stilbenes and Colitis

Resveratrol is a dietary polyphenol that interacts with gut microbiota to possess various biological activities. To identify the microbial metabolites of resveratrol, fresh feces from 12 volunteers were cultured in vitro. Their urine samples were collected after taking a commercial capsule containing 600 mg of resveratrol. Metabolites were characterized and quantified by UPLC-Q-Exactive plus orbitrap MS/MS. The results showed that dihydroresveratrol, 3-(4-hydroxyphenyl)-propionic acid, and lunularin were the major microbial metabolites of RSV with interindividual differences. 3-(4-Hydroxyphenyl)-propionic acid significantly attenuated the inflammatory response of LPS-treated RAW264.7 cells and DSS-induced colitis in antibiotics-treated pseudo-germ-free mice by regulating MAPK and NF-κB pathways. In contrast, dihydroresveratrol did not exhibit significant anti-inflammatory effects, and lunularin exhibited pro-inflammatory effects in cells. This study may help to better understand the health effects of resveratrol and its microbial metabolites.

Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Bibenzyls; Colitis; Dextran Sulfate; Lipopolysaccharides; Mice; Mice, Inbred C57BL; NF-kappa B; Phenols; Phenylpropionates; Polyphenols; Propionates; Resveratrol; Stilbenes; Tandem Mass Spectrometry

The pterostilbene skeleton is a promising chemical scaffold that exerts anti-inflammatory, anti-depressant, and anti-tumor effects. In this study, we aim to reduce in vivo and in vitro toxicity of compound 32 (preliminary work) and maintain its biological activity. A series of novel pterostilbene derivatives (D1-D43) were designed and synthesized, and their anti-inflammatory activities were screened. All compounds were screened to evaluate their inhibitory effect on LPS/Nigericin-induced IL-1β production and pyroptosis. The structure-activity relationships was deduced, and finally 1-((E)-4-(2-ethoxyethoxy)styryl)-3,5-dimethoxy-2-((E)-2-nitrovinyl)benzene (D22) was found to be a low-toxic compound with most potent inhibitory efficacy (against IL-1β: IC

Topics: Animals; Anti-Inflammatory Agents; Colitis; Inflammasomes; Mice; Mice, Inbred C57BL; NLR Family, Pyrin Domain-Containing 3 Protein; Stilbenes

Inflammatory bowel disease (IBD) is a non-specific chronic intestinal inflammatory disease, often presenting with abdominal pain, diarrhea, bloody stool, anorexia, and body loss. It is difficult to cure completely and a promising treatment is urgently needed. Natural compounds can offer promising chemical agents for treatment of diseases. Polydatin is a natural ingredient extracted from the dried rhizome of Polygonum cuspidatum, which has anti-inflammatory, anti-tumor, and dementia protection activities. The purpose of this study was to evaluate the therapeutic effect of polydatin on IBD and explore its possible mechanism. We found that polydatin could effectively suppress the differentiation of Th17 cells in vitro, but had no effect on the differentiation of Treg cells. Polydatin significantly alleviated colitis induced by dextran sulfate sodium (DSS) and 2, 4, 6-trinitrobenzenesulfonic acid (TNBS) in mice, and dramatically decreased the proportion of Th17 cells in spleen and mesenteric lymph nodes. Mechanism investigations revealed that polydatin specifically inhibited signal transducer and activator of transcription 3 (STAT3) phosphorylation by directly binding to STAT3, leading to Th17 cell reduction and thereby alleviating colitis. These findings provide novel insights into the anti-colitis effect of polydatin, which may be a promising drug candidate for the treatment of IBD.

Topics: Animals; Cell Differentiation; Colitis; Colon; Dextran Sulfate; Disease Models, Animal; Glucosides; Inflammatory Bowel Diseases; Mice; Mice, Inbred C57BL; STAT3 Transcription Factor; Stilbenes; T-Lymphocytes, Regulatory; Th17 Cells; Trinitrobenzenesulfonic Acid

The effectiveness of resveratrol (RES) on intestinal barrier dysfunction and colitis has been extensively studied. However, the specific effects of its microbial metabolites on gut barrier function remain unclear. Hence, we compared the protective effects of RES and its microbial metabolites dihydroresveratrol (DHR) and 3-(4-hydroxyphenyl)-propionic acid (4HPP) against intestinal barrier injury and colitis. Only 4HPP and RES significantly reduced paracellular permeability and the secretion of proinflammatory cytokines in lipopolysaccharides (LPS)-treated intestinal Caco-2 cells, which was consistent with the upregulation in tight junction (TJ) proteins. Furthermore, RES and 4HPP ameliorated intestinal barrier dysfunction and colonic inflammation in colitis mice, while DHR did not. In particular, the expressions of intestinal TJ proteins and Muc2 were restored by RES and 4HPP. The molecular mechanism involved the adenosine monophosphate-activated protein kinase (AMPK)-mediated activation of CDX2 and the regulation of the SIRT1/NF-κB pathway. These findings provide new insights into understanding the protective effects of RES against intestinal barrier damage and colitis.

Topics: AMP-Activated Protein Kinases; Animals; Caco-2 Cells; Colitis; Humans; Intestinal Mucosa; Mice; Permeability; Resveratrol; Stilbenes; Tight Junction Proteins; Tight Junctions

Studies have shown that the abnormal activation of the NLRP3 inflammasome is involved in a variety of inflammatory-based diseases. In this study, a high content screening model targeting the activation of inflammasome was first established and pterostilbene was discovered as the active scaffold. Based on this finding, total of 50 pterostilbene derivatives were then designed and synthesized. Among them, compound

Topics: Animals; Anti-Inflammatory Agents; Cell Line; Colitis; Dextran Sulfate; Female; Humans; Inflammasomes; Interleukin-1beta; Macrophages; Male; Mice, Inbred C57BL; Molecular Structure; NLR Family, Pyrin Domain-Containing 3 Protein; Pyroptosis; Stilbenes; Structure-Activity Relationship

Topics: Animals; Anti-Inflammatory Agents; Biomarkers; Colitis; Colon; Cytokines; Dextran Sulfate; Disease Models, Animal; Dose-Response Relationship, Drug; Gene Expression; Humans; Inflammation Mediators; Intestinal Mucosa; Nitric Oxide Synthase Type II; Organ Size; Plant Extracts; Rats; Spleen; Stilbenes

Polydatin (PD), a monocrystalline compound isolated from the root and rhizome of Polygonum cuspidatum, is widely used in inhibiting the inflammatory response and oxidative stress. PD has an anti-inflammatory effect on colitis mice; however, information regulating the mechanism by which maintains the intestinal epithelium barrier is currently scarce. Here, we assessed the anti-inflammatory and antioxidant of PD in lipopolysaccharide (LPS)-induced macrophages in vitro, and explored its effects on inhibiting intestinal inflammation and maintaining the intestinal epithelium barrier in dextran sodium sulfate (DSS)-induced colitis mice. Results showed that PD reduced the level of proinflammatory cytokines and enzymes, including tumor necrosis factor-α, interleukin-4 (IL-4), IL-6, cyclooxygenase-2, and inducible nitric oxide synthase, in LPS-induced macrophages, and improved the expression level of IL-10. PD maintained the expression of tight junction proteins in medium (LPS-induced macrophages medium)-induced MCEC cells. Additionally, PD inhibited the phosphorylation of nuclear factor-κB (NF-κB), p65, extracellular signal-regulated kinase-1/2, c-Jun N-terminal kinase, and p38 signaling pathways in LPS-induced macrophages and facilitated the phosphorylation of AKT and the nuclear translocation of Nrf2, improving the expression of HO-1 and NQO1. Furthermore, PD ameliorated the intestinal inflammatory response and improved the dysfunction of the colon epithelium barrier in DSS-induced colitis mice. Taken together, our results indicated that PD inhibited inflammation and oxidative stress, maintained the intestinal epithelium barrier, and the protective role of PD was associated with the NF-κB p65, itogen-activated protein kinases, and AKT/Nrf2/HO-1/NQO1 signaling pathway.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Colitis; Glucosides; Lipopolysaccharides; Macrophages; Mice; NF-kappa B; Stilbenes

