes and Alzheimer's disease and are consistent with the notion that geniposide might play an essential role on the phosphorylation of tau protein via enhancing insulin signaling and may convey a therapeutic benefit in Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Disease Models, Animal; Humans; Insulin; Iridoids; Mice; Mice, Transgenic; Phosphorylation; Presenilin-1; tau Proteins

Hemorrhagic cystitis is one of the devastating complications seen after receiving cyclophosphamide chemotherapy. Oleuropein is the most important phenolic compound of olive leaves that mediates most of its beneficial pharmacological properties. Herein, we investigated the possible uroprotective effect of oleuropein against cyclophosphamide induced hemorrhagic cystitis in a rat model. For this purpose, we measured bladder nitric oxide, reduced glutathione, catalase, tumor necrosis factor-alpha and vascular endothelial growth factor levels in addition to the bladder gene expression of intercellular adhesion molecule-1 after induction of hemorrhagic cystitis in the presence or absence of oleuropein. Histopathological examination of bladder tissues was also performed. After cyclophosphamide injection, we demonstrated a significant decrease in bladder reduced glutathione (39%) and catalase (55.4%) levels and a significant increase of nitric oxide (5.6 folds), tumor necrosis factor-alpha (3.3 folds), vascular endothelial growth factor (2 folds) and intercellular adhesion molecule-1 (8 folds) bladder contents when compared to those in normal control rats. Administration of oleuropein induced a marked elevation in bladder reduced glutathione (37.8%), catalase (100.4%) with a prominent reduction of bladder nitric oxide (40%), tumor necrosis factor-alpha (35.9%) and vascular endothelial growth factor (56.2%) levels along with downregulation of intercellular adhesion molecule-1 bladder expression (73.1%) in comparison to cyclophosphamide treated rats levels. Our data demonstrated that oleuropein counteracts the harmful effects of cyclophosphamide on the bladder through its antioxidant and anti-inflammatory activities. Oleuropein exerts a definite uroprotective effect against cyclophosphamide induced hemorrhagic cystitis in rats.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Cyclophosphamide; Cystitis; Disease Models, Animal; Gene Expression Regulation; Hemorrhage; Humans; Intercellular Adhesion Molecule-1; Iridoid Glucosides; Iridoids; Male; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Urinary Bladder

Qingkailing injection (QKLI) is a modern Chinese medicine preparation derived from a well-known classical formulation, An-Gong-Niu-Huang Wan. Although the clinical efficacy of QKLI has been well defined, its severe adverse drug reactions (ADRs) were extensively increased. Through thorough attempts to reduce ADR rates, it was realized that the effect-based rational use plays the key role in clinical practices. Hence, the pharmacokinetic-pharmacodynamic (PK-PD) model was introduced in the present study, aiming to link the pharmacokinetic profiles with the therapeutic outcomes of QKLI, and subsequently to provide valuable guidelines for the rational use of QKLI in clinical settings. The PK properties of the six dominant ingredients in QKLI were compared between the normal treated group (NTG) and the pyrexia model group (MTG). Rectal temperatures were measured in parallel with blood sampling for NTG, MTG, model control group (MCG), and normal control group (NCG). Baicalin and geniposide exhibited appropriate PK parameters, and were selected as the PK markers to map the antipyretic effect of QKLI. Then, a PK-PD model was constructed upon the bacalin and geniposide plasma concentrations vs. the rectal temperature variation values, by a two-compartment PK model with a Sigmoid Emax PD model to explain the time delay between the drug plasma concentration of PK markers and the antipyretic effect after a single dose administration of QKLI. The findings obtained would provide fundamental information to propose a more reasonable dosage regimen and improve the level of individualized drug therapy in clinical settings.

Topics: Animals; Antipyretics; Body Temperature; Disease Models, Animal; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Fever; Flavonoids; Iridoids; Male; Medicine, Chinese Traditional; Rats; Rats, Sprague-Dawley

Baicalin (BA) and jasminoidin (JA) exert an additive effect in the treatment of cerebral ischemia, but the underlying molecular mechanism is still unclear. One hundred mice with focal cerebral ischemia/re-perfusion injury were divided into 5 groups: BA, JA, combination therapy (BJ), sham and vehicle. The differentially expressed genes identified by microarray consisting of 374 cDNAs were uploaded into GeneGo MetaCore software for pathway analyses. Networks were constructed to visualize the interactions of the differentially expressed genes. Among the top ten pathways and processes, we found 5, 3, 2 overlapping pathways and 6, 4, 6 overlapping processes between the BA and JA, BA and BJ, JA and BJ groups, respectively; of which 1 pathway and 3 processes were shared by all the three groups. Six representative pathways and 3 processes were activated only in BJ, such as Gamma-secretase proteolytic targets,etc. These BJ representative targeting pathways showed both vertical (e.g. Cytoplasmic/mitochondrial transport of proapoptotic Bid Bmf and Bim) and horizontal (e.g. Endothelin-1/EDNRA signaling) convergences with those of the BA and JA groups based on the upstream and downstream relationship of cerebral ischemia network, which may help to reveal their additive mechanism in the treatment of cerebral ischemia. Network comparison identified important transcription factors that regulated some of the other BJ related genes, such as cMyb and NF-AT. Such a systemic approach based on multiple pathways and networks may provide a robust path to understand the complex pharmacological variations of combination therapies.

Topics: Animals; Brain Ischemia; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Therapy, Combination; Flavonoids; Gene Expression; Iridoids; Male; Mice; Microarray Analysis; Random Allocation; Reperfusion Injury

The suture-tendon interface is often the weakest link in tendon to bone repair of massive rotator cuff tears. Genipin is a low-toxicity collagen crosslinker derived from the gardenia fruit that has been shown to augment collagen tissue strength and mechanically arrest tendon-tear progression.. The purpose of the current study was to evaluate whether genipin crosslinking can sufficiently augment the suture-tendon interface to improve suture pullout strength using simple single-loop sutures and the modified Mason-Allen technique. The study also aimed to assess whether time of genipin treatment is a relevant factor in efficacy.. In an ex vivo (cadaveric) sheep rotator cuff tendon model, a total of 142 suture pullout tests were performed on 32 infraspinatus tendons. Each tendon was prepared with three single-loop stitches. Two groups were pretreated by incubation in genipin solution for either 4 hours or 24 hours. Two corresponding control groups were incubated in phosphate buffered saline for the same periods. The same test protocol was applied to tendons using modified Mason-Allen technique stitch patterns. Each suture was loaded to failure on a universal materials testing machine. Suture pullout force, stiffness, and work to failure were calculated from force-displacement data, and then compared among the groups.. Median single-loop pullout force on tendons incubated for 24 hours in genipin yielded an approximately 30% increase in maximum pullout force for single-loop stitches with a median of 73 N (range, 56-114 N) compared with 56 N (range, 40-69 N; difference of medians = 17 N; p = 0.028), with corresponding increases in the required work to failure but not stiffness. Genipin treatment for 4 hours showed no added benefit for suture-pullout behavior (46 N, [range, 35-95 N] versus 45 N, [range, 28-63 N]; difference of medians, 1 N; p = 1). No tested genipin crosslinking conditions indicated benefit for tendons grasped using the modified Mason-Allen technique after 4 hours (162 N, [range, 143-193 N] versus 140 N, [range, 129-151 N]; difference of medians, 22 N; p = 0.114) or after 24 hours of crosslinking (172 N, [range, 42-183 N] versus 164 N [range, 151-180 N]; difference of medians, 8 N; p = 0.886).. Exogenous collagen crosslinking in genipin can markedly improve resistance to pullout at the tendon-suture interface for simple stitch patterns while the modified Mason-Allen stitch showed no benefit in an ex vivo animal model.. Tendon strength augmentation by genipin pretreatment offers the potential to improve suture retention properties. Future studies are warranted for the development of clinically viable intraoperative delivery strategies and in vivo testing for safety and efficacy.

Topics: Animals; Biomechanical Phenomena; Collagen; Cross-Linking Reagents; Disease Models, Animal; Equipment Failure; Iridoids; Materials Testing; Orthopedic Procedures; Rotator Cuff Injuries; Sheep; Stress, Mechanical; Suture Techniques; Sutures

Peritoneal adhesions are a common complication after abdominal surgery. They cause small bowel obstruction, female infertility and chronic abdominal pain. Peritoneal adhesions also hamper uniform drug distribution in the peritoneal cavity, thereby reducing the efficacy of intraperitoneal chemotherapy after cytoreductive surgery.. The goal of this study was to develop a formulation that prevents peritoneal adhesions, evenly distributes in the abdominal cavity, and simultaneously extends residence time and improves local drug concentration. This report describes the formulation and characterization of genipin-crosslinked gelatin microspheres (GP-MS).. Spheroid gelatin microspheres were prepared by an emulsification solvent extraction method. A higher degree of crosslinking was obtained by increasing genipin concentration and crosslinking time. The degree of crosslinking allowed to tailor the degradation rate of GP-MS, hence their residence time. GP-MS did not affect cell viability. In vivo experiments showed excellent GP-MS biocompatibility and degradation characteristics. GP-MS were distributed evenly throughout the abdominal cavity. Adhesions were induced in Balb/c mice by application of an abraded peritoneal wall-cecum model. GP-MS-treated mice developed significantly less postsurgical adhesions compared to saline and Hyalobarrier(®) group. Histopathological examination showed a decrease of peritoneal inflammation over time in GP-MS-treated mice with complete recovery of peritoneal wounds post-operative day 14.. GP-MS are a promising strategy to prevent postoperative peritoneal adhesions and improve efficacy of postoperative intraperitoneal chemotherapy.

Topics: Abdominal Cavity; Animals; Cell Line, Tumor; Cell Survival; Cross-Linking Reagents; Disease Models, Animal; Emulsions; Female; Gelatin; Humans; Iridoids; Mice, Inbred BALB C; Microspheres; Peritoneum; Postoperative Complications; Surface-Active Agents; Tissue Adhesions

Atherosclerosis is a chronic inflammatory disease of the vascular walls. ApoCIII is an independent factor which promotes atherosclerotic processes. This study aimed to investigate whether Loganin administration inhibits the inflammatory response in vitro and in vivo. In the apoCIII-induced mouse adipocytes, the levels of cytokines, including TNF-α, MCP-1 and IL-6 were determined by enzyme-linked immunosorbent assay and their gene expressions were measured through RT-PCR. The phosphorylation of nuclear factor-κB (NF-κB) proteins was analyzed by Western blotting. Our results showed that Loganin markedly decreased TNF-α, MCP-1 and IL-6 concentrations as well as their gene expressions. Western blotting analysis indicated that Loganin suppressed the activation of NF-κB signaling. In the Tyloxapol-treated mouse model, Loganin reduced the contents of TC and TG in mouse serum. The results of Oil Red-O Staining showed that Loganin reduced the production of lipid droplets. So it is suggested that Loganin might be a potential therapeutic agent for preventing the inflammation stress in vitro and in vivo.

Topics: 3T3 Cells; Adipocytes; Animals; Anti-Inflammatory Agents; Atherosclerosis; Chemokine CCL2; Disease Models, Animal; Humans; Inflammation; Interleukin-6; Iridoids; Lipid Metabolism; Mice; NF-kappa B; Phosphorylation; Polyethylene Glycols; Signal Transduction; Tumor Necrosis Factor-alpha

This study aimed to explore whether the regulatory effect of miR-21 on α-synuclein expression in neurons is a potential mechanism by which geniopside (GP) protects the central nervous system from Parkinson disease (PD).. The human neuroblastoma cell line SH-SY5Y was induced to differentiate in vitro and treated with dimethyl sulfoxide (DMSO), N-methyl-4-phenylpyridinium iodide (MPP(+)), and MPP(+) together with GP. To identify the role of miR-21 in the regulation of lysosome-associated membrane protein 2 (LAMP2A) and α-synuclein, SH-SY5Y cells pretreated with MPP(+) were transfected with miR-21 mimic and miR-21 inhibitor. To identify whether GP could reduce the level of α-synuclein through miR-21/LAMP2A, SHSY5Y cells pretreated with GP were treated with miR-21 mimic or miR-21 inhibitor; meanwhile, a luciferase reporter assay was performed to confirm the direct target of miR-21. LAMP2A was overexpressed using a pCMV6-XL5-LAMP2A vector to confirm the role of LAMP2A in the regulation of α-synuclein by miR-21. In these in vitro experiments, the RNA and/or protein expressions of miR-21, LAMP2A, and α-synuclein in SH-SY5Y cells were determined by quantitative real-time polymerase chain reaction and/or western blotting, respectively. An in vivo PD mouse model was established through intraperitoneal injection with N-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP). The mice were treated with saline, MPTP, MPTP+GP, and MPTP+GP+miR-21 agomir. The numbers of TH(+) cells in the substantia nigra in different groups of mice were compared. The RNA and/or protein expressions of miR-21, LAMP2A, and α-synuclein were also determined.. The level of miR-21 in the cells or mice models was significantly higher than that in normal cells or normal mice, respectively, and GP significantly downregulated miR-21. GP also raised the protein and mRNA expressions of LAMP2A and reduced the protein level of α-synuclein in PD models. MiR-21 upregulated the expression of α-synuclein by directly targeting 3' UTR of LAMP2A. LAMP2A overexpression abolished the upregulating effect of miR-21 mimic on α-synuclein. MiR-21 mimics/agomir reversed the GP-induced downregulation of α-synuclein; miR-21 inhibitor effectively increased the downregulation of α-synuclein caused by GP.. GP exhibits neuroprotective properties by inhibiting α-synuclein expression in PD models through the miR-21/LAMP2A axis.

Topics: alpha-Synuclein; Animals; Cell Line, Tumor; Disease Models, Animal; Dopaminergic Neurons; Humans; Iridoids; Lysosomal-Associated Membrane Protein 2; Mice; MicroRNAs; Neuroprotective Agents; Parkinson Disease; Parkinsonian Disorders; Substantia Nigra; Tyrosine 3-Monooxygenase

Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease characterized by motor neurons degeneration and muscular atrophy. There is no effective SMA treatment. Loganin is a botanical candidate with anti-inflammatory, anti-oxidant, glucose-lowering and anti-diabetic nephropathy activities. The aim of this study is to investigate the potential protective effects of loganin on SMA using two cellular models, SMN-deficient NSC34 cells and SMA patient fibroblasts, and an animal disease model, SMAΔ7 mice. In SMN-deficient NSC34 cells, loganin increased cell viability, neurite length, and expressions of SMN, Gemin2, SMN-Gemin2 complex, p-Akt, p-GSK-3β, p-CREB, BDNF and Bcl-2. However, both AG1024 (IGF-1 R antagonist) and IGF-1 R siRNA attenuated the protective effects of loganin on SMN level and cell viability in SMN-deficient NSC34 cells. In SMA patient fibroblasts, loganin up-regulated levels of SMN, FL-SMN2, and Gemins, increased numbers of SMN-containing nuclear gems, modulated splicing factors, and up-regulated p-Akt. Furthermore, in the brain, spinal cord and gastrocnemius muscle of SMAΔ7 mice, loganin up-regulated the expressions of SMN and p-Akt. Results from righting reflex and hind-limb suspension tests indicated loganin improved muscle strength of SMAΔ7 mice; moreover, loganin activated Akt/mTOR signal and inhibited atrogin-1/MuRF-1 signal in gastrocnemius muscle of SMAΔ7 mice. Loganin also increased body weight, but the average lifespan of loganin (20mg/kg/day)-treated SMA mice was 16.80±0.73 days, while saline-treated SMA mice was 10.91±0.96 days. In conclusion, the present results demonstrate that loganin provides benefits to SMA therapeutics via improving SMN restoration, muscle strength and body weight. IGF-1 plays an important role in loganin neuroprotection. Loganin can be therefore a valuable complementary candidate for treatment of neuromuscular diseases via regulation of muscle protein synthesis and neuroprotection.

Topics: Animals; Apoptosis; Cell Line; Cytoprotection; Disease Models, Animal; Dose-Response Relationship, Drug; Fibroblasts; Genetic Predisposition to Disease; Humans; Insulin-Like Growth Factor I; Iridoids; Mice; Mice, Transgenic; Motor Activity; Motor Neurons; Muscle Proteins; Muscle Strength; Muscle, Skeletal; Muscular Atrophy, Spinal; Mutation; Nerve Degeneration; Neuroprotective Agents; Phenotype; Phosphorylation; Protein Biosynthesis; Proto-Oncogene Proteins c-akt; RNA Interference; Signal Transduction; SKP Cullin F-Box Protein Ligases; Survival of Motor Neuron 1 Protein; Time Factors; TOR Serine-Threonine Kinases; Transfection; Tripartite Motif Proteins; Ubiquitin-Protein Ligases; Weight Gain

Huang-Lian-Jie-Du-Decoction (HLJDD, Oren-gedoku-to in Japanese) is commonly used in traditional Chinese medicine (TCM) to treat ischemic stroke. This study investigated the efficacy of various combinations of the major components of HLJDD, berberine (A), baicalin (B), and jasminoidin (C), on the treatment of ischemic stroke modeled by middle cerebral artery occlusion (MCAO) in rats. The effects of A, B and C individually and their combinations were investigated using proton nuclear magnetic resonance (1H NMR)-based metabolomics complemented with neurologic deficit scoring, infarct volume measurement, biochemistry, histopathology and immunohistochemistry, as well as quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting. Ischemic stroke produces severe oxidative stress, which induces further damage. Our results show that the ABC combination treatment increased levels of cellular antioxidants that scavenged reactive oxygen species during ischemia-reperfusion via the nuclear erythroid 2-related factor 2 (Nrf2) signaling cascade. These protective effects were not observed with the other treatments. These results suggest that a combination of component herbs in HLJDD exhibit stronger effects than the individual herbs alone. Our integrated metabolomics approach also provides a tractable, powerful tool for understanding the science behind TCM formulations.

