Experimental Ulcerative Colitis Research Articles

The endogenous ligand for guanylate cyclase-C activation reliefs intestinal inflammation in the DSS colitis model.

Ulcerative colitis (UC) is a major type of inflammatory bowel disease (IBD) and significantly impacts patient quality of life. Previous research revealed that the guanylate cyclase-C (GC-C) signaling pathway is associated with the severity of UC. We aimed to investigate the effect of the GC-C agonist, guanylin (Gn), on inflammatory injury in mice with colitis. An experimental UC model was established in Balb/c mice. Mesalamine served as a positive control. The Gn overexpression vector was administered once per day for 1 week. Intestinal permeability of the mice was measured using fluorescein isothiocyanate-dextran after the treatment. Histopathologic grading was estimated to assess the inflammatory injury of the colon. The expression level of crucial mediators of the GC-C signaling pathway (Gn, Ugn and GC-C) and tight junction proteins (occludin, claudin-1 and ZO-1) was measured in the colon. Additionally, the level of pro-inflammatory cytokines (IL-8 and TNF-α) in serum was measured. After injecting the UC mice with the Gn overexpression vector, the body weight increased, and the frequency of loose stools and bloody stools was decreased. Intestinal permeability and histopathologic score were significantly reduced (P<0.05). The expression level of GC-C, Gn, Ugn, claudin-1 and ZO-1 was significantly increased (P<0.05). The level of IL-8 and TNF-α in the serum was significantly decreased (P<0.01). Therefore, the application of Gn overexpression vector can ameliorate the intestinal inflammatory injury and repair the mucosal barrier in colitis mice, which further suggests the clinical therapeutic potential of GC-C agonists in IBD.

Immunotropic effect of rectal suppositories with vitamin D3 in dynamics of experimental ulcer colitis

Purpose of the study—to develop a new dosage form—rectal suppositories with vitamin D3 and at the preclinical stage to analyze its clinical and immunological efficacy compared to 5-aminosalicylic acid (5-ASA) in the dynamics of experimental ulcerative colitis (UC) in rats.Materials and methods. UC was simulated by cutaneous and then rectal application of a 3% solution of oxazolone. Original rectal suppositories with 1500ME of vitamin D3 were administered per rectum every 12 hours, in the comparison group with the same interval, rectal suppositories with 50 mg of 5-ASA. To assess the clinical status, the Disease activity index (DAI) scale was used, the serum concentration of IgG, IgM, IL-6, IL-8 was determined by the enzyme immunoassay using rat-specific test systems on days 2 and 6 of the experiment.The results of the study. In experimental UC, DAI rises, and the concentration of IgG, IgM, IL-8 and IL-6 in serum increases on the 2nd and 6th day of the experiment. DAI increases as serum concentrations of IgG, IgM, IL-8 and IL-6 increase. The use of vitamin D3 in UC leads to a decrease in DAI and serum concentrations of IgG, IgM, IL-8, IL-6 mainly on the 6th day of observation. The use of rectal suppositories with 5-ASA in UC leads to a decrease in DAI and the concentration of IgM, IgG, IL-6, IL-8 on the 2nd and 6th day of observation.Conclusion. The efficacy of rectal suppositories containing 1500 IU of vitamin D3 in experimental UC was found to be comparable with the use of rectal suppositories with 5-ASA based on the assessment of the clinical status and serum concentration of IgM, IgG, IL-6, IL-8.

P2X7 receptor antagonist recovers ileum myenteric neurons after experimental ulcerative colitis.

