curcumin and Colitis

To evaluate the use of curcumin in inflammatory bowel disease.. ALTMEDEX, Comprehensive Database of Natural Medicines, MEDLINE/PubMed were searched from January 1980 through May 2009 using the terms curcumin, turmeric, ulcerative colitis, Crohn's disease, Curcuma longa, Curcuma domestica, Indian saffron, inflammatory bowel disease. Data was limited to human trials. References of identified articles were reviewed.. Data evaluating the use of curcumin in inflammatory bowel disease (including ulcerative colitis and Crohn's disease) is limited to two studies comprising data for only 99 patients. Curcumin in conjunction with mainstream therapy, consisting of sulfasalazine (SZ) or mesalamine (5-aminosalicylic acid [5-ASA] derivatives) or corticosteroids was shown to improve patient symptoms and allow for a decrease in the dosage of corticosteroids or 5-ASA derivatives. In one small study of 10 patients, some patients even stopped taking corticosteroids or 5-ASA.. Although two small studies have shown promising results, all authors conclude that larger-scale, double-blind trials need to be conducted to establish a role for curcumin in the treatment of ulcerative colitis. In addition to improving results when used in conjunction with conventional medications for UC, curcumin may pose a less-expensive alternative.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Colitis; Curcumin; Dose-Response Relationship, Drug; Humans; Inflammatory Bowel Diseases; Intestinal Mucosa; Patient Satisfaction; Randomized Controlled Trials as Topic

Topics: Animals; B-Lymphocytes, Regulatory; Colitis; Colitis, Ulcerative; Colon; Curcumin; Dextran Sulfate; Disease Models, Animal; Interleukin-1 Receptor-Associated Kinases; Mice; Myeloid Differentiation Factor 88; NF-kappa B; Signal Transduction

Ulcerative Colitis (UC) is a disease that negatively affects quality of life and is associated with sustained oxidative stress, inflammation and intestinal permeability. Vitamin D and Curcumin; It has pharmacological properties beneficial to health, including antioxidant and anti-inflammatory properties. Our study investigates the role of Vitamin D and Curcumin in acetic acid-induced acute colitis model. To investigate the effect of Vitamin D and Curcumin, Wistar-albino rats were given 0.4 mcg/kg Vitamin D (Post-Vit D, Pre-Vit D) and 200 mg/kg Curcumin (Post-Cur, Pre-Cur) for 7 days and acetic acid was injected into all rats except the control group. Our results; colon tissue TNF-α, IL-1β, IL-6, IFN-γ and MPO levels were found significantly higher and Occludin levels were found significantly lower in the colitis group compared to the control group (

Topics: Acetic Acid; Animals; Anti-Inflammatory Agents; Antioxidants; Colitis; Colitis, Ulcerative; Colon; Curcumin; Inflammation; Interleukin-6; Occludin; Quality of Life; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha; Vitamin D

Curcumin may have promising application in the prevention and amelioration of inflammatory bowel disease (IBD). However, the underlying mechanisms underpinning the ability of curcumin to interact with the gut and liver in IBD remains to be defined, which is the exploration aim of this study.. Curcumin supplementation not only prevented further loss of body weight and colon length in IBD mice but also improved diseases activity index (DAI), colonic mucosal injury, and inflammatory infiltration. Meanwhile, curcumin restored the composition of the gut microbiota, significantly increased Akkermansia, Muribaculaceae_unclassified, and Muribaculum, and significantly elevated the concentration of propionate, butyrate, glycine, tryptophan, and betaine in the intestine. For hepatic metabolic disturbances, curcumin intervention altered 14 metabolites, including anthranilic acid and 8-amino-7-oxononanoate while enriching pathways related to the metabolism of bile acids, glucagon, amino acids, biotin, and butanoate. Furthermore, SCC analysis revealed a potential correlation between the upregulation of intestinal probiotics and alterations in liver metabolites.. The therapeutic mechanism of curcumin against IBD mice occurs by improving intestinal dysbiosis and liver metabolism disorders, thus contributing to the stabilization of the gut-liver axis.

Topics: Animals; Chromatography, Liquid; Colitis; Colon; Curcumin; Dextran Sulfate; Disease Models, Animal; Dysbiosis; Inflammatory Bowel Diseases; Liver Diseases; Mice; Mice, Inbred C57BL; Tandem Mass Spectrometry

Restoration of immune homeostasis by targeting the balance between memory T helper (mTh) cells and memory follicular T helper (mTfh) cells is a potential therapeutic strategy against ulcerative colitis (UC). Because of its anti-inflammatory and immunomodulatory properties, curcumin (Cur) is a promising drug for UC treatment. However, fewer studies have demonstrated whether Cur can modulate the mTh/mTfh subset balance in mice with colitis.. To explore the potential mechanism underlying Cur-mediated alleviation of colitis induced by dextran sulfate sodium (DSS) in mice by regulating the mTh and mTfh immune homeostasis.. Cur effectively mitigates DSS-induced colitis, facilitates the restoration of mouse weight and colonic length, and diminishes the colonic weight and colonic weight index. Simultaneously, it hinders ulcer development and inflammatory cell infiltration in the colonic mucous membrane. While the percentage of Th1, mTh1, Th7, mTh7, Th17, mTh17, Tfh1, mTfh1, Tfh7, mTfh7, Tfh17, and mTfh17 cells decreased after Cur treatment of the mice for 7 d, and the frequency of mTh10, Th10, mTfh10, and Tfh10 cells in the mouse spleen increased. Further studies revealed that Cur administration prominently decreased the SOCS-1, SOCS-3, STAT3, p-STAT3, JAK1, p-JAK1, and NF-κB p65 protein expression levels in the colon tissue.. Cur regulated the mTh/mTfh cell homeostasis to reduce DSS-induced colonic pathological damage, potentially by suppressing the JAK1/STAT3/SOCS signaling pathway.

Topics: Animals; Colitis; Colitis, Ulcerative; Colon; Curcumin; Dextran Sulfate; Disease Models, Animal; Mice; Mice, Inbred C57BL; NF-kappa B

Solid evidence has emerged supporting the role of nonextractable polyphenols (NEPs) and dietary fibers (DFs) as gut microbiota modulators. This study aims to elucidate gut microbiota-dependent release of turmeric NEPs and examine the possible anti-inflammatory mechanism in the dextran sulfate sodium-induced ulcerative colitis (UC) model. 1.5% DSS drinking water-induced C57BL/6J mice were fed a standard rodent chow supplemented with or without 8% extractable polyphenols (EPs), NEPs, or DFs for 37 days. The bound curcumin, demethoxycurcumin, and bisdemethoxycurcumin in NEPs were released up to 181.5 ± 10.6, 65.2 ± 6.0, and 69.5 ± 7.6 μg/mL by in vitro gut microbiota-simulated fermentation and released into the colon of NEP-supplemented mice by 5.7-, 11.0-, and 7.8-fold higher than pseudo germ-free mice, respectively (

Topics: Animals; Coleoptera; Colitis; Colitis, Ulcerative; Colon; Curcuma; Dextran Sulfate; Dietary Fiber; Disease Models, Animal; Gastrointestinal Microbiome; Inflammation; Mice; Mice, Inbred C57BL; Polyphenols

Topics: Animals; Cell Differentiation; Colitis; Curcumin; Dextran Sulfate; Mice; Mice, Inbred BALB C; T Follicular Helper Cells; T-Lymphocytes, Helper-Inducer

Curcumin is a natural polyphenol compound with multiple pharmacologic activities. The present study aims to explore the potential therapeutic properties of curcumin on intestinal inflammatory diseases, including its anti-inflammatory, antioxidant, and anti-apoptotic properties, as well as their associations with altered intestinal microbiome.. Curcumin shows therapeutic potential against colitis. It may be served as an alternative medicine or adjuvant therapy in the treatment of colitis.

Topics: Animals; Bacteria; Colitis; Colon; Curcumin; Dextran Sulfate; Disease Models, Animal; Gastrointestinal Microbiome; Humans; Intestinal Mucosa; Mice; Mice, Inbred C57BL

Diabetes mellitus (DM) is one of the most common complications in patients with ulcerative colitis (UC). Curcumin has a wide range of bioactive and pharmacological properties and is commonly used as an adjunct to the treatment of UC and DM. However, the role of curcumin in UC complicated by DM has not been elucidated. Therefore, this study was conducted to construct a model of UC complicating diabetes by inducing UC in DB mice (spontaneously diabetic) with dextran sodium sulfate. In this study, curcumin (100 mg/kg/day) significantly improved the symptoms of diabetes complicated by UC, with a lower insulin level, heavier weight, longer and lighter colons, fewer mucosal ulcers and less inflammatory cell infiltration. Moreover, compared to untreated DB mice with colitis, curcumin-treated mice showed weaker Th17 responses and stronger Treg responses. In addition, curcumin regulated the diversity and relative abundance of intestinal microbiota in mice with UC complicated by DM at the phylum, class, order, family and genus levels. Collectively, curcumin effectively alleviated colitis in mice with type 2 diabetes mellitus by restoring the homeostasis of Th17/Treg and improving the composition of the intestinal microbiota.

Topics: Animals; Colitis; Colitis, Ulcerative; Colon; Curcumin; Dextran Sulfate; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Disease Models, Animal; Gastrointestinal Microbiome; Homeostasis; Humans; Mice; Mice, Inbred C57BL; T-Lymphocytes, Regulatory

To examine the effects of a negatively charged nanostructured curcumin microemulsion in experimental ulcerative colitis (UC) in rats.. Four percent acetic acid was used to induce UC. The animals were treated for seven days and randomly assigned to four groups: normal control (NC), colitis/normal saline (COL/NS), colitis/curcumin (COL/CUR), and colitis/mesalazine (COL/MES). The nanostructured curcumin was formulated with a negative zeta potential (-16.70 ± 1.66 mV). Dosage of the pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin 1-β (IL-1β), interleukin 6 (IL-6), and antioxidant enzymes (catalase, superoxide dismutase, and glutathione peroxidase), macro and microscopic evaluation of the colon tissue were analyzed.. The COL/CUR group had a higher level of antioxidant enzymes compared to the COL/MESgroup. The levels of TNF-α, IL-1β and IL-6 were significantly lower in the colonic tissue of the COL/CUR group rats, when compared to the COL/NS and COL/MES groups (p < 0.001). The presence of ulcers in the colonic mucosa in rats of the COL/NSgroup was significantly higher than in the COL/MES group (p < 0.001). In the NC and COL/CUR groups, there were no ulcers in the colonic mucosa.. The nanostructured microemulsion of curcumin, used orally, positively influenced the results of the treatment of UC in rats. The data also suggests that nanostructured curcumin with negative zeta potential is a promising phytopharmaceutical oral delivery system for UC therapy. Further research needs to be done to better understand the mechanisms of the negatively charged nanostructured curcumin microemulsion in UC therapy.

Topics: Animals; Antioxidants; Colitis; Colitis, Ulcerative; Colon; Curcumin; Interleukin-6; Rats; Tumor Necrosis Factor-alpha

The pathogenesis of inflammatory bowel disease (IBD) remains unclear. C66, a derivative of curcumin, reportedly exerts anti-inflammatory, antifibrotic and anti-apoptotic effects by targeting the JNK pathway. However, the effect of C66 against IBD is not clear. In this study, we aimed to investigate the effect of C66 against IBD.. C57BL/6J mice were treated with 2.5% DSS for 7 days, and then administered water for 3 days to develop the IBD mouse model. A mouse intestinal epithelial cell line, MODE-K, stimulated by lipopolysaccharide (LPS) was used as the in vitro model. The therapeutic effects of C66 were evaluated and the pharmacological mechanisms were explored.. Compared to the model group, C66 treatment significantly reduced colitis-associated damage, including a decrease in disease activity index (DAI), a higher body weight and longer colon. In addition, the infiltration of distal inflammatory cells, loss of crypt tissues, and destruction of epithelial cells were reduced in C66-treated group. In addition, C66 treatment reduced fibrotic areas and inflammatory responses in the colon tissues, leading to increased epithelial cell proliferation and decreased apoptosis in colon. Furthermore, C66 treatment decreased the levels of p-JNK and p-P65, indicating that C66 inhibits the activation of the JNK and NF-κB signaling pathways induced by DSS in colon tissues. Finally, in vitro data show that C66 inhibited LPS-induced inflammation and apoptosis in small intestinal epithelial cells.  CONCLUSIONS: The curcumin analog C66 exhibits its anti-inflammatory effect by inhibiting the DSS-induced activation of JNK/NF-κB signaling pathways. C66 may be a potential candidate for the treatment of IBD.

Topics: Animals; Colitis; Curcumin; Dextran Sulfate; Lipopolysaccharides; Mice; Mice, Inbred C57BL; NF-kappa B

Immune dysfunction is the crucial cause in the pathogenesis of inflammatory bowel disease (IBD), which is mainly related to lymphocytes (T or B cells, incl-uding memory B cells), mast cells, activated neutrophils, and macrophages. As the precursor of B cells, the activation of memory B cells can trigger and differentiate B cells to produce a giant variety of inducible B cells and tolerant B cells, whose dysfunction can easily lead to autoimmune diseases, including IBD.. To investigate whether or not curcumin (Cur) can alleviate experimental colitis by regulating memory B cells and Bcl-6-Syk-BLNK signaling.. Colitis was induced in mice with a dextran sulphate sodium (DSS) solution in drinking water. Colitis mice were given Cur (100 mg/kg/d) orally for 14 con-secutive days. The colonic weight, colonic length, intestinal weight index, occult blood scores, and histological scores of mice were examined to evaluate the curative effect. The levels of memory B cells in peripheral blood of mice were measured by flow cytometry, and IL-1β, IL-6, IL-10, IL-7A, and TNF-α expression in colonic tissue homogenates were analyzed by enzyme-linked immunosorbent assay. Western blot was used to measure the expression of Bcl-6, BLNK, Syk, and other signaling pathway related proteins.. After Cur treatment for 14 d, the body weight, colonic weight, colonic length, colonic weight index, and colonic pathological injury of mice with colitis were ameliorated. The secretion of IL-1β, IL-6, TNF-α, and IL-7A was statistically decreased, while the IL-35 and IL-10 levels were considerably increased. Activation of memory B cell subsets in colitis mice was confirmed by a remarkable reduction in the expression of IgM, IgG, IgA, FCRL5, CD103, FasL, PD-1, CD38, and CXCR3 on the surface of CD19. Cur could effectively alleviate DSS-induced colitis in mice by regulating memory B cells and the Bcl-6-Syk-BLNK signaling pathway.