The worldwide prevalence of obesity has significantly increased over the past few decades. It is currently believed that obesity is a risk factor for developing inflammatory bowel disease. Pterostilbene (PTS), a naturally occurring stilbene from blueberries, is known to have anticancer, anti-inflammation, antifibrosis, and antiobesity effects. The preventive effect of PTS on the susceptibility of high-fat diet (HFD) to dextran sulfate sodium (DSS)-induced colitis in mice was investigated. Beginning at 5 weeks of age, C57BL/6J mice were fed a normal diet, 50% HFD alone, or containing PTS, and DSS (2.5%, w/v) was given in drinking water at week 9 and week 11. The results demonstrated that PTS significantly attenuated HFD and DSS-induced plasma interleukin-6 accumulation. Moreover, PTS suppressed HFD/DSS-induced formation of aberrant crypt foci and reduced the colon weight-to-length ratio in HFD/DSS-induced colitis mice. Furthermore, PTS inhibited interleukin-1β (IL-1β), the C/EBP homologous protein (CHOP), cyclooxygenase-2, and transforming growth factor beta-1 (TGF-β1)/mothers against decapentaplegic homolog 2 expression and maintained mucin2 (Muc2) and E-cadherin expressions. In addition, post-treatment with PTS also decreased the colon weight-to-length ratio and loss of Muc2. Moreover, the CHOP, IL-1β, matrix metalloproteinase-2, and TGF-β1 expressions were significantly decreased in HFD/DSS-induced colitis mice after post-treatment with PTS. In conclusion, the results of the present study suggest that PTS is of significant interest for the prevention of HFD/DSS-induced colitis in C57BL/6J mice.

Topics: Animals; Colitis; Colon; Dextran Sulfate; Diet, High-Fat; Disease Models, Animal; Fibrosis; Inflammation; Matrix Metalloproteinase 2; Mice; Mice, Inbred C57BL; Stilbenes

Epidemiological surveys show that obesity and the western diet increase the risk of colitis. Studies have also confirmed that the high-fat-diet (HFD) promoted the deterioration of colitis-related indicators in mice. Compared with stilbenoids, the results showed that 3'-hydroxypterostilbene (HPSB) was found to be the most effective inhibitor for the antiadipogenesis and anti-inflammation. However, its role in ameliorating obesity-promoted colitis is still unknown. We intend to investigate the protective effect and related molecular mechanisms of HPSB on HFD promoted dextran sodium sulfate (DSS)-induced colitis in mice. The results indicate that colitis in the HFD+DSS group tends to be more apparent in the DSS-only group, while feeding 0.025% of HPSB at different stages can improve the colitis induced by HFD+DSS. HPSB significantly reduced the levels of interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) induced by HFD+DSS in mice. Furthermore, the Western blotting revealed that the administration of HPSB significantly downregulated cyclooxygenase-2 (COX-2), plasmalemma vesicle-associated protein-1 (PV-1), and phospho-signal transducer and activator of transcription 3 (p-STAT3) expressions in HFD+DSS treated mice. Presented results reveal that HPSB is a novel functional agent capable of preventing HFD exacerbated colitis.

Topics: Animals; Anti-Inflammatory Agents; Chemokine CCL2; Colitis; Dextran Sulfate; Diet, High-Fat; Disease Models, Animal; Humans; Interleukin-6; Male; Mice; Mice, Inbred C57BL; Obesity; STAT3 Transcription Factor; Stilbenes

Hypoxia inducible factor and nuclear factor-kappa beta pathways have been proposed as therapeutic targets for several inflammatory diseases. Caffeic acid phenethyl ester (CAPE) and piceatannol (PIC) are natural anti-inflammatory compounds; however, poor bioavailability and limited understanding of biomolecular mechanistic limits its clinical use. The aims of this study are to enhance bioavailability and investigate their impact on nuclear p65 and HIF-1α for the first time in experimental colitis.Dextran sulphate sodium was used to induce colitis in mice and effect of either free CAPE/PIC or CAPE/PIC loaded albumin nanoparticles treatment was observed on disease development and levels of cellular p65 and HIF-1α.Our results indicate that albumin nano-encapsulation of CAPE/PIC not only enhances its anti-inflammatory potential but also potentiates its ability to effectively modulate inflammation related biomolecular pathways. Hence, combining nanotechnology with natural compounds could result in development of new therapeutic options for IBD.

Topics: Albumins; Animals; Biological Availability; Caffeic Acids; Colitis; Dextran Sulfate; Disease Models, Animal; Drug Combinations; Drug Compounding; Drug Synergism; Gene Expression Regulation; Hypoxia-Inducible Factor 1, alpha Subunit; Mice; Nanoparticles; Particle Size; Phenylethyl Alcohol; Signal Transduction; Stilbenes; Transcription Factor RelA

Inflammation, oxidative stress and epithelial barrier dysfunction have been implicated in inflammatory bowel disease (IBD) pathology. The targeted inhibition of these features may represent a promising therapeutic strategy for IBD. Polydatin is an effective natural antioxidant that possesses strong antioxidant and anti-apoptotic properties. Thus, we studied the protective effects of polydatin treatments on a mouse model of experimental colitis.. Acute colitis was experimentally induced by adding 3% dextran sulfate sodium (DSS) to the drinking water provided to mice for 7 days and by administering different doses of polydatin (15, 30, or 45 mg/kg) during the same period. Mice were also treated with the Sonic hedgehog (Shh) pathway inhibitor cyclopamine to estimate the efficacy of polydatin and Shh inhibitors on colitis. The disease activity index (DAI), colon length, histology, levels of oxidative and apoptotic mediators and levels of Shh pathway components were evaluated.. The polydatin treatment significantly attenuated the DAI, colon shortening and histological damage. In addition, polydatin administration effectively decreased malondialdehyde (MDA) levels and increased the activities of the antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). Polydatin also inhibited apoptosis in mice with colitis by downregulating the expression of the pro-apoptotic proteins Bax, caspase 3 and cleaved caspase 3 and increasing the expression of the anti-apoptotic protein Bcl-2. Furthermore, polydatin modulated Shh signaling pathway activation. After polydatin treatment, the main components of the Shh pathway, including Shh, Patched (Ptc), Smoothened (Smo), and glioblastoma-1 (Gli1), were upregulated at the mRNA and protein levels. Blockade of the Shh pathway using cyclopamine abolished the effects of polydatin on mice with colitis.. Based on these observations, polydatin may suppress experimental colitis at least partially by regulating the Shh signaling pathway.