BACKGROUNDThe P2X7 receptor is expressed by enteric neurons and enteric glial cells. Studies have demonstrated that administration of a P2X7 receptor antagonist, brilliant blue G (BBG), prevents neuronal loss.AIMTo report the effects of BBG in ileum enteric neurons immunoreactive (ir) following experimental ulcerative colitis in Rattus norvegicus albinus.METHODS2,4,6-trinitrobenzene sulfonic acid (TNBS group, n = 5) was injected into the distal colon. BBG (50 mg/kg, BBG group, n = 5) or vehicle (sham group, n = 5) was given subcutaneously 1 h after TNBS. The animals were euthanized after 24 h, and the ileum was removed. Immunohistochemistry was performed on the myenteric plexus to evaluate immunoreactivity for P2X7 receptor, neuronal nitric oxide synthase (nNOS), choline acetyltransferase (ChAT), HuC/D and glial fibrillary acidic protein.RESULTSThe numbers of nNOS-, ChAT-, HuC/D-ir neurons and glial fibrillary acidic protein-ir glial cells were decreased in the TNBS group and recovered in the BBG group. The neuronal profile area (μm2) demonstrated that nNOS-ir neurons decreased in the TNBS group and recovered in the BBG group. There were no differences in the profile areas of ChAT- and HuC/D-ir neurons.CONCLUSIONOur data conclude that ileum myenteric neurons and glial cells were affected by ulcerative colitis and that treatment with BBG had a neuroprotective effect. Thus, these results demonstrate that the P2X7 receptor may be an important target in therapeutic strategies.

Synbiotics administration leads to attenuated mucosal inflammatory neutrophil infiltration and increased hematocrit in experimental ulcerative colitis.

The objective of the study was to estimate the effects of synbiotics on laboratory, macroscopic, and histopathologic features in dextran sulfate sodium (DSS) experimental colitis. A total of 40 Wistar rats received 5% of DSS in their drinking water for 8 days to induce ulcerative colitis (UC). Eight rats were sacrificed to confirm the presence of UC. The remaining rats were randomly assigned to two groups: the synbiotics group, which received synbiotics once per day and the control group, which received tap water for another 8 days. On the 8th day of DSS administration animals developed UC with bloody diarrhea. In the majority of the hematologic variables studied (hemoglobin [HB], red blood cells, platelets, mean corpuscular volume, and mean corpuscular HB), in bodyweight and histopathologic colitis score there was no significant difference between groups. However, the synbiotics group, compared to control, presented a significantly greater colon length on the 4th day, significantly increased hematocrit (HT) on the 8th day, and a significantly decreased number of myeloperoxidase positive cells on the 8th day. Furthermore, there was a trend toward histopathological and clinical improvement. Administration of synbiotics in the experimental UC results in an attenuation of mucosal inflammatory neutrophil infiltration and an increase in HT.

Anti-colitic effects of Physalin B on dextran sodium sulfate-induced BALB/c mice by suppressing multiple inflammatory signaling pathways

Ethnopharmacological relevancePhysalin B is one of the main active withanolide existed in Physalis alkekengi L. var. franchetii (Mast.) Makino, a famous traditional Chinese food and herbal medicine, which has been widely used as heat-clearing and toxin-resolving medicine for the treatment of various inflammatory disease, such as cough, excessive phlegm, pharyngitis, sore throat, pemphigus, eczema, and jaundice. Aim of the studyWe aimed to confirm the therapeutic effects of Physalin B on ulcerative colitis (UC) and enrich the further application of its traditional anti-inflammatory effect. Materials and methodsThe anti-UC effects of Physalin B were evaluated in Balb/c mice with dextran sulfate sodium (DSS) induction. The body weight, colon length, disease activity index (DAI) and pathological changes of colon tissue were measured. Cytokine levels were detected by ELISA. NF-κB pathway and protein levels of related pathways, such as signal transducer and activator of transcription 3 (STAT3), β-arrestin1 and NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome were detected by western blot. ResultsThe dose of Physalin B that is not cytotoxic could dramatically reduce the levels of TNF-α, IL-6 and IL-1β on LPS-stimulated RAW 264.7 cells. Meanwhile, Physalin B dramatically improved clinical signs and symptoms, alleviated body weight loss and colon length shortening in DSS-induced UC mice. Meanwhile, Physalin B also dramatically relieved the pathological damage, reduced in the activity of myeloperoxidase (MPO) and reestablished the balance of pro-inflammatory cytokines. Physalin B could suppress DSS-induced activation of NF-κB. Moreover, Physalin B also markedly suppressed the activation of STAT3, β-arrestin1 and NLRP3 inflammasome. ConclusionThis study preliminary confirmed the therapeutic effect of Physalin B on experimental acute UC mice and provided robust evidence support for the anti-inflammatory effect of Physalin B, suggesting that Physalin B might be a potential agent for the therapeutic efficacy on UC.