Topics: Animals; Berberine; Brain; Disease Models, Animal; Drug Synergism; Drugs, Chinese Herbal; Flavonoids; Free Radical Scavengers; Infarction, Middle Cerebral Artery; Iridoids; Male; Metabolomics; Neuroprotective Agents; NF-E2-Related Factor 2; Oxidative Stress; Phytotherapy; Plants, Medicinal; Proton Magnetic Resonance Spectroscopy; Rats, Sprague-Dawley; Reperfusion Injury

Alcohol-induced liver injury (ALD) shows obvious metabolic disorders, categorized by a wide range of metabolite abnormalities. High-throughput metabolomics technology appears to be an appropriate solution. In this study, a urine metabolic profile was assessed using a UPLC-Q-TOF/HDMS (liquid chromatography coupled to high resolution mass spectrometry) approach to investigate the underlying molecular mechanisms of ALD and the therapeutic effect of geniposide. The endogenous low-molecular-weight metabolites in the mouse model of ALD were observed and 48 specific biomarkers were identified. Geniposide was found to have a regulatory effect on 32 of them. Furthermore, targeted analysis of biomarkers showed clear separation between the model and geniposide treatment group. Fifteen biomarkers with high contribution to group differentiation were screened out. Also, a comprehensive analysis of a significant disturbance of multiple metabolic pathways indicated that geniposide could modify abnormal metabolism due to ethanol exposure, during which disorders relating to amino acid metabolism and the oxidative stress state could be alleviated. At the same time, accessory examinations, including plasma biochemical indicators and liver tissue pathological analysis, showed similar results. It was suggested that geniposide was effective as a hepatoprotective agent against ethanol-induced liver damage by re-balancing a wide range of metabolic disorders.

Topics: Animals; Biomarkers; Biopsy; Chemical and Drug Induced Liver Injury; Chromatography, Liquid; Cluster Analysis; Disease Models, Animal; Ethanol; Immunohistochemistry; Iridoids; Male; Mass Spectrometry; Metabolic Networks and Pathways; Metabolome; Metabolomics; Mice; Phenotype

Myocardial infarction causes a cascade of events, which leads to heart failure, debilitation and death. This study examined possible cardioprotective effect of oleuropein in rats with acute myocardial infarction. Male Sprague-Dawly rats were allocated to five groups: sham, myocardial infarction receiving vehicle, and three myocardial infarction receiving oleuropein at 10, 20, and 30 mg/kg/day for 7 days, and underwent sham operation or coronary ligation. Twenty-four hours later, animals underwent echocardiographic and hemodynamic studies, and infarct areas, serum concentrations of oxidative stress and inflammatory markers were determined. Myocardial infarction group receiving vehicle had significantly lower left ventricular developed and systolic pressures, rate of rise/decrease of left ventricular pressure, stroke volume, ejection fraction and cardiac output, and serum superoxide dismutase and glutathione reductase than those of sham group. Pretreatment with oleuropein prevented the reduction of these variables. Moreover, the group had a significantly higher serum malondialdehyde, interleukin-1β, TNF-α, creatin kinase-MB, and troponin I, lactate dehydrogenase, and infarct area than those of sham group. Pretreatment with oleuropein prevented the increase of these variables. The findings indicate that coronary ligation results in acute myocardial infarction characterized by impaired cardiac function, and oleuropein pretreatment prevented cardiac impairment partly by reducing oxidative stress and release of proinflammatory cytokines.

Topics: Animals; Biomarkers; Cardiotonic Agents; Creatine Kinase, MB Form; Disease Models, Animal; Electrocardiography; Hemodynamics; Interleukin-1beta; Iridoid Glucosides; Iridoids; L-Lactate Dehydrogenase; Male; Malondialdehyde; Myocardial Infarction; Oxidative Stress; Rats; Rats, Sprague-Dawley; Troponin I; Tumor Necrosis Factor-alpha; Ultrasonography; Vasodilator Agents

The receptor for advanced glycation end products (RAGE)-mediated signaling pathway is related to Aβ-induced pathogenic responses. Geniposide, a pharmacologically active component purified from gardenia fruit, could attenuate the oligomeric Aβ(1-42)-induced inflammatory response by blocking the ligation of Aβ to RAGE and suppressing the RAGE-mediated signaling in vitro. Here, we investigated whether geniposide can exert protective effects on the neuroinflammation and memory deficits in an Alzheimer's disease (AD) mouse model. The results indicate that geniposide treatment significantly suppresses RAGE-dependent signaling (activation of ERK and IκB/NF-κB), the production of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) and cerebral Aβ accumulation in vivo. Furthermore, we demonstrate that geniposide augments synaptic plasticity by attenuating the Aβ-induced reduction of long-term potentiation and increasing the miniature excitatory postsynaptic current (mEPSC) amplitude and frequency in hippocampal neurons. In addition, the intragastric administration of geniposide improves learning and memory in APP/PS1 mice. Taken together, these studies indicate that geniposide has profound multifaceted neuroprotective effects in an AD mouse model. Geniposide demonstrates its neuroprotection by inhibiting inflammation, ameliorating amyloid pathology and improving cognition. Thus, geniposide may be a potential therapeutic agent for halting and preventing AD progression.

Topics: Alzheimer Disease; Animals; Cells, Cultured; Disease Models, Animal; Iridoids; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neuroprotective Agents; Receptor for Advanced Glycation End Products; Receptors, Immunologic; Treatment Outcome

The aim of this study was to explore the anti-inflammatory effects of Geniposide (GE), an iridoid glycoside compound extracted from Gardenia jasminoides Ellis (GJ) fruit in adjuvant-induced arthritis (AA) rats and its pharmacokinetic (PK) basis. AA was induced by injecting with Freund's complete adjuvant (FCA). Male SD rats were subjected to treatment with GE (30, 60 and 120mg/kg) from day 17 to 24 after immunization. Fibroblast-like synoviocyte (FLS) proliferation was assessed by MTT. Interleukin (IL)-1, IL-6, TNF-α and IL-10 were determined using double-sandwich enzyme-linked immunosorbent assay (ELISA). Expression of p38 mitogen-activated protein kinases (p38MAPKs) related proteins in FLS was detected by Western blotting. PK profiles were simultaneously detected by ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UPLC-ESI-MS/MS) in AA rat plasma after oral administration of GE on day 17 after immunization. As a result, GE promoted the recovery of arthritis and inhibited the colonic inflammation damage in AA rats by decreasing the expression level of TNF-α, IL-1 and IL-6, increasing the production of IL-10 and inhibiting the expression of phospho-p38 (p-p38) related proteins in FLS. PK parameters (AUC, Cmax and t1/2) tended to be associated with dosage-related decreasing of efficacy index.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Cell Proliferation; Cells, Cultured; Colon; Cytokines; Disease Models, Animal; Fibroblasts; Freund's Adjuvant; Fruit; Gardenia; Humans; Iridoids; Male; p38 Mitogen-Activated Protein Kinases; Phytotherapy; Rats; Rats, Sprague-Dawley; Signal Transduction; Synovial Membrane

Ischemic preconditioning, which is mediated by cell signaling molecules, protects the heart from ischemia-reperfusion injury by limiting the infarct size. Oleuropein, the main polyphenolic constituent of olives, reduced the infarct size in normal and cholesterol-fed rabbits when it was administered at a nutritional dose. The aim of the present study was to compare the effects of oleuropein and preconditioning in terms of the cell signaling and metabolism pathways underlying myocardial protection. Rabbits were randomly divided into six groups: the control group received 5 % dextrose for six weeks, the preconditioning group was subjected to two cycles of preconditioning with 5 min ischemia/10 min reperfusion, the O6 group was treated with oleuropein for six weeks, the Chol group was fed a cholesterol-enriched diet and 5 % dextrose for six weeks, and the CholO6 and CholO3 groups were treated with cholesterol and oleuropein for six and three weeks, respectively; oleuropein was dissolved in 5 % dextrose solution and was administered orally at a dose of 20 mg × kg(-1) × day(-1). All animals were subsequently subjected to 30 min myocardial ischemia followed by 10 min of reperfusion. At that time, myocardial biopsies were taken from the ischemic areas for the assessment of oxidative and nitrosative stress biomarkers (malondialdehyde and nitrotyrosine), and determination of phosphorylation of signaling molecules involved in the mechanism of preconditioning (PI3K, Akt, eNOS, AMPK, STAT3). The tissue extracts NMR metabolic profile was recorded and further analyzed by multivariate statistics. Oxidative biomarkers were significantly reduced in the O6, CholO6, and CholO3 groups compared to the control, preconditioning, and Chol groups. Considering the underlying signaling cascade, the phosphorylation of PI3K, Akt, eNOS, AMPK, and STAT-3 was significantly higher in the preconditioning and all oleuropein-treated groups compared to the control and Chol groups. The NMR-based metabonomic study, performed through the analysis of spectroscopic data, depicted differences in the metabolome of the various groups with significant alterations in purine metabolism. In conclusion, the addition of oleuropein to a normal or hypercholesterolemic diet results in a preconditioning-like intracellular effect, eliminating the deleterious consequences of ischemia and hypercholesterolemia, followed by a decrease of oxidative stress biomarkers. This effect is exerted through inducing precondit

Topics: Animals; Cholesterol; Disease Models, Animal; Hypercholesterolemia; Iridoid Glucosides; Iridoids; Male; Malondialdehyde; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Olea; Oxidative Stress; Phosphatidylinositol 3-Kinases; Protective Agents; Rabbits; Signal Transduction; Tyrosine

Diabetic nephropathy is the most common cause of end-stage renal disease in patients with diabetes. Advanced glycation end-products (AGEs) play a prominent role in the development of diabetic nephropathy. We herein evaluated the effects of loganin on diabetic nephropathy in vivo.. We established a diabetic nephropathy model in C57BL/6J mice with diabetes induced by streptozotocin and fed with diets containing high level of AGEs. Diabetic symptoms, renal functions, and pathohistology of pancreas and kidney were evaluated. AGE-RAGE pathway and oxidative stress parameters were determined.. The model mice exhibited characteristic symptoms of diabetes including weight loss, polydipsia, polyphagia, polyuria, elevated blood glucose levels and low serum insulin levels during the experiments. However, loganin at doses of 0.02 and 0.1g/kg effectively improved these diabetic symptoms. Loganin reduced kidney/body weight ratio, 24h urine protein levels, and serum levels of urea nitrogen and creatinine in diabetic mice to different degrees compared to positive controls. Moreover, loganin improved the histology of pancreas and kidney, and alleviated the structural alterations in endothelial cells, mesangial cells and podocytes in renal cortex. Finally, we found that loganin reduced AGE levels in serum and kidney and downregulated mRNA and protein expression of receptors for AGEs in kidney in diabetic mice. Loganin also reduced the levels of malondialdehyde and increased the levels of superoxide dismutase in serum and kidney.. Loganin improved diabetic nephropathy in vivo associated with inhibition of AGE pathways, and could be a promising remedy for diabetic nephropathy.

Topics: Analysis of Variance; Animals; Blood Urea Nitrogen; Blotting, Western; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Disease Models, Animal; DNA Primers; Dose-Response Relationship, Drug; Gene Expression Regulation; Glycation End Products, Advanced; Iridoids; Kidney; Malondialdehyde; Mice; Mice, Inbred C57BL; Microscopy, Electron, Transmission; Molecular Structure; Oxidative Stress; Pancreas; Proteinuria; Receptor for Advanced Glycation End Products; Receptors, Immunologic; Reverse Transcriptase Polymerase Chain Reaction; Superoxide Dismutase

Zhi-Zi-Hou-Po decoction (ZZHPD), a traditional Chinese medicine (TCM) formula, has been used for treatment of depressive-like symptoms for centuries. However, studies of its antidepressant effect and mechanism are challenging, owing to the complex pathophysiology of depression and complexity of ZZHPD with multiple constituents acting on different metabolic pathways. The present study was designed to develop a liquid chromatography-mass spectrometry (LC-MS) method for simultaneous determination of depression biomarkers: tryptophan (Trp), phenylalanine (Phe), tyrosine (Tyr), indole-3-acetic acid (IAA), hippuric acid (HA), phenaceturic acid (PA), creatinine (Cr), glutamic acid (Glu), succinic acid (SA) and γ-aminobutyric acid (GABA), as well as to study the antidepressant effect and potential mechanism of ZZHPD based on holistic view of an organism. The analysis was performed on a CAPCELL PAK C18 column with methanol and 0.01% formic acid in water using gradient elution. The method showed a good linearity (r(2)>0.99) with the other validation parameters were within acceptance range. The results demonstrated Trp, Phe, Tyr, IAA, HA, Cr, Glu and SA levels were significant lower in model group, while PA and GABA were significant higher than those in control group. The rats with ZZHPD treatment showed a tendency of bringing the levels of all these biomarkers to normal except Cr and Glu. It could be a powerful manner to provide mechanistic insights into the therapeutic effects of complex prescriptions and further understand pathophysiology of depression to assist in clinical diagnosis.

Topics: Animals; Antidepressive Agents; Biomarkers; Chromatography, Liquid; Depression; Disease Models, Animal; Drugs, Chinese Herbal; Iridoids; Linear Models; Male; Mass Spectrometry; Rats; Rats, Sprague-Dawley; Reproducibility of Results; Sensitivity and Specificity

Our previous studies have shown that geniposide plays an essential role in glucose-stimulated insulin secretion from pancreatic β cells and also antagonizesAβ1-42-induced cytotoxicity examined using a primary cortical neuron assay. However, the mechanism by which geniposide appears to regulate insulin signaling in the brain is presently not well understood. In this study, we administered streptozotocin (STZ) to induce insulin-deficiency in an AD transgenic mouse model, and investigated the effects of geniposide on the β-amyloidogenic processing of amyloid precursor protein (APP) using in vitro and in vivo models. Our results indicate that treatment with STZ (90 mg/kg, i.p., once daily for two consecutive days) induced significant reduction in peripheral and brain insulin levels in both wild-type and APP/PS1 transgenic mice. Administration of geniposide for 4 weeks significantly decreased the concentrations of cerebral β-amyloid peptides (Aβ1-40 and Aβ1-42) in STZ-treated AD mice. Further experiments showed that geniposide up-regulated the protein levels of β-site APP cleaving enzyme (BACE1) and insulin-degrading enzyme (IDE), and decreased the protein levels of ADAM10 when examined using a primary cultured cortical neuron assay and in STZ-induced AD mice. Meanwhile, geniposide also directly enhanced the effects of insulin by reducing Aβ1-42 levels in primary cultured cortical neurons. Taken together, our findings provide a mechanistic link between diabetes and AD, and is consistent with the notion that geniposide might play an important role on APP processing via enhancing insulin signaling and may convey a therapeutic benefit in AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Brain; Cells, Cultured; Diabetes Mellitus, Experimental; Disease Models, Animal; Humans; Insulin; Iridoids; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Peptide Fragments; Presenilin-1

Geniposide as the major active component of Gardenia jasminoides Ellis has neuroprotective activity. This study elucidated the potential antidepressant-like effect of geniposide and its related mechanisms using a depression rat model induced by 3 consecutive weeks of chronic unpredictable mild stress (CUMS). Sucrose preference test, open field test (OFT) and forced swimming test (FST) were applied to evaluate the antidepressant effect of geniposide. Adrenocorticotropic hormone (ACTH) and corticosterone (CORT) serum levels, adrenal gland index and hypothalamic corticotrophin-releasing hormone (CRH) mRNA expression were measured to assess the activity of hypothalamus-pituitary-adrenal (HPA) axis. Hypothalamic glucocorticoid receptor α (GRα) mRNA expression and GRα protein expression in hypothalamic paraventricular nucleus (PVN) were also determined by real-time PCR and immunohistochemistry, respectively. We found that geniposide (25, 50, 100mg/kg) treatment reversed the CUMS-induced behavioral abnormalities, as suggested by increased sucrose intake, improved crossing and rearing behavior in OFT, shortened immobility and prolonged swimming time in FST. Additionally, geniposide treatment normalized the CUMS-induced hyperactivity of HPA axis, as evidenced by reduced CORT serum level, adrenal gland index and hypothalamic CRH mRNA expression, with no significant effect on ACTH serum level. Moreover, geniposide treatment upregulated the hypothalamic GRα mRNA level and GRα protein expression in PVN, suggesting geniposide could recover the impaired GRα negative feedback on CRH expression and HPA axis. These aforementioned therapeutic effects of geniposide were essentially similar to fluoxetine. Our results indicated that geniposide possessed potent antidepressant-like properties that may be mediated by its effects on the HPA axis.

Topics: Animals; Antidepressive Agents; Chronic Disease; Corticosterone; Corticotropin-Releasing Hormone; Depressive Disorder; Dietary Sucrose; Disease Models, Animal; Dose-Response Relationship, Drug; Feeding Behavior; Hypothalamo-Hypophyseal System; Iridoids; Male; Motor Activity; Pituitary-Adrenal System; Rats, Sprague-Dawley; Receptors, Glucocorticoid; RNA, Messenger; Stress, Psychological; Uncertainty

Sepsis, a systemic inflammatory response to infection, initiates a complex immune response consisting of an early hyperinflammatory response and a subsequent hypoinflammatory response that impairs the removal of infectious organisms. The importance of sepsis-induced immunosuppression and its contribution to mortality has recently emerged. Apoptotic depletion of T lymphocytes is a critical cause of immunosuppression in the late phase of sepsis. Genipin is a major active compound of gardenia fruit that has anti-apoptotic and anti-microbial properties. This study investigated the mechanisms of action of genipin on immunosuppression in the late phase of sepsis. Mice received genipin (1, 2.5 and 5mg/kg, i.v.) at 0 (immediately) and 24h after cecal ligation and puncture (CLP). Twenty-six hours after CLP, the spleen and blood were collected. Genipin improved the survival rate compared to controls. CLP increased the levels of FADD, caspase-8 and caspase-3 protein expression, which were attenuated by genipin. Genipin increased the level of anti-apoptotic B-cell lymphoma-2 protein expression, while it decreased the level of pro-apoptotic phosphorylated-Bim protein expression in CLP. CLP decreased the CD4(+) and CD8(+) T cell population, while it increased the regulatory T cell (Treg) population and the level of cytotoxic T lymphocyte-associated antigen 4 protein expression on Treg. These changes were attenuated by genipin. The splenic levels of interferon-γ and interleukin (IL)-2 were reduced, while the levels of IL-4 and IL-10 increased after CLP. Genipin attenuated these alterations. These findings suggest that genipin reduces immunosuppression by inhibiting T lymphocyte apoptosis in the late phase of sepsis.