Topics: Animals; Colitis; Curcumin; Cytokines; Dextran Sulfate; Disease Models, Animal; Inflammatory Bowel Diseases; Interleukin-10; Interleukin-6; Memory B Cells; Mice; Mice, Inbred C57BL; Signal Transduction; Tumor Necrosis Factor-alpha

Epigallocatechin gallate and tetrahydrocurcumin are aminated as colonic metabolites, preserving their bioactivities and improving their capabilities. We compared the bioactivities of unaminated (CUR) and aminated (AC) curcumin in inflammatory colitis-associated tumorigenesis. The anti-inflammatory and anticancer capabilities of CUR and AC were evaluated using RAW264.7 and HT29 cell lines, respectively. An azoxymethane/dextran sodium sulfate-induced colitis-associated carcinogenesis mouse model was used with CUR and two-dose AC interventions. AC had a greater anti-inflammatory effect but a similar anticancer effect as CUR in vitro. CUR and low-dose AC (LAC) significantly preserved colon length and reduced tumor number in vivo. Both CUR and LAC inhibited activation of the protein kinase B (AKT)/nuclear factor kappa B (NF-κB) signaling pathway, its downstream cytokines, and the interleukin (IL)-6/signal transducer and activator of transcription 3 (STAT3)/c-myelocytomatosis oncogene (c-MYC) pathway. However, only LAC significantly preserved E-cadherin, reduced N-cadherin, and facilitated beneficial gut microbial growth, including

Topics: Amination; Animals; Anti-Inflammatory Agents; Carcinogenesis; Colitis; Curcumin; Dextran Sulfate; Gastrointestinal Microbiome; Interleukin-6; Mice; NF-kappa B; STAT3 Transcription Factor

Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) characterized by diffuse inflammation of the colonic mucosa and a relapsing and remitting course. The current therapeutics are only modestly effective and carry risks for unacceptable adverse events, and thus more effective approaches to treat UC is clinically needed.. For this purpose, turmeric-derived nanoparticles with a specific population (TDNPs 2) were characterized, and their targeting ability and therapeutic effects against colitis were investigated systematically. The hydrodynamic size of TDNPs 2 was around 178 nm, and the zeta potential was negative (- 21.7 mV). Mass spectrometry identified TDNPs 2 containing high levels of lipids and proteins. Notably, curcumin, the bioactive constituent of turmeric, was evidenced in TDNPs 2. In lipopolysaccharide (LPS)-induced acute inflammation, TDNPs 2 showed excellent anti-inflammatory and antioxidant properties. In mice colitis models, we demonstrated that orally administrated of TDNPs 2 could ameliorate mice colitis and accelerate colitis resolution via regulating the expression of the pro-inflammatory cytokines, including TNF-α, IL-6, and IL-1β, and antioxidant gene, HO-1. Results obtained from transgenic mice with NF-κB-RE-Luc indicated that TDNPs 2-mediated inactivation of the NF-κB pathway might partially contribute to the protective effect of these particles against colitis.. Our results suggest that TDNPs 2 from edible turmeric represent a novel, natural colon-targeting therapeutics that may prevent colitis and promote wound repair in colitis while outperforming artificial nanoparticles in terms of low toxicity and ease of large-scale production.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents; Antioxidants; Colitis; Colitis, Ulcerative; Curcuma; Disease Models, Animal; Exosomes; Inflammation; Mice; Mice, Transgenic; NF-kappa B

Inflammatory bowel disease is characterized by a radical imbalance of inflammatory signaling pathways in the gastrointestinal tract, and it is categorized into two diseases, such as Crohn's disease and ulcerative colitis. In this study, we investigated anti-inflammatory activities using fermented Curcuma that contains butyrate (FB). Nitric oxide production in RAW 264.7 cells and the expression of inducible nitric oxide synthase in the intestinal mucosa appears to be enhanced in active ulcerative colitis. Here, the cytotoxicity, physiological activity, and anti-inflammatory efficacy of FB in colitis animals were investigated. To verify the anti-inflammatory effect, this study was conducted using the dextran sulfate sodium (DSS)-induced colitis mice model. As a result, non-toxicity was confirmed, and anti-inflammatory effects were revealed by inducing a reduction of LPS-induced NO production. In the DSS-induced colitis, reduced weight was recovered and a decrease in inflammatory factors Ig-E and TNF-α in the mesenteric lymph node (MLN) and spleen was induced, and it was confirmed to help with the morphological remodeling of the intestine. In conclusion, this paper suggests that FB can help to alleviate intestinal inflammation and to improve the intestinal environment, with the help of morphological remodeling.

Topics: Animals; Anti-Inflammatory Agents; Butyrates; Colitis; Colitis, Ulcerative; Colon; Curcuma; Cytokines; Dextran Sulfate; Disease Models, Animal; Mice; Mice, Inbred C57BL

Topics: Animals; Anti-Inflammatory Agents; Colitis; Colitis, Ulcerative; Colon; Curcuma; Cytokines; Dextran Sulfate; Disease Models, Animal; Gastrointestinal Microbiome; Inflammation; Mice; Mice, Inbred C57BL; Nanoparticle Drug Delivery System

The goal of this work was to assess the usability of yeast glucan particles (GPs) as carriers for curcumin and determine the beneficial effect of a pharmacological composite of curcumin in GPs on dextran sulfate sodium induced colitis in rats. The assessment of the anti-inflammatory effect of particular substances was evaluated on the basis of the calculated disease activity index and by assessment of cytokines and enzymes from the gut tissue - tumor necrosis factor α (TNF-α), transforming growth factor β1, interleukin (IL)-1β, IL-6, IL-10, IL-17, catalase, superoxide dismutase 2, myeloperoxidase (MPO), and matrix metalloproteinase 9. Composites of GPs with incorporated curcumin showed promising results with the capability to lower symptoms of colitis and significantly decrease the production of pro-inflammatory cytokines TNF-α, IL-1β, IL-6, and the activity of MPO, as well. The anti-inflammatory effect of the composites was greater than those of pure GPs or curcumin.

Topics: Animals; Anti-Inflammatory Agents; Colitis; Curcumin; Cytokines; Dextran Sulfate; Drug Carriers; Glucans; Interleukins; Male; Rats; Rats, Wistar; Saccharomyces cerevisiae

A major drawback of oral treatment of inflammatory bowel disease (IBD) is the non-specific distribution of drugs during long-term treatment. Despite its effectiveness as an anti-inflammatory drug, curcumin (CUR) is limited by its low bioavailability in IBD treatment. Herein, a pH-sensitive composite hyaluronic acid/gelatin (HA/GE) hydrogel drug delivery system containing carboxymethyl chitosan (CC) microspheres loaded with CUR was fabricated for IBD treatment. The composition and structure of the composite system were optimized and the physicochemical properties were characterized using infrared spectroscopy, X-ray diffraction, swelling, and release behavior studies. In vitro, the formulation exhibited good sustained release property and the drug release rate was 65% for 50 h. In vivo pharmacokinetic experiments indicated that high level of CUR was maintained in the colon tissue for more than 24 h; it also played an anti-inflammatory role by evaluating the histopathological changes through hematoxylin and eosin (H&E), myeloperoxidase (MPO), and immunofluorescent staining. Additionally, the formulation substantially inhibited the level of the main pro-inflammatory cytokines of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) secreted by macrophages, compared to the control group. The pharmacodynamic experiment showed that the formulation group of CUR@gels had the best therapeutic effect on colitis in mice. The composite gel delivery system has potential for the effective delivery of CUR in the treatment of colitis. This study also provides a reference for the design and preparation of a new oral drug delivery system with controlled release behavior.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents; Chitosan; Colitis; Colon; Curcumin; Drug Carriers; Drug Delivery Systems; Drug Liberation; Gelatin; Hyaluronic Acid; Hydrogels; Hydrogen-Ion Concentration; Inflammatory Bowel Diseases; Interleukin-6; Macrophages; Mice; Microscopy, Electron, Scanning; Microspheres; Rheology; Spectroscopy, Fourier Transform Infrared; Tumor Necrosis Factor-alpha; X-Ray Diffraction

Curcumin was reported as an anti-inflammatory agent. However, curcumin's poor bioavailability limited its clinical utility. Here, thirty ortho-substituted mono-carbonyl curcumin derivatives, containing acetone, cyclopentanone, cyclohexanone or 4-piperidione (NH, N-methyl or N-acrylyl) moieties replacing β-diketone moiety of curcumin, were investigated for anti-inflammatory activity. Two active ortho-trifluoromethoxy-substituted 4-piperidione-containing derivatives 22 and 24 owned good cell uptake ability, and displayed excellent anti-inflammatory activity in both lipopolysaccharide-induced Raw264.7 macrophages and a dextran sulfate sodium (DSS)-induced mouse model of colitis. They inhibited the production of nitric oxide, reactive oxygen species, malonic dialdehyde and cyclooxygenase-2; and the expression of pro-inflammatory cytokines interleukin-1β, tumor necrosis factor-α and myeloperoxidase; the phosphorylation of mitogen-activated protein kinases; and the nucleus translocation of p65. What's more, 22 or 24 oral administered reduced the severity of clinical symptoms of ulcerative colitis (body weight and disease activity index), and reduced obviously DSS-induced colonic pathological damage (the colon length and histopathology analysis). These results suggested that ortho-trifluoromethoxy-substituted 4-piperidione-containing mono-carbonyl curcumin derivatives 22 and 24 were potential anti-inflammatory agents; and offered the important information for design and discovery of more potent anti-inflammatory drug candidates.

Topics: Animals; Anti-Inflammatory Agents; Colitis; Colon; Curcumin; Dextran Sulfate; Disease Models, Animal; Lipopolysaccharides; Mice

Delivering hydrophobic molecules through the intestine can be challenging due to limited cargo solubility and the harsh biochemical environment of the stomach. Here, we show that a protein-based nanocarrier system based on the abundant protein histone and the natural cross-linker genipin can deliver hydrophobic cargos, such as dyes and therapeutic molecules, through the gastrointestinal tract. Using hydrophobic near-infrared dyes as model cargos, a panel of potential protein carriers was screened, and histone was identified as the one with the best loading capability. The resulting nanoparticles had a positive ζ potential and were mucoadhesive. Cross-linking of the amine-rich nanocarrier with genipin was particularly effective relative to other proteins and increased the stability of the system during incubation with pepsin. Cross-linking was required for successful delivery of a hydrophobic dye to the colon of mice after oral gavage. To assess the platform for therapeutic delivery, another hydrophobic model compound, curcumin, was delivered using cross-linked histone nanoparticles in a murine colitis model and significantly alleviated the disease. Taken together, these results demonstrate that histone is a cationic, mucoadhesive, and cross-linkable protein nanocarrier that can be considered for oral delivery.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Colitis; Cross-Linking Reagents; Curcumin; Drug Carriers; Female; Gastrointestinal Tract; Histones; Hydrophobic and Hydrophilic Interactions; Iridoids; Mice; Mice, Inbred ICR; Nanoparticles

Oral route colon-targeted drug delivery systems (CDDSs) are desirable for the treatment of ulcerative colitis (UC). However, CDDSs are challenging owing to the physiological and anatomical barriers associated with the gastrointestinal tract (GIT). In this study, we developed an effective enzyme-triggered controlled release system using curcumin-cyclodextrin (CD-Cur) inclusion complex as core and low molecular weight chitosan and unsaturated alginate resulting nanoparticles (CANPs) as shell. The formed CD-Cur-CANPs showed a narrow particle-size distribution and a compact structure.

Topics: Administration, Oral; Alginates; Animals; beta-Cyclodextrins; Chemistry, Pharmaceutical; Chitosan; Colitis; Curcumin; Cytokines; Delayed-Action Preparations; Dextran Sulfate; Disease Models, Animal; Drug Carriers; Drug Liberation; Hydrogen-Ion Concentration; Macrophages; Male; Mice; Mice, Inbred C57BL; Nanoparticles; Particle Size

To determine whether curcumin (Cur) can treat mice with experimentally-induced colitis by regulating follicular helper T cells (Tfh) and follicular regulatory T cells (Tfr) by inhibiting interleukin (IL)-21. In this study, 40 male C57BL/6 mice were randomly grouped into four groups, i.e., normal, trinitrobenzene sulfonic acid (TNBS), TNBS + curcumin, and TNBS + anti-IL-21. Mice with experimental colitis were induced by 100 mg/kg TNBS. The mice in the TNBS + Cur group were treated with 100 mg/kg curcumin for seven days, and mice in the TNBS + anti-IL-21 group were treated with anti-IL-21 (150 μg/mouse) once per week, intraperitoneally, starting on the second day after establishing the experimental colitis model. On day eight, the therapeutic effect of curcumin was evaluated by colon mucosa damage index (CMDI), histological examination, and disease activity index (DAI). Furthermore, the number of CD4 + CXCR5 + PD-1 + Tfh and CD4 + CXCR5 + FoxP3 + Tfr cells were measured by flow cytometry. The mRNA and protein expression of IL-21, Bcl-6, FOXP3, ICOS, and PD-1 in colonic mucosa was detected by reverse transcription polymerase chain reaction and the Western blot technique. Compared with the TNBS group, the DAI, CMDI, histological score, the number of CD4 + CXCR5 + PD-1 + Tfh cells, the expression of IL-21, Bcl-6, ICOS, and PD-1 were significantly decreased in the TNBS + curcumin group and TNBS + anti-IL-21 group; body weight, number of CD4 + CXCR5 + FoxP3 + Tfr cells, and the expression of FoxP3 were observably elevated in the TNBS + curcumin group (all P < 0.05). Curcumin may have a potential therapeutic effect on mice with colitis treated experimentally through regulation of the balance of Tfh and Tfr cells via inhibiting the synthesis of IL-21.

Topics: Animals; Colitis; Curcumin; Disease Models, Animal; Flow Cytometry; Interleukins; Intestinal Mucosa; Male; Mice; Mice, Inbred C57BL; RNA, Messenger; T Follicular Helper Cells; T-Lymphocytes, Regulatory; Trinitrobenzenesulfonic Acid

Telocytes (TCs) are a distinct type of interstitial cells that play a vital role in the pathogenesis of ulcerative colitis and colonic tissue hemostasis. The aim of this study was to examine the effect of nanocurcumin (NC) on the morphometric and immunohistochemical characterization of TCs in the ulcerative colitis (UC) rat model.. Forty rats were randomly divided into control, NC, UC, and UC+NC groups. At the end of the experiment, the colon was dissected and prepared for histopathological and immunohistochemical assessment. Tissue homogenates were prepared for real-time PCR assessment of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-. NC successfully targeted the colonic tissue, improved the mucosal lesion, preserve TCs distribution, and count through its anti-inflammatory and fibrinolytic properties.

Topics: Animals; Colitis; Colitis, Ulcerative; Colon; Curcumin; Disease Models, Animal; Fibrinolysis; Gene Expression Regulation; Immunohistochemistry; Inflammation; Interleukin-6; Intestinal Mucosa; Male; Nanoparticles; Rats; Rats, Wistar; Spectroscopy, Fourier Transform Infrared; Telocytes; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha; Vimentin

The role of mitochondrial dysfunction in the pathogenesis of inflammatory bowel diseases (IBD) is still being investigated. This study evaluated the therapeutic effect of curcumin (Cur), a polyphenolic electrophile in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced chronic colitis and mitochondrial dysfunction, in mice.. Colitis was induced by rectal instillation to mice of 30 mg kg. In vitro, a short-term Cur treatment controlled the dose and time dependent mitochondrial toxicity induced by TNBS, by collapsing the generation of superoxide anion and hydroperoxy lipids, rebalancing nitric oxide synthase and aconitase activities, and recoupling mitochondria. In vivo, a daily low-dose Cur abolished mice mortality which reached 27% in model group. Cur improved in a time dependent manner mucosal redox homeostasis, cell apoptosis, mucin depleted crypts and crypt abscesses by controlling prooxidant activity of myeloperoxidase and NO synthase associated to phagocytes influx, quenching hydroperoxy lipids, and reboosting GSH levels.. Cur, by quenching intra and extra mitochondrial ROS generation, rebalancing aconitase/fumarase and MDA/GSH ratios, and recoupling mitochondria, may support mithormesis priming and remitting in IBD.

Topics: Aconitate Hydratase; Animals; Apoptosis; Colitis; Colon; Curcumin; Inflammatory Bowel Diseases; Intestinal Mucosa; Lipid Peroxides; Male; Mice; Mitochondria; Mucins; Nitric Oxide Synthase; Oxidation-Reduction; Peroxidase; Reactive Oxygen Species; Superoxides; Trinitrobenzenesulfonic Acid

The objective of the present work was to develop and optimize multiparticulate pH-dependent bioadhesive pellets of curcumin and cyclosporine for the management of intestinal bowel disease (IBD). The bioadhesive sustained release pellets were intended for targeting the affected site for an improved therapeutic effect. Bioadhesive pellet cores of curcumin and cyclosporine were formulated using Carbopol 940 (CP940) and hydroxypropyl cellulose (HPC-H) by the extrusion/spheronization method, and drug delivery to the colon was controlled by the pH-sensitive polymer Eudragit® S100. Microcrystalline cellulose (Avicel PH101) was found to be the best forming agent for pellet core. The ratio of CP940 to HPC-H was kept at 1:1 to achieve 100% bioadhesion. The in vitro dissolution profiles of coated pellets depicted that 12.327 ± 0.342% of curcumin and 14.751 ± 0.112% of cyclosporine were released at the end of 6 h (at pH 6.8), whereas 71.278 ± 0.100% of curcumin and 76.76 ± 0.195% of cyclosporine were released at the end of 24 h (at pH 7.4). The drug release profile was found to follow zero-order kinetics for both drugs. The selected formulation was evaluated on an acetic acid-induced ulcerative colitis in the rat model to evaluate the efficiency of drug-loaded pellets coated with Eudragit®S100. The pharmacodynamic study revealed the therapeutic efficacy of Eudragit®S100-coated pellets of curcumin and cyclosporine in alleviating the conditions of the acetic acid-induced colitis model as reflected by weight gain as well as improvement of clinical, macroscopic and microscopic parameters of induced colitis, as compared with free curcumin and cyclosporine. The combination of curcumin and cyclosporine has been proven to have a synergistic effect for the successful management of IBD when used in a low dose as compared with individual drugs with high doses. Hence, curcumin- and cyclosporine-loaded bioadhesive pellets may act as a promising targeted drug delivery system in the management of IBD. Graphical abstract.