Protection against Dextran Sulfate Sodium-Induced Ulcerative Colitis in Mice by Neferine, A Natural Product from Nelumbo nucifera Gaertn.

Objective Ulcerative colitis (UC) is a long-lasting inflammatory disease of the colon. Epidemiological studies showed that the prevalence and incidence of UC are increasing worldwide in recent years. Neferine is a natural alkaloid isolated from Nelumbo nucifera Gaertn that exerts a variety of biological activities. This study was designed to evaluate the protective effect of neferine on dextran sulfate sodium (DSS)-induced experimental UC in mice. Materials and Methods In this experimental study, 4% DSS was used to induce a mice model of UC. Neferine (5 and 10 mg/kg) was administered by intraperitoneal injection (ip). Clinical symptoms and disease activity index (DAI) scores were recorded and calculated. Pathological changes of colon tissues were detected by Hematoxylin and Eosin (H&E) staining. The levels of inflammatory mediators were detected by ELISA kits. Western blotting and immunohistochemical analysis were used for the evaluation of protein expressions. Results Neferine treatment significantly alleviated DSS-induced UC by inhibiting weight loss, decreasing DAI scores, and alleviating the pathological changes in colon tissues. Furthermore, neferine significantly decreased serum levels of pro-inflammatory cytokines including tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and IL-6 and increased serum levels of anti-inflammatory cytokine IL-10. The increased myeloperoxidase (MPO) activity and nitric oxide (NO) in colon tissues were also inhibited. In addition, neferine significantly down-regulated inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), and intercellular cell adhesion molecule-1 (ICAM-1) expression in colon tissues. ConclusionThese results provided evidence that neferine could protect against DSS-induced UC symptoms in an experimental mice model. This effect might be mediated through inhibition of inflammation.

Cryptotanshinone protects dextran sulfate sodium-induced experimental ulcerative colitis in mice by inhibiting intestinal inflammation.

The incidence of ulcerative colitis (UC) is increasing in recent years. The protective effect of cryptotanshinone, a natural compound from Salvia miltiorrhiza Bunge, on UC was investigated both in vivo and in vitro models. UC model was established by dextran sulfate sodium administration in drinking water and cryptotanshinone was orally administrated. RAW264.7 cells were stimulated by lipopolysaccharide (LPS) with or without cryptotanshinone pretreatment. The body weights and disease activity index (DAI) were recorded. The pathological alterations were evaluated by H&E staining. The levels of pro-inflammatory cytokines in colon tissues and cell culture medium were determined with enzyme-linked immune sorbent assay (ELISA) kits. The protein expression was detected by Western blotting and immunohistochemistry. Results showed that cryptotanshinone significantly increased the body weight and colon length, reduced the score of DAI, and improved pathological changes. Furthermore, the expression of inducible nitric oxide synthase, cyclooxygenase-2, receptor-interacting protein kinase 3, NF-κB p65 and the secretion of tumor necrosis factor-α, IL-6 in colon tissues and LPS-stimulated cells were significantly inhibited by cryptotanshinone. Besides, cryptotanshinone significantly inhibited LPS-triggered toll-like receptor 4 luciferase reporter activity with an IC50 at 7.2 μM. In conclusion, cryptotanshinone ameliorated experimental UC possibly by inhibiting intestinal inflammation.

Glucocorticoids Promote the Onset of Acute Experimental Colitis and Cancer by Upregulating mTOR Signaling in Intestinal Epithelial Cells.