Topics: Animals; Apoptosis; Colitis; Dextran Sulfate; Glucosides; Hedgehog Proteins; Male; Mice; Mice, Inbred C57BL; Oxidative Stress; Signal Transduction; Stilbenes

Pterostilbene, a dimethyl ester analog of resveratrol, has anti-inflammatory and antioxidative effects and alters cell proliferation. Tristetraprolin (TTP) promotes the degradation of proinflammatory mediators via binding to adenosine and uridine- (AU-) rich elements (ARE) located in the 3'-untranslated regions of mRNAs. Here, we utilized pterostilbene 4'-

Topics: Animals; Colitis; Disease Models, Animal; Glucosides; Male; Mice; Mice, Knockout; Stilbenes; Tristetraprolin

3'-Hydroxypterostilbene (trans-3,5-dimethoxy-3',4'-hydroxystilbene) presents in Sphaerophysa salsula, Pterocarpus marsupium, and honey bee propolis and has been reported to exhibit several biological activities. Herein, we aimed to explore the chemopreventive effects of dietary 3'-hydroxypterostilbene and underlying molecular mechanisms on colitis-associated cancer using the azoxymethane (AOM)/dextran sodium sulfate (DSS) model. 3'-Hydroxypterostilbene administration effectively ameliorated the colon shortening and number of tumors in AOM/DSS-treated mice (3.2 ± 1.2 of the high-dose treatment versus 13.8 ± 5.3 of the AOM/DSS group, p < 0.05). Molecular analysis exhibited the anti-inflammatory activity of 3'-hydroxypterostilbene by a significant decrease in the levels of inducible nitric oxide synthase, cyclooxygenase-2, and interleukin-6 (IL-6) (p < 0.05). Moreover, dietary 3'-hydroxypterostilbene also significantly diminished IL-6/signal transducer and activator of transcription signaling and restored colonic suppressor of cytokine signaling 3 levels in the colonic tissue of mice (p < 0.05). Collectively, these results demonstrated for the first time the in vivo chemopreventive efficacy and molecular mechanisms of dietary 3'-hydroxypterostilbene against colitis-associated colonic tumorigenesis.

Topics: Animals; Anticarcinogenic Agents; Carcinogenesis; Colitis; Colonic Neoplasms; Cyclooxygenase 2; Disease Models, Animal; Humans; Interleukin-6; Male; Mice; Mice, Inbred ICR; Signal Transduction; STAT3 Transcription Factor; Stilbenes

The DNAX adaptor protein 12 (DAP12) is a transmembrane adaptor molecule that signals through the activation of Syk (Spleen Tyrosine Kinase) in myeloid cells. The purpose of this study is to investigate the role of DAP12 and Syk pathways in inflammatory bowel diseases (IBDs).. DAP12 deficient and DAP12 transgenic, overexpressing an increased amount of DAP12, mice and Syk deficient mice in the C57/BL6 background were used for these studies. Colitis was induced by administering mice with dextran sulfate sodium (DSS), in drinking water, or 2,4,6-trinitrobenzene sulfonic acid (TNBS), by intrarectal enema.. Abundant expression of DAP12 and Syk was detected in colon samples obtained from Crohn's disease patients with expression restricted to immune cells infiltrating the colonic wall. In rodents development of DSS colitis as measured by assessing severity of wasting diseases, global colitis score,and macroscopic and histology scores was robustly attenuated in DAP12-/- and Syk-/- mice. In contrast, DAP12 overexpression resulted in a striking exacerbation of colon damage caused by DSS. Induction of colon expression of proinflammatory cytokines and chemokines in response to DSS administration was attenuated in DAP12-/- and Syk-/- mice, whereas opposite results were observed in DAP12 transgenic mice. Treating wild-type mice with a DAP-12 inhibitor or a Syk inhibitor caused a robust attenuation of colitis induced by DSS and TNBS.. DAP12 and Syk are essential mediators in inflammation-driven immune dysfunction in murine colitides. Because DAP12 and Syk expression is upregulated in patients with active disease, present findings suggest a beneficial role for DAP12 and Syk inhibitors in IBD.

Topics: Adaptor Proteins, Signal Transducing; Adult; Animals; Antipruritics; Colitis; Cytokines; Disease Models, Animal; Female; Humans; Inflammation; Inflammatory Bowel Diseases; Intestinal Diseases; Ketotifen; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Transgenic; Stilbenes; Syk Kinase

Rhapontin (3, 3', 5-trihydroxy-4'-methoxystilbene-3-O-glucoside) has anti-thrombotic, anti-allergic and anti-diabetic activities. This study aimed to assess the protective effects of rhapontin on intestinal damage in vivo and in vitro. In a dextran sodium sulfate (DSS)-induced mouse model, oral administration of rhapontin (100mg/kg) significantly attenuated colonic pathological damage and remarkably inhibited infiltration by inflammatory cells, myeloperoxidase (MPO) activity, NLRP3 inflammasome activation and SIRT1 expression in the colon. Moreover, rhapontin prevented DSS-induced impairment in the colon epithelium barrier by increasing the expression of tight junction proteins, such as zonula occludens-1(ZO-1) and occludin, and reduced apoptosis-associated protein (cyt-c, the ratio of bcl-2/bax and cleaved-capase9) expression in the colon. The in vitro results showed that rhapontin significantly reduced NLRP3 inflammasome activation and cleaved caspase-1 expression as well as lowered IL-1β secretion in LPS-stimulated human-THP-1-derived macrophages. Further study revealed that compound EX257 (an SIRT1 inhibitor) blocked the inhibitory effects of rhapontin on NLRP3-dependent caspase-1 activation and IL-β production in activated macrophages. In addition, in TNF-α-stimulated intestinal epithelial NCM460 cells, rhapontin significantly increased the expressions of occludin and ZO-1 and notably reduced the ratio of bcl-2/bax and cleaved-capase9 expression through SRIT1 signaling. In sum, the protective effect of rhapontin is from blocking the NLRP3 priming cascade reaction and is dependent on SIRT1 activation. Our findings demonstrate that rhapontin might be a potential agent for the treatment of colitis by targeting SIRT1.

Topics: Animals; Anti-Inflammatory Agents; Apoptosis; Cell Line; Colitis; Colon; Dextran Sulfate; Epithelial Cells; Female; Humans; Mice; Mice, Inbred BALB C; Models, Animal; NLR Family, Pyrin Domain-Containing 3 Protein; Signal Transduction; Sirtuin 1; Stilbenes; Transcriptional Activation

Antibiotic-resistant bacteria is a major threat to human health and is predicted to become the leading cause of death from disease by 2050. Despite the recent resurgence of research and development in the area, few antibiotics have reached the market, with most of the recently approved antibiotics corresponding to new uses for old antibiotics, or structurally similar derivatives thereof. We have recently reported an in silico approach that led to the design of an entirely new class of antibiotics for the bacteria-specific mechanosensitive ion channel of large conductance: MscL. Here, we present the preclinical development of one such antibiotic, Ramizol, a first generation antibiotic belonging to that class. We present the lack of interaction between Ramizol and other mammalian channels adding credibility to its MscL selectivity. We determine the pharmacokinetic profile in a rat model and show <0.1% of Ramizol is absorbed systemically. We show this non-systemic nature of the antibiotic translates to over 70% survival of hamsters in a Clostridium difficile colitis model. Lastly, initial in vitro data indicate that resistance to Ramizol occurs at a low frequency. In conclusion, we establish the potential of Ramizol as an effective new treatment for C. difficile associated disease.