Topics: Animals; Colitis; Colon; Curcumin; Cyclosporine; Drug Delivery Systems; Hydrogen-Ion Concentration; Inflammatory Bowel Diseases; Rats; Solubility

Curcumin is an antioxidant and anti-inflammatory molecule known to be a potent inhibitor of nuclear factor kappa B (NF-kappa B). In this study, we aimed to investigate the therapeutic effects of curcumin on colitis induced by a 2,4,6-trinitrobenzene sulfonic acid (TNBS).. After the induction of colitis under anesthesia, 42 rats were divided into six groups as follows; the curcumin oral group, curcumin (20 mg/kg); the corn oil oral group, corn oil (20 mg/kg) using gastric gavage, the curcumin rectal group, curcumin; the corn oil rectal group, corn oil; the control group, 1 mL saline solution (0.9% NaCl) were administered using the rectal route. In the sham group, only rectal catheterization was performed. At the end of the seven day, the blood and intestinal tissue samples were obtained for histopathological examination and for MPO, MDA, NO, PDGF, IL-6, TNF-alpha, NF-kappaB.. The macroscopic damage score was significantly higher in curcumin oral, corn oil oral and saline groups when compared to the sham group (p<0.05). The significant differences between groups were evaluated using the biochemical analysis of intestinal tissue for IL-6, NO, NF-κB, PDGF, TNF-α, MDA, MPO (p<0.05). NF-κB levels of blood in curcumin oral, curcumin rectal, sham, corn oil oral, corn oil rectal groups were significantly increased when compared to saline rectal group (p≤0.001). NF-κB serum levels of corn oil rectal and control group (p≤0.001) were lower than the sham group (p=0.012).. The effects of curcumin improved possibly by modulating the NF-κB signaling pathway should be considered against colitis alone or in combination with the conventional anti-colitic therapies in future studies.

Topics: Animals; Antioxidants; Colitis; Curcumin; NF-kappa B; Platelet-Derived Growth Factor; Rats; Signal Transduction; Trinitrobenzenesulfonic Acid

Topics: Administration, Oral; Animals; Apoptosis; Azoxymethane; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Colitis; Colorectal Neoplasms; Curcumin; Cytokines; Dextran Sulfate; Disease Models, Animal; Disease Progression; Drug Synergism; Female; Inflammation; Inflammation Mediators; Intestines; Irinotecan; Macrophages; Mice; Mice, Inbred C57BL; Nanoparticles; RAW 264.7 Cells

Rebaudioside A (RA) has nanocarrier characteristics that allow it to self-assemble into micelles in aqueous solutions. The purpose of this study was to determine if a self-nanomicellizing solid dispersion based on RA could be utilized as an oral nano-drug delivery system.. Curcumin (Cur) served as a model hydrophobic drug, and a Cur-loaded self-nanomicellizing solid dispersion based on RA (RA-Cur) was formulated. The properties of RA-Cur in the solid state and in aqueous solution were characterized. The antioxidant activity and mechanism of RA-Cur endocytosis were also investigated. The pharmacokinetics, biodistribution in the intestinal tract, and anti-inflammation properties were also evaluated in vivo.. RA-Cur could be easily fabricated, and it self-assembled into ultrasmall micelles (particle size ~4 nm) in a homogeneous distribution state (polydispersity index <0.2) when dissolved in water. Cur was readily encapsulated into RA micelles and this improved its water solubility (to 14.34±1.66 mg/mL), as well as its in vitro release and membrane permeability. The antioxidant activities of Cur in RA-Cur were also significantly improved. Biodistribution in the intestinal tract confirmed a significant enhancement of Cur absorption in the duodenum, jejunum, and ileum by encapsulation in RA-Cur, and the absorption of RA-Cur was governed by mixed transcytosis mechanisms. Pharmacokinetic tests of RA-Cur in rats revealed a dramatic 19.06-fold enhancement of oral bioavailability when compared to free Cur. More importantly, oral administration of RA-Cur could efficiently ameliorate ulcerative colitis in a mouse model induced by dextran sodium sulfate.. Self-nanomicellizing solid dispersions based on RA have great potential as novel oral nano-drug delivery systems for hydrophobic drugs such as Cur.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Biological Availability; Colitis; Curcumin; Dextran Sulfate; Diterpenes, Kaurane; Drug Delivery Systems; Male; Mice; Micelles; Rats; Tissue Distribution

High-fat diets (HFDs) and adiposity increase colorectal cancer risk, in part by elevating pro-inflammatory cytokines that activate pro-cancerous signaling pathways. Curcumin (CUR), a dietary polyphenol and salsalate (SAL), an non-steroidal anti-inflammatory drug (NSAID) lacking the gastrotoxicity of aspirin, each suppress inflammatory signaling, but via different cellular pathways.. A/J mice (n = 110) are fed a low-fat diet (LFD, 10% kcal), a HFD (60% kcal), a HFD containing 0.4% CUR, a HFD containing 0.3% SAL, or a HFD containing both agents (CUR/SAL). All mice receive six injections of azoxymethane. Compared to LFD-fed mice, HFD-fed mice display elevated colonic cytokines, crypt cell proliferation, and increased tumorigenesis (p < 0.05). CUR/SAL significantly reduces colonic cytokines (p < 0.01), suppresses activation of the PI3K/Akt/mTOR/NF-κB/Wnt pathways (p < 0.01), activates AMPK (p < 0.01), attenuates abnormal proliferation of the colonic mucosa (p < 0.05), and reduces tumor multiplicity and burden (p < 0.05), in comparison to the HFD control. In contrast, CUR or SAL alone does not suppress abnormal crypt cell proliferation or tumor multiplicity, and is largely ineffective in modifying activation of these signaling pathways.. These observations demonstrate the superiority of the CUR/SAL over the individual agents and provide a scientific basis for future translational studies in obese subjects and/or those habitually consuming HFDs.

Topics: Adiposity; Animals; Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Proliferation; Colitis; Colorectal Neoplasms; Curcumin; Diet, High-Fat; Intestinal Mucosa; Male; Mice, Inbred Strains; Obesity; Precancerous Conditions; Salicylates; Signal Transduction

Curcumin and resveratrol are two natural products, which have been described as potential anti‑inflammatory, anti‑tumor, and anti‑oxidant molecules. The aims of the present study were to investigate the protective effect of curcumin and resveratrol on dextran sulfate sodium (DSS)‑induced ulcerative colitis (UC) in mice, in addition to understanding the underlying molecular mechanisms. In order to accomplish this, BALB/c mice received drinking water containing 3.5% DSS. Curcumin (50 mg/kg/day) or resveratrol (80 mg/kg/day) were administered orally for 7 days. Survival rate, body weight, disease activity index score, colon length, pro‑inflammatory cytokines, and the expression autophagy‑associated proteins, and mechanistic target of rapamycin (mTOR) and sirtuin 1 (SIRT1) were measured. Curcumin or resveratrol treatment prolonged the survival of mice with UC, reduced body weight loss and attenuated the severity of the disease compared with the DSS‑treated mice. This effect was associated with a substantial clinical amelioration of the disruption of the colonic architecture and a significant reduction in pro‑inflammatory cytokine production. Furthermore, curcumin or resveratrol significantly downregulated the expression of autophagy‑related 12, Beclin‑1 and microtubule‑associated protein light chain 3 II, and upregulated the expression of phosphorylated mTOR and SIRT1 in the colon tissue, compared with those in the DSS‑treated group. These results suggest that curcumin and resveratrol exert protective effects on DSS‑induced UC, partially through suppressing the intestinal inflammatory cascade reaction, reducing autophagy and regulating SIRT1/mTOR signaling.

Topics: Animals; Anti-Inflammatory Agents; Biopsy; Colitis; Curcumin; Cytokines; Dextran Sulfate; Disease Models, Animal; Fluorescent Antibody Technique; Inflammation Mediators; Intestinal Mucosa; Male; Mice; Resveratrol; Sirtuin 1; TOR Serine-Threonine Kinases

Inflammatory bowel disease (IBD) is regarded as a kind of chronic and unspecific intestinal inflammatory disorder. Its exact pathogenesis has not been elucidated. Curcumin, as an herbal drug, has been used in the treatment of IBD due to its immunoregulation. Autophagy has been reported to play an important role in the mechanism of IBD. In the present study, we focused on the autophagic regulation role of curcumin in the murine model of dextran sulfate sodium (DSS)-induced colitis.. We investigated the effects of curcumin on the progress of DSS-induced acute colitis in mice by evaluating the disease activity index (DAI) and histopathological score. Meanwhile, the mRNA and protein expression of autophagy-related key genes from colon tissues comprising autophagy-related 5 (ATG5), LC3-phosphatidylethanolamine conjugate (LC-3II), beclin-1, and B cell lymphoma 2 (bcl-2) was examined by quantitative reverse transcription polymerase chain reaction and Western blot. Furthermore, the mRNA and protein expression of cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL) 6, IL-10, and IL-17A, was examined. Autophagosome was also examined under transmission electron microscopy.. Both DAI and histopathological score increased in mice with DSS-induced colitis and obviously decreased after curcumin intervention. The expression levels of TNF-α, IL-6, IL-17, ATG5, LC-3II, and beclin-1 were significantly higher in mice with colitis than in normal ones, whereas those of IL-10 and bcl-2 decreased accordingly. However, curcumin intervention adjusted the expression level of those factors toward normal level. The number of autophagosome in the colon epithelia increased after DSS stimulation and decreased after curcumin administration.. Curcumin could prevent the development of DSS-induced colitis through the inhibition of excessive autophagy and regulation of following cytokine networks.

Topics: Adaptive Immunity; Animals; Anti-Inflammatory Agents, Non-Steroidal; Autophagy; Colitis; Curcumin; Cytokines; Dextran Sulfate; Intestines; Male; Mice; Mice, Inbred BALB C

The incidence of inflammatory bowel disease (IBD) increases gradually in Western countries with high need for novel therapeutic interventions. Mannich curcuminoids, C142 or C150 synthetized in our laboratory, have been tested for anti-inflammatory activity in a rat model of TNBS (2,4,6-trinitrobenzenesulphonic acid) induced colitis. Treatment with C142 or C150 reduced leukocyte infiltration to the submucosa and muscular propria of the inflamed gut. C142 or C150 rescued the loss of body weight and C150 decreased the weight of standard colon preparations proportional with 20% less tissue oedema. Both C142 and C150 curcumin analogues caused 25% decrease in the severity of colonic inflammation and haemorrhagic lesion size. Colonic MPO (myeloperoxidase) enzyme activity as an indicator of intense neutrophil infiltration was 50% decreased either by C142 or C150 Mannich curcuminoids. Lipopolysaccharide (LPS) co-treatment with Mannich curcuminoids inhibited NF-κB (nuclear factor kappa B) activity on a concentration-dependent manner in an NF-κB-driven luciferase expressing reporter cell line. Co-treatment with LPS and curcuminoids, C142 or C150, resulted in NF-κB inhibition with 3.57 μM or 1.6 μM half maximal effective concentration (EC

Topics: Animals; Anti-Inflammatory Agents; Colitis; Curcumin; Humans; Inflammatory Bowel Diseases; Interleukin-4; Interleukin-6; Leukocytes, Mononuclear; Male; NF-kappa B; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

Anemia is frequently encountered in patients with inflammatory bowel disease (IBD), decreasing the quality of life and significantly worsening the prognosis of the disease. The pathogenesis of anemia in IBD is multifactorial and results mainly from intestinal blood loss in inflamed mucosa and impaired dietary iron absorption. Multiple studies have proposed the use of the polyphenolic compound curcumin to counteract IBD pathogenesis since it has significant preventive and therapeutic properties as an anti-inflammatory agent and very low toxicity, even at high dosages. However, curcumin has been shown to possess properties consistent with those of an iron-chelator, such as the ability to modulate proteins of iron metabolism and decrease spleen and liver iron content. Thus, this property may further contribute to the development and severity of anemia of inflammation and iron deficiency in IBD. Herein, we evaluate the effects of curcumin on systemic iron balance in the dextran sodium sulfate (DSS) model of colitis in C57Bl/6 and BALB/c mouse strains that were fed an iron-sufficient diet. In these conditions, curcumin supplementation caused mild anemia, lowered iron stores, worsened colitis and significantly decreased overall survival, independent of the mouse strain. These findings suggest that curcumin usage as an anti-inflammatory supplement should be accompanied by monitoring of erythroid parameters to avoid exacerbation of iron deficiency anemia in IBD.

Topics: Anemia, Iron-Deficiency; Animals; Anti-Inflammatory Agents, Non-Steroidal; Colitis; Curcumin; Dextran Sulfate; Female; Iron, Dietary; Mice, Inbred BALB C; Mice, Inbred C57BL

Diversion colitis is still very common in our country, since the stoma creation is a common practice especially in situations of trauma. needing treatment for this condition.. To evaluate the therapeutic effect of rectal infusion of Curcuma longa (turmeric) in the excluded intestinal segment of rats.. Eighteen Wistar rats were used and submitted to colostomy: control group (n=8) under rectal saline infusion and group CL, receiving intra-rectal infusion of Curcuma longa extract (n=10). After 21 days of treatment they were submitted to euthanasia; the intestinal segment excluded from intestinal transit was resected and sent to histopathological evaluation, classifying the degree of inflammation and of vascular congestion.. The average of inflammation was 2.7 in the control group vs. 2.6 in the CL group (p=0.3125), while the mean vascular congestion was 2.3 and 2.1, respectively, in the control and CL groups (p=0.1642).. Intra-rectal infusion of Curcuma longa extract was not able to minimize the inflammatory process or vascular congestion in the diversion colitis of rats subjected to colostomy.

Topics: Administration, Rectal; Animals; Colitis; Colostomy; Curcuma; Disease Models, Animal; Male; Plant Extracts; Rats; Rats, Wistar

Inflammation is highly associated with colon carcinogenesis. Epigenetic mechanisms could play an important role in the initiation and progression of colon cancer. Curcumin, a dietary phytochemical, shows promising effects in suppressing colitis-associated colon cancer in azoxymethane-dextran sulfate sodium (AOM-DSS) mice. However, the potential epigenetic mechanisms of curcumin in colon cancer remain unknown. In this study, the anticancer effect of curcumin in suppressing colon cancer in an 18-week AOM-DSS colon cancer mouse model was confirmed. We identified lists of differentially expressed and differentially methylated genes in pairwise comparisons and several pathways involved in the potential anticancer effect of curcumin. These pathways include LPS/IL-1-mediated inhibition of RXR function, Nrf2-mediated oxidative stress response, production of NO and ROS in macrophages and IL-6 signaling. Among these genes, Tnf stood out with decreased DNA CpG methylation of Tnf in the AOM-DSS group and reversal of the AOM-DSS induced Tnf demethylation by curcumin. These observations in Tnf methylation correlated with increased and decreased Tnf expression in RNA-seq. The functional role of DNA methylation of Tnf was further confirmed by in vitro luciferase transcriptional activity assay. In addition, the DNA methylation level in a group of inflammatory genes was decreased in the AOM+DSS group but restored by curcumin and was validated by pyrosequencing. This study shows for the first time epigenomic changes in DNA CpG methylation in the inflammatory response from colitis-associated colon cancer and the reversal of their CpG methylation changes by curcumin. Future clinical epigenetic studies with curcumin in inflammation-associated colon cancer would be warranted.