The therapeutic effects of glucocorticoids on colitis and colitis-associated cancer are unclear. In this study, we investigated the therapeutic roles of glucocorticoids in acute experimental ulcerative colitis and colitis-associated cancer in mice and their immunoregulatory mechanisms. Murine acute ulcerative colitis was induced by dextran sulfate sodium (DSS) and treated with dexamethasone (Dex) at different doses. Dex significantly exacerbated the onset and severity of DSS-induced colitis and potentiated mucosal inflammatory macrophage and neutrophil infiltration, as well as cytokine production. Furthermore, under inflammatory conditions, the expression of the glucocorticoid receptor (GR) did not change significantly, while mammalian target of rapamycin (mTOR) signaling was higher in colonic epithelial cells than in colonic immune cells. The deletion of mTOR in intestinal epithelial cells, but not that in myeloid immune cells, in mice significantly ameliorated the severe course of colitis caused by Dex, including weight loss, clinical score, colon length, pathological damage, inflammatory cell infiltration and pro-inflammatory cytokine production. These data suggest that mTOR signaling in intestinal epithelial cells, mainly mTORC1, plays a critical role in the Dex-induced exacerbation of acute colitis and colitis-associated cancer. Thus, these pieces of evidence indicate that glucocorticoid-induced mTOR signaling in epithelial cells is required in the early stages of acute ulcerative colitis by modulating the dynamics of innate immune cell recruitment and activation.

Anti-Ulcerative Effect of Curcumin-Galactomannoside Complex on Acetic Acid-Induced Experimental Model by Inhibiting Inflammation and Oxidative Stress.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease that affects the mucosa and submucosa of colon. The pathogenesis of ulcerative colitis (UC) is related to reduced antioxidant capacity and increased inflammatory processes. Reactive oxygen metabolites are the potent inflammatory mediators that may be involved in tissue injury in inflammatory bowel disease. Conventional drug therapies for UC come with a myriad of side effects which further raise the need for natural bioactive agents. Curcumin has proven to be beneficial in the prevention and treatment of a number of inflammatory diseases, but due its poor bioavailability, thetherapeutic applications are limited. Thus, to enhance its bioavailability, a new formulation- curcumin-galactomannoside (CGM)- was made by complexing curcumin with galactomannans derived from fenugreek. The present study aims to evaluate the effects of CGM on experimental UC model. Adult male Wistar rats were divided into 5 groups: normal control rats (NC); ulcerative colitis control rats (UC); UC + sulfasalazine (SS) treated; UC + curcumin (CM) treated; and UC + CGM supplemented for 21days. The colonic mucosal injury was assessed by macroscopic and histological examination, along with evaluation of antioxidant status, inflammatory mediators, and gene expressions. Administration of CGM significantly enhanced antioxidant activities and decreased the level of inflammatory mediators and also suppressed the expression of inflammatory markers as compared with other groups. In conclusion, findings from these results reveal that CGM exerts marked curative effects on acute experimental colitis, possibly by regulating the antioxidant status and modulating inflammatory cascade.

Obacunone Protects Against Ulcerative Colitis in Mice by Modulating Gut Microbiota, Attenuating TLR4/NF-κB Signaling Cascades, and Improving Disrupted Epithelial Barriers.

Obacunone, a natural limonoid compound abundantly distributed in citrus fruits, possesses various biological properties, such as antitumor, antioxidant, and antiviral activities. Recent studies suggested an anti-inflammatory activity of obacunone in vitro, but its efficacy on intestinal inflammation remains unknown. This study was designed to evaluate the effects and mechanisms of obacunone in ameliorating intestinal inflammation in a mouse model of ulcerative colitis (UC). We found that obacunone efficiently alleviated the severity of dextran sulfate sodium (DSS)-induced mouse UC by modulating the abnormal composition of the gut microbiota and attenuating the excessive activation of toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) signaling. The intestinal epithelial barrier was disrupted in DSS colitis mice, which was associated with activation of inflammatory signaling cascades. However, obacunone promoted the expression of tight junction proteins (TJP1 and occludin) and repressed the activation of inflammatory signaling cascades. In summary, our findings demonstrated that obacunone attenuated the symptoms of experimental UC in mice through modulation of the gut microbiota, attenuation of TLR4/NF-κB signaling cascades, and restoration of intestinal epithelial barrier integrity.