Topics: Animals; Anti-Bacterial Agents; Benzoates; Clostridioides difficile; Clostridium Infections; Colitis; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Resistance, Multiple, Bacterial; Male; Mesocricetus; Microbial Sensitivity Tests; Rats; Rats, Sprague-Dawley; Stilbenes

To determine the therapeutic efficacy of resveratrol on ulcerative colitis (UC) and its underlying mechanisms.. The mouse UC model was developed using 5% dextran sulfate sodium. Mice were randomly divided into four groups: normal control, UC model group, resveratrol low-dose group (RLD; 50 mg/kg per day), and resveratrol high-dose group (RHD; 100 mg/kg per day).. The results showed that RLD regulates Treg/Th17 balance mainly through reducing the number of Th17 cells, whereas RHD regulates Treg/Th17 balance through both downregulating the number of Th17 cells and upregulating the number of Treg cells. Resveratrol can also regulate the level of plasma and intestinal mucosal cytokines including interleukin (IL)-10, transforming growth factor-β1, IL-6, and IL-17. The expressions of hypoxia inducible factor (HIF)-1α, mammalian target of rapamycin (mTOR), and signal transducer and activator of transcription 3 were significantly decreased in the intestinal tissues of mice treated with resveratrol.. The therapeutic efficacy of resveratrol in UC is dose dependent and closely associated with the regulation of Treg/Th17 balance and the HIF-1α/mTOR signaling pathway.

Topics: Animals; Colitis; Colon; Cytokines; Dextran Sulfate; Disease Models, Animal; Dose-Response Relationship, Drug; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation Mediators; Male; Mice, Inbred BALB C; Resveratrol; Signal Transduction; Spleen; STAT3 Transcription Factor; Stilbenes; T-Lymphocytes, Regulatory; Th17 Cells; Time Factors; TOR Serine-Threonine Kinases

Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory disease in humans constituting a major health concern today whose prevalence has been increasing over the world. Production of reactive oxygen species (ROS) and disturbed capacity of antioxidant defense in IBD subjects have been reported. Antioxidants may play a significant role in IBD treatment. This study aimed at evaluating ameliorative effects of intraperitoneal resveratrol pretreatment on trinitrobenzene sulphonic acid (TNBS)-induced colitis in rats. Thirty five Wistar-Albino female rats were divided equally into five groups. Inflammation was induced by the intrarectal administration of TNBS under anesthesia. Intraperitoneal administration of resveratrol (RSV) at a concentration of 10mg/kg/day for 5 days before the induction of colitis significantly reduced microscopy score and malondialdehyde (MDA) levels and increased glutathione peroxidase (GSH Px) activity compared to TNBS and vehicle groups. Also an insignificant increase in catalase (CAT) activity was observed in the RSV treated group compared to TNBS and vehicle groups. In this paper, the most recent patent on the identification and treatment of IBD was indicated. In conclusion, antioxidant RSV proved to have a beneficial effect on TNBS colitis in rats. In light of these advantageous results, the RSV can be considered as adjuvant agent in IBD treatments.

Topics: Animals; Antioxidants; Colitis; Female; Inflammatory Bowel Diseases; Oxidative Stress; Peroxidase; Rats; Rats, Wistar; Resveratrol; Stilbenes; Superoxide Dismutase; Trinitrobenzenesulfonic Acid

Piceatannol (PCT), an anti-colitic natural product, undergoes extensive Phase II hepatic metabolism, resulting in very low bioavailability. We investigated whether colon-targeted delivery of PCT could enhance anti-colitic effects and how therapeutic enhancement occurred at the molecular level. Molecular effects of PCT were examined in human colon carcinoma cells and inflamed colons. The anti-colitic effects of PCT in a colon-targeted capsule (colon-targeted PCT) were compared with PCT in a gelatin capsule (conventional PCT) in a trinitrobenzene sulfonic acid-induced rat colitis model. Colon-targeted PCT elicited greatly enhanced recovery of the colonic inflammation. In HCT116 cells, PCT inhibited nuclear factor kappaB while activating anti-colitic transcription factors, nuclear factor-erythroid 2 (NF-E2) p45-related factor 2, and hypoxia-inducible factor-1. Colon-targeted PCT, but not conventional PCT, modulated production of the target gene products of the transcription factors in the inflamed colonic tissues. Rectal administration of PCT, which simulates the therapeutic action of colon-targeted PCT, also ameliorated rat colitis and reproduced the molecular effects in the inflamed colonic tissues. Colon-targeted delivery increased therapeutic efficacy of PCT against colitis, likely resulting from multitargeted effects exerted by colon-targeted PCT. The drug delivery technique may be useful for therapeutic optimization of anti-colitic lead compounds including natural products.

Topics: Administration, Oral; Administration, Rectal; Animals; Anti-Inflammatory Agents; Biomarkers; Capsules; Chemistry, Pharmaceutical; Colitis; Colon; Disease Models, Animal; Gastrointestinal Agents; Gelatin; Gene Expression Regulation; HCT116 Cells; Humans; Inflammation Mediators; Male; Mice; Rats, Sprague-Dawley; RAW 264.7 Cells; Signal Transduction; Stilbenes; Technology, Pharmaceutical; Transfection; Trinitrobenzenesulfonic Acid

TNF-α converting enzyme (TACE) processes the membrane TNF-α to release the bioactive soluble TNF-α. Several evidences suggest the involvement of TNF-α and TACE in inflammatory bowel disease (IBD). Tissue inhibitor of metalloproteinase (TIMP)-3, an endogenous inhibitor of TACE, is positively associated with silent information regulator (SIRT)-1. We aimed to study the expression of TACE, TIMP-3 and SIRT-1 at different stages of colitis and how TACE is regulated in response to SIRT-1 activation. Acute colitis was induced by 3.5% dextran sulfate sodium (DSS) in drinking water for 5days and levels of cytokines and mRNA expression of TACE, TIMP-3 and SIRT-1 were measured in colon at different time intervals. Next, the effect of SIRT-1 activator (resveratrol) or a selective TACE inhibitor (compound 11p) treatment was evaluated. Elevated levels of TNF-α, interleukin (IL)-6, IL-1β, interferon (IFN)-γ and IL-17 were observed during DSS exposure phase which restored to the normal level after DSS removal. A significant increase in TACE and suppression in TIMP-3 and SIRT-1 mRNA level was observed during DSS exposure phase which reverts back to normal towards the remission phase. Treatment with resveratrol significantly elevated SIRT-1 and TIMP-3 and suppressed TACE mRNA expression and was associated with amelioration of disease. Furthermore, treatment with selective TACE inhibitor significantly suppressed body weight loss, disease activity index, colonic myeloperoxidase activity and the elevated levels of cytokines after DSS challenge. These results strongly emphasize the involvement of TACE in colon inflammation and inhibition of TACE directly or indirectly via SIRT-1 activation ameliorates colitis.