Topics: Animals; Azoxymethane; Colitis; Colon; Colonic Neoplasms; Curcumin; Dextran Sulfate; Disease Models, Animal; DNA Methylation; Epigenesis, Genetic; Inflammation; Male; Mice; Mice, Inbred C57BL; Oxidative Stress; Transcriptome

Colorectal-cancer (CRC) is the third leading cause of death due to cancer, supporting the need for identification of novel anticancer drug to improve the efficacy of current-therapy. There is growing bodies of data showing the antitumor-activity of curcumin, although it is associated with low absorption. The aim of current study was explored the therapeutic-potential of novel phytosomal curcumin as well as its application in combination with 5-Flurouracil (5-FU) in a mouse-model of colitis-associated colon-cancer. The anti-proliferative-activity of phytosomal curcumin was assessed in 2- and 3-dimensional cell-culture-models as well as in a mouse-model of colitis-associated colon-cancer. The expression-levels of CyclinD1, beclin, E-cadherin, and p-GSK3a/b were investigated by qRT-PCR and/or Western-blotting. We evaluated the anti-inflammatory of this agent by pathological-evaluation and disease-activity-index (DAI). Moreover, oxidant/antioxidant activity was examined by malondialdehyde (MDA), total-thiols (T-SH), superoxide-dismutase (SOD), and catalase (CAT) activity parameters. Our data showed that phytosomal curcumin and its combination with 5-FU inhibited cell growth and invasive behavior of CRC cells through modulation of Wnt-pathway and E-cadherin. Combination of curcumin with 5-FU dramatically reduced the tumor-number and tumor-size in both distal and middle parts of colon in colitis-associated colon cancer followed by reduction in DAI. Also, curcumin suppressed the colonic inflammation and notably recovered the increased levels of MDA, decreased thiol level and reduced activity of CAT. We demonstrated the antitumor-activity of novel form of curcumin in CRC, supporting further investigations on the therapeutic-potential of this approach in colorectal-cancer.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Colitis; Colonic Neoplasms; Colorectal Neoplasms; Curcumin; Humans; Mice, Inbred C57BL; Signal Transduction

On the basis of preliminary in vitro experience, we assessed whether an enriched nutritional formulation with estrogen receptor (ER)-beta agonist and anti-inflammatory properties may prevent inflammation-associated colorectal cancer (CRC) in an animal model. Study sample enclosed 110 C57BL/6J male mice. Forty underwent dietary supplement safety assessment (20 standard diet and 20 enriched formulation). Seventy were treated with azoxymethane (AOM)/dextran sulfate sodium and divided into two groups: 35 received standard diet and 35 enriched formulation (curcumin, boswellic acids, silymarin and maltodextrins). Miniature colonoscopy demonstrated colitis and solid lesion development in five mice/group 100 days after first AOM injection. Mice were killed after 10 days. In each group, four subgroups received intraperitoneal bromodeoxyuridine (BrdU) injection at 24th/48th/72nd/96th hour before killing. Anti-inflammatory effect and chemoprevention were evaluated by lesion number/size, histological inflammation/dysplasia/neoplasia assessment, pro-inflammatory cytokine messenger RNA (mRNA), ER-beta/ER-alpha/BrdU immunohistochemistry and TUNEL immunofluorescence. Standard formulation assumption was associated with colon shortening compared with enriched one (P = 0.04), which reduced solid lesion number and size (P < 0.001 for both), histological inflammation score (P = 0.04), pro-inflammatory cytokine mRNA expression (P < 0.001), number of low-grade dysplasia (LGD; P = 0.03) and high-grade dysplasia (P < 0.001) areas. CRC was observed in 69.6% in standard and 23.5% in enriched formulation assuming animals (P < 0.001). Enriched formulation induced lower ER-alpha expression in CRC (P < 0.001) and higher ER-beta expression in LGD (P < 0.001) being associated to higher epithelial turnover (BrdU; P<0.001) in normal mucosa and increased apoptosis in LGD and CRC (P < 0.001 for both). Our results are promising for a successful anti-inflammatory and chemopreventive effect of enriched formulation in CRC arising from inflamed tissue.

Topics: Animals; Anti-Inflammatory Agents; Apoptosis; Azoxymethane; Chemoprevention; Colitis; Colon; Colonoscopy; Colorectal Neoplasms; Curcumin; Cytokines; Dextran Sulfate; Disease Models, Animal; Food, Fortified; Immunohistochemistry; Male; Mice; Mice, Inbred C57BL; Polysaccharides; Real-Time Polymerase Chain Reaction; Receptors, Estrogen; Silymarin; Triterpenes

Inflammatory Bowel Diseases (IBD) is a debilitating condition that affects ~70,000 new people every year and has been described as "an expensive disease with no known cure". In addition, IBD increases the risk of developing colon cancer. The current therapeutics for IBD focus on the established disease where the immune dysfunction and bowel damage have already occurred but do not prevent or delay the progression. The current work describes a polymer-based anti-inflammatory technology (Ora-Curcumin-S) specifically targeted to the luminal side of the colon for preventing and/or treating IBD. Ora-Curcumin-S was prepared by molecular complexation of curcumin with a hydrophilic polymer Eudragit® S100 using co-precipitation method. Curcumin interacted with the polymer non-covalently and existed in an amorphous state as demonstrated by various physicochemical techniques. Ora-Curcumin-S is a polymer-drug complex, which is different than solid dispersions in that the interactions are retained even after dissolving in aqueous buffers. Ora-Curcumin-S was >1000 times water soluble than curcumin and importantly, the enhanced solubility was pH-dependent, which was observed only at pHs above 6.8. In addition, around 90% of Ora-Curcumin-S was stable in phosphate buffer, pH 7.4 and simulated intestinal fluid after 24 h, in contrast to 10-20% unformulated curcumin. Ora-Curcumin-S inhibited Monophosphoryl Lipid-A and E. coli induced inflammatory responses in dendritic cells and cells over expressing Toll-Like Receptor-4 (TLR-4) suggesting that Ora-Curcumin-S is a novel polymer-based TLR-4 antagonist. Preliminary pharmacokinetics in mice showed targeted delivery of soluble curcumin to the colon lumen without exposing to the systemic circulation. Furthermore, Ora-Curcumin-S significantly prevented colitis and associated injury in a mouse model of ulcerative colitis estimated using multiple preclinical parameters: colonoscopy pictures, body weight, colon length, colon edema, spleen weight, pro-inflammatory signaling and independent pathological scoring. Overall, the outcome of this innovative proof-of-concept study provides an exciting and locally-targeted pathway for a dietary therapeutic option for IBD patients to help limit colonic inflammation and thus susceptibility to colitis-associated colorectal cancer.

Topics: Animals; Anti-Inflammatory Agents; Cell Line; Colitis; Curcumin; Drug Compounding; Feces; Humans; Mice, Inbred BALB C; Mice, Inbred C57BL; Polymethacrylic Acids

NLRP3 inflammasome mediates IL-1β maturation, therefore plays a vital role in the development of IBD. Curcumin is known for possessing strong anti-inflammatory property.. The present study was to investigate the protective effects of curcumin on dextran sulfate sodium (DSS)-induced colitis through inhibiting NLRP3 inflammasome activation and IL-1β production.. LPS-primed macrophages were treated with curcumin prior to DSS triggering NLRP3 inflammasome activation, IL-1β secretion and ASC oligomerization were observed. The mechanisms of curcumin in the inhibition of DSS-induced inflammasome activation were explored. Curcumin or caspase-1/NLRP3 inhibitor was administrated respectively in DSS-induced colitis mouse model. The changes of body weight, disease activity index, colon length were measured. Additionally, mature IL-1β and other inflammatory cytokines, MPO activity and histopathological damage were analyzed for the evaluation of colitis severity.. NLRP3 inflammasome activation was dramatically inhibited by curcumin in DSS-stimulated macrophages, as evidenced by decreased IL-1β secretion, less caspase-1 activation and ASC specks. Mechanistically, curcumin prevented DSS-induced K. Curcumin could strongly suppress DSS-induced NLRP3 inflammsome activation and alleviate DSS-induced colitis in mice, thus it may be a promising candidate drug in clinical application for IBD therapy.

Topics: Animals; Caspase 1; Colitis; Curcumin; Dextran Sulfate; Female; Inflammasomes; Interleukin-1beta; Lipopolysaccharides; Macrophages, Peritoneal; Mice; NLR Family, Pyrin Domain-Containing 3 Protein

Curcumin, a dietary compound from turmeric, has beneficial effects on inflammatory diseases such as inflammatory bowel disease. Most previous studies have focused on the structure-activity relationship of the thiol-reactive α,β-unsaturated carbonyl groups of curcumin, so little is known about the roles of methoxy groups in biological activities of curcumin. Here we synthesized a series of curcumin analogues with different substitution groups (R = H-, Br-, Cl-, F-, NO

Topics: Animals; Anti-Inflammatory Agents; Colitis; Colon; Curcumin; Cyclooxygenase 2; Humans; Macrophages; Male; Mice; Mice, Inbred C57BL; Molecular Structure; Structure-Activity Relationship; Tumor Necrosis Factor-alpha

Ulcerative colitis (UC) is a main form of inflammatory bowel disease (IBD). Asafoetida (ASF) and turmeric have traditionally been used for the treatment of various inflammatory diseases, including UC, because ASF is rich in sulfur compounds and turmeric contains curcumin (CUR). Turmeric nanofiber (TNF), the modified cell wall component of turmeric is considered to play important role in the human diet, health and can be used as a carrier agent to encapsulate bioactive components. A novel gut health product (GHP) was formulated by encapsulation of ASF and CUR complex onto TNF. The GHP was characterized by UPLC, GC-MS, FTIR, XRD, SEM with EDS and DSC studies. GHP was evaluated for anti-colitis activity in a rat model of 5% dextran sulfate sodium (DSS) induced UC. Treatment with GHP significantly attenuated the disease activity index, colitis score, histopathological changes and myeloperoxidase activity. GHP has significant protective effects against DSS induced colitis.

Topics: Animals; Colitis; Curcuma; Curcumin; Ferula; Nanofibers; Rats

Curcumin is a hydrophobic polyphenol derived from turmeric, a traditional Indian spice. Curcumin exhibits various biological functions, but its clinical application is limited due to its poor absorbability after oral administration. A newly developed nanoparticle curcumin shows improved absorbability in vivo. In this study, we examined the effects of nanoparticle curcumin (named Theracurmin) on experimental colitis in mice.. BALB/c mice were fed with 3% dextran sulfate sodium (DSS) in water. Mucosal cytokine expression and lymphocyte subpopulation were analyzed by real-time PCR and flow cytometry, respectively. The profile of the gut microbiota was analyzed by real-time PCR.. Treatment with nanoparticle curcumin significantly attenuated body weight loss, disease activity index, histological colitis score and significantly improved mucosal permeability. Immunoblot analysis showed that NF-κB activation in colonic epithelial cells was significantly suppressed by treatment with nanoparticle curcumin. Mucosal mRNA expression of inflammatory mediators was significantly suppressed by treatment with nanoparticle curcumin. Treatment with nanoparticle curcumin increased the abundance of butyrate-producing bacteria and fecal butyrate level. This was accompanied by increased expansion of CD4+ Foxp3+ regulatory T cells and CD103+ CD8α- regulatory dendritic cells in the colonic mucosa.. Treatment with nanoparticle curcumin suppressed the development of DSS-induced colitis potentially via modulation of gut microbial structure. These responses were associated with induction of mucosal immune cells with regulatory properties. Nanoparticle curcumin is one of the promising candidates as a therapeutic option for the treatment of IBD.

Topics: Animals; Colitis; Curcumin; Cytokines; Dextran Sulfate; Disease Models, Animal; Gastrointestinal Microbiome; Intestinal Mucosa; Mice; Mice, Inbred BALB C; Nanoparticles; T-Lymphocytes, Regulatory

Curcumin has powerful anti-inflammatory and antioxidant effects and it has been used for treatment of distal ulcerative colitis. The therapeutic effects of curcumin have not yet been evaluated in diversion colitis. The aim of the present study was to evaluate the anti-inflammatory effects of curcumin on colonic mucosa devoid of a faecal stream. Thirty-six rats were subjected to a proximal colostomy and distal colonic fistulation. They were divided into two groups, which were sacrificed two or four weeks after the intervention. Each group was divided into three subgroups treated with the daily application of enemas containing saline or an oily extract of curcumin at 50 mg/kg/day or 200 mg/kg/day. Colitis was diagnosed by histological analysis. Inflammatory grades were assessed using a previously validated scoring system. The infiltration of neutrophils was evaluated based on the tissue expression of myeloperoxidase (MPO), as determined by immunohistochemistry, and a computer-assisted image analysis program. The Mann-Whitney test was used to compare inflammation grades and myeloperoxidase levels among groups, and ANOVA was used to verify the variance over time, with the level of significance set at 5% (p<0.05) for both tests. Enemas containing curcumin improved the inflammation of the mucosa without a faecal stream and reduced the tissue contents of MPO. MPO tissue levels did not vary with time or between the concentrations of curcumin used. Enemas with curcumin improved the inflammation of the colonic mucosa, reduced the inflammatory grade and decreased the tissue content of MPO in colon segments without a faecal stream.

Topics: Animals; Anti-Inflammatory Agents; Colitis; Colon; Curcumin; Disease Models, Animal; Enema; Intestinal Mucosa; Male; Oxidative Stress; Peroxidase; Rats; Rats, Wistar

Association between circulating lipopolysaccharide (LPS) and metabolic diseases (such as type 2 diabetes and atherosclerosis) has shifted the focus from high-fat high-cholesterol containing Western-type diet (WD)-induced changes in gut microbiota per se to release of gut bacteria-derived products (e.g., LPS) into circulation due to intestinal barrier dysfunction as the possible mechanism for the chronic inflammatory state underlying the development of these diseases. We demonstrated earlier that oral supplementation with curcumin attenuates WD-induced development of type 2 diabetes and atherosclerosis. Poor bioavailability of curcumin has precluded the establishment of a causal relationship between oral supplementation and it is in vivo effects. We hypothesized that curcumin attenuates WD-induced chronic inflammation and associated metabolic diseases by modulating the function of intestinal epithelial cells (IECs) and the intestinal barrier function. The objective of the present study was to delineate the underlying mechanisms. The human IEC lines Caco-2 and HT-29 were used for these studies and modulation of direct as well as indirect effects of LPS on intracellular signaling as well as tight junctions were examined. Pretreatment with curcumin significantly attenuated LPS-induced secretion of master cytokine IL-1β from IECs and macrophages. Furthermore, curcumin also reduced IL-1β-induced activation of p38 MAPK in IECs and subsequent increase in expression of myosin light chain kinase involved in the phosphorylation of tight junction proteins and ensuing disruption of their normal arrangement. The major site of action of curcumin is, therefore, likely the IECs and the intestinal barrier, and by reducing intestinal barrier dysfunction, curcumin modulates chronic inflammatory diseases despite poor bioavailability.

Topics: Caco-2 Cells; Cell Communication; Colitis; Colon; Curcumin; Dose-Response Relationship, Drug; Epithelial Cells; HT29 Cells; Humans; Intestinal Absorption; Intestinal Mucosa; Lipopolysaccharides; Tight Junctions

Colorectal cancer (CRC) remains the leading cause of cancer-related death in the world. Aspirin (ASA) and curcumin (CUR) are widely investigated chemopreventive candidates for CRC. However, the precise mechanisms of their action and their combinatorial effects have not been evaluated. The purpose of the present study was to determine the effect of ASA, CUR, and their combination in azoxymethane/dextran sulfate sodium (AOM/DSS)-induced colitis-accelerated colorectal cancer (CAC). We also aimed to characterize the differential gene expression profiles in AOM/DSS-induced tumors as well as in tumors modulated by ASA and CUR using RNA-seq. Diets supplemented with 0.02% ASA, 2% CUR or 0.01% ASA+1% CUR were given to mice from 1week prior to the AOM injection until the experiment was terminated 22weeks after AOM initiation. Our results showed that CUR had a superior inhibitory effect in colon tumorigenesis compared to that of ASA. The combination of ASA and CUR at a lower dose exhibited similar efficacy to that of a higher dose of CUR at 2%. RNA isolated from colonic tissue from the control group and from tumor samples from the experimental groups was subjected to RNA-seq. Transcriptomic analysis suggested that the low-dose combination of ASA and CUR modulated larger gene sets than the single treatment. These differentially expressed genes were situated in several canonical pathways important in the inflammatory network and liver metastasis in CAC. We identified a small subset of genes as potential molecular targets involved in the preventive action of the combination of ASA and CUR. Taken together, the current results provide the first evidence in support of the chemopreventive effect of a low-dose combination of ASA and CUR in CAC. Moreover, the transcriptional profile obtained in our study may provide a framework for identifying the mechanisms underlying the carcinogenesis process from normal colonic tissue to tumor development as well as the cancer inhibitory effects and potential molecular targets of ASA and CUR.