Flos lonicerae flavonoids attenuate experimental ulcerative colitis in rats via suppression of NF-κB signaling pathway.

This study sought to isolate active Flos lonicerae flavonoids and evaluate their anti-oxidative and anti-inflammatory effects as well as investigate the molecular mechanistic action of these flavonoids in the rat model of ulcerative colitis (UC). Total flavonoids and three flavonoids (hyperoside, lonicerin, and luteolin) were isolated from honeysuckle and purified via column purification. Rat model of UC was established via 2,4,6-trinitrobenzene sulfonic acid (TNBS) intoxication. The anti-oxidative and anti-inflammatory effects of the three flavonoids against TNBS-induced UC were evaluated by measuring appropriate biomarkers via assay kit. The effects of hyperoside, lonicerin, and luteolin on the regulation of nuclear factor-kappa B (NF-κB) pathway were investigated using Western blot (WB) and real-time polymerase chain reaction (RT-PCR) while their protective effects on UC were also elucidated. Pretreatment with flavonoids (hyperoside, lonicerin, and luteolin at 25-100mg/kg) and sulfasalazine (SSZ, positive control at 100mg/kg) substantially attenuated TBNS-induced UC. Also, the flavonoids significantly reduced the levels of respective serum oxidative and proinflammatory markers such as superoxide dismutase (SOD), myeloperoxidase (MPO), malondialdehyde (MDA), prostaglandins E2 (PGE2), tumor necrosis factor-alpha (TNF-α), interleukin-beta (IL-β), and C-reactive protein (CRP). In addition, the flavonoids remarkably inhibited the expression of NF-κB signaling pathway. F. lonicerae flavonoids (hyperoside, lonicerin, and luteolin) demonstrated potent anti-UC activities in TBNS-induced UC rat model via anti-oxidative and anti-inflammatory effects through the inhibition of NF-κB signaling pathway.

Circulating S100A8/A9 is potentially a biomarker that could reflect the severity of experimental colitis in rats

AimsThe clinical significance of circulating S100A8/A9 (calprotectin) in patients with ulcerative colitis (UC) is poorly understood. We examined whether serum S100A8/A9 is a good biomarker for UC, and whether the serum level is a useful index for the severity of the disease. Main methodsExperimental animal (rats) were used to verify clinical significance of serum S100A8/A9 as a biomarker. Rats treated with 5% dextran sulfate sodium (DSS) alone (UCR) or with 5%DSS plus tacrolimus (TMR) were subjected to the experiment. The serum concentrations of rat S100A8/A9 (r-S100A8/A9) and other inflammatory biomarkers, such as C-reactive protein (CRP) and inflammatory cytokines, in the both groups were measured using enzyme-linked immunosorbent assays (ELISAs). The tissue damage in the large intestinal tract was visualized by hematoxylin-eosin staining. The relationship between the serum concetrations of these inflammatory biomarkers and the histological scores of the rectal tissue was statistically analyzed. Principle findingsAs determined by the ELISAs, the serum concentration of r-S100A8/A9 in the UCR hardly correlated with those of not only CRP but also some inflammatory cytokines. The deterioration of the rectal tissue, mainly epithelium structure of a large intestine, in the UCR was clearly observed, but was not so severe as that in the TMR. The histological scores of the rectal tissue in the UCR significantly correlated with the serum level of r-S100A8/A9, but not with other inflammatory biomarkers. Furthermore, macrophages actively produced r-S100A8/A9 in response to stimulation with lipopolysaccharide and quickly secreted it in circulation. Therefore, the serum level of r-S100A8/A9 suggestively changes in accordance with the severity of experimental UC. ConclusionCirculating r-S100A8/A9 is a useful biomarker for experimental UC, and its serum level correlates with the disease severity as judged by histological score.