Topics: Adjuvants, Immunologic; Animals; Apoptosis; Caspase 3; Cecum; Cytokines; Disease Models, Animal; Fas-Associated Death Domain Protein; Gardenia; Humans; Immunosuppression Therapy; Iridoids; Male; Mice; Mice, Inbred ICR; Proto-Oncogene Proteins c-bcl-2; Sepsis; T-Lymphocyte Subsets; T-Lymphocytes, Regulatory; Th1-Th2 Balance

Oleuropein, a phenolic compound found in abundance in olive leaves, has beneficial effects on various diseases. However, it is unknown whether an oleuropein-rich diet is efficacious against type 2 diabetic phenotypes. In this study, we investigated the effects of the oleuropein-containing supplement OPIACE, whose oleuropein content exceeds 35% (w/w), on the diabetic phenotypes in type 2 diabetes model Tsumura Suzuki Obese Diabetes (TSOD) mouse. TSOD mice were fed OPIACE at 4 weeks of age, i.e., before the TSOD mice exhibited diabetic phenotypes. We revealed that OPIACE attenuated hyperglycemia and impaired glucose tolerance in TSOD mice over the long-term (from 10 to 24 weeks of age) but had no effect on obesity. Furthermore, we demonstrated that OPIACE mildly reduced oxidative stress in TSOD mice by 26.2% and attenuated anxiety-like behavioral abnormality in aged TSOD mice. The results suggest that oleuropein suppresses the progression of type 2 diabetes and diabetes-related behavioral abnormality over the long-term.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Diet; Disease Models, Animal; Glucose Tolerance Test; Humans; Hyperglycemia; Iridoid Glucosides; Iridoids; Male; Mice; Mice, Obese

Genipin, a hydrolyzed metabolite of geniposide extracted from the fruit of Gardenia jasminoides Ellis, has shown promise in alleviating depressive symptoms, however, the antidepressant mechanism of genipin remains unclear and incomprehensive. In this study, the metabolic profiles of aqueous and lipophilic extracts in liver of the chronic unpredictable mild stress (CUMS)-induced rat with genipin treatment were investigated using proton nuclear magnetic resonance ((1)H NMR) spectroscopy coupled with multivariate data analysis. Significant differences in the metabolic profiles of rats in the CUMS model group (MS) and the control group (NS) were observed with metabolic effects including decreasing in choline, glycerol and glycogen, increasing in lactate, alanine and succinate, and a disordered lipid metabolism, while the moderate dose (50mg/kg) of genipin could significantly regulate the concentrations of glycerol, lactate, alanine, succinate and the lipid to their normal levels. These biomakers were involved in metabolism pathways such as glycolysis/gluconeogensis, tricarboxylic acid (TCA) cycle and lipid metabolism, which may be helpful for understanding of antidepressant mechanism of genipin.

Topics: Animals; Antidepressive Agents; Behavior, Animal; Body Weight; Depression; Disease Models, Animal; Iridoids; Liver; Magnetic Resonance Spectroscopy; Male; Metabolome; Metabolomics; Rats, Sprague-Dawley; Stress, Psychological

Scleral cross-linking (CXL) is a novel attempt to slow down the axial elongation process in animal eyes. As a natural CXL reagent, genipin would be also effective for the prevention of myopia process. Thus, the present study was designed to evaluate the effects of scleral cross-linking using genipin on the form-deprivation (FD) myopia process of guinea pigs.. Twenty-seven 3-week-old pigmented guinea pigs were randomly divided into three groups. Group A (n = 8) is the untreated control group. Group B (n = 8) is the FD control group, where all eyes were induced with monocular FD for 21 days. In Group C (n = 11), a sub-Tenon injection of 0.10 mL 0.50 % genipin was performed on FD eyes at day 0, 7 and 14 during the 21-day monocular FD. The ocular refraction, axial length, biomechanical test and light and electron microscopy were measured on all eyes to check the efficacy and safety of this scleral CXL technique.. Compared with Group A, significant increases in myopic refractive errors, axial elongation and reductions of scleral fibril diameter and density were observed in the 21-day FD eyes of Group B (P < 0.05). In Group C, the scleral CXL resulted in less myopia and axial elongation as compared with Group B (P < 0.05); a significant thickening of scleral fibrils was found after sub-Tenon injections of genipin; no histological damage on the retina or choroid was observed in Group C at the end of this study.. The FD myopia in guinea pig eyes was effectively blocked by the scleral CXL using sub-Tenon injections of genipin. No histological damage was found on the retina or choroid of these treated eyes. Further studies are needed to examine the long-term efficacy and safety of this CXL technique.

Topics: Animals; Axial Length, Eye; Cholagogues and Choleretics; Cross-Linking Reagents; Disease Models, Animal; Elasticity; Guinea Pigs; Injections, Intraocular; Iridoids; Myopia; Refraction, Ocular; Sclera; Sensory Deprivation

Parkinson's disease (PD) is a chronic neurodegenerative disease, and there is no cure for it at present. We tested the drug Geniposide, an active component of Gardenia jasminoides Ellis which is used in traditional Chinese medicine. Geniposide has shown neuroprotective and growth-factor like effects in several in vivo and in vitro studies. In the present study, Geniposide had been tested in an acute PD mouse model induced by four 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intraperitoneal injections. Geniposide treatment (100mg/kg ip.) for 8 days after MPTP treatment (30mg/kg ip.) improved the locomotor and exploratory activity of mice (open field), and improved bradykinesia and movement balance of mice (rotarod, swim test). Geniposide treatment also restored tyrosine hydroxylase (TH) positive dopaminergic neuron numbers in the substantia nigra pars compacta. Drug treatment also increased levels of growth factor signaling molecule Bax and reduced the apoptosis signaling molecule Bcl-2. Caspase 3 activation was also reduced in the substantia nigra. We conclude that Geniposide exerted its neuroprotective effect by enhancing growth factor signaling and the reduction of apoptosis. Geniposide is an ingredient in Chinese traditional medicine with few known side effects and shows potential as a drug treatment for Parkinson's disease.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Apoptosis; bcl-2-Associated X Protein; Caspase 3; Cell Proliferation; Disease Models, Animal; Iridoids; Male; Mice; Mice, Inbred C57BL; Motor Activity; Neurons; Neuroprotective Agents; Parkinson Disease; Pars Compacta; Proto-Oncogene Proteins c-bcl-2; Psychomotor Performance; Swimming; Tyrosine 3-Monooxygenase

The healthy effects of plant polyphenols, some of which characterize the so-called Mediterranean diet, have been shown to arise from epigenetic and biological modifications resulting, among others, in autophagy stimulation. Our previous work highlighted the beneficial effects of oleuropein aglycone (OLE), the main polyphenol found in the extra virgin olive oil, against neurodegeneration both in cultured cells and in model organisms, focusing, in particular, autophagy activation. In this study we investigated more in depth the molecular and cellular mechanisms of autophagy induction by OLE using cultured neuroblastoma cells and an OLE-fed mouse model of amylod beta (Aβ) deposition. We found that OLE triggers autophagy in cultured cells through the Ca2+-CAMKKβ-AMPK axis. In particular, in these cells OLE induces a rapid release of Ca2+ from the SR stores which, in turn, activates CAMKKβ, with subsequent phosphorylation and activation of AMPK. The link between AMPK activation and mTOR inhibition was shown in the OLE-fed animal model in which we found that decreased phospho-mTOR immunoreactivity and phosphorylated mTOR substrate p70 S6K levels match enhanced phospho-AMPK levels, supporting the idea that autophagy activation by OLE proceeds through mTOR inhibition. Our results agree with those reported for other plant polyphenols, suggesting a shared molecular mechanism underlying the healthy effects of these substances against ageing, neurodegeneration, cancer, diabetes and other diseases implying autophagy dysfunction.

Topics: AMP-Activated Protein Kinases; Animals; Autophagy; Disease Models, Animal; Humans; Iridoid Glucosides; Iridoids; Mice; Signal Transduction; TOR Serine-Threonine Kinases

Water extract of the fixed combination of Gardenia jasminoides Ellis fruit, Citrus aurantium L. fruit and Magnolia officinalis Rehd. et Wils. bark, traditional name - Zhi-Zi-Hou-Po (ZZHPD) is used for treatment of depressive-like symptoms in traditional Chinese medicine for centuries.. The present study aimed to explore antidepressant-like effects and potential mechanisms of ZZHPD in a rat model of chronic unpredictable mild stress (CUMS).. Antidepressant-like effects of ZZHPD were investigated through behavioral tests, and potential mechanism was assessed by neuroendocrine system, neurotrophin and hippocampal neurogenesis.. Antidepressant-like effects of ZZHPD (3.66, 7.32 and 14.64 g/kg/day) were estimated through coat state test, sucrose preference test, forced swimming test and open-field test. Effects of ZZHPD on hypothalamic-pituitary-adrenal (HPA) axis were evaluated by hormones measurement and dexamethasone suppression test. In addition, the expression of brain-derived neurotrophic factor (BDNF) in hippocampus was measured, as well as hippocampal neurogenesis was investigated by doublecortin (DCX) and 5-bromo-2-deoxyuridine/neuronal nuclei (BrdU/NeuN).. The results demonstrated that ZZHPD significantly reversed the depressive-like behaviors, normalized the levels of adrenocorticotropic hormone (ACTH) and corticosterone (CORT), restored the negative feedback loop of HPA axis and improved the levels of BDNF, DCX and BrdU/NeuN compared with those in CUMS-induced rats.. The above results revealed that ZZHPD exerted antidepressant-like effects possibly by normalizing HPA axis function, increasing expression of BDNF in hippocampus and promoting hippocampal neurogenesis.

Topics: Adrenocorticotropic Hormone; Animals; Antidepressive Agents; Brain-Derived Neurotrophic Factor; Citrus; Corticosterone; Depression; Disease Models, Animal; Doublecortin Protein; Drugs, Chinese Herbal; Fruit; Gardenia; Hippocampus; Hypothalamo-Hypophyseal System; Iridoids; Magnolia; Male; Molecular Structure; Neurogenesis; Pituitary-Adrenal System; Plant Bark; Plant Extracts; Rats; Rats, Sprague-Dawley; Stress, Psychological

Inflammasomes are cytoplasmic, multiprotein complexes that trigger caspase-1 activation and IL-1β maturation in response to diverse stimuli. Although inflammasomes play important roles in host defense against microbial infection, overactive inflammasomes are deleterious and lead to various autoinflammatory diseases. In the current study, we demonstrated that genipin inhibits the induction of IL-1β production and caspase-1 activation by NLRP3 and NLRC4 inflammasomes. Furthermore, genipin specifically prevented NLRP3-mediated, but not NLRC4-mediated, ASC oligomerization. Notably, genipin inhibited autophagy, leading to NLRP3 and NLRC4 inflammasome inhibition. UCP2-ROS signaling may be involved in inflammasome suppression by genipin. In vivo, we showed that genipin inhibited NLRP3-dependent IL-1β production and neutrophil flux in LPS- and alum-induced murine peritonitis. Additionally, genipin provided protection against flagellin-induced lung inflammation by reducing IL-1β production and neutrophil recruitment. Collectively, our results revealed a novel role in inhibition of inflammatory diseases for genipin that has been used as therapeutics for centuries in herb medicine.

Topics: Animals; Apoptosis Regulatory Proteins; Autophagy; Calcium-Binding Proteins; CARD Signaling Adaptor Proteins; Carrier Proteins; Caspase 1; Chemokines; Cytokines; Disease Models, Animal; Flagellin; Inflammasomes; Ion Channels; Iridoids; Lipopolysaccharides; Macrophage Activation; Macrophages; Mice; Mice, Knockout; Mitochondrial Proteins; NLR Family, Pyrin Domain-Containing 3 Protein; Peritonitis; Pneumonia; Protein Multimerization; Reactive Oxygen Species; Uncoupling Protein 2

Translational research needs valid animal models of disease to discover new pathogenetic aspects and treatments. In Alzheimer's disease (AD), transgenic models are of great value for AD research and drug testing.. It was the aim of this study to analyze the power of dietary polyphenols against neurodegeneration by investigating the effects of oleuropein aglycone (OLE), the main phenol in the extra virgin olive oil (EVOO), a key component of the Mediterranean diet (MD), in a mouse model of amyloid-β deposition.. TgCRND8 mice (3.5 months old), expressing the mutant KM670/671NL+V717F h-βAPP695 transgene, and wild-type (wt) mice were used to study in vivo the effects of an 8-week dietary supplementation with OLE (50 mg/kg of diet) [Grossi et al: PLoS One 2013;8:e71702], following the European Communities Council Directive 86/609 (DL 116/92) and National Guidelines (permit number: 283/2012-B).. OLE administration ameliorates memory dysfunction, raises a significant autophagic response in the cortex and promotes the proliferation of newborn cells in the subgranular zone of the dentate gyrus of the hippocampus.. Our findings support the beneficial effects of EVOO and highlight the possibility that continuous intake of high doses of OLE, both as a nutraceutical or as a food integrator, may prevent/delay the appearance of AD and reduce the severity of its symptoms.

Topics: Alzheimer Disease; Animal Feed; Animals; Brain; Diet, Mediterranean; Disease Models, Animal; Humans; Iridoid Glucosides; Iridoids; Mice, Transgenic; Neuroprotective Agents; Olive Oil; Plant Oils; Translational Research, Biomedical

The transcription factor NF-κB orchestrates many pro-inflammatory signals and its inhibition is considered a promising strategy to combat inflammation. Here we report the characterization of the natural product plumericin as a highly potent inhibitor of the NF-κB pathway with a novel chemical scaffold, which was isolated via a bioactivity-guided approach, from extracts of Himatanthus sucuuba, an Amazonian plant traditionally used to treat inflammation-related disorders.. A NF-κB luciferase reporter gene assay was used to identify NF-κB pathway inhibitors from H. sucuuba extracts. Monitoring of TNF-α-induced expression of the adhesion molecules VCAM-1, ICAM-1 and E-selectin by flow cytometry was used to confirm NF-κB inhibition in endothelial cells, and thioglycollate-induced peritonitis in mice to confirm effects in vivo. Western blotting and transfection experiments were used to investigate the mechanism of action of plumericin.. Plumericin inhibited NF-κB-mediated transactivation of a luciferase reporter gene (IC50 1 μM), abolished TNF-α-induced expression of the adhesion molecules VCAM-1, ICAM-1 and E-selectin in endothelial cells and suppressed thioglycollate-induced peritonitis in mice. Plumericin exerted its NF-κB pathway inhibitory effect by blocking IκB phosphorylation and degradation. Plumericin also inhibited NF-κB activation induced by transfection with the constitutively active catalytic subunit of the IκB kinase (IKK-β), suggesting IKK involvement in the inhibitory action of this natural product.. Plumericin is a potent inhibitor of NF-κB pathways with a new chemical scaffold. It could be further explored as a novel anti-inflammatory lead compound.

Topics: Animals; Anti-Inflammatory Agents; Apocynaceae; Cell Adhesion Molecules; Disease Models, Animal; Dose-Response Relationship, Drug; HEK293 Cells; Human Umbilical Vein Endothelial Cells; Humans; I-kappa B Kinase; I-kappa B Proteins; Indenes; Inflammation; Inflammation Mediators; Iridoids; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Phosphorylation; Plant Extracts; Signal Transduction; Thioglycolates; Transfection

Intracerebral-ventricular (ICV) injection of streptozotocin (STZ) induces an insulin-resistant brain state that may underlie the neural pathogenesis of sporadic Alzheimer disease (AD). Our previous work showed that prior ICV treatment of glucagon-like peptide-1 (GLP-1) could prevent STZ-induced learning memory impairment and tau hyperphosphorylation in the rat brain. The Chinese herbal medicine geniposide is known to relieve symptoms of type 2 diabetes. Because geniposide is thought to act as a GLP-1 receptor agonist, we investigated the potential therapeutic effect of geniposide on STZ-induced AD model in rats. Our result showed that a single injection of geniposide (50 μM, 10 μL) to the lateral ventricle prevented STZ-induced spatial learning deficit by about 40% and reduced tau phosphorylation by about 30% with Morris water maze test and quantitative immunohistochemical analysis, respectively. It has been known that tau protein can be phosphorylated by glycogen synthase kinase-3 (GSK3) and STZ can increase the activity of GSK3β. Our result with Western blot analysis showed that central administration of geniposide resulted in an elevated expression of GSK3β(pS-9) but suppressed GSK3β(pY-216) indicating that geniposide reduced STZ-induced GSK3β hyperactivity. In addition, ultrastructure analysis showed that geniposide averted STZ-induced neural pathology, including paired helical filament (PHF)-like structures, accumulation of vesicles in synaptic terminal, abnormalities of endoplasmic reticulum (ER) and early stage of apoptosis. In summary, our study suggests that the water soluble and orally active monomer of Chinese herbal medicine geniposide may serve as a novel therapeutic agent for the treatment of sporadic AD.