Topics: Animals; Aspirin; Colitis; Colonic Neoplasms; Curcumin; Drug Therapy, Combination; Gene Expression Profiling; Mice; Mice, Inbred C57BL; Sequence Analysis, RNA

To measure the tissue sulfomucin and sialomucin content of the colon mucosa without fecal flow, subjected to intervention with curcumin, and the influence of the concentration used and the intervention time.. Thirty-six rats were subjected to proximal right colostomy and distal mucous fistula. They were divided into two groups according to whether sacrifice was performed two or four weeks after the intervention. Each group was divided into three subgroups according to the enema applied daily: saline alone; curcumin at 50 mg/kg/day or curcumin at 200 mg/kg/day. Acid mucins were diagnosed using the Alcian blue technique. The mucin content was quantified by means of computer-assisted image analysis. The significance level of 5% was used throughout (p < 0.05).. There were dose-related increases in the quantities of sulfomucins in the animals subjected to interventions with curcumin, both after two weeks (p < 0.00001) and after four weeks (p < 0.00001). There were increases in sialomucin quantity that were concentration-related (p < 0.00001) and time-related (p < 0.00001).. Curcumin enemas increase the quantity of acid mucins in the intestinal flow in the excluded colon, with dose and time dependency.

Topics: Animals; Colitis; Colon; Colostomy; Curcuma; Enema; Feces; Gastrointestinal Transit; Image Processing, Computer-Assisted; Intestinal Mucosa; Male; Mucins; Plant Extracts; Plant Oils; Rats, Wistar; Reference Values; Reproducibility of Results; Sialomucins; Time Factors; Treatment Outcome

The aim of this study was to provide insight into how curcumin reduces colon inflammation in the Mdr1a(-/-) mouse model of human inflammatory bowel disease using a combined transcriptomics and proteomics approach. Mdr1a(-/-) and FVB control mice were randomly assigned to an AIN-76A (control) diet or AIN-76A+0.2% curcumin. At 21 or 24weeks of age, colonic histological injury score (HIS) was determined, colon mRNA transcript levels were assessed using microarrays and colon protein expression was measured using 2D gel electrophoresis and LCMS protein identification. Colonic HIS of Mdr1a(-/-) mice fed the AIN-76A diet was higher (P<.001) than FVB mice fed the same diet; the curcumin-supplemented diet reduced colonic HIS (P<.05) in Mdr1a(-/-) mice. Microarray and proteomics analyses combined with new data analysis tools, such as the Ingenuity Pathways Analysis regulator effects analysis, showed that curcumin's antiinflammatory activity in Mdr1a(-/-) mouse colon may be mediated by activation of α-catenin, which has not previously been reported. We also show evidence to support curcumin's action via multiple molecular pathways including reduced immune response, increased xenobiotic metabolism, resolution of inflammation through decreased neutrophil migration and increased barrier remodeling. Key transcription factors and other regulatory molecules (ERK, FN1, TNFSF12 and PI3K complex) activated in inflammation were down-regulated by dietary intervention with curcumin.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B; Colitis; Curcumin; Diet; Disease Models, Animal; Inflammatory Bowel Diseases; Mice; Models, Molecular

To explore the effect of curcumin (Cur) on the subpopulation and costimulatory molecules of dendritic cells (DCs) in spleen from colitis mice.. Forty male C57/BL mice were randomly divided into 4 groups: normal group, model group, Cur group and mesalazine group. Colitis was induced by 2, 4, 6-trinitrobenzene sulfonic acid (TNBS). On the 8th day following 7-day treatment with Cur, the mice were sacrificed and the length and mass of mouse colon were measured. And then the spleens were separated to prepare DCs. The numbers of CD205(+), CD4(+)CD205(+), CD8(+)CD205(+) DCs and the levels of major histocompability complex II (MHC-II), Toll-like receptor 2 (TLR2), TLR4 and CD83 expression were detected by flow cytometry. And we observed the pathological injury of colon.. Compared with model group, the colonic mass index was reduced, the length of colon was lengthened, and the pathological injury was remitted. Meanwhile, the percents of CD205(+), CD4(+)CD205(+), CD8(+)CD205(+) DCs and the levels of MHC-II, TLR2 and TLR4 were down-regulated, however, the CD83 expression was up-regulated.. Treatment efficacy of Cur on experimental colitis might be involved in regulating subpopulation and co-stimulatory molecules of dendritic cells in spleen from mice with colitis.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antigens, CD; Cells, Cultured; Colitis; Colon; Curcumin; Dendritic Cells; Flow Cytometry; Histocompatibility Antigens Class II; Male; Mice, Inbred C57BL; Random Allocation; Spleen; Toll-Like Receptor 2; Toll-Like Receptor 4; Trinitrobenzenesulfonic Acid

Selective drug delivery to inflamed tissues is of widespread interest for the treatment of inflammatory bowel disease (IBD). Because a lack of physiological lipids has been described in patients suffering IBD, and some lipids present immunomodulatory properties, we hypothesize that the combination of lipids and anti-inflammatory drugs together within a nanocarrier may be a valuable strategy for overcoming IBD. In the present study, we investigated and compared the in vitro and in vivo efficacy of three lipid-based nanocarriers containing curcumin (CC) as an anti-inflammatory drug for treating IBD in a murine DSS-induced colitis model. These nanocarriers included self-nanoemulsifying drug delivery systems (SNEDDS), nanostructured lipid carriers (NLC) and lipid core-shell protamine nanocapsules (NC). In vitro, a 30-fold higher CC permeability across Caco-2 cell monolayers was obtained using NC compared to SNEDDS (NC>SNEDDS>NLC and CC suspension). The CC SNEDDS and CC NLC but not the CC NC or CC suspension significantly reduced TNF-α secretion by LPS-activated macrophages (J774 cells). In vivo, only CC NLC were able to significantly decrease neutrophil infiltration and TNF-α secretion and, thus, colonic inflammation. Our results show that a higher CC permeability does not correlate with a higher efficacy in IBD treatment, which suggests that lipidic nanocarriers exhibiting increased CC retention at the intestinal site, rather than increased CC permeability are efficient treatments of IBD.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Caco-2 Cells; Cell Line; Cell Survival; Colitis; Curcumin; Dextran Sulfate; Drug Carriers; Drug Delivery Systems; Female; Humans; Inflammatory Bowel Diseases; Lipids; Macrophages; Mice, Inbred C57BL; Microscopy, Confocal; Nanoparticles; Tumor Necrosis Factor-alpha

In this study, we investigated the preventive effects of curcumin using dextran sulfate sodium (DSS)-induced colitis and the potential role of curcumin in regulation of anti-inflammation through S-nitrosylation. After curcumin treatment for 6days, the body weight and disease activity index of DSS-induced mice was alleviated and the colonic length was also rescued. Western blot presented that the protein expression of iNOS can be reduced by curcumin. Consistently, mRNA level of iNOS and pro-inflammatory cytokines, such as TNFα, IL-1β, and IL-6, was also repressed. Moreover, Curcumin reduced the amount of nitrite in DSS-induced colitis but not affected total S-nitrosylation level on proteins on day 6, indicating that curcumin inhibited NO oxidation. Furthermore, the protection of S-nitrosylation on IKKβ in DSS-induced colitis for 6days by curcumin caused the repression of IκB phosphorylation and NF-κB activation. In conclusion, this study verified that curcumin-mediated S-nitrosylation may be as an important regulator for anti-inflammation in DSS-induced colitis of mice.

Topics: Animals; Anti-Inflammatory Agents; Colitis; Colon; Curcumin; Cytokines; Dextran Sulfate; I-kappa B Kinase; Inflammation Mediators; Male; Mice; Mice, Inbred BALB C; NF-kappa B; Nitric Oxide Synthase Type II; Nitrogen Oxides; Signal Transduction

In this work, thiolated chitosan/alginate composite microparticulates (CMPs) coated by Eudragit S-100 were developed for colon-specific delivery of 5-aminosalicylic acid (5-ASA) and curcumin (CUR), and the use of it as a multi drug delivery system for the treatment of colitis. The physicochemical properties of the CMPs were evaluated. In vitro release was performed in gradually pH-changing medium simulating the conditions of different parts of GIT, and the results showed that the Eudragit S-100 coating has a pH-sensitive release property, which can avoid drug being released at a pH lower than 7. An everted sac method was used to evaluate the mucoadhesion of CMPs. Ex vivo mucoadhesive tests showed CMPs have excellent mucosa adhesion for the colonic mucosa of rats. In vivo treatment effect of enteric microparticulates systems was evaluated in colitis rats. The results showed superior therapeutic efficiency of this drug delivery system for the colitis rats induced by TNBS. Therefore, the enteric microparticulates systems combined the properties of pH dependent delivery, mucoadhesive, and control release, and could be an available tool for the treatment of human inflammatory bowel disease.

Topics: Animals; Chitosan; Colitis; Colon; Curcumin; Drug Carriers; Inflammatory Bowel Diseases; Mesalamine; Polymethacrylic Acids; Rats

Curcumin displays a protective role in rat models of intestinal inflammation. However, the mechanism of how curcumin affects on intestinal inflammation is less known. The purpose of the current study is to explore the signal pathway in which the curcumin protecting rat from intestinal inflammation.. The intestinal inflammation rat models were made by TNBS treatment. Curcumin was added to their diet 5 days before the TNBS instillation. After that, body weight change, score of macroscopic assessment of disease activity and microscopic scoring were utilized to analyse the severity of the induced inflammation. In addition, the level of pro-inflammatory cytokines and anti-inflammatory were detected to determine the effect of curcumin on intestinal inflammation. The JAK/STAT pathway of pro-inflammation response was also evaluated. Finally, the impact of curcumin on apoptosis in intestinal inflammation was assessed by TUNEL staining.. Rats pretreated with curcumin significantly reversed the decrease of body weight and increase of colon weight derived from TNBS-induced colitis. Histological improvement was observed in response to curcumin. In addition, curcumin attenuated TNBS-induced secretion of pro-inflammatory cytokines and M1/M2 ratio, while stimulated the secretion of anti-inflammatory cytokines. The inhibition of pro-inflammation response was mediated by SOCS-1, which could efficiently suppress JAK/STAT pathways. Furthermore, curcumin efficiently suppressed the TNBS-induced apoptosis, and reduced the accumulation of cytochrome C in cytosol.. The anti-inflammatory effect of curcumin is realized by enhancing SOCS-1 expression and inhibiting JAK/STAT pathways. Curcumin also plays an anti-apoptotic role in TNBS-induced intestinal inflammation. We propose that curcumin may have therapeutic implications for human intestinal inflammation.

Topics: Animals; Apoptosis; Colitis; Colon; Curcumin; Janus Kinases; Macrophages; Male; Rats; Rats, Sprague-Dawley; Signal Transduction; STAT Transcription Factors; Trinitrobenzenesulfonic Acid

Compound turmeric has been widely used as a remedy for infectious diseases in China. It is a classic multi-herb prescription in traditional Chinese medicine, commonly used in the treatment of enteritis, pneumonia, and abdominal pain for hundreds of years. However, throughout this history, the powder of multi-herbs was directly swallowed, which is currently difficult to administer to patients. The extract of Chinese herbal medicine is made by semi-bionic extraction technology, which is great progress in the modernization of powders of traditional Chinese medicine. The aim of this work is to investigate the protective effects of semi-bionic extraction of compound turmeric (SET) on acute enteritis (AE) induced by dextran sulfate sodium (DSS) in rats.. SET was extracted in artificial gastric juice or artificial intestinal juice and mixed. After vacuum drying, the SET powder was dissolved in distilled water. Adult male Sprague-Dawley rats were randomly divided into six groups. Rats were given salazosulfapyridine (SASP, 175.0mg/kg) or SET (0.42 or 0.21g/kg) before intragastric administration of 5% DSS solutions (0.75g/kg). The treatments lasted 7 days. The food intake in 24h, disease activity index (DAI), and wet/dry (W/D) weight ratios and histological changes in colon tissue were measured. The tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-1β, IL-8, and IL-10 in serum were determined at 1, 4, or 7 d after DSS challenge. Myeloperoxidase (MPO), malonaldehyde (MDA), diamine oxidase (DAO), and glutathione peroxidase (GSH-Px) activities in colon tissue were determined at 7 d. In addition, the nuclear factor-kappa (NF-κ B) and intercellular cell adhesion molecule-1 (ICAM-1) activations in colon tissue were analyzed by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot.. In rats with AE, SET significantly reduced DAI at 7 d after DSS treatment, increased the body weight of rats and the food intake in 24h at 3 or 6 d after DSS challenge, and reduced the colon W/D ratio. SET also reduced the TNF-α, IL-6, IL-1β, and IL-8 in serum and increased IL-10 in serum at 4 and 7 d. In addition, SET decreased MPO, MDA, DAO, and GSH-Px activities in colon and attenuated histological changes in the colon at 7 d after DSS treatment. Further studies demonstrated that SET significantly inhibited NF-κB and ICAM-1 activations in colon tissue.. The current study demonstrated that SET has potent protective effects on DSS-induced AE in rats through its anti-inflammatory and anti-oxidant activities.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Chemical Fractionation; Colitis; Colon; Curcuma; Cytokines; Dextran Sulfate; Disease Models, Animal; Gastric Juice; Gastrointestinal Agents; Gene Expression Regulation; Inflammation Mediators; Intestinal Secretions; Male; Oxidative Stress; Phytotherapy; Plant Extracts; Plants, Medicinal; Rats, Sprague-Dawley; Time Factors

Intestinal microbiota influences the progression of colitis-associated colorectal cancer. With diet being a key determinant of the gut microbial ecology, dietary interventions are an attractive avenue for the prevention of colitis-associated colorectal cancer. Curcumin is the most active constituent of the ground rhizome of the Curcuma longa plant, which has been demonstrated to have anti-inflammatory, antioxidative, and antiproliferative properties.. Il10 mice on 129/SvEv background were used as a model of colitis-associated colorectal cancer. Starting at 10 weeks of age, wild-type or Il10 mice received 6 weekly intraperitoneal injections of azoxymethane (AOM) or phosphate-buffered saline (PBS) and were started on either a control or a curcumin-supplemented diet. Stools were collected every 4 weeks for microbial community analysis. Mice were killed at 30 weeks of age.. Curcumin-supplemented diet increased survival, decreased colon weight/length ratio, and, at 0.5%, entirely eliminated tumor burden. Although colonic histology indicated improvement with curcumin, no effects of mucosal immune responses have been observed in PBS/Il10 mice and limited effects were seen in AOM/Il10 mice. In wild-type and in Il10 mice, curcumin increased bacterial richness, prevented age-related decrease in alpha diversity, increased the relative abundance of Lactobacillales, and decreased Coriobacterales order. Taxonomic profile of AOM/Il10 mice receiving curcumin was more similar to those of wild-type mice than those fed control diet.. In AOM/Il10 model, curcumin reduced or eliminated colonic tumor burden with limited effects on mucosal immune responses. The beneficial effect of curcumin on tumorigenesis was associated with the maintenance of a more diverse colonic microbial ecology.

Topics: Animals; Azoxymethane; Carcinogens; Cell Transformation, Neoplastic; Colitis; Colon; Colorectal Neoplasms; Curcumin; Dietary Supplements; Disease Models, Animal; Immunity, Mucosal; Intestinal Mucosa; Mice; Mice, 129 Strain; Mice, Knockout; Microbiota

Nano-scaled particles have been found to preferentially accumulate in inflamed regions. Local delivery of anti-inflammatory drugs loaded in nanoparticles to the inflamed colonic site is of great interest for inflammatory bowel disease (IBD) treatment. Curcumin (CC) is an anti-inflammatory local agent, which presents poor ADME properties. Hence, we evaluated, both in vitro and in vivo, the local delivery of CC using pH-sensitive polymeric nanoparticles (NPs) combining both poly(lactide-co-glycolide) acid (PLGA) and a polymethacrylate polymer (Eudragit(®) S100). CC-NPs significantly enhanced CC permeation across Caco-2 cell monolayers when compared to CC in suspension. CC-NPs significantly reduced TNF-α secretion by LPS-activated macrophages (J774 cells). In vivo, CC-NPs significantly decreased neutrophil infiltration and TNF-α secretion while maintaining the colonic structure similar to the control group in a murine DSS-induced colitis model. Our results support the use of nanoparticles made of PLGA and Eudragit(®) S100 combination for CC delivery in IBD treatment.