Sex differences of subpopulation composition of lymphocytes in the peripheral blood in experimental acute and chronic ulcerative colitis

We studied sex differences lymphocytes subpopulations of peripheral blood in adult C57Bl/6 mice during acute and chronic colitis, induced with 1% DSS. We measured subpopulations of lymphocytes with flow cytometry. We showed that in the control group the female mice had statistically significantly higher values of the relative number of regulatory and cytotoxic T lymphocytes comparing to the males. During acute colitis the females showed an increase in the relative number of Thelpers and a decrease of cytotoxic Tlymphocytes, which reflects the activation of immune response. The males had a decrease in the absolute number of leukocytes, lymphocytes and cytotoxic and regulatory T lymphocytes, probably because of an increase in migration of these cells to the inflammation locus and local lymph nodes. In chronic colitis the females had a decrease in the absolute number of leukocytes, lymphocytes, T helpers, cytotoxic T lymphocytes and B lymphocytes when comparing with acute colitis. During chronic colitis the males had a decrease in the absolute number of T helpers and B lymphocytes but an increase of regulatory T cells in comparison with the control group; in comparison with acute colitis the males with chronic colitis had higher relative and absolute number of regulatory T cells. The increase of T regulatory lymphocytes is due to an increase in their proliferation rate in the thymus and increase of their migration to the inflammatory locus – the colon. Future clinical studies may be based on these results, which show that the treatment of colitis, especially with immunotropic agents, must take sex differences into account.

Rho kinase Blockade Ameliorates DSS-Induced Ulcerative Colitis in Mice Through Dual Inhibition of the NF-κB and IL-6/STAT3 Pathways.

Inflammatory bowel disease (IBD) has received much attention due to its increasing worldwide incidence and potential increased risk of colorectal cancer. The protective function of a Rho-associated protein kinase inhibitor (Y-27632) against 2,4,6-trinitrobenzene sulfonic acid (TNBS) induced mouse colitis has been proven in previous studies, but the concrete therapeutic mechanism of Y-27632 is still not completely illuminated. This current research is intended for further investigation of the effect and mechanism of Y-27632 in a mouse model of acute experimental ulcerative colitis induced by dextran sulfate sodium (DSS). A total of 24 male BALB/c mice were randomly separated into the following three groups (n = 8 per group) and injected intraperitoneally with the corresponding reagents for 7days: control group (PBS), DSS group (PBS), and Y-27632 group (PBS and Y-27632; 10mg/kg). Our data indicated that Y-27632 could significantly improve the severity of colitis, as evidenced by the disease activity index (DAI) scores, histological damage, and colon length. Additionally, Y-27632 treatment significantly decreased CD68 and proinflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-17F (IL-17F), and interleukin-6 (IL-6). Furthermore, Y-27632 potently and pleiotropically suppressed nuclear factor-κB (NF-κB) and signal transduction and transcriptional activator 3 (STAT3) activation as well as the activity of prosurvival genes that are dependent on these transcription factors. In summary, the study demonstrates that Y-27632 exerts ameliorative effects on colonic inflammation mediated through dual inhibition of the NF-κB and IL-6/STAT3 pathways and thus is likely to function as a prospective novel treatment for human ulcerative colitis (UC).

Aqueous extract of Bruguiera gymnorrhiza leaves protects against dextran sulfate sodium induced ulcerative colitis in mice via suppressing NF-κB activation and modulating intestinal microbiota.