Topics: Alzheimer Disease; Animals; Antibiotics, Antineoplastic; Apoptosis; Disease Models, Animal; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Hippocampus; Iridoids; Male; Maze Learning; Memory Disorders; Microscopy, Electron, Transmission; Phosphorylation; Rats; Rats, Sprague-Dawley; Signal Transduction; Streptozocin; tau Proteins; Vacuoles

Cerebral ischemia is considered to be a highly complex disease resulting from the complicated interplay of multiple pathways. Disappointedly, most of the previous studies were limited to a single gene or a single pathway. The extent to which all involved pathways are translated into fusing mechanisms of a combination therapy is of fundamental importance.. We report an integrative strategy to reveal the additive mechanism that a combination (BJ) of compound baicalin (BA) and jasminoidin (JA) fights against cerebral ischemia based on variation of pathways and functional communities.. We identified six pathways of BJ group that shared diverse additive index from 0.09 to 1, which assembled broad cross talks from seven pathways of BA and 16 pathways of JA both at horizontal and vertical levels. Besides a total of 60 overlapping functions as a robust integration background among the three groups based on significantly differential subnetworks, additive mechanism with strong confidence by networks altered functions.. These results provide strong evidence that the additive mechanism is more complex than previously appreciated, and an integrative analysis of pathways may suggest an important paradigm for revealing pharmacological mechanisms underlying drug combinations.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Disease Models, Animal; Drug Therapy, Combination; Drugs, Chinese Herbal; Flavonoids; Infarction, Middle Cerebral Artery; Iridoids; Male; Mice; Mice, Inbred Strains; Microarray Analysis; Molecular Sequence Data; Principal Component Analysis; Reperfusion Injury; Signal Transduction

Geniposide is a bioactive substance derived from gardenia, which has been used in traditional Chinese preparation, such as "Xing-Nao-Jing" (XNJ) for stroke treatment. Stroke and the ingredients of herbal preparation affect the pharmacokinetics of geniposide. A comparative pharmacokinetic study of geniposide in stroke and sham-operated rats after administration of XNJ and geniposide was proceeded to evaluate the effect of stroke on pharmacokinetics of geniposide, while the influence of other components in XNJ was determined by using gardenia extract and geniposide-borneol compounds in rats with stroke to compare.. Stroke was induced by middle cerebral artery occlusion followed by reperfusion 2h later. Plasma concentration of geniposide was determined by HPLC. Various pharmacokinetic parameters were estimated from the plasma concentration versus time data using non-compartmental methods.. The maximum plasma concentration (Cmax) and area under the curve (AUC0-t) in stroke after administration of XNJ were 5.97±3.82 μg/mL, and 570.06±274.32 μg·min/mL, respectively, which were 5 times compared with sham-operated rats or the stroke-afflicted rats given geniposide. In stroke, the Cmax and AUC(0-t) of geniposide-borneol group and gardenia extraction group were close to XNJ group and geniposide group, respectively. The geniposide-borneol group had a higher value.. Stroke improved the absorption of geniposide in XNJ. Borneol may be the key ingredient in XNJ improving the absorption of geniposide.

Topics: Animals; Area Under Curve; Camphanes; Chromatography, High Pressure Liquid; Disease Models, Animal; Drugs, Chinese Herbal; Gardenia; Iridoids; Male; Models, Biological; Rats; Rats, Sprague-Dawley; Stroke

Huanglian-Zhizi couplet medicine comes from classical prescription Huang-Lian-Jie-Du-Tang (HLJDT), which has been proven by previous researches to be an effective compound for cerebral ischemia. This paper explores the integrated pharmacokinetics of gardenia acid and geniposide-time-antioxidant efficacy after the oral administration of Huanglian-Zhizi couplet medicine from HLJDT in rats with middle cerebral artery occlusion (MCAO). To investigate the differences in pharmacokinetics and antioxidant effect of Huanglian-Zhizi and HLJDT in MCAO rats, which have been scarcely reported, an oral dose, 24 crud drug g/kg, of Huanglian-Zhizi and 40 crud drug/kg of HLJDT were administered in two groups of normal rats and two groups of Sprague-Dawley (SD) MCAO rats, respectively. At different time points, concentrations of gardenia acid and geniposide were determined by high performance liquid chromatography (HPLC), and levels of superoxide dismutase (SOD) were calculated by ELIASA. Pharmacokinetic parameters including AUC, MRT, t1/2, T max , C max were estimated by statistical moment analysis using a data analysis system (DAS) 2.0. An AUC based on weighting approach was used for integrating gardenia acid and geniposide. Finally, the concentration-time efficacy profiles were obtained. The integrated pharmacokinetics profiles of index components could reveal the pharmacokinetics behavior of Huanglian-Zhizi and HLJDT, corresponding to the antioxidant efficacy.

Topics: Administration, Oral; Animals; Antioxidants; Chromatography, High Pressure Liquid; Disease Models, Animal; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Enzyme-Linked Immunosorbent Assay; Infarction, Middle Cerebral Artery; Iridoids; Phytotherapy; Rats, Sprague-Dawley; Superoxide Dismutase; Time Factors

The mechanism of oleuropein's antihypertensive effects was examined in rat model of simultaneous type 2 diabetes and renal hypertension (diabetic hypertensive). Five groups of male Sprague-Dawley rats including a control, a diabetic-hypertensive group receiving vehicle, and three diabetic-hypertensive groups receiving oleuropein at 20, 40, or 60 mg/kg/day were used. The duration of diabetes was 10 weeks; during the last 4 weeks of which, animals were hypertensive and received vehicle or oleuropein. Systolic blood pressure, glucose and malondialdehyde, heart rate, and maximal response to phenylephrine (PE) in the absence of nitro-L-arginine methyl ester (L-NAME) of oleuropein-treated groups were significantly lower than those of vehicle-treated group. Erythrocyte superoxide dismutase, maximal response to PE in the presence of L-NAME, and maximal response to acetylcholine (Ach) of oleuropein-treated groups were significantly higher than those of vehicle-treated group. The findings indicate that antihypertensive effects of oleuropein might be partly mediated by improving the release of nitric oxide, and antioxidant and sympathoplegic activities.

Topics: Acetylcholine; Animals; Antihypertensive Agents; Arginine; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Disease Models, Animal; Endothelium, Vascular; Hypertension, Renal; Iridoid Glucosides; Iridoids; Male; Molecular Structure; Nitric Oxide; Rats; Rats, Sprague-Dawley; Superoxide Dismutase

Genipin, an important bioactive component from Gardenia jasminoides Eills, was demonstrated to possess antidepressant-like effects in a previous study. However, the molecular mechanism of antidepressant-like effects on genipin was not clear. The present study aimed to investigate the possible mechanism of antidepressant-like effects on genipin with a chronic unpredictable mild stress (CUMS)-induced depression model in rats. In CUMS-induced depressive rats, bodyweight and 1% sucrose consumption decreased significantly compared with the normal control group. Furthermore, these changes could be significantly reversed by genipin application. The levels of 5-hydroxytryptamine (5-HT), norepinephrine (NE) in the hippocampus decreased and the level of 5-hydroxyindole acetic acid (5-HIAA) increased in the CUMS-induced depressive rats. However, pre-treatments with genipin significantly increased the levels of 5-HT, NE and decreased the level of 5-HIAA in the hippocampus. The concentration of cAMP in the hippocampus was increased by genipin compared to the CUMS-exposed model group. The mRNA expressions of 5-hydroxytryptamine 1A receptor (5-HT1AR), cAMP response element binding protein (CREB) and brain-derived neurotrophic factor (BDNF) in rats were decreased exposed to CUMS, which were reversed by genipin-treated rats exposed to CUMS. Compared to the CUMS-exposed model group, the mRNA expression of 5-hydroxytryptamine 2A receptor (5-HT(2A)R) was decreased significantly by genipin-treated rats. The mRNA and protein expression of CREB, BDNF were increased in genipin-treated rats compared to the CUMS-exposed model group. Moreover, the levels of corticosterone in serum were decreased by genipin-treated compared to the CUMS-exposed model group. These results suggest that the possible mechanism of antidepressant-like effects on genipin, at least in one part, resulted from monoaminergic neurotransmitter system and the potential dysfunctional regulation of the post-receptor signaling pathway, which particularly affected the 5-HT(1A)R, 5-HT(2A)R and BDNF levels in the hippocampus.

Topics: Animals; Antidepressive Agents; Brain-Derived Neurotrophic Factor; Depression; Disease Models, Animal; Hippocampus; Iridoids; Male; Phytotherapy; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Receptors, Serotonin; Serotonin; Synaptic Transmission

Oxidative stress and mitochondrial dysfunction appear early and contribute to the disease progression in Alzheimer's disease (AD), which can be detected extensively in AD patients brains as well as in transgenic AD mice brains. Thus, treatments that result in attenuation of oxidative stress and mitochondrial dysfunction may hold potential for AD treatment. Geniposide, a pharmacologically active component purified from gardenia fruit, exhibits anti-oxidative, antiinflammatory and other important therapeutic properties. However, whether geniposide has any protective effect on oxidative stress and mitochondrial dysfunction in AD transgenic mouse model has not yet been reported. Here, we demonstrate that intragastric administration of geniposide significantly reduces oxidative stress and mitochondrial dysfunction in addition to improving learning and memory in APP/PS1 mice. Geniposide exerts protective effects on mitochondrial dysfunction in APP/PS1 mice through suppressing the mitochondrial oxidative damage and increasing the mitochondrial membrane potential and activity of cytochrome c oxidase. These studies indicate that geniposide may attenuate memory deficits through the suppression of mitochondrial oxidative stress. Thus, geniposide may be a potential therapeutic reagent for halting and preventing AD progress.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Brain; Disease Models, Animal; Electron Transport Complex IV; Humans; Iridoids; Male; Malondialdehyde; Maze Learning; Membrane Potential, Mitochondrial; Memory Disorders; Mice, Inbred C57BL; Mice, Transgenic; Mitochondria; Nootropic Agents; Oxidative Stress; Presenilin-1; Random Allocation; Reactive Oxygen Species

To study the gastroprotective effect and in vivo antioxidant potential of a standardized iridoid fraction from B. prionitis leaves (BPE) against different gastric ulcer models in rats.. The standardized iridoid fraction from BPE at 50, 100, and 200 mg/kg body weight was administered orally, twice daily for 5 days for prevention from aspirin, ethanol, cold-restraint stress (CRS), and pylorus ligation (PL)-induced ulcers. Estimation of the antioxidant enzyme activity was carried out in a CRS-induced ulcer model, and various gastric secretion parameters including volume of gastric juice, acid output, and pH value were estimated in the PL-induced ulcer model.. BPE showed a dose-dependent ulcer protective effect in PL (18.67%-66.26% protection), aspirin (24.65%-63.25% protection), CRS (20.77%-59.42% protection), and EtOH (16.93%-77.04% protection)-induced ulcers. BPE treatment in PL-rats showed a decrease in acid-pepsin secretion, and enhanced mucin and mucosal glycoproteins. However, BPE reduced the ulcer index with significant decrease in LPO (P < 0.01-0.001), SOD (P < 0.01-0.001), and an increase in CAT (P < 0.01-0.001), activity in the CRS-induced model.. The data shows that the iridoid fraction from BPE possesses anti-ulcerogenic and antioxidant potential.

Topics: Acanthaceae; Animals; Anti-Ulcer Agents; Disease Models, Animal; Humans; Iridoids; Male; Plant Extracts; Protective Agents; Rats; Rats, Wistar; Stomach Ulcer

Osteoarthritis, characterized by a loss of articular cartilage accompanied with inflammation, is the most common age-associated degenerative disease. Monotropein, an iridoids glycoside isolated from the roots of Morinda officinalis How, has been demonstrated to exhibit anti-inflammatory activity. In the present study, monotropein was firstly to exhibit cartilage protective activity by down regulating the pro-inflammatory cytokines in the knee synovial fluid in vivo. The anti-apoptotic and anti-catabolic effects of monotropein on rat OA chondrocytes treated by IL-1β were investigated in vitro. In cultured chondrocytes, monotropein attenuated apoptosis in a dose-dependent manner in response to IL-1β stimulation. Moreover, treatment with monotropein, the expressions of MMP-3 and MMP-13 were significantly decreased, the expression of COL2A1 was increased. Taken together, these findings suggested that monotropein exerted anti-apoptosis and anti-catabolic activity in chondrocytes, which might support its possible therapeutic role in OA.

Topics: Animals; Anti-Inflammatory Agents; Apoptosis; Blotting, Western; Cell Survival; Cells, Cultured; Chondrocytes; Disease Models, Animal; Interleukin-1beta; Iridoids; Matrix Metalloproteinase 13; Matrix Metalloproteinase 3; Morinda; Osteoarthritis; Plant Roots; Primary Cell Culture; Rats, Inbred Strains

To investigate the therapeutic effects and acting mechanism of a combination of Chinese herb active components, i.e., a combination of baicalin, jasminoidin and cholic acid (CBJC) on Alzheimer's disease (AD).. Male rats were intracerebroventricularly injected with ibotenic acid (IBO), and CBJC was orally administered. Therapeutic effect was evaluated with the Morris water maze test, FDG-PET examination, and histological examination, and the acting mechanism was studied with DNA microarrays and western blotting.. CBJC treatment significantly attenuated IBO-induced abnormalities in cognition, brain functional images, and brain histological morphology. Additionally, the expression levels of 19 genes in the forebrain were significantly influenced by CBJC; approximately 60% of these genes were related to neuroprotection and neurogenesis, whereas others were related to anti-oxidation, protein degradation, cholesterol metabolism, stress response, angiogenesis, and apoptosis. Expression of these genes was increased, except for the gene related to apoptosis. Changes in expression for 5 of these genes were confirmed by western blotting.. CBJC can ameliorate the IBO-induced dementia in rats and may be significant in the treatment of AD. The therapeutic mechanism may be related to CBJC's modulation of a number of processes, mainly through promotion of neuroprotection and neurogenesis, with additional promotion of anti-oxidation, protein degradation, etc.

Topics: Alzheimer Disease; Animals; Cholic Acid; Dementia; Disease Models, Animal; Drug Combinations; Drugs, Chinese Herbal; Flavonoids; Humans; Ibotenic Acid; Iridoids; Male; Neuroprotective Agents; Oligonucleotide Array Sequence Analysis; Rats

Mitochondria dysfunction has been reported in various kidney diseases but how it leads to kidney fibrosis and how this is regulated is unknown. Here we found that mitochondrial uncoupling protein 2 (UCP2) was induced in kidney tubular epithelial cells after unilateral ureteral obstruction in mice and that mice with ablated UCP2 resisted obstruction-induced kidney fibrosis. We tested this association further in cultured NRK-52E cells and found that TGF-β1 remarkably induced UCP2 expression. Knockdown of UCP2 largely abolished the effect of TGF-β1, whereas overexpression of UCP2 promoted tubular cell phenotype changes. Analysis using a UCP2 mRNA-3'-untranslated region luciferase construct showed that UCP2 mRNA is a direct target of miR-30e. MiR-30e was downregulated in tubular cells from fibrotic kidneys and TGF-β1-treated NRK-52E cells. A miR-30e mimic significantly inhibited TGF-β1-induced tubular-cell epithelial-mesenchymal transition, whereas a miR-30e inhibitor imitated TGF-β1 effects. Finally, genipin, an aglycone UCP2 inhibitor, significantly ameliorated kidney fibrosis in mice. Thus, the miR-30e/UCP2 axis has an important role in mediating TGF-β1-induced epithelial-mesenchymal transition and kidney fibrosis. Targeting this pathway may shed new light for the future of fibrotic kidney disease therapy.

Topics: Animals; Cell Line; Disease Models, Animal; Epithelial Cells; Epithelial-Mesenchymal Transition; Extracellular Matrix; Fibrosis; Humans; Ion Channels; Iridoids; Kidney Diseases; Kidney Tubules; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; MicroRNAs; Mitochondrial Proteins; Rats; Recombinant Proteins; RNA Interference; Signal Transduction; Time Factors; Transfection; Transforming Growth Factor beta1; Uncoupling Protein 2; Ureteral Obstruction

The presence of amyloid aggregates of the 42 amino acid peptide of amyloid beta (Aβ42) in the brain is the characteristic feature of Alzheimer's disease (AD). Amyloid beta (Aβ deposition is also found in muscle fibers of individuals affected by inclusion body myositis (sIBM), a rare muscular degenerative disease affecting people over 50. Both conditions are presently lacking an effective therapeutic treatment. There is increasing evidence to suggest that natural polyphenols may prevent the formation of toxic amyloid aggregates; this applies also to oleuropein aglycone (OLE), the most abundant polyphenol in extra virgin olive oil, previously shown to hinder amylin and Aβ aggregation. Here we evaluated the ability of OLE to interfere with Aβ proteotoxicity in vivo by using the transgenic CL2006 and CL4176 strains of Caenorhabditis elegans, simplified models of AD and of sIBM, which express human Aβ in the cytoplasm of body wall muscle cells. OLE-fed CL2006 worms displayed reduced Aβ plaque deposition, less abundant toxic Aβ oligomers, remarkably decreased paralysis and increased lifespan with respect to untreated animals. A protective effect was also observed in CL4176 worms but only when OLE was administered before the induction of the Aβ transgene expression. These effects were specific, dose-related, and not mediated by the known polyphenolic anti-oxidant activity, suggesting that, in this model organism, OLE interferes with the Aβ aggregation skipping the appearance of toxic species, as already shown in vitro for Aβ42.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Animals, Genetically Modified; Caenorhabditis; Disease Models, Animal; Humans; Iridoid Glucosides; Iridoids; Peptide Fragments; Pyrans; Vasodilator Agents

To evaluate the effect of collagen cross-linking induced by genipin in porcine sclera.. Porcine cadaver eyes were treated with genipin at concentrations (by w/v) of 0.01%, 0.03%, 0.1%, 0.3%, 1.0% for 15 and 30 min. Riboflavin/ultraviolet A(UVA)-treated and untreated samples were used as controls. After treatment, scleral strips of 4.0 × 10.0 mm were cut. Twenty-four hours later, the stress-strain parameters of the strips were measured using a biomaterial microtester. The stress and Young's modulus at 8% strain were evaluated.. Compared with untreated groups, after treatment with genipin for 15 min, the stress was increased by 66-246%, depending on the concentration of genipin. As for the 30-min groups, the stress was 171-444% higher than that of the control. The difference of the Young's modulus between genipin 15-min groups, except the 0.01% groups (p = 0.095), also had statistical significance (p < 0.05). The Young's modulus had significant difference between the untreated group and the genipin 30-min groups (all p < 0.05). Of 0.3% genipin for 15 min or 0.01% genipin for 30 min had a similar stress-strain curve with those of eyes treated with the riboflavin/UVA group. The sclera exhibited a bluish colour which became deeper with increase concentration and cross-linking time.. Collagen cross-linking induced by genipin could increase the biomechanical strength in porcine sclera. The effect depends on the concentration and treatment time of genipin.

Topics: Adhesives; Animals; Collagen; Cross-Linking Reagents; Disease Models, Animal; Elasticity; Iridoids; Myopia; Sclera; Swine

Nyctanthes arbortristis Linn (Oleaceae) is widely distributed in sub-Himalayan regions and southwards to Godavari, India commonly known as Harsingar and Night Jasmine. In continuation of our drug discovery program on Indian medicinal plants, we isolated arbortristoside-A (AT) and 7-O-trans-cinnamoyl-6β-hydroxyloganin (6-HL) from the seeds of N. arbortristis. AT and 6-HL exhibited anti ulcer activity in experimentally induced ulcer models including cold restraint stress (CRU), alcohol (AL), pylorus ligation-induced gastric ulcer (PL) models and they also showed ulcer healing effect in chronic acetic acid-induced ulcer model (AC).