Topics: Acute Disease; ADAM Proteins; ADAM17 Protein; Animals; Colitis; Colon; Cytokines; Dextran Sulfate; Female; Inflammation; Kinetics; Mice; Mice, Inbred C57BL; Resveratrol; Sirtuin 1; Stilbenes; Time Factors; Tissue Inhibitor of Metalloproteinase-3

To investigate whether resveratrol (3,4,5-trihydroxy-trans-stilbene) inhibits collagen I synthesis induced by insulin growth factor-1 (IGF-1) in intestinal fibroblasts, and to explore the possible molecular mechanisms.. Male Sprague-Dawley rats were randomly divided into two groups: a control group and a 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis group. After 21 d of TNBS administration, the degree of inflammation and fibrosis in colon was measured by HE staining and Masson's trichrome staining. Western blotting was used to examine collagen I, IGF-1 and silent information regulator 1 (SIRT1) protein expression in colitis tissues. Western blotting and quantitative real-time polymerase chain reaction were used to characterize collagen I protein and col1a2 mRNA expression in mouse intestinal fibroblasts and CCD-(18)Co cells treated with IGF-1. A MEK inhibitor (U0126) was used to determine whether IGF-1-induced collagen I expression was mediated by extracellular signal-regulated kinase 1/2 (ERK1/2)-dependent mechanism. Effects of resveratrol on collagen I protein level, insulin growth factor-1 receptor (IGF-1R) and ERK1/2 phosphorylation levels were also examined after IGF-1 treatment in fibroblasts. To evaluate whether SIRT1 was necessary for the anti-fibrosis effect of resveratrol, cells were transfected with SIRT1-specific small interfering RNAs, wild-type SIRT1, and deacetylase-inactive mutant SIRT1.. Collagen I and IGF-1 expression was increased, and SIRT1 expression was decreased (0.67 ± 0.04 vs 1.05 ± 0.07, P < 0.001) in TNBS-induced colitis compared with the control group. In vitro, IGF-1 could induce collagen I expression, mainly through the ERK 1/2 signal pathway. Resveratrol reduced basal and IGF-1-induced collagen I gene and protein expression in intestinal fibroblasts. Overexpression of wild-type SIRT1, not deacetylase-inactive mutant SIRT1, decreased expression of collagen I induced by IGF-1. Moreover, silencing SIRT1 restored collagen I expression in fibroblasts challenged with resveratrol. However, disruption of SIRT1 did not influence the anti-fibrotic effects of resveratrol and IGF-1-induced collagen I expression. Further analysis revealed that resveratrol significantly decreased phosphorylation of IGF-1R and its downstream signaling molecules by inhibiting IGF-1 binding to its receptor.. Our data suggest that resveratrol effectively inhibits collagen I synthesis in IGF-1-stimulated fibroblasts, partly by inhibiting IGF-1R activation, and SIRT1 is also responsible for the process.

Topics: Animals; Cell Line; Colitis; Collagen Type I; Colon; Disease Models, Animal; Down-Regulation; Extracellular Signal-Regulated MAP Kinases; Fibroblasts; Fibrosis; Insulin-Like Growth Factor I; Male; MAP Kinase Kinase Kinases; Mice; Mutation; Phosphorylation; Rats, Sprague-Dawley; Receptor, IGF Type 1; Resveratrol; RNA Interference; RNA, Messenger; Signal Transduction; Sirtuin 1; Stilbenes; Transfection; Trinitrobenzenesulfonic Acid

The pleiotropic effects of resveratrol include anti-inflammatory, antioxidant, and anticancer activities, and thus unique possibilities exist to explore mechanistic pathways of chemoprevention. The aim of this study was to investigate the role of microRNA (miRNA) alterations induced by resveratrol in the context of chemopreventive mechanisms against dextran sodium sulfate (DSS)-induced colitis-associated tumorigenesis in the Apc(Min/+) mouse. To that end, Apc(Min/+) mice were exposed to 2% DSS to enhance intestinal inflammation and polyp development. Concurrently, mice received either vehicle or resveratrol treatment via oral gavage for 5 weeks. Interestingly, treatment of DSS-exposed mice with resveratrol resulted in decreased number and size of polyps, fewer histologic signs of cell damage, and decreased proliferating epithelial cells in intestinal mucosa compared with vehicle. Resveratrol treatment dramatically reversed the effects of DSS on the numbers of specific inflammatory CD4(+) T cells, CD8(+) T cells, B cells, natural killer T cells, and myeloid-derived suppressor cells in mesenteric lymph nodes. Resveratrol treatment also decreased interleukin-6 (IL-6) and tumor necrosis factor-α protein levels and reduced IL-6 and cyclooxygenase-2 mRNA expression. Microarray analysis revealed 104 miRNAs exhibiting >1.5-fold differences in expression in the intestinal tissue of resveratrol-treated mice. Among them, two miRNAs with anti-inflammatory properties, miRNA-101b and miRNA-455, were validated to be upregulated with resveratrol treatment by reverse-transcription polymerase chain reaction. Pathway analysis revealed that numerous differentially regulated miRNAs targeted mRNAs associated with inflammatory processes with known roles in intestinal tumorigenesis. These results suggest that resveratrol mediates anti-inflammatory properties and suppresses intestinal tumorigenesis through miRNA modulation.

Topics: Animals; Carcinogenesis; Cell Proliferation; Colitis; Colon; Colonic Polyps; Cyclooxygenase 2; Dextran Sulfate; Epithelial Cells; Female; Gene Expression Regulation; Interleukin-6; Intestinal Polyps; Lymphocytes; Male; Mice; Mice, Mutant Strains; MicroRNAs; Resveratrol; Stilbenes; Tumor Necrosis Factor-alpha

To investigate the mechanisms underlying the biological activity of piceatannol (PCT), a hydroxystilbene natural product that has anti-colitic properties, we examined whether PCT could modulate hypoxia-inducible factor (HIF)-1 activity in human colon carcinoma cells. PCT induced HIF-1α protein, leading to induction of its target gene products, vascular endothelial growth factor and heme oxygenase-1, which are involved in amelioration of colitis. PCT induction of HIF-1α resulted from HIF-1α protein stabilization, which occurred through inhibition of HIF-prolyl hydroxylase-2 (HPH-2). PCT inhibition of HPH-2 was reversed by addition of ascorbate, a cofactor of HPH-2, but not the cosubstrate, 2-ketoglutarate, to the reaction mixture of an in vitro von Hippel-Lindau (VHL) capture assay, and pretreatment with ascorbate abrogated PCT induction of cellular HIF-1α. Moreover, PCT prevented hydroxylation of cellular HIF-1α and attenuated coimmunoprecipitation of Flag-VHL protein and HA-HIF-1α over-expressed in human embryonic kidney 293 cells. Structural analysis using derivatives of PCT revealed that the catechol moiety in PCT was required for the stabilization of HIF-1α protein. Taken together, PCT activation of HIF-1 resulting from inhibition of HPH-2 may be a molecular mechanism for an anti-colitic effect of the natural product.