Ulcerative colitis (UC) is tightly associated with inflammation response and oxidative stress. As a folk medicine applied in treatment of diarrhea, Bruguiera gymnorrhiza also possesses anti-inflammatory and anti-oxidative activities, which indicated that B. gymnorrhiza may exert anti-colitis effect. To investigate effect and mechanism of B. gymnorrhiza on experimental UC. Aqueous extract of B. gymnorrhiza leaves (ABL) was used for investigation in the present study. Murine UC was established through access to 3% dextran sulfate sodium (DSS) for 7 days. Meanwhile, mice accepted treatment with ABL (25, 50, 100mg/kg) or sulfasalazine (200mg/kg) once daily. On the last day, disease activity index (DAI) including body weight loss, fecal character and degree of bloody diarrhea was evaluated, colon segments were obtained for length measurement and further analysis and feces were collected for intestinal microbiota analysis. ABL ameliorated DAI scores, colon length shortening and histopathological damage in DSS-induced colitis mice obviously. SOD activity, levels of MDA and GSH altered by colitis were restored remarkably after ABL treatment. ABL inhibited increases in levels of colonic COX-2, iNOS, TNF-α, IL-6, IL-1β, IL-4, IL-10 and IL-11 in colitis mice. Moreover, ABL prominently suppressed NF-κB p65 and IκB phosphorylation and down-regulated mRNA levels of COX-2, iNOS, TNF-α, IL-6 and IL-1β elevated by colitis. As shown in microbiota analysis, ABL modulated composition of intestinal microbiota of colitis mice. ABL exhibited protective effect against DSS-induced ulcerative colitis through suppressing NF-κB activation and modulating intestinal microbiota.

Влияние витамина D3 в составе оригинальных ректальных суппозиториев на показатели окислительной модификации белков в толстом кишечнике при экспериментальном язвенном колите

Влияние витамина D3 в составе оригинальных ректальных суппозиториев на показатели окислительной модификации белков в толстом кишечнике при экспериментальном язвенном колите

Role of dietary maize formulations in the healing of experimental acetic acid induced ulcerative colitis in male rats.

Dietary factors do not only contribute to remission of diseases but also play important roles in the progression of medical conditions. We investigated the effect of different formulations of maize diets on the healing of experimental acetic acid-induced ulcerative colitis (UC) in male rats. Thirty-five (35) male Wistar rats (150-170 g) were randomly divided into control (CTR), UC, UC + high maize diet (HMD), UC + low maize diet (LMD), and UC + maize-free diet (MFD) groups. CTR, UC, UC + HMD, UC + LMD, and UC + MFD groups were administered different formulations of dietary maize ranging from 0% to 70%. Body weight change (BWC), colon weight, macroscopic ulcer score, catalase, glutathione (GSH), tumor necrosis factor-α (TNF-α), myeloperoxidase, diarrhea score, superoxide dismutase (SOD), Ki-67 expression, and histological studies were done. Results were analyzed using SPSS 23. UC + LMD and UC + MFD groups showed a duration-dependent reduction in negative BWC, respectively. When compared with UC group, UC + LMD and UC + MFD significantly increased (P < 0.05) GSH and SOD respectively but had no effect on TNF-α and diarrhea score. UC + HMD increased diarrhea and macroscopic ulcer scores with Ki-67 expression highest in UC + MFD. The study indicated that consumption of either LMD or maize-free diet by colitic rats relatively enhanced healing of UC.

NCoR1 Protects Mice From Dextran Sodium Sulfate-Induced Colitis by Guarding Colonic Crypt Cells From Luminal Insult.

Background & AimsColonic stem cells are essential for producing the mucosal lining, which in turn protects stem cells from insult by luminal factors. Discovery of genetic and biochemical events that control stem cell proliferation and differentiation can be leveraged to decipher the causal factors of ulcerative colitis and aid the development of more effective therapy.MethodsWe performed in vivo and in vitro studies from control (nuclear receptor corepressor 1 [NCoR1F/F]) and intestinal epithelial cell–specific NCoR1-deficient mice (NCoR1ΔIEC). Mice were challenged with dextran sodium sulfate to induce experimental ulcerative colitis, followed by colitis examination, barrier permeability analysis, cell proliferation immunostaining assays, and RNA sequencing analysis. By using crypt cultures, the organoid-forming efficiency, cell proliferation, apoptosis, and histone acetylation were analyzed after butyrate and/or tumor necrosis factor α treatments.ResultsNCoR1ΔIEC mice showed a dramatic increase in disease severity in this colitis model, with suppression of proliferative cells at the crypt base as an early event and a concomitant increase in barrier permeability. Genome expression patterns showed an important role for NCoR1 in colonic stem cell proliferation and secretory cell differentiation. Colonic organoids cultured from NCoR1ΔIEC mice were more sensitive to butyrate-induced cell growth inhibition and apoptosis, which were exaggerated further by tumor necrosis factor α co-treatment, which was accompanied by increased histone acetylation.ConclusionsNCoR1 regulates colonic stem cell proliferation and secretory cell differentiation. When NCoR1 is disrupted, barrier protection is weakened, allowing luminal products such as butyrate to penetrate and synergistically damage the colonic crypt cells. Transcript profiling: RNA sequencing data have been deposited in the GEO database, accession number: GSE136153.