Topics: Acetic Acid; Alcohols; Animals; Anti-Ulcer Agents; Cinnamates; Disease Models, Animal; Female; Iridoid Glucosides; Iridoids; Oleaceae; Phytotherapy; Plant Extracts; Plants, Medicinal; Proton Pump Inhibitors; Pylorus; Rats; Rats, Sprague-Dawley; Seeds; Stomach Ulcer; Stress, Physiological

Our group recently reported the strong anti-inflammatory effects of geniposide (Gen), a bioactive iridoid glucoside derived from gardenia jasminoides, in a mouse acute lung injury model. Herein, we hypothesized that Gen might also have potential therapeutic benefits in treatment of asthma, which was tested in a mouse model of ovalbumin (Ova)-induced allergic airway inflammation. Ova-sensitized and -challenged BALB/c mice, as compared with control animals, displayed airway hyperresponsiveness (AHR), bronchoalveolar lavage eosinophilia, mucus hypersecretion, and increased T help 2 (Th2)-associated cytokine and chemokine amounts, as well as serum Ova-specific immunoglobulin E (IgE) level. Being compared with the Ova-induced hallmarks of asthma, intraperitoneal Gen treatment prevented eosinophilic pulmonary infiltration, attenuated the increases in interleukin (IL)-4, IL-5, and IL-13, and reduced eotaxin and vascular cell adhesion molecule 1 (VCAM-1) expression. Also, Gen significantly ameliorated the Ova-driven airway hyperresponsiveness, mucus hypersecretion, and allergen-specific IgE level, which are the cardinal pathophysiological symptoms in allergic airway diseases. In addition, the efficacy of Gen was comparable to that of dexamethasone (Dex), a currently available anti-asthmatic drug. Collectively, our findings reveal that the development of immunoregulatory strategies based on Gen may be considered as an effective adjuvant therapy for allergic asthma.

Topics: Allergens; Animals; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Cell Count; Cytokines; Disease Models, Animal; Female; Immunoglobulin E; Iridoids; Lung; Mice; Mice, Inbred BALB C; Ovalbumin

Zhi-Zi-Hou-Pu decoction (ZZHPD) is a traditional prescription which has been used to treat "Yu-syndrome" (depression and melancholia) in Chinese herbal medication.. To evaluate antidepressant activities of ZZHPD, its fractions and possible mechanism(s) of action.. ZZHPD (1241, 2482 and 4964 mg/kg), n-butanol fraction (ZH-BA, 1454 mg/kg), cyclohexane fraction (ZH-CH, 17 mg/kg) and aqueous fraction (ZH-AQ, 3493 mg/kg) were administered orally to different groups of mice for seven consecutive days. Forced Swimming Test (FST) and Tail Suspension Test (TST) were conducted 60 min after the last administration to evaluate the antidepressant effect. Norepinephrine, dopamine and 5-hydroxytryptamine levels in discrete brain parts were determined by HPLC-FD immediately after behavioral tests.. ZZHPD at 2482, 4964 mg/kg, ZH-BA (1454 mg/kg), ZH-CH (17 mg/kg) or clomipramine hydrochloride (20 mg/kg) significantly (p < 0.05) reduced the duration of immobility in FST and TST without affecting locomotor activities in the open field test. Observed from score plot of principle component analysis of monoamine levels in different groups, the monoamine profile of ZZHPD-treated mice were similar to that of the normal control mice. HPLC-UV analysis indicated that iridoid glycosides, flavones and neolignans might be the active chemicals.. The results demonstrated significant antidepressant-like effect of ZZHPD in mice which was related to monoaminergic system, ZH-BA and ZH-CH could be the active fractions responsible for the antidepressant effect of ZZHPD.

Topics: 1-Butanol; Administration, Oral; Animals; Antidepressive Agents; Behavior, Animal; Biogenic Monoamines; Brain; Chromatography, High Pressure Liquid; Cyclohexanes; Depression; Disease Models, Animal; Dopamine; Drugs, Chinese Herbal; Hindlimb Suspension; Iridoids; Male; Mice; Motor Activity; Norepinephrine; Plants, Medicinal; Principal Component Analysis; Serotonin; Solvents; Spectrophotometry, Ultraviolet; Stress, Psychological; Time Factors; Water

Gardenia jasminoides J. Ellis (Rubiaceae) is a shrub tree species distributed all over the world. Now its pharmacological activities such as anti-atherosclerosis have been extensively studied.. To offer pharmacological proof for its further clinical application in cardiovascular diseases, the antithrombotic activities of the aqueous extract of G. jasminoides (GJ-ext) were studied in mouse and rat models.. GJ-ext was administrated orally to detect the effects on the models of carrageenan-induced tail thrombosis and arteriovenous shunt thrombosis. The effects of GJ-ext and geniposide (p.o.) on antiplatelet aggregation were examined. Geniposide and genipin were studied on venous thrombosis by oral administration.. GJ-ext (67, 133 and 266 mg/kg) and aspirin (50 mg/kg), respectively, decreased the length of tail thrombus with average thrombus inhibition rate of 21.9, 55.7, 65.8 and 57.6% at 48 h and 19.0, 54.5, 69.3 and 56.9% at 72 h after carrageenan injection and, meanwhile, improved thrombosis induced by arteriovenous shunt (silk thread) with 36.3, 45.5, 86.4 and 63.7% inhibition rate of thrombus respectively, and the ED(50) of GJ-ext was 160.8 mg/kg. Furthermore, GJ-ext (67 mg/kg) and geniposide (20 mg/kg) significantly inhibited platelet aggregation induced by thrombin/collagen with 45.1%/19.3% and 52.8%/26.2% aggregation rate. Geniposide (10-40 mg/kg) and genipin (5-20 mg/kg) inhibited venous thrombosis induced by tight ligation of the inferior vena cava, their ED(50) values were 18.4 and 8.6 mg/kg, respectively.. This study indicated that GJ-ext and geniposide demonstrated remarkable antithrombotic activities and supported their therapeutic uses for thrombotic diseases.

Topics: Administration, Oral; Animals; Arteriovenous Shunt, Surgical; Aspirin; Carrageenan; Disease Models, Animal; Dose-Response Relationship, Drug; Fibrinolytic Agents; Fruit; Gardenia; Iridoids; Male; Mice; Mice, Inbred ICR; Plant Extracts; Plants, Medicinal; Platelet Aggregation; Platelet Aggregation Inhibitors; Rats; Rats, Sprague-Dawley; Solvents; Time Factors; Venous Thrombosis; Water

Dietary olive oil supplementation and more recently, olive oil phenols have been recommended as important therapeutic interventions in preventive medicine. Ole has several pharmacological properties, including antioxidant, anti-inflammatory, antiatherogenic, anticancer, antimicrobial, and antiviral and for these reasons, is becoming an important subject of study in recent years. The aim of this study was to investigate the effects of Ole aglycone on the modulation of the secondary events in mice subjected to intestinal IRI. This was induced in mice by clamping the superior mesenteric artery and the celiac trunk for 30 min, followed by release of the clamp, allowing reperfusion for 1 h. After 60 min of reperfusion, animals were killed for histological examination of the ileum tissue and immunohistochemical localization of proinflammatory cytokines (TNF-α and IL-1β) and adhesion molecules (ICAM-1 and P-sel); moreover, by Western blot analysis, we investigated the activation of NF-κB and IκBα. In addition, we evaluated the apoptosis process, as shown by TUNEL staining and Bax/Bcl-2 expressions. The results obtained by the histological and molecular examinations showed in Ole aglycone-treated mice, a decrease of inflammation and apoptosis pathway versus SAO-shocked mice. In conclusion, we propose that the olive oil compounds, in particular, the Ole aglycone, could represent a possible treatment against secondary events of intestinal IRI.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Blotting, Western; Cell Adhesion Molecules; Cytokines; Disease Models, Animal; Immunohistochemistry; In Situ Nick-End Labeling; Intestinal Diseases; Iridoid Glucosides; Iridoids; Male; Mice; Olive Oil; Plant Oils; Polyphenols; Pyrans; Reperfusion Injury

We investigated the hypothesis that exogenous collagen cross-linking can augment intact regions of tendon to mitigate mechanical propagation of partial tears. We first screened the low toxicity collagen cross-linkers genipin, methylglyoxal and ultra-violet (UV) light for their ability to augment tendon stiffness and failure load in rat tail tendon fascicles (RTTF). We then investigated cross-linking effects in load bearing equine superficial digital flexor tendons (SDFT). Data indicated that all three cross-linking agents augmented RTTF mechanical properties but reduced native viscoelasticity. In contrast to effects observed in fascicles, methylglyoxal treatment of SDFT detrimentally affected tendon mechanical integrity, and in the case of UV did not alter tendon mechanics. As in the RTTF experiments, genipin cross-linking of SDFT resulted in increased stiffness, higher failure loads and reduced viscoelasticity. Based on this result we assessed the efficacy of genipin in arresting tendon tear propagation in cyclic loading to failure. Genipin cross-linking secondary to a mid-substance biopsy-punch significantly reduced tissue strains, increased elastic modulus and increased resistance to fatigue failure. We conclude that genipin cross-linking of injured tendons holds potential for arresting tendon tear progression, and that implications of the treatment on matrix remodeling in living tendons should now be investigated.

Topics: Animals; Collagen; Cross-Linking Reagents; Disease Models, Animal; Elasticity; Horses; Iridoids; Lacerations; Pyruvaldehyde; Rats; Recovery of Function; Tendon Injuries; Tendons; Ultraviolet Therapy; Wound Healing

Oleuropein (OE) is a well-known antioxidant polyphenol from olive oil. The purpose of this study was to determine the potential neuroprotective effects of oleuropein in an experimental spinal cord injury model.. Rats were randomly divided into four groups of 21 rats each as follows: sham-operated group, trauma group, and OE treatment groups (20 mg/kg, i.p., immediately and 1 hour after spinal cord injury). Spinal cord samples were taken 24 hours after injury and studied for determination of malondialdehyde and glutathione levels, histopathological assessment, immunohistochemistry of Bax and Bcl-2, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling reaction. Behavioral testing was performed weekly up to 6 weeks post-injury.. The results showed that malondialdehyde levels were significantly decreased, and glutathione levels were significantly increased in OE treatment groups. Greater Bcl-2 and attenuated Bax expression could be detected in the OE-treated rats. OE significantly reduced terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive reaction and improved behavioral function than the trauma group.. These findings indicate that OE may be effective in protecting rat spinal cord from secondary injury.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Disease Models, Animal; Female; Glutathione; Iridoid Glucosides; Iridoids; Lipid Peroxidation; Malondialdehyde; Neuroprotective Agents; Pyrans; Rats; Rats, Sprague-Dawley; Recovery of Function; Spinal Cord Injuries

Olives and olive products, an inevitable part of the Mediterranean diet, possess various beneficial effects, such as a decreased risk of cardiovascular disease and cancer. Oleuropein is a non-toxic secoiridoid found in the leaves and fruits of olive (Olea europaea L.). In this study, we have investigated the hepatoprotective activity of oleuropein in carbon tetrachloride (CCl(4))-induced liver injury in male BALB/cN mice. Oleuropein in doses of 100 and 200mg/kg was administered intraperitoneally (ip) once daily for 3 consecutive days, prior to CCl(4) administration (the preventive treatment), or once daily for 2 consecutive days 6h after CCl(4) intoxication (the curative treatment). CCl(4) intoxication resulted in a massive hepatic necrosis and increased plasma transaminases. Liver injury was associated with oxidative/nitrosative stress evidenced by increased nitrotyrosine formation as well as a significant decrease in superoxide dismutase activity and glutathione levels. CCl(4) administration triggered inflammatory response in mice livers by inducing expression of nuclear factor-kappaB, which coincided with the induction of tumor necrosis factor-alpha, cyclooxygenase-2 and inducible nitric oxide synthase. In both treatment protocols, oleuropein significantly attenuated oxidative/nitrosative stress and inflammatory response and improved histological and plasma markers of liver damage. Additionally, in the curative regimen, oleuropein prevented tumor necrosis factor-beta1-mediated activation of hepatic stellate cells, as well as the activation of caspase-3. The hepatoprotective activity of oleuropein was, at least in part, achieved through the NF-E2-related factor 2-mediated induction of heme oxygenase-1. The present study demonstrates antioxidant, anti-inflammatory, antiapoptotic, and antifibrotic activity of oleuropein, with more pronounced therapeutic than prophylactic effects.

Topics: Animals; Antioxidants; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Glutathione; Heme Oxygenase-1; Iridoid Glucosides; Iridoids; Male; Mice; Mice, Inbred BALB C; Oleaceae; Oxidative Stress; Pyrans; Superoxide Dismutase

A new lignan glucoside, (+)-(7S,8R,8'R)-lyoniresinol 9-O-β-D-(6″-O-trans-sinapoyl)glucopyranoside (1), and a new iridoid glucoside, 10-O-trans-sinapoylgeniposide (2), together with eight known compounds, were isolated from the fruits of Gardenia jasminoides Ellis. The structures of the isolates were elucidated by extensive spectroscopic studies, including UV, IR, 1D and 2D NMR, ESI-MS, HR-ESI-MS, and CD experiments. The short-term-memory-enhancement activities of some compounds were evaluated on an Aβ transgenic drosophila model.

Topics: Alzheimer Disease; Animals; Animals, Genetically Modified; Disease Models, Animal; Drosophila; Fruit; Gardenia; Glycosides; Humans; Iridoids; Lignans; Memory, Short-Term; Molecular Structure; Nootropic Agents; Phytotherapy; Plant Extracts

Geniposide, a main iridoid glucoside component of gardenia fruit, has been shown to possess anti-inflammatory activity. However, its potential use for acute lung injury (ALI) has not yet been studied. The aim of this study was to evaluate the anti-inflammatory properties of geniposide using a mouse ALI model. ALI was induced by intranasal injection of lipopolysaccharide (LPS). Pretreatment of mice with geniposide (20, 40, or 80 mg/kg) resulted in a marked reduction in inflammatory cells and total protein concentration in the bronchoalveolar lavage fluid (BALF) of mice. Levels of inflammatory mediators, including tumour necrosis factor- α (TNF- α), interleukin-6 (IL-6), and interleukin-10 (IL-10), were significantly altered after treatment with geniposide. Histological studies using hematoxylin and eosin (H&E) staining demonstrate that geniposide substantially inhibited LPS-induced alveolar wall changes, alveolar haemorrhage, and neutrophil infiltration in lung tissue, with evidence of reduced myeloperoxidase (MPO) activity. In addition, we investigated potential signal transduction mechanisms that could be implicated in geniposide activity. Our results suggest that geniposide may provide protective effects against LPS-induced ALI by mitigating inflammatory responses and that the compound's mechanism of action may involve blocking nuclear factor-kappaB (NF- κB) and mitogen-activated protein kinases (MAPK) signalling pathway activation.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Fruit; Gardenia; Iridoid Glucosides; Iridoids; Lipopolysaccharides; Lung; Male; Mice; Mice, Inbred BALB C; Mitogen-Activated Protein Kinase Kinases; NF-kappa B; Peroxidase; Plants, Medicinal; Random Allocation; Signal Transduction

Barleria prionitis Linn. (Family: Acanthaceae), one of the important Ayurvedic medicinal plant in India, has long been used to treat variety of ailments including swellings, gout, arthritic and rheumatic disorders, nervine and skin diseases, and also acts as immunorestorative.. The present study was aimed to explore in vitro and in vivo immunomodulatory activities of the iridoids fraction i.e. n-butanol fraction of methanol extract from Barleria prionitis aerial parts (IFBp).. IFBp was studied for in vitro [nitroblue tetrazolium (NBT) test and neutrophils candidacidal assay] and in vivo immunomodulatory activity on cellular and humoral immune responses to the antigenic challenge by sheep red blood cells (SRBCs) and by neutrophil adhesion test, phagocytic activity and cyclophosphamide-induced myelosuppression. The study comprised the preliminary phytochemical screening, HPTLC standardization and maximum tolerable dose determination of IFBp.. IFBp (50, 100 and 200μg/ml) significantly (P≤0.01) increased the intracellular killing activity of stimulated neutrophils assayed by in vitro NBT reduction test and neutrophils candidacidal assay. Pretreatment of IFBp (100 and 200mg/kg; p.o.) evoked a significant increase in percent neutrophils and neutrophils adhesion to nylon fibres. Oral administration of IFBp augmented the humoral immune response to SRBCs, evidenced by increase in antibody titres and dose dependently potentiated the delayed-type hypersensitivity reaction induced by SRBCs in mice. IFBp potentiated significantly (P≤0.01) the macrophage phagocytic activity and ameliorated the red blood cells, total white blood cells and platelets count and haemoglobin concentration, and also restored the myelosuppressive effects induced by cyclophosphamide. The content (% w/w; mean±SD, n=3) of main iridoids i.e. shanzhiside methyl ester and barlerin was found to be 21.55±2.40 and 10.03±1.69 in IFBp of BP, respectively.. The present investigation reveals that IFBp is a potent immunostimulant, stimulating both the specific and non-specific immune mechanisms.