Topics: Ascorbic Acid; Cell Line, Tumor; Colitis; Colonic Neoplasms; HEK293 Cells; Heme Oxygenase-1; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Hypoxia-Inducible Factor-Proline Dioxygenases; Procollagen-Proline Dioxygenase; Stilbenes; Vascular Endothelial Growth Factor A

Resveratrol, a naturally occurring polyphenol has received significant attention as a potent anti-inflammatory agent. Inflammatory bowel disease (IBD) is a chronic intestinal inflammation caused by hyperactivated effector immune cells that produce proinflammatory cytokines. Myeloid derived suppressor cells (MDSCs) are a heterogeneous population characterized by the co-expression of CD11b(+) and Gr-1(+) and have long been known for their immunosuppressive function. We report that resveratrol effectively attenuated overall clinical scores as well as various pathological markers of colitis in IL-10(-/-) mice by down regulating Th1 responses. Resveratrol lessened the colitis-associated decrease in body weight and increased levels of serum amyloid A (SAA), CXCL10 and colon TNF-α, IL-6, RANTES, IL-12 and IL-1β concentrations. After resveratrol treatment, the percentage of CXCR3 expressing T cells was decreased in the spleen, mesenteric lymph nodes (MLN), and intestinal lamina propria (LP). However, the percentage and absolute numbers of CD11b(+) and Gr-1(+)cells in the lamina propria (LP) and spleen were increased after resveratrol treatment as compared with the vehicle treatment. Co-culture of resveratrol-induced CD11b(+) Gr-1(+) cells with T cells, attenuated T cell proliferation, and most importantly reduced IFN-γ and GM-CSF production by LP derived T cells from vehicle treated IL-10(-/-) mice with chronic colitis. The current study suggests that administration of resveratrol into IL-10(-/-) mice induces immunosuppressive CD11b(+) Gr-1(+) MDSCs in the colon, which correlates with reversal of established chronic colitis, and down regulation of mucosal and systemic CXCR3(+) expressing effector T cells as well as inflammatory cytokines in the colon. The induction of immunosuppressive CD11b(+) Gr-1(+) cells by resveratrol during colitis is unique, and suggests an as-yet-unidentified mode of anti-inflammatory action of this plant polyphenol.

Topics: Animals; CD11b Antigen; Cell Proliferation; Cell Separation; Chronic Disease; Colitis; Cytokines; Disease Progression; Enzyme-Linked Immunosorbent Assay; Feces; Flow Cytometry; Immunoglobulin A; Immunoglobulin G; Interleukin-10; Mice; Mice, Knockout; Mucous Membrane; Myeloid Cells; Receptors, Chemokine; Receptors, CXCR3; Resveratrol; Serum Amyloid A Protein; Spleen; Stilbenes; T-Lymphocytes; Weight Loss

The polyphenolic compound 2,3,5,4'-tetrahydroxystilbene-2-O-beta-D-glucoside (THSG) has been shown to possess anti-inflammatory effects. Here, we examined the effects of THSG on experimental mice with colitis induced by acetic acid and whether the underlying mechanisms were associated with the PPAR-γ and NF-κB pathways. Mice were randomized into six equal groups: normal, colitis model, THSG (10, 30, 60 mg·kg(-1)) and mesalazine. The mice were administered 10, 30, 60 mg·kg(-1) THSG or 100 mg·kg-1 mesalazine or saline once daily by intragastric administration for 7 days after induction of colitis by acetic acid irrigation. THSG dramatically attenuated acetic acid-induced colon lesions, including reversing the body weight loss and improving histopathological changes. THSG apparently decreased the increase of malondialdehyde (MDA) which is a marker of lipid peroxidation. THSG appears to exert its beneficial effects on acetic acid-induced experimental colitis through upregulation of PPAR-γ mRNA and protein levels and inhibition of the NF-κB pathway, which in turn decreases the protein overexpression of the downstream inflammatory mediators TNF-α, IL-6 and COX-2. The effect of THSG 60 mg·kg(-1) on PPAR-γ mRNA expression was higher than that of mesalazine. THSG may thus be a promising new candidate or lead compound for the treatment of IBD.

Topics: Acetic Acid; Animals; Anti-Inflammatory Agents, Non-Steroidal; Colitis; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Drugs, Chinese Herbal; Glucosides; Interleukin-6; Male; Malondialdehyde; Mesalamine; Mice; NF-kappa B; PPAR gamma; Stilbenes; Tumor Necrosis Factor-alpha

Inflammatory bowel disease is a chronic, relapsing, and tissue-destructive disease. Resveratrol (3,4,5-trihydroxy-trans-stilbene), a naturally occurring polyphenol that exhibits beneficial pleiotropic health effects, is recognized as one of the most promising natural molecules in the prevention and treatment of chronic inflammatory disease and autoimmune disorders. In the present study, we investigated the effect of resveratrol on dextran sodium sulfate (DSS)-induced colitis in mice and found that it effectively attenuated overall clinical scores as well as various pathological markers of colitis. Resveratrol reversed the colitis-associated decrease in body weight and increased levels of serum amyloid A, tumor necrosis factor-alpha, interleukin (IL-6), and IL-1beta. After resveratrol treatment, the percentage of CD4(+) T cells in mesenteric lymph nodes (MLN) of colitis mice was restored to normal levels, and there was a decrease in these cells in the colon lamina propria (LP). Likewise, the percentages of macrophages in MLN and the LP of mice with colitis were decreased after resveratrol treatment. Resveratrol also suppressed cyclooxygenase-2 (COX-2) expression induced in DSS-exposed mice. Colitis was associated with a decrease in silent mating type information regulation-1 (SIRT1) gene expression and an increase in p-inhibitory kappaB expression and nuclear transcription factor-kappaB (NF-kappaB) activation. Resveratrol treatment of mice with colitis significantly reversed these changes. This study demonstrates for the first time that SIRT1 is involved in colitis, functioning as an inverse regulator of NF-kappaB activation and inflammation. Furthermore, our results indicate that resveratrol may protect against colitis through up-regulation of SIRT1 in immune cells in the colon.

Topics: Administration, Oral; Animals; CD4 Lymphocyte Count; Colitis; Colon; Cyclooxygenase 2; Cytokines; Dextran Sulfate; Down-Regulation; Female; Intestinal Mucosa; Lymph Nodes; Macrophages; Mesentery; Mice; Mice, Inbred C57BL; Mucous Membrane; NF-kappa B; Resveratrol; Sirtuin 1; Stilbenes

Resveratrol is a naturally occurring polyphenol that exhibits pleiotropic health beneficial effects, including anti-inflammatory, cardio-protective, and cancer-protective activities. It is recognized as one of the more promising natural molecules in the prevention and treatment of chronic inflammatory and autoimmune disorders. Ulcerative colitis is an idiopathic, chronic inflammatory disease of the colon associated with a high colon cancer risk. Here, we used a dextran sulfate sodium (DSS) mouse model of colitis, which resembles human ulcerative colitis pathology. Resveratrol mixed in food ameliorates DSS-induced colitis in mice in a dose-dependent manner. Resveratrol significantly improves inflammation score, downregulates the percentage of neutrophils in the mesenteric lymph nodes and lamina propria, and modulates CD3(+) T cells that express tumor necrosis factor-alpha and IFN-gamma. Markers of inflammation and inflammatory stress (p53 and p53-phospho-Ser(15)) are also downregulated by resveratrol. Because chronic colitis drives colon cancer risk, we carried out experiments to determine the chemopreventive properties of resveratrol. Tumor incidence is reduced from 80% in mice treated with azoxymethane (AOM) + DSS to 20% in mice treated with AOM + DSS + resveratrol (300 ppm). Tumor multiplicity also decreased with resveratrol treatment. AOM + DSS-treated mice had 2.4 +/- 0.7 tumors per animal compared with AOM + DSS + 300 ppm resveratrol, which had 0.2 +/- 0.13 tumors per animal. The current study indicates that resveratrol is a useful, nontoxic complementary and alternative strategy to abate colitis and potentially colon cancer associated with colitis.