Topics: Animals; Anti-Inflammatory Agents; Caco-2 Cells; Cell Line; Colitis; Colon; Curcumin; Dextran Sulfate; Disease Models, Animal; Drug Carriers; Female; Humans; Hydrogen-Ion Concentration; Inflammatory Bowel Diseases; Lactic Acid; Macrophages; Mice, Inbred C57BL; Nanoparticles; Neutrophils; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Polymethacrylic Acids; Tumor Necrosis Factor-alpha

Although a series of studies have shown that curcumin can exert anti-inflammatory effects in colitis by inhibiting NF-κB activation, whether these anti-inflammatory effects of curcumin are also attributed to its ability to inhibiting STAT3 pathway has never been tested in experimental colitis to date. The purpose of the study was to investigate whether curcumin could exert its therapeutic effects in experimental colitis by inhibiting STAT3 pathway.. Curcumin was administered in experimental colitis induced by dextran sulfate sodium (DSS). The disease activity index (DAI) and histological score were observed. The phospho-STAT3 was assessed by western blot analysis. The DNA-binding activity of STAT3 dimers was evaluated by electrophoretic mobility shift assay (EMSA). The expression of tumor necrosis factor (TNF)-α and interleukin (IL)-1β was measured by enzyme-linked immunosorbent assay. Myeloperoxidase (MPO) activity was determined by using MPO assay kit.. A significant improvement was observed in DAI and histological score in mice with curcumin, and the increases in phospho-STAT3 activity, DNA-binding activity of STAT3 dimers, MPO activity, IL-1β, and TNF-α expression in mice with DSS-induced colitis were significantly reduced following treatment with curcumin.. Curcumin exerts beneficial effects in experimental colitis by the suppression of STAT3 pathway, which may therefore provide a better understanding of the mechanism of action for curcumin in treating colitis.

Topics: Animals; Colitis; Colon; Curcumin; Dextran Sulfate; Down-Regulation; Interleukin-1beta; Male; Mice; Mice, Inbred BALB C; Peroxidase; Phosphorylation; Signal Transduction; STAT3 Transcription Factor; Tumor Necrosis Factor-alpha

The Notch and NF-κB signaling pathways regulate stem cell function and inflammation in the gut, respectively. We investigate whether a functional cross talk exists between the two pathways during transmissible murine colonic hyperplasia (TMCH) caused by Citrobacter rodentium (CR). During TMCH, NF-κB activity and subunit phosphorylation in colonic crypts of NIH Swiss mice at days 6 and 12 were associated with increases in downstream target CXC chemokine ligand (CXCL)-1/keratinocyte-derived chemokine (KC) expression. Blocking Notch signaling acutely for 5 days with the Notch blocker dibenzazepine (DBZ) failed to inhibit crypt NF-κB activity or CXCL-1/KC expression. Chronic DBZ administration for 10 days, however, blocked Notch and NF-κB signaling in the crypts and abrogated hyperplasia. Intriguingly, chronic Notch inhibition was associated with significant increases in IL-1α, granulocyte colony-stimulating factor, monocyte chemoattractant protein 1, macrophage inflammatory protein 2, and KC in the crypt-denuded lamina propria or whole distal colon, with concomitant increases in myeloperoxidase activity. In core-3(-/-) mice, which are defective in intestinal mucin, DBZ administration replicated the results of NIH Swiss mice; in Apc(Min/+) mice, which are associated with CR-induced elevation of NF-κB-p65(276) expression, DBZ reversed the increase in NF-κB-p65(276), which may have blocked rapid proliferation of the mutated crypts. DBZ further blocked reporter activities involving the NF-κB-luciferase reporter plasmid or the Toll-like receptor 4/NF-κB/SEAPorter HEK-293 reporter cell line, while ectopic expression of Notch-N(ICD) reversed the inhibitory effect. Dietary bael (Aegle marmelos) extract (4%) and curcumin (4%) restored Notch and NF-κB cross talk in NIH Swiss mice, inhibited CR/DBZ-induced apoptosis in the crypts, and promoted crypt regeneration. Thus functional cross talk between the Notch and NF-κB pathways during TMCH regulates hyperplasia and/or inflammation in response to CR infection.

Topics: Animals; Cell Proliferation; Chemokines; Citrobacter rodentium; Colitis; Colon; Curcumin; Cytokines; Dibenzazepines; Enterobacteriaceae Infections; Mice; NF-kappa B; Receptors, Notch

Curcumin is a widely used spice with anti-inflammatory and anticancer properties. It has been reported to have beneficial effects in experimental colitis. This study explored whether curcumin improves colonic inflammation in a rat colitis model through inhibition of the TLR4/NF-κB signaling pathway and IL-27 expression. After induction of colitis with 2,4,6-trinitrobenzene sulfonic acid, rats were intragastrically administered with curcumin or sulfasalazine daily for one week. Rat intestinal mucosa was collected for evaluation of the disease activity index, colonic mucosa damage index, and histological score. Myeloperoxidase activity was detected by immunohistochemistry, and mRNA and protein expression levels of TLR4, NF-κB, and IL-27 in colonic mucosa were detected by RT-PCR and Western blot. Compared with the untreated colitis group, the curcumin-treated group showed significant decreases in the disease activity index, colonic mucosa damage index, histological score, myeloperoxidase activity, and expressions of NF-κB mRNA, IL-27 mRNA, TLR4 protein, NF-κB p65 protein, and IL-27 p28 protein (p < 0.05). TLR4 mRNA expression did not differ between groups. Disease activity index decreased more rapidly in the curcumin-treated group than in the sulfasalazine-treated group (p < 0.05). There was no significant difference in TLR4, NF-κB, and IL-27 mRNA and proteins between curcumin-treated and sulfasalazine-treated groups. Curcumin shows significant therapeutic effects on 2,4,6-trinitrobenzene sulfonic acid-induced colitis that are comparable to sulfasalazine. The anti-inflammatory actions of curcumin on colitis may involve inhibition of the TLR4/NF-κB signaling pathway and of IL-27 expression.

Topics: Animals; Anti-Inflammatory Agents; Colitis; Colon; Curcumin; Disease Models, Animal; Gastrointestinal Agents; Inflammation; Interleukins; Intestinal Mucosa; Male; NF-kappa B; Peroxidase; Random Allocation; Rats; Signal Transduction; Sulfasalazine; Toll-Like Receptor 4; Transcription Factor RelA; Trinitrobenzenesulfonic Acid

The up regulation of gut mucosal cytokines such as tumor necrosis factor (TNF)-α and oxidative stress have been related to inflammatory bowel diseases (IBD) such as ulcerative colitis (UC) and Crohn's disease (CD). This study investigated an immune-mediated model of colitis. TNF-α injected intraperitonally to mice induced a dose-dependent recruitment of neutrophils into abdominal mesentery. The leukocytes influx induced by TNF-α (10 μg kg(-1) body weight) increased by 3 fold liver and colon damage scores. TNF-α-colitis was characterized by hemorrhagic edemas and crypt abscesses massively infiltrated by inflammatory cells, namely neutrophils. Moreover, TNF-α-toxicity resulted in liver steatosis and foci of necrosis infiltrated by Kupffer cells and neutrophils in parenchyma and around the centrilobular veins. The involvement of oxidative stress was evaluated using aminoguanidine (AG) as selective inhibitor of inducible NO synthase (iNOS) and curcumin (Cur), the polyphenolic antioxidant of turmeric (Curcuma longa L.). TNF-α-toxicity led to significant increase in myeloperoxidase (MPO, an index of neutrophils infiltration), nitrites (stable nitric oxide metabolites) and malondialdehyde (MDA, a marker of lipid peroxides) levels and cell apoptosis in liver and colon. AG and Cur treatments significantly attenuated the hallmarks of oxidative stress, neutrophils influx and ROS-related cellular and histological damages, in TNF-α-treated mice. Taken together, our results provide insights into the role of phagocytes-derived oxidants in TNF-α-colitis in mice. Cur and AG, by inhibiting neutrophils priming and iNOsynthase could be effective against oxidative bowel damages induced in IBD by imbalanced gut immune response.

Topics: Animals; Antioxidants; Apoptosis; Colitis; Curcumin; Guanidines; Liver; Male; Mice; Neutrophils; Nitric Oxide; Nitric Oxide Synthase Type II; Oxidative Stress; Peroxidase; Tumor Necrosis Factor-alpha

Curcuma has long been used as an anti-inflammatory agent in inflammatory bowel disease. Since gastrointestinal motility is impaired in inflammatory states, the aim of this work was to evaluate if Curcuma Longa had any effect on intestinal motility.. The biological activity of Curcuma extract was evaluated against Carbachol induced contraction in isolated mice intestine. Acute and chronic colitis were induced in Balb/c mice by Dextran Sulphate Sodium administration (5% and 2.5% respectively) and either Curcuma extract (200 mg/kg/day) or placebo was thereafter administered for 7 and 21 days respectively. Spontaneous contractions and the response to Carbachol and Atropine of ileum and colon were studied after colitis induction and Curcuma administration.. Curcuma extract reduced the spontaneous contractions in the ileum and colon; the maximal response to Carbachol was inhibited in a non-competitive and reversible manner. Similar results were obtained in ileum and colon from Curcuma fed mice. DSS administration decreased the motility, mainly in the colon and Curcuma almost restored both the spontaneous contractions and the response to Carbachol after 14 days assumption, compared to standard diet, but a prolonged assumption of Curcuma decreased the spontaneous and Carbachol-induced contractions.. Curcuma extract has a direct and indirect myorelaxant effect on mouse ileum and colon, independent of the anti-inflammatory effect. The indirect effect is reversible and non-competitive with the cholinergic agent. These results suggest the use of curcuma extract as a spasmolytic agent.

Topics: Animals; Anti-Arrhythmia Agents; Anti-Inflammatory Agents; Atropine; Carbachol; Cardiotonic Agents; Colitis; Colon; Curcuma; Ileum; Inflammation; Intestines; Male; Mice; Mice, Inbred BALB C; Muscle Relaxants, Central; Plant Extracts

Curcumin is a polyphenol with a variety of pharmacologic effects. We evaluate the effect of dietary curcumin on the severity of repeated colitis-associated colorectal cancer.. Six-week-old C57BL/6 mice were randomized into two dietary groups: standard diet and curcumin at 0.6% diet. The mice were exposed to 15 cycles of 0.7% dextran sodium sulphate for 1 week followed by distilled water for 10 days. After curcumin diet, the disease activity index presented a statistical reduction in the last cycles, macroscopic tumors were not seen and the microscopic study showed minor neoplasic lesions with respect to standard diet-group. β-Catenin translocation to the cytoplasm and/or nucleus was observed in the tumor tissue, but this translocation and its intensity were significantly minor in the curcumin diet-DSS animals. Cytokines as tumor necrosis factor-α and IFN-γ were significantly diminished in DSS-animals fed with curcumin. Conversely, non-modification of p53 expression was observed and cyclo-oxygenase-2 and inducible nitric oxide synthase were significantly reduced in the curcumin diet-DSS group.. We demonstrate the protective/preventive effect of curcumin in the progression of colorectal cancer associated to colitis, which was correlated with a lowered immunoreactivity of ß-catenin, a non-modification of p53 expression, a reduction of proinflammatory cytokine levels and a decrease of inflammatory protein overexpression.

Topics: Animals; beta Catenin; Cell Nucleus; Colitis; Colon; Colorectal Neoplasms; Curcumin; Cyclooxygenase 2; Cytokines; Cytoplasm; Diet; Female; Mice; Mice, Inbred C57BL; Nitric Oxide Synthase Type II; Precancerous Conditions; Protein Transport; Random Allocation; Severity of Illness Index; Tumor Suppressor Protein p53

Both fish oil (FO) and curcumin have potential as anti-tumour and anti-inflammatory agents. To further explore their combined effects on dextran sodium sulphate (DSS)-induced colitis, C57BL/6 mice were randomised to four diets (2 × 2 design) differing in fatty acid content with or without curcumin supplementation (FO, FO+2 % curcumin, maize oil (control, MO) or MO+2 % curcumin). Mice were exposed to one or two cycles of DSS in the drinking-water to induce either acute or chronic intestinal inflammation, respectively. FO-fed mice exposed to the single-cycle DSS treatment exhibited the highest mortality (40 %, seventeen of forty-three) compared with MO with the lowest mortality (3 %, one of twenty-nine) (P = 0·0008). Addition of curcumin to MO increased (P = 0·003) mortality to 37 % compared with the control. Consistent with animal survival data, following the one- or two-cycle DSS treatment, both dietary FO and curcumin promoted mucosal injury/ulceration compared with MO. In contrast, compared with other diets, combined FO and curcumin feeding enhanced the resolution of chronic inflammation and suppressed (P < 0·05) a key inflammatory mediator, NF-κB, in the colon mucosa. Mucosal microarray analysis revealed that dietary FO, curcumin and FO plus curcumin combination differentially modulated the expression of genes induced by DSS treatment. These results suggest that dietary lipids and curcumin interact to regulate mucosal homeostasis and the resolution of chronic inflammation in the colon.

Topics: Acute Disease; Animals; Anti-Inflammatory Agents, Non-Steroidal; Chronic Disease; Colitis; Colon; Curcumin; Cytokines; Dextran Sulfate; Dietary Supplements; Fish Oils; Gene Expression Profiling; Gene Expression Regulation; Intestinal Mucosa; Irritants; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Oligonucleotide Array Sequence Analysis; Random Allocation; Survival Analysis

Topics: Animals; Colitis; Colon; Curcumin; Cytokines; Dietary Supplements; Fish Oils; Gene Expression Regulation; Male

The aim of this study was to investigate the effects of xanthorrhizol (5-(1,5-dimethyl-4-hexenyl)-2-methylphenol, XA) in a mouse model of dextran sulfate sodium (DSS)-induced colitis.. Experimental colitis was induced by exposing male BALB/c mice to 5% DSS in drinking water for 7days. XA (10 or 100mg/kg) was administered orally once a day, together with the DSS. We evaluated body weight, colon length, histological changes, and myeloperoxidase (MPO) activity. A cDNA microarray was used to assess the gene expression profiles that were affected by XA and DSS treatment and a co-citation analysis was used to examine the biological relationship between XA-responsive genes and colitis.. Decreased body weight, shortened colon length, and damaged colon were observed in the group that was exposed to DSS. Oral administration of XA (10 or 100mg/kg) rescued these symptomatic and histopathological features. The DSS-induced increase in MPO activity, which was used as an index of neutrophil infiltration, was significantly decreased after treatment with XA. Microarray analysis revealed that XA treatment regulated the expression of 34 genes that were altered by exposure to DSS, and that these XA-responsive genes were associated with colonic inflammation. Furthermore, co-citation analysis and graphing of XA-responsive genes revealed a network associated with the gene that encodes for MPO.. These results suggest that XA attenuates acute DSS-induced colitis, possibly by modulating the expression of genes mostly associated with colonic inflammation.

Topics: Animals; Colitis; Curcuma; Dextran Sulfate; Gene Expression Profiling; Gene Expression Regulation; Inflammation; Male; Mice; Mice, Inbred BALB C; Phenols; Plant Extracts

Curcumin is a tumeric-derived, water-insoluble polyphenol with potential beneficial health effects for humans. It has been shown to have preventive as well as therapeutic effects in chemically induced murine models of colitis. To investigate whether curcumin exerts a similar effect on the spontaneous colitis in interleukin (IL)-10 gene-deficient mice, we gavaged these mice daily for 2 weeks with 200 mg/kg per day curcumin emulsified in carboxymethyl cellulose, a food additive generally used as a viscosity modifier. Mice fed the curcumin/carboxymethyl cellulose mixture and those receiving carboxymethyl cellulose alone demonstrated similar reductions in histological injury score and colon weight/length ratio compared to water-fed controls. However, significant reductions in pro-inflammatory cytokine release in intestinal explant cultures were only seen in mice treated with the curcumin mixture. Our data demonstrate that in IL-10 gene-deficient mice, both oral curcumin and carboxymethyl cellulose, appear to have modifying effects on colitis. However, curcumin has additional anti-inflammatory effects mediated through a reduced production of potent pro-inflammatory mucosal cytokines.