Topics: 1-Butanol; Acanthaceae; Adjuvants, Immunologic; Animals; Bone Marrow Diseases; Candida albicans; Cell Adhesion; Cyclophosphamide; Disease Models, Animal; Erythrocytes; Hemagglutination; Hemagglutination Tests; Humans; Hypersensitivity, Delayed; Immunity, Cellular; Immunity, Humoral; Iridoids; Male; Maximum Tolerated Dose; Methanol; Mice; Neutrophil Activation; Neutrophils; Phagocytosis; Phytotherapy; Plant Components, Aerial; Plants, Medicinal; Sheep; Solvents; Time Factors

Stem cell transplantation has been widely acknowledged for their immense potential in regenerative medicine. In these procedures, the implanted cells need to maintain both their viability and functional properties for effective therapeutic outcomes. This has long been a subject of major concern and intensive studies. Microencapsulation of stem cells within polymeric microcapsules can be an efficient approach to achieve this goal, particularly for heart diseases. This study reports the use of biocompatible, fluorogenic genipin-cross-linked alginate chitosan (GCAC) microcapsules in delivery of human adipose stem cells (hASCs) with an aim to increase the implant retention in the infarcted myocardium for maximum clinical benefits. In vitro results show, under hypoxic conditions, the microencapsulated cells overexpressed significantly higher amount of biologically active vascular endothelial growth factor (VEGF). We investigated on the in vivo potential using immunocompetent female rats after induction of myocardial infarction. For this, animal groups (n = 8) received empty control microcapsules, 1.5 × 10(6) free male hASCs, or 1.5 × 10(6) microencapsulated male hASCs. Results show significant retention (3.5 times higher) of microencapsulated hASCs compared to free hASCs after 10 weeks of transplantation. Microencapsulated hASCs showed significantly attenuated infarct size compared to free hASCs and empty microcapsule group (21.6% ± 1.1% vs. 27.2% ± 3.1% vs. 33.3% ± 3.2%; p < 0.05), enhanced vasculogenesis, and improved cardiac function (fractional shortening: 24.2% ± 2.1% vs. 19.1% ± 0.5% vs. 12.0% ± 4.0%; p < 0.05). These data suggest that microencapsulated hASCs can contribute significantly to the improvement in cardiac functions. Their greater retentions exhibit reduced fibrosis and cardiac dysfunction in experimental animals. However, further research is needed to fully comprehend the underlying biological and immunological effects of microencapsulated hASCs, which jointly play important roles in cardiac repair.

Topics: Adipocytes; Alginates; Animals; Cell Differentiation; Cells, Cultured; Chitosan; Coronary Vessels; Disease Models, Animal; Female; Glucuronic Acid; Hexuronic Acids; Humans; Iridoids; Male; Myocardial Infarction; Myocardium; Neovascularization, Pathologic; Rats; Rats, Inbred Lew; Regenerative Medicine; Stem Cell Transplantation; Stem Cells; Vascular Endothelial Growth Factor A

Refined Qing-Kai-Ling (QKL), a modified Chinese medicine, consists of three main ingredients (Baicalin, Jasminoidin and Desoxycholic acid), plays a synergistic effect on the treatment of the acute stage of ischemic stroke. However, the rules of the combination and synergism are still unknown. Based on the ischemic stroke mice model, all different kinds of combination of Baicalin, Jasminoidin, and Desoxycholic acid were investigated by the methods of neurological examination, microarray, and genomics analysis. As a result, it confirmed that the combination of three drugs offered a better therapeutical effect on ischemic stroke than monotherapy of each drug. Additionally, we used Ingenuity pathway Analysis (IPA) and principal component analysis (PCA) to extract the dominant information of expression changes in 373 ischemia-related genes. The results suggested that 5 principal components (PC1-5) could account for more than 95% energy in the gene data. Moreover, 3 clusters (PC1, PC2+PC5, and PC3+PC4) were addressed with cluster analysis. Furthermore, we matched PCs on the drug-target networks, the findings demonstrated that Baicalin related with PC1 that played the leading role in the combination; Jasminoidin related with PC2+PC5 that played a compensatory role; while Desoxycholic acid had the least performance alone which could relate with PC3+PC4 that played a compatible role. These manifestations were accorded with the principle of herbal formulae of Traditional Chinese Medicine (TCM), emperor-minister-adjuvant-courier. In conclusion, we firstly provided scientific evidence to the classic theory of TCM formulae, an initiating holistic viewpoint of combination therapy of TCM. This study also illustrated that PCA might be an applicable method to analyze the complicated data of drug combination.

Topics: Animals; Cluster Analysis; Computational Biology; Deoxycholic Acid; Disease Models, Animal; Drug Combinations; Drugs, Chinese Herbal; Enzyme Inhibitors; Flavonoids; Gene Expression Profiling; Gene Expression Regulation; Iridoids; Ischemia; Male; Mice; Models, Statistical; Oligonucleotide Array Sequence Analysis; Polymerase Chain Reaction; Principal Component Analysis; Stroke

To investigate the anti-anaphylactic, anti-inflammatory and membrane stabilizing properties of plumerianine (compound 1) isolated from the root bark of Plumeria acutifolia Poir.. The anti-anaphylactic activity of compound 1 (10, 25 and 50 mg/kg) was studied by using models such as passive cutaneous anaphylaxis, passive paw anaphylaxis and its anti-inflammatory activity against carrageenin induced paw edema and cotton pellet granuloma in albino rats was also investigated using ketotifen and indomethacin as reference drugs.. A dose-dependent beneficial effect was observed on leakage of evans blue dye in skin challenged with antigen and on paw anaphylaxis induced by antiserum. The compound 1 also exhibited significant (P<0.01) inhibition of rat paw edema and granuloma tissue formation, including significant protection of RBC against the haemolytic effect of hypotonic solution, an indication of membrane-stabilizing activity.. Anti-anaphylactic activity of compound 1 may be possibly due to inhibition of the release of various inflammatory mediators. Anti-inflammatory activity of compound may be related to the inhibition of the early phase and late phase of inflammatory events.

Topics: Anaphylaxis; Animals; Anti-Allergic Agents; Anti-Inflammatory Agents; Apocynaceae; Disease Models, Animal; Erythrocyte Membrane; Erythrocytes; Female; Iridoids; Male; Mice; Plant Bark; Plant Extracts; Rats, Wistar

Penstemon gentianoides (Kunth) Poir. and Penstemon campanulatus (Cav.) Willd. (Plantaginaceae) are important medicinal plants in Mexico used by indigenous people for their anti-inflammatory effects and to also reduce rheumatic pains.. In addition to radical scavenging activity, the anti-inflammatory activity of the extracts, fractions and compounds of these plants were investigated and reported here for the first time.. The anti-inflammatory activities of MeOH, CH(2)Cl(2), and ethyl acetate extracts and iridoid, flavonoids, and phenylpropanoids from Penstemon gentianoides and P. campanulatus were studied in the TPA-induced mouse ear edema model. In addition, antioxidant activity against DPPH, crocin and β-carotene were investigated.. All extracts were tested and a selection of known compounds significantly (p <0.05) inhibited mouse ear edema. The results showed that CH(2)Cl(2) extracts of roots and stems from P. gentianoides and ethyl acetate extracts of leaves from P. gentianoides and P. campanulatus, as well as luteolin, diosmetin, penstemide and verbascoside produced the most positive results. Of all substances tested, the CH(2)Cl(2) extract of P. gentianoides roots was the most powerful inhibitor (ED(50)=0.07 mg/ear), with activity comparable to that of indomethacin. These extracts, compounds purified, as well as known compounds, inhibited oxidation of β-carotene and crocin.. These findings showed that the iridoid monoterpenes, flavonoids and phenylpropanoids present in these plants species may all contribute to the observed anti-inflammatory activity. Additionally, the observed antioxidant activity is correlated with the anti-inflammatory activity of these plants and the phytochemicals derived from them.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Disease Models, Animal; Edema; Flavonoids; Indomethacin; Inflammation; Iridoids; Male; Medicine, Traditional; Mexico; Mice; Penstemon; Plant Extracts; Rats; Rats, Wistar; Solvents

Oleuropein, a secoiridoid derived from olives and olive oil, has been known to possess antimicrobial, antioxidative, and anticancer activities. The purpose of the present study was to determine whether oleuropein has a protective effect against hepatic steatosis induced by a high fat diet (HFD) and to elucidate its underlying molecular mechanisms in mice.. Male C57BL/6N mice were fed a normal diet (ND), HFD, or an oleuropein-supplemented diet (OSD) for 10 weeks. The plasma and hepatic lipid levels were determined, and the hepatic gene and protein expression levels were analysed via RT-PCR and Western blotting, respectively.. The supplementation of HFD with oleuropein reversed the HFD-induced increases in liver weight along with plasma and hepatic lipid levels in mice. The expression of Wnt10b inhibitor genes, such as secreted firizzed-related sequence protein 5 and dickkopf homolog 2, was downregulated, whereas the β-catenin protein expression was upregulated in the liver of OSD-fed mice compared to HFD-fed mice. Fibroblast growth factor receptor 1 (FGFR1), phosphoextracellular-signal-regulated kinase 1/2, cyclin D, and E2F transcription factor 1, along with several key transcription factors and their target genes involved in adipogenesis, were downregulated by oleuropein. OSD-fed mice exhibited decreased expression of the toll-like-receptor-(TLR)-mediated signaling molecules (TLR2, TLR4, and myeloid differentiation primary-response gene 88) and proinflammatory cytokines, in their livers, as compared to HFD mice.. These results suggest that the protective effects of oleuropein against HFD-induced hepatic steatosis in mice appear to be associated with the Wnt10b- and FGFR1-mediated signaling cascades involved in hepatic lipogenesis, along with the TLR2- and TLR4-mediated signaling implicated in hepatic steatosis.

Topics: Animals; Antioxidants; beta Catenin; Body Weight; Dietary Fats; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Fatty Liver; Gene Expression; Iridoid Glucosides; Iridoids; Lipogenesis; Liver; Liver Cirrhosis; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Organ Size; Pyrans; Signal Transduction; Toll-Like Receptors

Nonalcoholic steatohepatitis (NASH), a metabolic disorder of the liver, may gradually evolve into fibrosis or cirrhosis. Recent studies have suggested that geniposide can effectively inhibit experimental liver fibrosis. Therefore, the aim of this study was to determine whether geniposide can influence the early phase of fibrogenesis in an animal model of NASH.. Male Sprague-Dawley rats were given a high fat diet alone or the same diet combined with geniposide at doses of 25, 50 or 100 mg/kg for six weeks. Ten rats received corresponding solvent as a normal control.. Treatment with geniposide could improve liver histology through reducing the elevated liver index (liver weight/body weight), serum alanine aminotransferase and aspartate aminotransferase. Total cholesterol, triglycerides and free fatty acids in serum and liver decreased in geniposide-treated rats. Furthermore, geniposide increased serum insulin levels but reduced serum tumour necrosis factor-α level in high-fat diet rats. In addition, geniposide suppressed expression of CYP2E1 and increased peroxisome proliferator-activated receptor-α (PPARα) expression. These benefits may be associated with increased superoxide dismutase and decreased malondialdehyde in liver.. Geniposide exerts protective effects against hepatic steatosis in rats fed with a high fat diet; the underlying mechanism may be associated with its antioxidant actions or regulation of adipocytokine release and expression of PPARα.

Topics: Alanine Transaminase; Animals; Anti-Inflammatory Agents; Aspartate Aminotransferases; Cytochrome P-450 CYP2E1; Dietary Fats; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Fatty Liver; Insulin; Iridoids; Lipid Metabolism; Male; Malondialdehyde; Non-alcoholic Fatty Liver Disease; PPAR alpha; Rats; Rats, Sprague-Dawley; Superoxide Dismutase; Tumor Necrosis Factor-alpha

Several olive oil phenolic compounds, such us oleuropein have attracted considerable attention because of their antioxidant activity, anti-atherosclerotic and anti-inflammatory properties. The aim of this study was to investigate the effects of oleuropein aglycone, a hydrolysis product of oleuropein, in a mouse model of carrageenan-induced pleurisy.. Mice were anaesthetized and subjected to a skin incision at the level of the left sixth intercostals space. The underlying muscle was dissected and saline or saline containing 2% λ-carrageenan was injected into the pleural cavity.. Injection of carrageenan elicited an acute inflammatory response characterized by: infiltration of neutrophils in lung tissues (P < 0.01 versus sham. P < 0.01 versus carrageenan) and subsequent lipid peroxidation (P < 0.01 versus sham. P < 0.01 versus carrageenan), increased production of tumor necrosis factor-α and interleukin-1β (P < 0.01 versus sham. P < 0.01 versus carrageenan), increased expression of adhesion molecules, increased synthesis of nitric oxide (P < 0.01 versus sham. P < 0.01 versus carrageenan), nitrotyrosine and poly-ADP-ribose (P < 0.01 versus sham. P < 0.01 versus carrageenan). Administration of oleuropein aglycone 30 min after the challenge with carrageenan, caused a significant reduction of all the parameters of inflammation measured.. Thus, we propose that olive oil phenolic constituents may be useful in the treatment of various inflammatory diseases.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Carrageenan; Disease Models, Animal; Hydrolysis; Intercellular Adhesion Molecule-1; Interleukin-1beta; Iridoid Glucosides; Iridoids; Lipid Peroxidation; Lung; Male; Mice; Nitric Oxide; Olive Oil; P-Selectin; Phenols; Plant Oils; Pleurisy; Poly Adenosine Diphosphate Ribose; Pyrans; Tumor Necrosis Factor-alpha; Tyrosine

The aim of this study was to investigate the effect of oleuropein aglycone, an olive oil compound, on the modulation of the inflammatory response in mice subjected to collagen-induced arthritis (CIA). CIA was induced in mice by an intradermal injection of 100 μl of an emulsion containing 100 μg of bovine type II collagen (CII) and complete Freund's adjuvant (CFA) at the base of the tail. On day 21, a second injection of CII in CFA was administered. Mice developed erosive hind paw arthritis when immunized with CII in CFA. Macroscopic clinical evidence of CIA first appeared as periarticular erythema and edema in the hind paws. The incidence of CIA was 100% by day 28 in the CII-challenged mice and the severity of CIA progressed over a 35-day period with resorption of bone. The histopathology of CIA included erosion of the cartilage at the joint. Treatment with oleuropein aglycone starting at the onset of arthritis (day 25) ameliorated the clinical signs at days 26 to 35 and improved histological status in the joint and paw. The degree of oxidative and nitrosative damage was also significantly reduced in oleuropein aglycone-treated mice. Plasma levels of the proinflammatory cytokines were also significantly reduced by oleuropein aglycone. In addition, we have confirmed the beneficial effects of oleuropein aglycone on an experimental model of CIA in a therapeutic regimen of post-treatment, with treatment started at day 28, demonstrating that oleuropein aglycone exerts an anti-inflammatory effect during chronic inflammation and ameliorates the tissue damage associated with CIA.

Topics: Alcohol Oxidoreductases; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Cattle; Collagen Type II; Cytokines; Dinoprostone; Disease Models, Animal; Disease Progression; Drug Administration Schedule; Drug Evaluation, Preclinical; Iridoid Glucosides; Iridoids; Joints; Male; Mice; Mice, Inbred DBA; Nitric Oxide Synthase Type II; Olive Oil; Peroxidase; Plant Oils; Pyrans

Diabetes mellitus can cause dysfunction of the central nervous system called "diabetic encephalopathy." Although insulin and various oral drugs are used to treat diabetes, they do not completely prevent the development of diabetic encephalopathy, and novel strategies for the prevention and treatment are urgently needed. Catalpol, an iridoid glycoside, has properties of anti-inflammation, antioxidant and decreasing blood glucose level and thus has the possibility of treating diabetic encephalopathy. Therefore, the study was designed to investigate the effects of catalpol on diabetic encephalopathy in rats. A single dose of 65 mg/kg streptozotocin was injected intraperitoneally to induce diabetes. Intragastric infusion of catalpol was performed for 6 weeks with the doses of 10, 50 and 100 mg/kg, respectively. The Y-type maze test, biochemical measurement, Nissl staining and the terminal deoxynucleotidyl transferase-mediated UTP nick end labeling methods were used to evaluate the neuropathological changes and the effects of catalpol on diabetic rats. The results showed that streptozotocin-induced diabetes produced obvious neuron damage and cognitive dysfunction coupling with markedly increased oxidative stress in the brain. Long-term oral supplementation of catalpol improved neuronal injury and cognitive dysfunction by attenuating oxidative stress. The effects that catalpol could both increase the nerve growth factor concentration and decrease the blood glucose level were related with the function of defending against oxidative stress of catalpol. The study suggested that oral supplementation of catalpol might be a potential therapeutic strategy for the treatment and/or prevention of diabetic encephalopathy.

Topics: Administration, Oral; Animals; Behavior, Animal; Blood Glucose; Body Weight; Catalase; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Dietary Supplements; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Glucosides; Glutathione Peroxidase; In Situ Nick-End Labeling; Iridoid Glucosides; Iridoids; Lipid Peroxidation; Male; Malondialdehyde; Maze Learning; Nerve Growth Factor; Oxidative Stress; Rats; Rats, Sprague-Dawley; Superoxide Dismutase; Time Factors

The traditional Japanese (kampo) medicine inchinkoto (ICKT) is used in Eastern Asia as a choleretic and hepatoprotective agent. Previously, we reported that ICKT ameliorates murine concanavalin A (con A)-induced hepatitis via suppression of interferon (IFN)-gamma and interleukin (IL)-12 production. In the present study, we investigated the active ingredients of ICKT.. ICKT and extracts of its component herbs were fractionated, and their effects on liver injury and cytokine production in vivo (biochemical markers of liver injury and cytokine levels in serum) and in vitro (cytokine and nitrite production in the cultures of splenocytes and peritoneal macrophages).. Decoctions of component herbs, Artemisiae Capillari Spica (Artemisia capillaris Thunberg: 'Inchinko' in Japanese), Gardeniae Fructus (Gardenia jasminoides Ellis: 'Sanshishi') and Rhei Rhizoma (Rheum palmatum Linné: 'Daio') were administered orally. Inchinko and Sanshishi decreased serum transaminases and IFN-gamma concentrations. Examination of fractions of component herbs suggested that capillarisin, a component of Inchinko, has potent hepatoprotective activity in vivo. In in vitro studies, capillarisin and genipin, an intestinal metabolite of geniposide that is contained in Sanshishi, were examined. IFN-gamma production was significantly suppressed by capillarisin and genipin in con A-stimulated splenocyte culture. Genipin also suppressed IL-1beta, IL-6, and IL-12p70 synthesis. Capillarisin and genipin decreased nitrite release from IFN-gamma-stimulated macrophages.. These results suggested that both Inchinko and Sanshishi may contribute to the protective effects of ICKT against con A hepatitis. Capillarisin was found to be potently hepatoprotective, and genipin may also contribute, especially via modulation of cytokine production.