Topics: Animals; Antineoplastic Agents, Phytogenic; Carcinogens; Cell Separation; Colitis; Colonic Neoplasms; Female; Flow Cytometry; Immunohistochemistry; Inflammation; Male; Mice; Mice, Inbred C57BL; Precancerous Conditions; Resveratrol; Stilbenes; T-Lymphocytes

Topics: Aging; Animals; Colitis; Colonic Neoplasms; Humans; Inflammation Mediators; Mice; NF-kappa B; Resveratrol; Sirtuin 1; Stilbenes

Resveratrol, a naturally occurring polyphenolic antioxidant, has been shown to exhibit chemoprophylactic effects on cancer development. Previously, we reported that 2,3',4,4',5'-pentamethoxy-trans-stilbene (PMS), a methoxylated resveratrol derivative, exerted a highly potent anti-proliferative effect on human colon cancer cells as compared with its parent compound. In the present study, the chemopreventive effect of PMS was evaluated in a mouse model of colitis-associated colon carcinogenesis.. Seven-week-old Balb/c mice were injected i.p. with 10 mg.kg(-1) azoxymethane (AOM). After 1 week, 3% dextran sodium sulphate (DSS) was administered in the drinking water for 7 days followed by 14 days of tap water for recovery, and this cycle was repeated twice.. Intragastric administration of PMS (25, 50 mg.kg(-1) body weight) for 16 weeks significantly reduced the multiplicity of colonic neoplasms by 15% and 35% (P < 0.01) respectively. Moreover, PMS at 50 mg.kg(-1) inhibited colon cancer cell proliferation and promoted apoptosis. Such changes were accompanied by reduction of Akt (protein kinase B) phosphorylation, inactivation of beta-catenin and down-regulation of inducible nitric oxide synthase. In parallel, in vitro studies also demonstrated that PMS inhibited proliferation and induced apoptosis in the murine colon adenocarcinoma cell line Colon26 with concomitant inhibition of Akt phosphorylation and inactivation of beta-catenin.. PMS effectively suppressed colon carcinogenesis in an AOM/DSS animal model and may merit further clinical investigation as a chemoprophylactic agent against colitis-associated colon cancer in humans.

Topics: Adenocarcinoma; Animals; Apoptosis; Azoxymethane; Cell Line, Tumor; Cell Proliferation; Colitis; Colonic Neoplasms; Colorectal Neoplasms; Dextran Sulfate; Disease Models, Animal; Dose-Response Relationship, Drug; Male; Mice; Mice, Inbred BALB C; Stilbenes

There is no pharmaceutical or definitive surgical cure for inflammatory bowel diseases (IBDs). The naturally occurring polyphenol resveratrol exerts anti-inflammatory properties. However, its rapid metabolism diminishes its effectiveness in the colon. The design of prodrugs to targeting active molecules to the colon provides an opportunity for therapy of IBDs. Herein we explore the efficacy of different resveratrol prodrugs and pro-prodrugs to ameliorate colon inflammation in the murine dextran sulfate sodium (DSS) model. Mice fed with a very low dose (equivalent to 10 mg for a 70 kg-person) of either resveratrol-3-O-(6'-O-butanoyl)-β-D-glucopyranoside (6) or resveratrol-3-O-(6'-O-octanoyl)-β-D-glucopyranoside (7) did not develop colitis symptoms and improved 6-fold the disease activity index (DAI) compared to resveratrol. Our results indicate that these pro-prodrugs exerted a dual effect: (1) they prevented the rapid metabolism of resveratrol and delivered higher quantities of resveratrol to the colon and (2) they reduced mucosal barrier imbalance and prevented diarrhea, which consequently facilitated the action of the delivered resveratrol in the colon mucosa.

Topics: Acute-Phase Proteins; Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Line; Colitis; Colon; Cytokines; Dextran Sulfate; Diarrhea; Dinoprostone; Feces; Gastrointestinal Transit; Glucosides; Humans; Intestinal Absorption; Intestinal Mucosa; Mice; Mice, Inbred C57BL; Peroxidase; Prodrugs; Resveratrol; Stereoisomerism; Stilbenes; Structure-Activity Relationship

The naturally occurring polyphenol resveratrol has been acknowledged with health-beneficial properties. Most of the studies dealing with its in vivo effects assay huge doses, not representative from a dietary point of view. Our aim was to ascertain whether resveratrol can exert anti-inflammatory activity in vivo at an attainable dietary dose. Rats were fed with 1 mg of resveratrol/kg/day (a human equivalent dose) for 25 days, and in the last 5 days, 5% dextran sulfate sodium (DSS) was administered to induce colitis. Effects on colon tissue damage, gut microbiota, reactive oxygen species, inflammatory markers and nitric oxide production as well as gene expression profile with microarrays were evaluated. Resveratrol increased lactobacilli and bifidobacteria as well as diminished the increase of enterobacteria upon DSS treatment. Resveratrol significantly protected the colonic mucosa architecture, reduced body weight loss, diminished the induced anemia and reduced systemic inflammation markers, colonic mucosa prostaglandin E(2), cycloxygenase-2, prostaglandin E synthase and nitric oxide levels. In addition, the expression of 2,655 genes in distal colon mucosa related to important pathways was varied. These results reinforce the concept of resveratrol as a dietary beneficial compound in intestinal inflammation at doses possibly attainable with resveratrol-enriched nutraceuticals.

Topics: Animals; Anti-Inflammatory Agents; Colitis; Colon; Dextran Sulfate; Diet; Feces; Male; Oligonucleotide Array Sequence Analysis; Rats; Rats, Inbred F344; Resveratrol; Stilbenes

Inflammatory tissue injury has been implicated in tumor promotion and progression. 3,5,4'-trihydroxy-trans-stilbene (resveratrol) and 3,4,3', 5'-tetrahydroxy-trans-stilbene (piceatannol), 2 structurally related plant polyphenols, have been reported to possess antioxidant, anti-inflammatory, and chemopreventive properties. This study was aimed at investigating the possible protective effects of resveratrol and piceatannol against dextran sulfate sodium (DSS)-induced inflammation in mouse colonic mucosa. Administration of DSS (2.5%) in drinking water for 7 days to male ICR mice resulted in colitis and elevated expression of inducible nitric oxide synthase (iNOS) and activation of nuclear factor-kappa B (NF-kappaB), a major transcription factor known to upregulate proinflammatory gene expression. Phosphorylation of extracellular signal-regulated kinase (ERK) and signal transducer and activator of transcription-3 (STAT3) was also enhanced after DSS treatment. Oral administration of resveratrol or piceatannol (10 mg/kg body weight each) for 7 constitutive days attenuated the DSS-induced inflammatory injury, upregulation of iNOS expression, and activation of NF-kappaB, STAT3, and ERK.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Colitis; Colonic Neoplasms; Dextran Sulfate; DNA-Binding Proteins; Down-Regulation; Drug Therapy, Combination; Extracellular Signal-Regulated MAP Kinases; I-kappa B Kinase; Inflammatory Bowel Diseases; Male; Mice; Mice, Inbred ICR; NF-kappa B; Nitric Oxide Synthase Type II; Phosphorylation; Resveratrol; STAT3 Transcription Factor; Stilbenes; Time Factors

Piceatannol (3,5,3',4'-tetrahydroxy-trans-stilbene; PIC) is a polyphenol found in grapes. It is known as a protein kinase inhibitor that modifies multiple cellular targets, exerting immunosuppressive and antitumorigenic activities in several cell lines. The purpose of the present work was to evaluate the anti-inflammatory effect of PIC on dextran sulfate sodium (DSS)-induced colitis. Experimental colitis was induced in BALB/c mice by dissolving 5% DSS in their drinking water for 7 days. PIC (1, 2.5, 5, or 10 mg/kg body weight) was administrated daily per oral route for 7 days. A significant blunting of weight loss and clinical signs was observed in DSS-exposed, PIC-treated mice when compared to vehicle-treated mice. This was associated with a remarkable amelioration of the disruption of the colonic architecture, a significant reduction in colonic myeloperoxidase (MPO) activity, and a decrease in production of inflammatory mediators such as nitric oxide (NO), prostaglandin (PG) E2, and pro-inflammatory cytokines. The present data indicate that further evaluation of the potential of PIC as an agent for the prevention and/or treatment of inflammatory bowel diseases in human clinical studies is warranted.