Synthesis and evaluation of a prodrug of 5-aminosalicylic acid for the treatment of ulcerative colitis.

Objective(s):This study is aimed to design and synthesize a prodrug of 5-aminosalicylic acid and evaluate its ameliorative effect on experimental ulcerative colitis (UC).Materials and Methods:5-Aminosalicylic acid-alanine (5-ASA-ALA) was synthesized and characterized. Its stability study was conducted in rat plasma and in the gastrointestinal tract environment, its transport characteristic was assessed using the Caco-2 cells. Its colon-targeting property was evaluated by the pharmacokinetic study, and incubation studies. A series of indicators were used to investigate its therapeutic effect on experimental colitis, including the survival rate and body weight of mice, the disease activity index (DAI), the colonic damage score and colon index, the myeloperoxidase (MPO) activity and the levels of malondialdehyde (MDA), total superoxide dismutase (SOD), glutathione (GSH) and glutathione peroxidase (GSH-Px) in colonic tissues.Results:5-ASA-ALA was barely absorbed in the Caco-2 monolayer or into the rat blood. It was remarkably stable when incubated in the upper gastrointestinal tract, while gradually hydrolyzed in the colon of rats. When orally administered to mice, 5-ASA-ALA had significantly greater therapeutic effect on colitis than the positive control. Conclusion:5-ASA-ALA is demonstrated to be a promising oral colon-targeting prodrug of 5-ASA and has potential application in UC treatment.

SUPPRESSION OF GHRELIN SIGNALING EXACERBATES ULCERATIVE COLITIS IN OLDER MICE

The aging process is characterized by increased chronic low-grade inflammation, aka inflamm-aging, which offend is accompanied by ‘leaky gut’ syndrome. Inflamm-aging is a highly significant risk factor for both morbidity and mortality in the older adult population (>65 years of age). In addition, there is a growing prevalence of inflammatory bowel disease (IBD), a chronic inflammatory condition of the gastrointestinal tract in the older adult population. The pathogenesis of late-onset IBD is suggested to be more complex compared with younger IBD patients; the causes determining the age of IBD onset remain unexplained. Ghrelin is a 28-amino-acid peptide hormone mainly produced by X/A-like cells of the stomach, with well-characterized functions in growth hormone secretion, food intake, adiposity and insulin resistance. Ghrelin’s biological relevant receptor is Growth Hormone Secretagogue Receptor (GHS-R). Ghrelin and ghrelin mimetics have been considered viable candidates for treating cachexia, sarcopenia, and gastrointestinal disorders. As expected, we observed that the expression of tight junction proteins in colon mucosal layer decreases with age. When challenged with dextran sulfate sodium (DSS) to induce experimental ulcerative colitis, 18-months old male C57BL/6 mice exhibited exacerbated disease activity scores compared to young male mice (5-months), showing worsened pathology such as rectal bleeding and difficulty in defecation. DSS-induced colitis was exacerbated in both ghrelin-deficient (Ghrl-/-) and ghrelin receptor-deficient (Ghsr-/-) mice. Together, these data suggest endogenous ghrelin signaling contributes to susceptibility to colitis, and ghrelin signaling pathway may present a novel target for prevention and treatment of leaky gut syndrome in aging.