Topics: Animals; Artemisia; Chemical and Drug Induced Liver Injury; Chromones; Concanavalin A; Cytokines; Disease Models, Animal; Gardenia; Hepatitis; Interferon-gamma; Iridoid Glycosides; Iridoids; Liver; Macrophages; Magnoliopsida; Male; Medicine, Kampo; Mice; Mice, Inbred BALB C; Nitrites; Phytotherapy; Plant Extracts; Rheum; Transaminases

Oxidative stress may play an important role in the pathogenesis of non-alcoholic steatohepatitis (NASH). Oleuropein, the active constituent of olive leaf, possesses anti-oxidant, hypoglycaemic, and hypolipidaemic activities. We aimed to investigate the preventive effects of olive leaf extract on hepatic fat accumulation in a rat model of NASH.. Spontaneously hypertensive/NIH-corpulent rats were fed a diet of AIN-93G with or without olive leaf extract (500, 1000, 2000 mg/kg diet, and control; 5 rats each) for 23 weeks. Serological and histopathological findings, anti-oxidative activity, and the alteration of fatty acid synthesis in the liver were evaluated.. Histopathologically, a diet of AIN-93G containing more than 1000 mg/kg olive leaf extract had a preventive effect for the occurrence of NASH. Thioredoxin-1 expression in the liver was more evident in rats fed this diet, and 4-hydroxynonenal expression in the liver was less evident in these rats. There were no significant differences in the activities of hepatic carnitine palmitoyltransferase, fatty acid synthase, malic enzyme, and phosphatidic acid phosphohydrolase among the groups.. Our data suggest that olive leaf extract may help prevent NASH, presumably through its anti-oxidative activity.

Topics: Aldehydes; Animal Feed; Animals; Antioxidants; Blood Chemical Analysis; Disease Models, Animal; Fatty Liver; Iridoid Glucosides; Iridoids; Liver; Male; Olea; Organ Size; Oxidative Stress; Plant Leaves; Pyrans; Rats; Rats, Inbred SHR; Thioredoxins

The protective effect of an iridoid catalpol extracted and purified from the traditional Chinese medicinal herb Rehmannia glutinosa on the neuronal degeneration of nigral-striatal dopaminergic pathway was studied in a chronic 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine (MPTP)/probenecid C57BL/6 mouse model and in 1-methyl-4-phenylpyridimium (MPP(+)) intoxicated cultured mesencephalic neurons. Rotarod performance revealed that the locomotor ability of mice was significantly impaired after completion of model production and maintained thereafter for at least 4 weeks. Catalpol orally administered for 8 weeks (starting from the second week of model production) dose dependently improved the locomotor ability. HPLC revealed that catalpol significantly elevated striatal dopamine levels without changing the metabolite/dopamine ratios. Nor did it bind to dopamine receptors. Therefore it is unlikely that catalpol resembles any of the known compounds for treating Parkinsonism. Instead, catalpol dose dependently raised the tyrosine hydroxylase (TH) neuron number in substantia nigra pars compacta (SNpc), the striatal dopamine transporter (DAT) density and the striatal glial cell derived neurotrophic factor (GDNF) protein level. Linear regression revealed that both the TH neuron number and DAT density were positively correlated to the GDNF level. In the cultured mesencephalic neurons, MPP(+) decreased the dopaminergic neuron number and shortened the neurite length, whereas catalpol showed protective effect dose dependently. Furthermore, the expression of GDNF mRNA was up-regulated by catalpol to a peak nearly double of normal control in neurons intoxicated with MPP(+) for 24 h but not in normal neurons. The GDNF receptor tyrosine kinase RET inhibitor 4-amino-5-(4-methyphenyl)-7-(t-butyl)-pyrazolo-[3,4-d]pyrimidine (PP1) abolished the protective effect of catalpol either partially (TH positive neuron number) or completely (neurite length). Taken together, catalpol improves locomotor ability by attenuating the neuronal degeneration of nigral-striatal dopaminergic pathway, and this attenuation is at least partially through elevating the striatal GDNF expression.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Brain; Cells, Cultured; Chronic Disease; Corpus Striatum; Disease Models, Animal; Dopamine; Dose-Response Relationship, Drug; Glial Cell Line-Derived Neurotrophic Factor; Glucosides; Iridoid Glucosides; Iridoids; Male; Mesencephalon; Mice; Mice, Inbred C57BL; Motor Activity; Nerve Degeneration; Neural Pathways; Neurons; Neuroprotective Agents; Probenecid; Substantia Nigra

The present study aimed to investigate the antidepressant potential of genipin and its possible mechanisms. Mouse models of depression including the forced swimming test (FST) and the tail suspension test (TST) were used to evaluate the effects of genipin. A possible mechanism was explored in the test of antagonism of reserpine-induced ptosis and hypothermia in mice. The contents of monoamine neurotransmitters and their metabolites including epinephrine (NE), 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in mice hippocampi were determined by HPLC-ECD. The results showed that intra-gastric administration of genipin at 50, 100, 200mg/kg or fluoxetine at 7.5mg/kg for 7 days significantly reduced the duration of immobility in FST and TST, while it did not affect the locomotor activity in the open field test (OFT). However, the effect was not dose-dependent. When the mice were treated with genipin or fluoxetine for 7 days, both of them could antagonize reserpine-induced ptosis and hypothermia. The 5-HT and NE contents in mice hippocampi were decreased after the peritoneal injection of reserpine at 2.0mg/kg. The pre-treatment with genipin at 50, 100, 200mg/kg or fluoxetine at 7.5mg/kg for 7 days could elevate the contents of NE and 5-HT in mice hippocampi significantly. The results suggest that compared with fluoxetine, genipin exerts antidepressant-like effects significantly. A possible mechanism, at least in part, is the regulation of the 5-HT and NE levels in the hippocampus.

Topics: Animals; Antidepressive Agents; Behavior, Animal; Biogenic Monoamines; Blepharoptosis; Depression; Disease Models, Animal; Fluoxetine; Hindlimb Suspension; Hippocampus; Hypothermia; Iridoid Glycosides; Iridoids; Male; Mice; Mice, Inbred ICR; Motor Activity; Reserpine

To study the effect of geniposide on treating experimental CP rats.. The animal model of CP was made with rats by injecting hemorrhoid injection. Rats in experiment group were randomly devided into model group, Qianliekang tablets group (2 g x kg(-1)) and geniposide high, middle, low dose groups (20, 10, 5 mg x kg(-1)). Subsequently, the state of all rats, prostate index, WBC and lecithine corpuscle, LDH5/LDH1, and prostatic histopathological changes were observed. Count of total cellular score (TCS) and quantitation of inflammatory cell, fibroblasts, glandular organ, calculation of glandular cavity area, and their changes of morphology were analyzed.. Compared with model group, the prostate index, WBC and LDHS/LDH1 of the rats in Qianliekang tablets group, high dose geniposide group and middle dose geniposide group were significantly decreased, while the quantities of lecithine corpuscle were remarkably increased (P < 0.01 or P < 0.05). Compared with model group, the number of inflammatory cells and fibroblasts in Qianliekang tablets group, high dose geniposide group were decreased, and the quantity of glandular organ and area of glandular cavity in these groups were increased (P < 0.05 or P < 0.01).. Geniposide of high and middle dose can reduce leucocytes infiltration, restrain the hyperplasia of fibrous tissue, and recover the secretion function of prostate. It show that geniposide is significantly potential to cure rats which are exposed to chronic prostatitis.

Topics: Animals; Body Weight; Chronic Disease; Disease Models, Animal; Dose-Response Relationship, Drug; Iridoids; Isoenzymes; L-Lactate Dehydrogenase; Lactate Dehydrogenase 5; Leukocyte Count; Male; Prostate; Prostatitis; Rats; Rats, Sprague-Dawley

To study the antitumor effect of phlomiol extracted from Phlomis younghusbandii in vivo and in vitro. The inhibitory effect of phlomiol on two kinds of human tumor cells proliferation was assayed by MTT method. Transplant tumor models of S180 and H22 were used. After transplantation, different doses of phlomiol were given to the mice for 14 days. The inhibitory rates were calculated. MTT method was used to assess the proliferation of T spleen lymphocyte cells and the activity of NK cells in tumor-bearing mice with S180. Phlomiol (50-100 mg x L(-1)) inhibited the proliferation of three kinds of tumor cells in vitro, antitumor effect of phlomiol was in a dose-dependent manner (r = 0.989, P < 0.05). The inhibitory rates of phlomiol (2.5, 5, 10 mg x kg(-1)) were 28.5%-65.0% and 35.0%-74.5% in tumor-bearing mice with S180 and H22 respectively, It could stimulate the spleen T-cells in tumor-bearing mice with S180 and increase the activity of the NK cells. Phlomiol could inhibit the proliferation of three kinds of tumor cells in vitro, present antitumor effect on the tumor-bearing mice, and improve the immunological function.

Topics: Animals; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Humans; Iridoid Glucosides; Iridoids; Lymphocytes; Male; Mice; Mice, Inbred ICR; Neoplasms; Phlomis

Oleuropein, an active constituent of olive leaf, has a variety of pharmacological activities associated with its capacity to scavenge reactive oxygen species. Oleuropein is also reported to have protective effects against non-alcoholic fatty liver disease (NAFLD) in vivo. In this study, gene expression profiling of hepatic tissues was examined, and transcription factors (TFs) with target genes that were modulated by oleuropein were identified to gain insights into the molecular mechanisms for the hepatoprotective action of this compound. C57BL/6N mice were fed either a high-fat diet (HFD) or 0.03% oleuropein-supplemented HFD for 10 weeks, after which their livers were subjected to oligo DNA microarray analysis. The oleuropein with which the HFD was supplemented reduced the hepatic mRNA level of the genes that encoded the key regulators of the hepatic fatty acid uptake and transport. In addition, the oleuropein reduced the expression of a number of hepatic genes involved in the oxidative stress responses and detoxification of lipid peroxidation products and proinflammatory cytokine genes. The (putative) candidate TFs that bound to the promoters of the genes regulated at least threefold (both up and down) by oleuropein were implicated in the lipogenesis, inflammation, insulin resistance, fibrosis, and cell proliferation and differentiation, which implies that the mechanisms that underlie the beneficial effects of oleuropein on NAFLD may be multifactorial.

Topics: Animals; Dietary Fats; Disease Models, Animal; Fatty Liver; Gene Expression Profiling; Gene Expression Regulation; Iridoid Glucosides; Iridoids; Lipid Metabolism; Liver; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Nutrigenomics; Oligonucleotide Array Sequence Analysis; Pyrans; Transcription Factors

We examined anti-amnesic activity of the methanolic extract of Cornus officinalis fruits (COT) and a major constituent, loganin using scopolamine-induced (1 mg/kg body weight, s.c.) amnesic mice with both passive avoidance and the Morris water maze tests. Oral treatment of mice with COT (100 mg/kg body weight) and loganin (1 and 2 mg/kg body weight) significantly mitigated scopolamine-induced memory deficits in passive avoidance test. In the Morris water maze test, oral treatment of loganin significantly ameliorated scopolamine-induced memory deficits showing the formation of long-term and/or short-term spatial memory. Moreover, loganin (2 mg/kg body weight) significantly inhibited acetylcholinesterase activity by as much as 45% of control in the mouse hippocampus. These results indicate that loganin may exert antiamnesic activity in in vivo through acetylcholinesterase inhibition.

Topics: Acetylcholinesterase; Administration, Oral; Amnesia; Animals; Avoidance Learning; Behavior, Animal; Cholinesterase Inhibitors; Cognition; Cornus; Disease Models, Animal; Dose-Response Relationship, Drug; Fruit; Hippocampus; Iridoids; Male; Memory, Short-Term; Mice; Mice, Inbred ICR; Nootropic Agents; Scopolamine; Time Factors

Jasminum officinale L. var. grandiflorum (JOG) is a folk medicine used for the treatment of hepatitis in south of China. Phytochemical studies showed that secoiridoid glycosides are the typical constituents of this plant.. The present study was undertaken to evaluate the effect of oleuropein (Ole) derived from the flowers of JOG on hepatitis B virus (HBV) replication in HepG2 2.2.15 cell line in vitro and duck hepatitis B virus (DHBV) replication in ducklings in vivo.. The extracellular hepatitis B e antigen (HBeAg) and hepatitis B surface antigen (HBsAg) concentrations in cell culture medium were determined by ELISA. DHBV in duck serum was analyzed by dot blot.. Ole blocks effectively HBsAg secretion in HepG2 2.2.15 cells in a dose-dependent manner (IC(50)=23.2 microg/ml). Ole (80 mg/kg, intraperitoneally, twice daily) also reduced viremia in DHBV-infected ducks.. Ole therefore warrants further investigation as a potential therapeutic agent for HBV infection.

Topics: Animals; Antiviral Agents; Cell Line; Disease Models, Animal; Dose-Response Relationship, Drug; Ducks; Flowers; Hepatitis B; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B Virus, Duck; Hepatitis, Viral, Animal; Humans; Iridoid Glucosides; Iridoids; Jasminum; Phytotherapy; Plant Extracts; Pyrans; Viremia; Virus Replication

The purpose of this work is to study the effect of catalpol, an iridoid from Rehmannia glutinosa on neurodegenerative changes induced by beta-amyloid peptide Abeta(25-35) or Abeta(25-35)+ibotenic acid and the underlying mechanism. Results showed that catalpol significantly improved the memory deficits in the neurodegenerative mouse model produced by injection of Abeta(25-35)+ibotenic acid to the nucleus magnocellularis basalis, yet it is neither a cholinesterase inhibitor nor a muscarinic (M) receptor agonist. Instead, the choline acetyl transferase (ChAT) activity and the M receptor density in brain were significantly decreased in the model mice and catalpol could significantly elevate their levels. Furthermore, the brain-derived neurotrophic factor (BDNF) content in brain was significantly decreased in the model mice and catalpol elevated it to normal level (83%+/-3% and 102%+/-2% of normal respectively). There is a significant positive correlation between BDNF content and memory. Primary culture of forebrain neurons revealed that aggregated Abeta(25-35) induced significant decrease of ChAT positive neuron number, neurite outgrowth length, and M receptor density, while catalpol added to the culture medium 2 h prior to Abeta addition showed significant dose dependent protective effect. Notably, 24 h and 48 h after the addition of Abeta to the cultured cells, the BDNF mRNA level in the neurons decreased to 76%+/-7% and 66%+/-3% of control without catalpol treatment, but became 128%+/-17% and 131%+/-23% of control with catalpol treatment. When the action of BDNF was inhibited by k252a in the cultured neurons, the protective effect of catalpol was completely (neurite outgrowth length) or partially (ChAT positive neuron number and the M receptor density) abolished. Taken together, catalpol improves memory and protects the forebrain neurons from neurodegeneration through increasing BDNF expression. Whether catalpol could reverse the neurodegenerative changes already present before its application remains to be further studied.

Topics: Amyloid beta-Peptides; Animals; Brain; Brain-Derived Neurotrophic Factor; Cells, Cultured; Choline O-Acetyltransferase; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Glucosides; Iridoid Glucosides; Iridoids; Learning; Memory; Mice; Mice, Inbred ICR; Neurites; Neurodegenerative Diseases; Neurons; Neuroprotective Agents; Peptide Fragments; Rats; Rats, Sprague-Dawley; Receptors, Muscarinic

Seven new iridoid glucosides, 6''-O-trans-sinapoylgenipin gentiobioside (1), 6''-O-trans-p-coumaroylgenipin gentiobioside (2), 6''-O-trans-cinnamoylgenipin gentiobioside (3), 6'-O-trans-p-coumaroylgeniposide (4), 6'-O-trans-p-coumaroylgeniposidic acid (5), 10-O-succinoylgeniposide (6), and 6'-O-acetylgeniposide (7), two new monoterpenoids, 11-(6-O-trans-sinapoylglucopyranosyl)gardendiol (8) and 10-(6-O-trans-sinapoylglucopyranosyl)gardendiol (9), and three known ones, 6'-O-trans-sinapoylgeniposide (10), geniposide (11), and 10-O-acetylgeniposide (12), were isolated from the fruit of Gardenia jasminoides. The structures of these compounds were elucidated on the basis of 1D and 2D NMR spectra analyses. Furthermore, short-term memory assays on an Abeta transgenic drosophila model showed that compounds 4 and 6-12 can improve the short-term memory capacity to varying degrees, with compounds 4 and 7 being the most active ones, suggesting that these compounds may have a potential antagonism effect against Alzheimer's disease.

Topics: Alzheimer Disease; Animals; Animals, Genetically Modified; Disease Models, Animal; Drosophila; Fruit; Gardenia; Iridoids; Memory, Short-Term; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Stereoisomerism

Gardeniae fructus (GF) has been used in traditional medicine for the treatment of inflammatory disease.. To evaluate the therapeutic effect of GF gel on the resolution of ecchymoses in rats.. Fifty hind limbs (in 25 Sprague-Dawley rats) were evaluated. The ecchymoses were produced by dropping a 100-g weight from a height of 20 cm on the posterior side of the hind limbs 25 times. Then, 0.5 g of hydrolyzed GF extracted gel was applied to the right hind limbs and 0.5 g of gel without GF extract powder was applied to the left hind limbs. The area of the ecchymosis was measured, and histological analysis was performed.. The area affected by the ecchymosis after 5 days was 15% in the control group and 2% in the GF gel group (p=.002). The mean duration for the ecchymosis was 5.8 days in the control group and 4.5 days in the GF gel group. The extravasated red blood cells and inflammation were less prominent in the GF gel group than in the control group.. The results of this study showed that hydrolyzed gel of GF extract, containing genipin, was effective for the treatment of ecchymoses in a rat model.