Topics: Animals; Colitis; Colon; Dextran Sulfate; Female; Immunohistochemistry; Inflammation Mediators; Mice; Mice, Inbred BALB C; NF-kappa B; Peroxidase; STAT3 Transcription Factor; Stilbenes; Vitis

Reactive oxygen metabolites (ROMs) and inducible nitric oxide synthase (iNOS) are involved in pathogenesis of inflammatory bowel disease. In this study, we examined the effects of 2,3,5,4'-tetrahydroxystilbene-2-O-beta-D-glucoside (THSG), an active component extracted from Polygonum multiflorum Thunb, on acetic acid-induced acute colitis and mitomycin C-induced chronic colitis. The inflammatory degree was assessed by histology and myeloperoxidase (MPO) activity. Nitric oxide (NO), malondialdehyde (MDA) and superoxide dismutase (SOD) levels were determined with biochemical methods. In addition, inducible nitric oxide synthase (iNOS) expression was immunohistochemically studied. In acetic acid-induced acute model, THSG (60 and 120 mg/kg) significantly ameliorated colon damage, inhibited the increase of acetic acid-induced MPO activity, depressed MDA and NO level, and enhanced SOD activity. Moreover, the effects of 120 mg/kg THSG were better than that of positive control drug, 5-aminosalicylic acid (5-ASA). In mitomycin C-induced model, THSG (60 mg/kg) administered for 7 days and 24 days, significantly improved colon damage and inhibited MPO activity and MDA content while increased SOD activity only on the 7th day and debased NO level on the 24th day. Furthermore, on the 24th day, the effects of THSG were prior to that of 5-ASA. Additionally, THSG (60 mg/kg) could inhibit iNOS expression in both models. In conclusion, THSG exerts protective effects on experimental colitis through alleviating oxygen and nitrogen free radicals level and down-regulating iNOS expression.

Topics: Acetic Acid; Acute Disease; Animals; Anti-Inflammatory Agents; Antioxidants; Chronic Disease; Colitis; Colon; Disease Models, Animal; Dose-Response Relationship, Drug; Gastrointestinal Agents; Glucosides; Malondialdehyde; Mesalamine; Mice; Mitomycin; Nitric Oxide; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Peroxidase; Polygonum; Stilbenes; Superoxide Dismutase; Time Factors

Neutrophil infiltration, proinflammatory cytokines, eicosanoid generation and oxidative stress have been implicated in colitis. Resveratrol is a polyphenolic compound found in grapes and wine, with multiple pharmacological actions, including anti-inflammatory, antioxidant, antitumour and immunomodulatory activities. In a previous report, we documented that resveratrol decreases the degree of inflammation associated with acute experimental colonic inflammation, but its effects on chronic experimental colitis remain undetermined. The aim of this research was to investigate the effects of resveratrol on the chronic colonic injury caused by intracolonic instillation of trinitrobenzenesulphonic acid (TNBS) in rats. The inflammatory response was assessed by histology and myeloperoxidase activity. Tumour necrosis factor alpha (TNF-alpha) production, histological and histochemical analysis of the lesions were also carried out. We determined the production of prostaglandin (PG) E2 and D2 in colon mucosa, as well as cyclooxygenase (COX)-1 and -2 and nuclear transcription factor NF-kappa B (NF-kappaB) p65 protein expression. Finally, since resveratrol has been found to modulate apoptosis, we intended to elucidate its effects on colonic mucosa under chronic inflammatory conditions. Resveratrol (10 mg kg(-1) day(-1)) significantly attenuated the damage score and corrected the disturbances in morphology associated to injury. In addition, the degree of neutrophil infiltration and the levels of TNF-alpha were significantly ameliorated. Resveratrol did not modify PGD2 levels but returned the decreased PGE2 values to basal levels and also reduced COX-2 and the NF-kappaB p65 protein expression. Furthermore, treatment of rats with resveratrol caused a significant increase of TNBS-induced apoptosis in colonic cells. In conclusion, resveratrol reduces the damage in chronic experimentally induced colitis, alleviates the oxidative events, returns PGE2 production to basal levels and stimulates apoptosis in colonic cells.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Colitis; Colon; Cyclooxygenase 1; Cyclooxygenase 2; Dinoprostone; Gene Expression Regulation; Inflammation; Male; Membrane Proteins; NF-kappa B; Peroxidase; Phytoalexins; Prostaglandin D2; Rats; Rats, Wistar; Resveratrol; Sesquiterpenes; Stilbenes; Terpenes; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha; Wine

Oxidative stress, neutrophil infiltration, proinflammatory cytokines and eicosanoid generation are clearly involved in the pathogenesis of intestinal bowel disease. Resveratrol, a polyphenolic compound found in grapes and wine, has been shown to have anti-inflammatory, antioxidant, antitumour and immunomodulatory activities, however, its effects on experimental colitis remain unknown. We have investigated the effects of resveratrol on the colon injury caused by intracolonic instillation of trinitrobenzenesulphonic acid (TNBS) in rats. We determined the production of prostaglandin (PG)E(2) and PGD(2) in colon mucosa and the expression of cyclo-oxygenases (COX)-1 and -2 immunohistochemically. The inflammatory response was assessed by histology and myeloperoxidase activity, as an index of neutrophil infiltration. Interleukin-1 beta production, histological and histochemical analysis of the lesions were also carried out. Finally, since resveratrol has been found to modulate apoptosis we intended to elucidate its effects on colonic mucosa under early acute inflammatory conditions. Resveratrol (5-10mg/kg/day) significantly reduced the degree of colonic injury, the index of neutrophil infiltration and the levels of the cytokine. Resveratrol did not revert the increased PGE(2) levels but produced a significant fall in the PGD(2) concentration. Compared with inflamed colon, no changes in staining for COX-1 were observed in colon of resveratrol and TNBS-treated rats. In contrast, COX-2 expression was decreased. Furthermore, resveratrol enhanced apoptosis compared with already high level induced by TNBS. In conclusion, resveratrol reduces the damage in experimentally induced colitis, alleviates the oxidative events and stimulates apoptosis.

Topics: Animals; Antioxidants; Apoptosis; Colitis; Flavonoids; Inflammation; Male; Oxidative Stress; Phenols; Polyphenols; Rats; Rats, Wistar; Resveratrol; Stilbenes; Vitis