Topics: Administration, Oral; Analysis of Variance; Animals; Carboxymethylcellulose Sodium; Colitis; Curcumin; Disease Models, Animal; Emulsions; Enzyme-Linked Immunosorbent Assay; Interferon-gamma; Interleukin-10; Interleukin-17; Mice; Peroxidase

Damage of the intestinal epithelial barrier by xenobiotics or reactive oxygen species and a dysregulated immune response are both factors involved in the pathogenesis of inflammatory bowel diseases (IBD). Curcumin and rutin are polyphenolic compounds known to have antioxidant and anti-inflammatory activities, but their mechanism(s) of action are yet to be fully elucidated. Multidrug resistance gene-deficient (mdr1a-/- ) mice spontaneously develop intestinal inflammation, predominantly in the colon, with pathology similar to IBD, so this mouse model is relevant for studying diet-gene interactions and potential effects of foods on remission or development of IBD. The present study tested whether the addition of curcumin or rutin to the diet would alleviate colonic inflammation in mdr1a-/- mice. Using whole-genome microarrays, the effect of dietary curcumin on gene expression in colon tissue was also investigated. Twelve mice were randomly assigned to each of three diets (control (AIN-76A), control +0.2% curcumin or control +0.1% rutin) and monitored from the age of 7 to 24 weeks. Curcumin, but not rutin, significantly reduced histological signs of colonic inflammation in mdr1a-/- mice. Microarray and pathway analyses suggested that the effect of dietary curcumin on colon inflammation could be via an up-regulation of xenobiotic metabolism and a down-regulation of pro-inflammatory pathways, probably mediated by pregnane X receptor (Pxr) and peroxisome proliferator-activated receptor alpha (Ppara) activation of retinoid X receptor (Rxr). These results indicate the potential of global gene expression and pathway analyses to study and better understand the effect of foods in modulating colonic inflammation.

Topics: Animals; Anti-Inflammatory Agents; ATP Binding Cassette Transporter, Subfamily B; Base Sequence; Colitis; Colon; Curcumin; Dietary Supplements; Fibrosis; Gene Expression; Gene Expression Regulation; Genome-Wide Association Study; Inflammatory Bowel Diseases; Liver; Mice; Mice, Knockout; Models, Animal; Molecular Sequence Data; Random Allocation; Reverse Transcriptase Polymerase Chain Reaction; Rutin; Staining and Labeling

Curcumin ameliorates colitis whether it reverses colitis-induced reduction in colonic contractility remains to be investigated.. To investigate the effect of curcumin on colitis-induced reduction of carbachol-induced contraction in colon segments from rats treated with trinitrobenzenesulphonic acid.. Colitis was induced in rats by intra rectal administration of trinitrobenzenesulphonic acid and followed for 5 days. A group of animals which received trinitobenzene sulphonic acids was treated with curcumin (100 mg/Kg and 200 mg/kg body weight) 2 hrs prior to induction of colitis. The controls received phosphate buffered saline in a similar fashion. Markers of inflammation and contractility of colon were assayed using standard procedures.. Induction of colitis was associated with increased myeloperoxidase activity and malondialdehyde levels, gross histological changes characterized by infiltration of inflammatory cells. All these changes were prevented by treatment with curcumin (100 mg/kg). Treatment with curcumin also reduced the histological scores from 3.34+/-0.40 to 1.75+/-0.30 confirming an anti-inflammatory effect of curcumin in this experimental model of colitis. Colonic reactivity to carbachol was decreased in colitis affecting the maximum response but not sensitivity. Treatment with curcumin had no effect on sensitivity of the colon to carbachol in any of the preparations. Curcumin however reversed the decrease in carbachol-induced contraction associated with trinitrobenzenesulphonic acid treatment. The same dose of curcumin had no effect on either the potency of or the maximum response to carbachol in control rats. Tissue expression of NF-kB was increased in colon segments from trinitrobenzenesulphonic acid -treated rats and this was inhibited in rats treated with curcumin.. Based on these findings it is concluded that curcumin prevented the reduction in carbachol-induced contraction in trinitrobenzenesulphonic acid -treated rats by modulating NF-kB signaling pathway.

Topics: Animals; Carbachol; Colitis; Colon; Curcumin; Disease Models, Animal; Male; Muscle Contraction; NF-kappa B; Rats; Rats, Sprague-Dawley; Signal Transduction

Curcumin, an active ingredient of Curcumin longa mediates its anti-inflammatory effects through inhibition of NFkB. Several pathways including toll-like receptors (TLR) induce NFkB leading to inflammation. In this study, we investigated the effects of curcumin on the expression of TLR-4 and MyD88, the upstream signaling pathway in experimental colitis induced in the Sprague-Dawley male rats by intra-rectal administration of trinitrobenzenesulfonic acid (TNBS). The animals which received TNBS were divided into two groups: Group 1, received aqueous suspension of curcumin (100 mg/Kg body weight) 2 h prior to inducing colitis, and the treatment was repeated every day for 5 days, and Group 2 and non-colitis (Group 3) animals received phosphate buffered saline (PBS) in a similar fashion. Non-colitis animals (Group 4) received curcumin and served as controls. Animals were sacrificed on day 5 post-TNBS by cervical dislocation, colon was taken out, and cleaned with PBS. Levels of TLR-4, MyD88, and NFkB proteins were measured using ECL Western blot analysis, and TLR-4 mRNA by a competitive RT-PCR method. Colitis was confirmed histologically by measuring myeloperoxidase (MPO) activity and malondialdehyde (MDA) levels in the colonic tissues. TNBS-induced increase in the level of MPO activity and MDA concentrations was reversed by curcumin treatment, whereas the same dose of curcumin did not affect their levels in the non-colitis animals. Increases in the levels of TLR-4, MyD88, and NFkB proteins in inflamed tissue were also suppressed significantly by curcumin treatment. The level of TLR-4 mRNA remained unchanged in the colitis animals. These findings demonstrate that signaling pathway of curcumin-induced inhibition of inflammation involves TLR-4 and MyD88, and therefore may serve as an important therapeutic target in IBD.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Colitis; Colon; Curcumin; Male; Models, Animal; Myeloid Differentiation Factor 88; Peroxidase; Rats; Rats, Sprague-Dawley; RNA, Messenger; Signal Transduction; Toll-Like Receptor 4

This project was undertaken with a view to optimize the treatment of inflammatory bowel disease through a novel drug delivery approach for localized treatment in the colon. Curcumin has poor aqueous solubility, poor stability in the gastrointestinal tract and poor bioavailability. The purpose of the study was to prepare and evaluate the anti-inflammatory activity of solid lipid microparticles (SLMs) of curcumin for the treatment of inflammatory bowel disease in a colitis-induced rat model by a colon-specific delivery approach.. We have developed a novel formulation approach for treating experimental colitis in the rat model. SLMs of curcumin were prepared with various lipids, such as palmitic acid, stearic acid and soya lecithin, with an optimized percentage of poloxamer 188. The SLMs of curcumin were characterized for particle size, drug content, drug entrapment, in-vitro release, surface morphology and infrared, differential scanning calorimetry and X-ray studies. The colonic delivery system of SLM formulations of curcumin were further investigated for their anti-angiogenic and anti-inflammatory activity using chick embryo and rat colitis models.. Particle size, drug content, drug entrapment and in-vitro release studies showed that formulation F4 containing one part stearic acid and 0.5% surfactant had the smallest diameter of 108 microm, 79.24% entrapment and exhibited excellent in-vitro release characteristics when compared with other formulations and pure curcumin. SLMs of curcumin (F4) proved to be a potent angio-inhibitory compound, as demonstrated by inhibition of angiogenesis in the chorioallantoic membrane assay. Rats treated with curcumin and its SLM complex showed a faster weight gain compared with dextran sulfate solution (DSS) control rats. The increase in whole colon length appeared to be significantly greater in SLM-treated rats when compared with pure curcumin and DSS control rats. An additional finding in the DSS-treated rats was chronic cell infiltration with predominance of eosinophils. Decreased mast cell numbers in the mucosa of the colon of SLMs of curcumin and pure curcumin-treated rats was observed.. The degree of colitis caused by administration of DSS was significantly attenuated by colonic delivery of SLMs of curcumin. Being a nontoxic natural dietary product, curcumin could be useful in the therapeutic strategy for inflammatory bowel disease patients.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Chick Embryo; Chorioallantoic Membrane; Colitis; Curcumin; Disease Models, Animal; Drug Carriers; Glycine max; Intestinal Mucosa; Lecithins; Lipids; Male; Microspheres; Neovascularization, Pathologic; Palmitic Acid; Particle Size; Rats; Rats, Sprague-Dawley; Stearic Acids

The purpose of the study was to prepare and evaluate the anti-inflammatory activity of cyclodextrin (CD) complex of curcumin for the treatment of inflammatory bowel disease (IBD) in colitis-induced rat model. Inclusion complexes of curcumin were prepared by common solvent and kneading methods. These complexes were further evaluated for increase in solubility of poorly soluble curcumin. The inclusion complexes were characterized for enhancement in solubility, in vitro dissolution, surface morphology, infrared, differential scanning calorimetry, and X-ray studies. Solubility, phase solubility, and in vitro dissolution studies showed that curcumin has higher affinity for hydroxypropyl-beta-CD (HPbetaCD) than other CDs. HPbetaCD complex of curcumin was further investigated for its antiangiogenic and anti-inflammatory activity using chick embryo and rat colitis model. HPbetaCD complex of curcumin proved to be a potent angioinhibitory compound, as demonstrated by inhibition of angiogenesis in chorioallantoic membrane assay. Curcumin- and HPbetaCD-treated rats showed a faster weight gain compared to dextran sulfate solution (DSS) controls. Whole colon length appeared to be significantly longer in HPbetaCD-treated rats than pure curcumin and DSS controls. An additional finding in the DSS-treated rats was the predominance of eosinophils in the chronic cell infiltrate. Decreased mast cell numbers in the mucosa of the colon of CD of curcumin- and pure-curcumin-treated rats was observed. This study concluded that the degree of colitis caused by administration of DSS was significantly attenuated by CD of curcumin. Being a nontoxic natural dietary product, curcumin could be useful in the therapeutic strategy for IBD patients.

Topics: Angiogenesis Inhibitors; Animals; Anti-Inflammatory Agents, Non-Steroidal; Calorimetry, Differential Scanning; Capsules; Chemistry, Pharmaceutical; Chick Embryo; Chorioallantoic Membrane; Colitis; Curcumin; Cyclodextrins; Dextran Sulfate; Drug Carriers; Drug Delivery Systems; Gelatin; Hydrogen-Ion Concentration; Male; Rats; Rats, Sprague-Dawley; Solubility; Solvents; Spectrophotometry, Infrared; Spectrophotometry, Ultraviolet; X-Ray Diffraction

The gut is home to a large number of Treg, with both CD4(+) CD25(+) Treg and bacterial antigen-specific Tr1 cells present in normal mouse intestinal lamina propria. It has been shown recently that intestinal mucosal DC are able to induce Foxp3(+) Treg through production of TGF-beta plus retinoic acid (RA). However, the factors instructing DC toward this mucosal phenotype are currently unknown. Curcumin has been shown to possess a number of biologic activities including the inhibition of NF-kappaB signaling. We asked whether curcumin could modulate DC to be tolerogenic whose function could mimic mucosal DC. We report here that curcumin modulated BM-derived DC to express ALDH1a and IL-10. These curcumin-treated DC induced differentiation of naïve CD4(+) T cells into Treg resembling Treg in the intestine, including both CD4(+)CD25(+) Foxp3(+) Treg and IL-10-producing Tr1 cells. Such Treg induction required IL-10, TGF-beta and retinoic acid produced by curcumin-modulated DC. Cell contact as well as IL-10 and TGF-beta production were involved in the function of such induced Treg. More importantly, these Treg inhibited antigen-specific T-cell activation in vitro and inhibited colitis due to antigen-specific pathogenic T cells in vivo.

Topics: Animals; Antigen Presentation; Bone Marrow Cells; Cell Differentiation; Cell Separation; Colitis; Curcumin; Dendritic Cells; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Immune Tolerance; Immunity, Mucosal; Immunologic Factors; Immunomodulation; Intestinal Mucosa; Intestines; Mice; Mice, Inbred C57BL; Mice, Knockout; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; T-Lymphocyte Subsets; T-Lymphocytes, Regulatory

Curcumin (diferulolylmethane) demonstrates profound anti-inflammatory effects in intestinal epithelial cells (IEC) and in immune cells in vitro and exhibits a protective role in rodent models of chemically induced colitis, with its presumed primary mechanism of action via inhibition of NF-kappaB. Although it has been demonstrated effective in reducing relapse rate in ulcerative colitis patients, curcumin's effectiveness in Crohn's disease (CD) or in Th-1/Th-17 mediated immune models of CD has not been evaluated. Therefore, we investigated the effects of dietary curcumin (0.1-1%) on the development of colitis, immune activation, and in vivo NF-kappaB activity in germ-free IL-10(-/-) or IL-10(-/-);NF-kappaB(EGFP) mice colonized with specific pathogen-free microflora. Proximal and distal colon morphology showed a mild protective effect of curcumin only at 0.1%. Colonic IFN-gamma and IL-12/23p40 mRNA expression followed similar pattern ( approximately 50% inhibition at 0.1%). Secretion of IL-12/23p40 and IFN-gamma by colonic explants and mesenteric lymph node cells was elevated in IL-10(-/-) mice and was not decreased by dietary curcumin. Surprisingly, activation of NF-kappaB in IL-10(-/-) mice (phospho-NF-kappaBp65) or in IL-10(-/-);NF-kappaB(EGFP) mice (whole organ or confocal imaging) was not noticeably inhibited by curcumin. Furthermore, we demonstrate that IL-10 and curcumin act synergistically to downregulate NF-kappaB activity in IEC and IL-12/23p40 production by splenocytes and dendritic cells. In conclusion, curcumin demonstrates limited effectiveness on Th-1 mediated colitis in IL-10(-/-) mice, with moderately improved colonic morphology, but with no significant effect on pathogenic T cell responses and in situ NF-kappaB activity. In vitro studies suggest that the protective effects of curcumin are IL-10 dependent.

Topics: Animals; Colitis; Colon; Curcumin; Diet; Dose-Response Relationship, Drug; Epithelial Cells; Gene Expression Regulation; Immunohistochemistry; Interleukin-10; Intestinal Mucosa; Mice; Mice, Knockout; NF-kappa B; Specific Pathogen-Free Organisms; Spleen; Th1 Cells

Curcumin (diferulolylmethane) has been shown to have a protective role in mouse models of inflammatory bowel diseases (IBD) and to reduce the relapse rate in human ulcerative colitis (UC), thus making it a potentially viable supportive treatment option. Trinitrobenzene sulfonic acid (TNBS) colitis in NKT-deficient SJL/J mice has been described as Th1-mediated inflammation, whereas BALB/c mice are believed to exhibit a mixed Th1/Th2 response.. We therefore investigated the effect of dietary curcumin in colitis induced in these 2 strains.. In the BALB/c mice, curcumin significantly increased survival, prevented weight loss, and normalized disease activity. In the SJL/J mice, curcumin demonstrated no protective effects. Genomewide microarray analysis of colonic gene expression was employed to define the differential effect of curcumin in these 2 strains. This analysis not only confirmed the disparate responses of the 2 strains to curcumin but also indicated different responses to TNBS. Curcumin inhibited proliferation of splenocytes from naive BALB/c mice but not SJL/J mice when nonspecifically stimulated in vitro with concanavalin A (ConA). Proliferation of CD4(+) splenocytes was inhibited in both strains, albeit with about a 2-fold higher IC(50) in SJL/J mice. Secretion of IL-4 and IL-5 by CD4(+) lymphocytes of BALB/c mice but not SJL/J mice was significantly augmented by ConA and reduced to control levels by curcumin.. The efficacy of dietary curcumin in TNBS colitis varies in BALB/c and SJL/J mouse strains. Although the exact mechanism underlying these differences is unclear, the results suggest that the therapeutic value of dietary curcumin may differ depending on the nature of immune dysregulation in IBD.