Topics: Animals; Disease Models, Animal; Ecchymosis; Gardenia; Hydrogels; Iridoid Glycosides; Iridoids; Phytotherapy; Plant Extracts; Plant Structures; Rats; Rats, Sprague-Dawley

To study the effect of geniposide-acid(GA) on the anti-inflammatory action for adjuvant-induced arthritis (AA) rats and the proliferation of synoviocytes in AA rats and the feasible mechanism of apoptosis in vitro.. Forty-eight health male Wistar rats were divided randomly into six groups and were administered respectively with 200, 100, 50 mg x kg(-1) GA and 0.75 mg x kg(-1) MTX and normal sodium (normal or model control group) for four weeks when right posterior paw pads of rats excluding normal control group were injected intrademally with complete Freund's adjuvant after 19 days. The left posterior paws swelling degree, swelling inhibition ratio and arthritis index of secondary inflamation were detected. The TNF-alpha and IL-1beta proteins in serum of rats were assayed by enzyme linked immunosorbent assay (ELISA) kits. The synovial fibroblasts of AA rats were exposed to 1-4 micromol x L(-1) GA or 4 micromol x L(-1) MTX. The effect of GA on the proliferation of synoviocytes was detected by MTT assay. The morphologic change of apoptosis cells was observed by Hoechst/PI double stainning and fluorescence microscope. The rate of apoptosis cells was analyzed by flow cytometry. The mRNA expresstion of Bcl-2 and Bax gene was detected by reverse transcription PCR (RT-PCR).. 200 mg kg(-1) or 100 mg kg(-1) GA could decrease significantly the paw swelling degree, arthritis index and the level of TNF-alpha and IL-1beta proteins in serum of AA rats (P < 0.05 or P < 0.01) with 25.4%, 21.37% of the swelling inhibition ratio respectivly, 34.61%, 28% of protein inhibition ratio of TNF-alpha and 29.05%, 21.65% of that of IL-1beta. GA(1-4 micromol x L(-1)) inhibitated significantly the proliferation of synoviocytes culcured for 5 days. Flow cytometry showed that 1, 2, 4 micromol x L(-1) GA increased obviously the rate of apoptosis cells, the apoptosis ratios were 15.8%, 24.3%, 40.7% respectivly (P < 0.01). RT-PCR showed GA could decrease the expression level of Bcl-2 gene but increase that of Bax gene (P < 0.05 or P < 0.01).. GA could inhibit the secondary inflamation of AA rats and decrease the level of TNF-alpha and IL-1beta protein in the AA rats serum. GA could inhibit the proliferation of AA rat synoviocytes in vitro and induce apoptosis which mechanism was concerned with down-regulating the mRNA expression of Bcl-2 and up-regulating that of Bax.

Topics: Animals; Anti-Inflammatory Agents; Apoptosis; Arthritis, Experimental; Cytokines; Disease Models, Animal; Freund's Adjuvant; Glucosides; Humans; Iridoid Glucosides; Iridoids; Male; Random Allocation; Rats; Rats, Wistar; Synovial Fluid

We have studied scrovalentinoside, an iridoid with anti-inflammatory properties isolated from Scrophularia auriculata ssp. pseudoauriculata, as an anti-inflammatory agent in different experimental models of delayed-type hypersensitivity. We found that scrovalentinoside reduced the edema induced by oxazolone at 0.5 mg/ear and sheep red blood cells at 10 mg/kg. The observed effect occurred during the last phase or inflammatory response; during the earlier phase or induction of the delayed-type hypersensitivity reaction, no significant activity was noted. Thus, scrovalentinoside reduced both the edema and cell infiltration in vivo and reduced lymphocyte proliferation in vitro, affecting the cycle principally during the first 48 h. Whereas cells stimulated with phytohemagglutinin changed from the G(0)/G(1) phase to the S and G(2)/M phases, when these same cells were treated with scrovalentinoside (100 microM), they remained in the G(0)/G(1) phase. Finally, scrovalentinoside inhibited the production of the pro-inflammatory mediators' TNF-alpha, IFN-gamma, IL-1beta, IL-2, IL-4, LTB(4), and NO, but had no effect on the production of the anti-inflammatory cytokine IL-10.

Topics: Animals; Anti-Inflammatory Agents; Blotting, Western; Cell Cycle; Cell Proliferation; Disease Models, Animal; Edema; Female; Glycosides; Humans; Hypersensitivity, Delayed; Inflammation Mediators; Iridoid Glycosides; Iridoids; Macrophages; Mice; Oxazolone; Phytohemagglutinins; Plant Preparations; Plants, Medicinal; Rats; Receptors, Glucocorticoid; Scrophularia; T-Lymphocytes

Angiogenic therapies may need to select a stable agent to be delivered. In the study, a nonpeptide angiogenic agent, ginsenoside Rg(1) (Rg(1)), was encapsulated in the gelatin microspheres (MSs) crosslinked with genipin and intramuscularly injected into a rat model with infarcted myocardium. bFGF was used as a control. After swelling in an aqueous environment, the MSs without crosslinking became collapsed and stuck together. For those crosslinked, the swollen MSs appeared to be more stable with an increasing the degree of crosslinking. After it was released from MSs in vitro, the remaining activity of bFGF on HUVEC proliferation reduced significantly, while that of Rg(1) remained constant. An inspection of the retrieved hearts revealed a large aneurysmal left ventricle (LV) with a thinned myocardium and a significant myocardial fibrosis for that treated with the Empty MSs (without drug encapsulation). However, those receiving the MSs encapsulated with bFGF or Rg(1) attenuated the enlargement of the LV cavity and the development of myocardial fibrosis. The densities of microvessels found in the border zones of the infarct treated with the bFGF or Rg(1) MSs were significantly greater than that treated with the Empty MSs. These results indicated that Rg(1), a stable angiogenic agent, successfully enhanced the myocardial perfusion and preserved the infarcted LV function.

Topics: Angiogenesis Inducing Agents; Animals; Cell Proliferation; Cells, Cultured; Chemistry, Pharmaceutical; Coronary Circulation; Cross-Linking Reagents; Disease Models, Animal; Drug Carriers; Drug Compounding; Endothelial Cells; Feasibility Studies; Fibroblast Growth Factor 2; Fibrosis; Gelatin; Ginsenosides; Humans; Injections, Intramuscular; Iridoid Glycosides; Iridoids; Male; Microspheres; Myocardial Infarction; Neovascularization, Physiologic; Particle Size; Rats; Rats, Sprague-Dawley; Solubility; Time Factors; Ventricular Function, Left; Ventricular Remodeling

Patients with diabetes mellitus are likely to develop certain complication such as retinopathy, nephropathy and neuropathy as a result of oxidative stress and overwhelming free radicals. Treatment of diabetic patients with antioxidant may be of advantage in attenuating these complications. Oleuropein, the active constituent of olive leaf (Olea europaea), has been endowed with many beneficial and health promoting properties mostly linked to its antioxidant activity. This study aimed to evaluate the significance of supplementation of oleuropein in reducing oxidative stress and hyperglycemia in alloxan-induced diabetic rabbits. After induction of diabetes, a significant rise in plasma and erythrocyte malondialdehyde (MDA) and blood glucose as well as alteration in enzymatic and non-enzymatic antioxidants was observed in all diabetic animals. During 16 weeks of treatment of diabetic rabbits with 20 mg/kg body weight of oleuropein the levels of MDA along with blood glucose and most of the enzymatic and non-enzymatic antioxidants were significantly restored to establish values that were not different from normal control rabbits. Untreated diabetic rabbits on the other hand demonstrated persistent alterations in the oxidative stress marker MDA, blood glucose and the antioxidant parameters. These results demonstrate that oleuropein may be of advantage in inhibiting hyperglycemia and oxidative stress induced by diabetes and suggest that administration of oleuropein may be helpful in the prevention of diabetic complications associated with oxidative stress.

Topics: Animals; Antioxidants; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Disease Models, Animal; Hypoglycemic Agents; Iridoid Glucosides; Iridoids; Oleaceae; Phytotherapy; Plant Leaves; Pyrans; Rabbits

Swertia chirata, is a bitter plant, used in the Indian system of medicine (Ayurveda) for various human ailments. Our laboratory was the first to report the chemopreventive effect of this plant. The antiproliferative and pro-apoptotic action of amarogentin rich fraction of S. chirata is now demonstrated on a mouse skin carcinogenesis model. Immunohistochemical localization revealed a reduction in proliferating and increase in apoptotic cells in skin lesion following treatment, also reflected in the expression of molecular markers--Cox-II and caspase-3 proteins. It may be possible to calculate relative risk, relative protection and attributable risk from the action of test agents on proliferation and apoptosis.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Apoptosis; Caspase 3; Cell Proliferation; Cyclooxygenase 2; Disease Models, Animal; Down-Regulation; Electrophoresis, Polyacrylamide Gel; Glucosides; In Situ Nick-End Labeling; Iridoids; Male; Medicine, Traditional; Membrane Proteins; Mice; Phytotherapy; Plant Extracts; Skin Neoplasms; Swertia; Up-Regulation

Allergic inflammation of the airways has a critical role in asthma development. We investigated a suppressive effect of verproside (3,4-dihydroxy catalpol) isolated from the extract of Pseudolysimachion longifolium on asthmatic parameters--such as immunoglobulin E (IgE) level, cytokine release, eosinophilia, airway hyperresponsiveness and mucus hypersecretion--in an OVA-sensitized/challenged mouse model. Verproside significantly inhibited the increase of total IgE and the cytokines IL-4 and IL-13 in plasma and bronchoalveolar lavage fluid, and also effectively suppressed airway hyperresponsiveness, eosinophilia and mucus hypersecretion in OVA-induced asthmatic mice. The efficacy of verproside was comparable to montelukast, an anti-asthmatic drug that is currently available. These results suggest that verproside could be a major marker in herbal medicines that are used for asthma treatment, and could also act as a lead for anti-asthmatic drugs.

Topics: Acetates; Animals; Anti-Asthmatic Agents; Asthma; Bronchoalveolar Lavage Fluid; Cyclopropanes; Disease Models, Animal; Female; Glucosides; Immunoglobulin E; Interleukin-13; Interleukin-4; Iridoid Glucosides; Iridoids; Lung; Methacholine Chloride; Mice; Mice, Inbred BALB C; Molecular Structure; Mucus; Ovalbumin; Plant Extracts; Pneumonia; Pulmonary Eosinophilia; Quinolines; Sulfides; Veronica

Our previous study described the neuroprotective effects of catalpol in gerbil ischemic model, in which catalpol was shown to prevent hippocampal neurons from death and ameliorate the cognitive ability of the animals. In the study, we focused on investigating the neuroprotective mechanism of catalpol. Animals were randomly assigned three groups as sham-operated, ischemia-treated with saline and ischemia-treated with catalpol. Transient global ischemia was produced by a 5 min occlusion of the bilateral common carotid arteries. Catalpol was intraperitoneally injected at the dose of 5 mg/kg immediately after reperfusion and repeatedly at 12, 24, 48 and 72 h. Histology as well as immunohistochemistry and TUNEL (the terminal deoxynucleotidyl transferase-mediated UTP nick end label) analysis were performed on serial slices through the dorsal hippocampus after gerbils were sacrificed. The results showed that 5 min transient global ischemia followed by 4 days reperfusion caused significant increases in TUNEL-positive and Bax-positive cells in hippocampal CA1 subfield. Catalpol not only significantly reduced TUNEL-positive and Bax-positive cells but also significantly increased Bcl-2-positive cells. All these suggested that catalpol could effectively inhibit apoptosis by modulating the expressions of Bcl-2 and Bax genes.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Brain Infarction; Brain Ischemia; Disease Models, Animal; Drug Administration Schedule; Drugs, Chinese Herbal; Female; Gene Expression Regulation, Enzymologic; Gerbillinae; Glucosides; Hippocampus; Immunohistochemistry; In Situ Nick-End Labeling; Iridoid Glucosides; Iridoids; Male; Nerve Degeneration; Neuroprotective Agents; Proto-Oncogene Proteins c-bcl-2; Reperfusion Injury; Treatment Outcome

To compare the individual effects of baicalin and jasminoidin with the combined effect of them on cerebral ischemia-reperfusion injury, and test whether the combined administration of baicalin and jasminoidin can improve the therapeutic effect. Male Sprague-Dawley rats underwent focal cerebral ischemia for 1.5 h and reperfusion for 24 h. Just before reperfusion, tested drugs (baicalin, jasminoidin, a drug combination consisting of baicalin and jasminoidin, or nimodipine) were intravenously treated. Diffusion weighted imaging (DWI) of magnetic resonance imaging (MRI), behavior examination, 2,3,5-triphenyltetrazolium chloride (TTC) staining, histological examination, and real-time PCR for BDNF and caspase-3 were performed. All of the drug treatments could significantly ameliorate the results of TTC and histological examination, and the baicalin/jasminoidin combination did so most prominently. This combination could also significantly ameliorate DWI of MRI and behavior examination results, and promote the expression of BDNF and inhibit the expression of caspase-3. On the whole, both baicalin and jasminoidin have a preventive effect against ischemic stroke, although their effects are not very strong. However, the combination of baicalin and jasminoidin can significantly improve their effectiveness. This may be related to its better regulation on the BDNF and caspase-3.

Topics: Analysis of Variance; Animals; Brain; Brain Ischemia; Brain-Derived Neurotrophic Factor; Caspase 3; Disease Models, Animal; Drug Combinations; Drug Therapy, Combination; Drugs, Chinese Herbal; Flavonoids; Iridoids; Male; Neuroprotective Agents; Nimodipine; Pyrans; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Statistics, Nonparametric

The neuroprotection of catalpol and its mechanism was evaluated in cerebral ischemic model in gerbils. Three groups were designed as sham-operated, ischemia-treated, respectively, with catalpol and saline. Catalpol was injected intraperitoneally immediately after reperfusion and repeatedly at 12, 24, 48 and 72 h with the dose of 5.0 mg/kg. The neuroprotection was estimated by the indexes of behavior and histology. Behavioral testing was performed in Y-maze and the survival neurons in CA1 subfield were counted under a microscope after behavioral testing. In addition, apoptosis induced by ischemia was also examined by using the terminal deoxynucleotidyl transferase-mediated UTP nick end labeling method. It was shown that catalpol significantly attenuated apoptosis, rescued hippocampal CA1 neurons and reduced cognitive impairment. In order to make clear the mechanism of catalpol's neuroprotection, the activities of endogenous antioxidants and nitric oxide synthase together with the content of lipid peroxide in cortex and hippocampus were assayed. The results proved that catalpol significantly reduced the content of lipid peroxide, increased the activity of glutathione peroxidase and decreased the activity of nitric oxide synthase. All these suggested that catalpol was a potential neuroprotective agent and its neuroprotective effects were achieved at least partly by promoting endogenous antioxidant enzymatic activities and reducing the formation of nitric oxide.

Topics: Animals; Apoptosis; Behavior, Animal; Brain Ischemia; Disease Models, Animal; Female; Gerbillinae; Glucosides; Glutathione Peroxidase; Hippocampus; In Situ Nick-End Labeling; Iridoid Glucosides; Iridoids; Lipid Peroxides; Male; Maze Learning; Neurons; Neuroprotective Agents; Nitric Oxide Synthase

The aim of the study was the evaluation of the action of a new natural drug--Naran S, elaborated in the Department of Inorganic Chemistry of the Medical University of Lublin (patent registration P.332066) in the treatment of inflammatory conditions of the oral cavity mucous membrane. The experiment was conducted on male Wistar rats. Topical inflammation of the gum was induced by injecting a complete Freund adjuvant (AF) (Calbiochem) into the inter-dental papilla of the lower incisors. The material was taken, fixed and stained with hematoxylin and eosin and by the use of the Masson's method after 24 hours, 1, 2, and 4 weeks following the injection time. Morphology of the mucous membrane was examined and it was noticed that in the group treated with Naran S infusion the complete rebuilding of the epithelial strata, collagen fibres took place. The shape of the cells was regular and there occurred the elimination of the tissue fluid in the proper mucous membrane. The results obtained in the study allow to claim that the topically given plant drug thanks to its contents of biologically active substance such as: iridoids, flavonoids, phenol acids, tannins, displays curative activity in the therapy of the inflammatory conditions of the oral cavity mucous membrane.

Topics: Animals; Anti-Inflammatory Agents; Disease Models, Animal; Flavonoids; Freund's Adjuvant; Gingiva; Gingivitis; Iridoids; Male; Mouth Mucosa; Mouthwashes; Periodontitis; Periodontium; Phenols; Phytotherapy; Plant Extracts; Rats; Rats, Wistar; Tannins; Treatment Outcome

The effectiveness of the natural drug--Naran S was studied in the therapy of the topical inflammation of the oral cavity mucous membrane. The experiment was conducted on male Wistar rats that were subjected to induction of inflammatory condition by injecting Freund adjuvant and rinsing oral cavity with the infusion of the drug for the period of 28 days. The analysis of the ultra structure of the epithelium cells was conducted with the use of transmission electron microscope. It was observed that under the influence of the drug, the epithelium undergoes renewal, the cells are joined with thick desmosomes, the nuclei have the proper areolas and the mitochondrium matrix is not oedematic.

Topics: Animals; Anti-Inflammatory Agents; Disease Models, Animal; Flavonoids; Freund's Adjuvant; Gingiva; Iridoids; Male; Mouth Mucosa; Mouthwashes; Phenols; Phytotherapy; Plant Extracts; Rats; Rats, Wistar; Regeneration; Tannins

Geniposide is one of the constituents of Gardenia fruit (Gardenia jasminoides Ellis, Rubiaceae), which has been used in traditional medicine. Although its anti-inflammatory and antithrombotic effects have been reported, the way it acts is still unclear. We have investigated the effects of geniposide and its metabolite genipin on thrombogenesis and platelet aggregation. In an in vivo model, geniposide and genipin significantly (P < 0.05) prolonged the time required for thrombotic occlusion induced by photochemical reaction in the mouse femoral artery. In an in vitro study, both geniposide and genipin inhibited collagen-induced, but did not inhibit arachidonate-induced, mouse platelet aggregation. However aspirin, a cyclooxygenase inhibitor, inhibited arachidonate-induced platelet aggregation but only partially inhibited the collagen-induced one. We also showed, by measuring PLA(2)-catalyzed arachidonic acid release, that geniposide inhibited phospholipase A(2) (PLA(2)) activity. We conclude that geniposide showed an antithrombotic effect in vivo due to the suppression of platelet aggregation. PLA(2) inhibition by geniposide is one possible anti-platelet mechanism.

Topics: Animals; Disease Models, Animal; Fibrinolytic Agents; Fruit; Iridoid Glycosides; Iridoids; Male; Mice; Phospholipases A; Phytotherapy; Plant Extracts; Platelet Aggregation; Pyrans; Rubiaceae; Thrombosis