Topics: Animals; Colitis; Concanavalin A; Curcumin; Diet; Disease Models, Animal; Inflammatory Bowel Diseases; Lymphocytes; Male; Mice; Mice, Inbred BALB C; Mice, Inbred Strains; Microarray Analysis; Reverse Transcriptase Polymerase Chain Reaction; Species Specificity; Trinitrobenzenesulfonic Acid

Ulcerative colitis (UC) is a nonspecific inflammatory disorder characterized by oxidative and nitrosative stress, leucocyte infiltration and up-regulation of pro-inflammatory cytokines. Mitogen-activated protein kinases (MAPKs), such as the p38 and the c-Jun N-terminal kinase (JNK) modulate the transcription of many genes involved in the inflammatory process. Curcumin is a polyphenol derived from Curcuma longa, which is known to have anti-inflammatory activity. The aim of this study was to study the effects and mechanisms of action of curcumin, on chronic colitis in rats. Inflammation response was assessed by histology and myeloperoxidase activity (MPO). We determined the production of Th1 and Th2 cytokines and nitrites in colon mucosa, as well as the expression of inducible nitric oxide synthase (iNOS), cyclo-oxygenase(COX)-1 and-2 by western blotting and inmmunohistochemistry. Finally, we studied the involvement of MAPKs signaling in the protective effect of curcumin in chronic colonic inflammation. Curcumin (50-100 mg/kg/day) were administered by oral gavage 24 h after trinitrobenzensulfonic acid (TNBS) instillation, and daily during 2 weeks before sacrifice. Curcumin significantly attenuated the damage and caused substantial reductions of the rise in MPO activity and tumour necrosis factor alpha (TNF)-alpha. Also curcumine was able to reduce nitrites colonic levels and induced down-regulation of COX-2 and iNOS expression, and a reduction in the activation of p38 MAPK; however, no changes in the activation of JNK could be observed. In conclusion, we suggest that inhibition of p38 MAPK signaling by curcumin could explain the reduced COX-2 and iNOS immunosignals and the nitrite production in colonic mucosa reducing the development of chronic experimental colitis.

Topics: Animals; Chronic Disease; Colitis; Curcumin; Cyclooxygenase 2; Female; Gene Expression Regulation, Enzymologic; Male; MAP Kinase Signaling System; Nitric Oxide; Nitric Oxide Synthase Type II; p38 Mitogen-Activated Protein Kinases; Rats; Rats, Wistar; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha

Curcumin is a phenolic natural product isolated from the rhizome of Curcuma longa (turmeric). We evaluated the effects of curcumin on the development of dextran sulfate sodium (DSS)-induced experimental colitis. BALB/c mice were fed a chow containing either 3.5% (wt/wt) DSS or 3.5% DSS + 2.0% (wt/wt) curcumin. The body weight loss was more apparent in DSS-treated mice than in DSS + curcumin-treated mice. The disease activity index, histological colitis score, and MPO activity were all significantly higher in DSS-treated mice than in DSS plus curcumin-treated mice. Microscopically, mucosal edema, cellular infiltration, and epithelial disruption were much more severe in DSS-treated mice than in DSS + curcumin-treated mice. In DSS + curcumin-treated mice, NF-kappaB activation was blocked in the mucosa. In conclusion, the development of DSS-induced colitis was significantly attenuated by curcumin. Being a nontoxic natural dietary product, curcumin could be useful in treatment of IBD patients.

Topics: Animals; Antineoplastic Agents; Colitis; Colon; Curcumin; Dextran Sulfate; Disease Models, Animal; Immunohistochemistry; Male; Mice; Mice, Inbred BALB C; Peroxidase; Plasma Substitutes

A protective role of the transient potential vanilloid receptor 1 (TRPV1) in intestinal inflammation induced by dinitrobenzene sulphonic acid (DNBS) has been recently demonstrated. Curcumin, the major active component of turmeric, is also able to prevent and ameliorate the severity of the damage in DNBS-induced colitis. We evaluated the possibility that curcumin (45 mg kg(-1) day p.o. for 2 days before and 5 days after the induction of colitis) was able to reduce DNBS-induced colitis in mice, by acting as a TRPV1 agonist. Macroscopic damage score, histological damage score and colonic myeloperoxidase (MPO) activity were significantly lower (by 71%, 65% and 73%, respectively; P < 0.01), in animals treated with curcumin compared with untreated animals. Capsazepine (30 mg kg(-1), i.p.), a TRPV1 receptor antagonist, completely abolished the protective effects of curcumin. To extend these data in vitro, Xenopus oocytes expressing rat TRPV1 were examined. Capsaicin-evoked currents (3.3 micromol L(-1)) disappeared subsequent either to removal of the agonist or subsequent to the addition of capsazepine. However, curcumin (30 micromol L(-1)) was ineffective both as regard direct modification of cell membrane currents and as regard interference with capsaicin-mediated effects. As sensitization of the TRPV1 receptor by mediators of inflammation in damaged tissues has been shown previously, our results suggest that in inflamed, but not in normal tissue, curcumin can interact with the TRPV1 receptor to mediate its protective action in DNBS-induced colitis.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzenesulfonates; Capsaicin; Cell Membrane; Colitis; Curcumin; Male; Membrane Potentials; Mice; Mice, Inbred BALB C; Oocytes; Peroxidase; Severity of Illness Index; TRPV Cation Channels; Xenopus

Curcumin is a widely used spice with anti-inflammatory and anti-cancer properties. It has been reported that curcumin held therapeutic effects on experimental colitis by inhibition of nuclear factor kappa B (NF-kappaB). The peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor with anti-tumor and anti-inflammatory effects and its activation may inhibit the nuclear translocation of NF-kappaB. Several studies have shown that PPARgamma ligands had an important therapeutic effect in colitis. However there is no report about the alteration of PPARgamma in trinitrobenzene sulphonic acid (TNBS)-induced colitis treated with curcumin. In this study, we administered curcumin (30 mg/kg/day) by intraperitoneal injection immediately after colitis was induced and the injection lasted for two weeks. have evaluated the effects of curcumin on the colitis induced by trinitrobenzene sulphonic acid (TNBS). Curcumin (30 mg/kg d) was administered by intraperitoneal just after colitis was induced and lasted for two weeks. Therapeutic effects of dexamethasone (Dex, 2 mg/kg d) alone and the combined effects of curcumin+Dex were also examined. We found that curcumin improved long-term survival rate of disease-bearing rats, promoted rat body weight recovery, and decreased macroscopic scores of the colitis. The expression levels of PPARgamma, 15-deoxy-D12,14-prostaglandin J(2) (15d-PGJ(2)) and prostaglandin E(2) (PGE(2)) were all increased, but the expression level of cyclooxygenase-2 (COX-2) was decreased in rats after administration of curcumin. Treatment with Dex improved PPARgamma expression and inhibited the expression of COX-2, 15d-PGJ(2) and PGE(2). Combined effects of curcumin+Dex were similar to that of Dex. In summary, curcumin showed therapeutic effects on TNBS-induced colitis and the mechanisms by which curcumin exerts its effects may involve activation of PPARgamma and its ligands.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Colitis; Colon; Curcumin; Cyclooxygenase 2; Cytokines; Dexamethasone; Dinoprostone; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Gene Expression; PPAR gamma; Prostaglandin D2; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Specific Pathogen-Free Organisms; Time Factors; Trinitrobenzenesulfonic Acid; Weight Loss

To explore the possible mechanisms of curcumin in rat colitis induced by trinitrobenzene sulfonic (TNBS) acid.. Rats with TNBS acid-induced colitis were treated with curcumin (30 mg/kg or 60 mg/kg per day ip). Changes of body weight and histological scores as well as survival rate were evaluated. Leukocyte infiltration was detected by myeloperoxidase (MPO) activity assay. The expression of cyclooxygenase-2 (COX-2) was detected by RT-PCR and Western blot. Inflammation cytokines were determined by RT-PCR. Local concentration of prostaglandin E(2) (PGE(2)) in colon mucosa was determined by ELISA.. Curcumin improved survival rate and histological image, decreased the macroscopic scores and MPO activity. Also curcumin reduced the expression of COX-2 and inflammation cytokines. In addition, treatment with curcumin increased the PGE(2) level.. Curcumin has therapeutic effects on TNBS acid-induced colitis, the mechanisms seem to be related to COX-2 inhibition and PGE(2) improvement.

Topics: Animals; Body Weight; Chronic Disease; Colitis; Colon; Curcumin; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Dinoprostone; Gene Expression Regulation, Enzymologic; Interferon-gamma; Intestinal Mucosa; Leukocytes; Nitric Oxide Synthase Type II; Rats; Rats, Sprague-Dawley; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha

To investigate the therapeutic effects of curcumin (Cur) on trinitrobenzene sulphonic acid (TNBS)-induced colitis and the effects of Cur on the balance of Th1/Th2 cytokines.. Colitis was induced by TNBS and treated with Cur (30 mg/kg/d, ip), dexamethasone (Dex, 2 mg/kg/d), or Cur plus dexamethasone (Cur+Dex, 30 mg/kg/d Cur ip+2 mg/kg/d Dex,ip). mRNA in colon mucosa were detected by real-time quantitative polymerase chain reaction. Intracellular cytokines were detected by flow cytometry and concentrations of cytokines in sera were detected by enzyme-linked immunosorbent analysis.. Both Cur and Dex improved body weight loss, ameliorated histological images and decreased macroscopic score and myeloperoxidase activity. Cur decreased the expression of Th1 cytokines (IL-12, IFN-gamma, TNF-alpha, IL-1) and increased the expression of Th2 cytokines (IL-4 and IL-10) in colon mucosa. Cur also increased the proportion of IFN-gamma/IL-4 in splenocytes and circulation. Dex and Cur+Dex decreased the expression of Th1 cytokines but could not increase the expression of Th2 cytokines and the proportion of IFN-gamma/IL-4.. Cur exerted therapeutic effects on colitis by regulating the shift from Th1 to Th2.

Topics: Animals; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Colitis; Colon; Curcumin; Cytokines; Dexamethasone; Interferon-gamma; Interleukin-12; Intestinal Mucosa; Peroxidase; Rats; Rats, Sprague-Dawley; RNA, Messenger; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha

To ascertain the molecule mechanism of nuclear factor-kappaB (NF-kappaB) inhibitor curcumin preventive and therapeutic effects in rats' colitis induced by trinitrobenzene sulfonic acid (TNBS).. Sixty rats with TNBS-induced colitis were treated with 2.0% curcumin in the diet. Thirty positive control rats were treated with 0.5% sulfasalazine (SASP). Thirty negative control rats and thirty model rats were treated with general diet. Changes of body weight together with histological scores were evaluated. Survival rates were also evaluated. Cell nuclear NF-kappaB activity in colonic mucosa was evaluated by using electrophoretic mobility shift assay. Cytoplasmic IkappaB protein in colonic mucosa was detected by using Western Blot analysis. Cytokine messenger expression in colonic tissue was assessed by using semiquantitative reverse-transcription polymerase chain reaction.. Treatment with curcumin could prevent and treat both wasting and histopathologic signs of rats with TNBS-induced intestinal inflammation. In accordance with these findings, NF-kappaB activation in colonic mucosa was suppressed in the curcumin-treated groups. Degradations of cytoplasmic IkappaB protein in colonic mucosa were blocked by curcumin treatment. Proinflammatory cytokine messenger RNA expression in colonic mucosa was also suppressed.. This study shows that NF-kappaB inhibitor curcumin could prevent and improve experimental colitis in murine model with inflammatory bowel disease (IBD). The findings suggest that NF-kappaB inhibitor curcumin could be a potential target for the patients with IBD.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Body Weight; Colitis; Curcumin; Cytokines; Cytoplasm; Gene Expression; I-kappa B Proteins; Intestinal Mucosa; Male; NF-kappa B; Rats; Rats, Wistar; Survival Rate; Trinitrobenzenesulfonic Acid

Numerous therapies used for inflammatory bowel disease (IBD) target the transcription factor NF-kappaB, which is involved in the production of cytokines and chemokines integral for inflammation. Here we show that curcumin, a component of the spice turmeric, is able to attenuate colitis in the dinitrobenzene sulfonic acid (DNB)-induced murine model of colitis. When given before the induction of colitis it reduced macroscopic damage scores and NF-kappaB activation. This was accompanied by a reduction in myeloperoxidase activity, and using semiquantitative RT-PCR, an attenuation of the DNB-induced message for IL-1beta was detected. Western blotting analysis revealed that there was a reproducible DNB-induced activation of p38 MAPK detected in intestinal lysates by using a phosphospecific antibody. This signal was significantly attenuated by curcumin. Furthermore, we show that the immunohistochemical signal is dramatically attenuated at the level of the mucosa by curcumin. We conclude that the widely used food additive curcumin is able to attenuate experimental colitis through a mechanism correlated with the inhibition of the activation of NF-kappaB and effects a reduction in the activity of p38 MAPK. We propose that this agent may have therapeutic implications for human IBD.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzenesulfonates; Biomarkers; Colitis; Curcumin; Disease Models, Animal; Humans; Intestinal Mucosa; MAP Kinase Signaling System; Mice; Mice, Inbred C3H; Mitogen-Activated Protein Kinases; NF-kappa B; p38 Mitogen-Activated Protein Kinases

1 Inflammmatory bowel disease (IBD) is characterized by oxidative and nitrosative stress, leucocyte infiltration and upregulation of proinflammatory cytokines. In this study, we have investigated the protective effects of curcumin, an anti-inflammatory and antioxidant food derivative, on 2,4,6- trinitrobenzene sulphonic acid-induced colitis in mice, a model for IBD. 2 Intestinal lesions (judged by macroscopic and histological score) were associated with neutrophil infiltration (measured as increase in myeloperoxidase activity in the mucosa), increased serine protease activity (may be involved in the degradation of colonic tissue) and high levels of malondialdehyde (an indicator of lipid peroxidation). 3 Dose-response studies revealed that pretreatment of mice with curcumin (50 mg kg(-1) daily i.g. for 10 days) significantly ameliorated the appearance of diarrhoea and the disruption of colonic architecture. Higher doses (100 and 300 mg kg(-1)) had comparable effects. 4 In curcumin-pretreated mice, there was a significant reduction in the degree of both neutrophil infiltration (measured as decrease in myeloperoxidase activity) and lipid peroxidation (measured as decrease in malondialdehyde activity) in the inflamed colon as well as decreased serine protease activity. 5 Curcumin also reduced the levels of nitric oxide (NO) and O(2)(-) associated with the favourable expression of Th1 and Th2 cytokines and inducible NO synthase. Consistent with these observations, nuclear factor-kappaB activation in colonic mucosa was suppressed in the curcumin-treated mice. 6 These findings suggest that curcumin or diferuloylmethane, a major component of the food flavour turmeric, exerts beneficial effects in experimental colitis and may, therefore, be useful in the treatment of IBD.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Colitis; Curcuma; Curcumin; Cytokines; Dose-Response Relationship, Drug; Female; Intestinal Mucosa; Malondialdehyde; Mice; Mice, Inbred BALB C; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Peroxidase; Phytotherapy; Plant Extracts; RNA, Messenger; Serine Endopeptidases; Superoxides; Trinitrobenzenesulfonic Acid

Curcumin is known to have a variety of pharmacologic effects, including antitumor, anti-inflammatory, and anti-infectious activities. The pleiotropic effects of curcumin are attributable at least in part to inhibition of transcriptional factor nuclear factor kappaB (NF-kappaB). However, the effect of curcumin on intestinal inflammation has hitherto not been evaluated. The aim of this study was to determine whether treatment with curcumin prevents and ameliorates colonic inflammation in a mouse model of inflammatory bowel disease.. Mice with trinitrobenzene sulfonic acid (TNBS)-induced colitis were treated with 0.5%, 2.0%, or 5.0% curcumin in the diet, and changes in body weight together with histologic scores were evaluated. Colonic T-cell subsets were characterized, and NF-kappaB in colonic mucosa was detected by immunohistochemistry. NF-kappaB activity in the colonic mucosa was evaluated using electrophoretic mobility shift assay. Cytokine messenger RNA expression in colonic tissue was assessed by semiquantitative reverse-transcription polymerase chain reaction.. Treatment of mice with curcumin prevented and improved both wasting and histopathologic signs of TNBS-induced colonic inflammation. Consistent with these findings, CD4(+) T-cell infiltration and NF-kappaB activation in colonic mucosa were suppressed in the curcumin-treated group. Suppression of proinflammatory cytokine messenger RNA expression in colonic mucosa was also observed.. This study has shown for the first time that treatment with curcumin can prevent and improve murine experimental colitis. This finding suggests that curcumin could be a potential therapeutic agent for the treatment of patients with inflammatory bowel disease.

Topics: Animals; Body Weight; Colitis; Colon; Curcumin; Cytokines; Dose-Response Relationship, Drug; Gene Expression; Intestinal Mucosa; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; NF-kappa B; Survival Rate; Trinitrobenzenesulfonic Acid