Gilaburu (Viburnum opulus L.) fruit extract has potential therapeutic and prophylactic role in a rat model of acetic acid-induced oxidant colonic damage.

ETHNOPHARMACOLOGICAL RELEVANCE: Ulcerative colitis (UC) which has a global impact on the health care system with its recurrent and incompletely curable characteristics, affects the patients' quality of life. Gilaburu (GB; Viburnum opulus L.) is a fruit with rich polyphenol ingredient which is used ethnobotanically in Türkiye for medicinal purposes (for example, to pass kidney stones, to treat stomach, heart, and liver diseases, hemorrhages, hypertension, ulcers, common cold, tuberculosis, rheumatic and menstrual pain, and diabetes). On the other hand, the effects of GB in the experimental UC model have not been studied. AIM OF THE STUDY: This study aimed to explore the potential antioxidant and anti-inflammatory effects of GB fruit extract in improving acetic acid (AA)-induced UC. MATERIALS AND METHODS: Starting immediately after (AA + GB group) or 1 week before (GB + AA + GB group) the colitis induced by intrarectal AA (5%; v/v) administration, the rats orally received GB (100 mg/kg) once per day for 3 days. The control and AA groups were administered orally saline (1 ml), while the AA + SS group were administered sulfasalazine (SS; 100 mg/kg; orally) as a positive control once per day for 3 days. Distal colonic tissue specimens were obtained for the histological and biochemical [myeloperoxidase (MPO), malondialdehyde (MDA), glutathione (GSH), chemiluminescence (CL), caspase-3, 8-hydroxy-2'-deoxyguanosine (8-OHdG), matrix metalloproteinase (MMP)-9, transforming growth factor (TGF)-ß1, smad-3 and cytokine (tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, IL-8, interferon (IFN)-γ), measurements] evaluations on the 3rd day. RESULTS: Elevated macroscopic and microscopic damage scores, high tissue wet weight values, increased tissue-associated MPO, MDA, CL, caspase-3, 8-OHdG, cytokines (TNF-α, IL-1ß, IL-6, IL-8), MMP-9, TGF-ß1, smad-3 levels, and decreased GSH values of the AA group were all reversed by GB treatments (AA + GB and GB + AA + GB groups) (p < 0.05-0.001). However, sulfasalazine treatment (AA + SS group) did not change the IL-8, 8-OHdG, MMP-9, and TGF-ß1 measurements significantly. CONCLUSIONS: Gilaburu shows both anti-inflammatory and antioxidant effects against AA-induced colonic damage by suppressing neutrophil infiltration, regulating inflammatory mediators, inhibiting reactive species production, lipid peroxidation, and apoptosis, conserving endogenous antioxidant glutathione, and ameliorating oxidative DNA damage. Since the current ulcerative colitis drugs display limited benefits and adverse side effects, potential therapeutic and/or prophylactic role of gilaburu can be evaluated in ulcerative colitis.

Chemical components and protective effects of Atractylodes japonica Koidz. ex Kitam against acetic acid-induced gastric ulcer in rats.

BACKGROUND: Atractylodes japonica Koidz. ex Kitam. (A. japonica, Chinese name: Guan-Cangzhu, Japanese name: Byaku-jutsu), a perennial herb, which is mainly distributed in northeast area of China, it's often used to treat digestive system diseases such as gastric ulcer (GU). However, the mechanism of its potential protective effects against GU remains unclear. AIM: To investigate the protective effects of A. japonica on acetic acid-induced GU rats. METHODS: The chemical constituents of A. japonica were determined by ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) analysis. The rat model of GU was simulated by acetic acid method. The pathological changes of gastric tissues were evaluated by hematoxylin-eosin stain, the levels of epidermal growth factor (EGF), EGF receptor (EGFR), nuclear factor kappa-B (NF-κB), interleukin-1ß (IL-1ß), IL-10, Na+-K+-ATPase (NKA) in serum and gastric tissues were determined by enzyme-linked immunosorbent assay, and the mRNA expressions of EGFR, NF-κBp65, IkappaBalpha (IκBα) and Zonula Occludens-1 (ZO-1) in gastric tissues were determined by real-time reverse transcription polymerase chain reaction, and the efficacy was observed. Then, plasma metabolomic analysis was performed by UPLC-MS/MS to screen the specific potential biomarkers, metabolic pathways and to explore the possible mechanisms. RESULTS: 48 chemical constituents were identified. Many of them have strong pharmacological activity, the results also revealed that A. japonica significantly improved the pathological damage of gastric tissues, increased the expression levels of IL-10, IκBα related to anti-inflammatory factors, decreased the expression levels of IL-1ß, NF-κB, NF-κBp65, related to proinflammatory factors, restored the levels of factors about EGF, EGFR, ZO-1 associated with ulcer healing and the levels of factors about NKA associated with energy metabolism. Metabolomic analysis identified 10 potential differential metabolites and enriched 7 related metabolic pathways. CONCLUSION: These findings contribute to the understanding of the potential mechanism of A. japonica to improve acetic acid-induced GU, and will be of great importance for the development and clinical application of natural drugs related to A. japonica.

Genistein and/or sulfasalazine ameliorate acetic acid-induced ulcerative colitis in rats via modulating INF-γ/JAK1/STAT1/IRF-1, TLR-4/NF-κB/IL-6, and JAK2/STAT3/COX-2 crosstalk.

Ulcerative Colitis (UC) is a chronic idiopathic inflammatory bowel disease in which the colon's lining becomes inflamed. Exploring herbal remedies that can recover mucosal damage is becoming popular in UC. The study aims to investigate the probable colo-protective effect of a natural isoflavone, genistein (GEN), and/or a drug, sulfasalazine (SZ), against acetic acid (AA)-induced UC in rats, in addition to exploring the possible underlying mechanisms. UC was induced by the intrarectal installation of 1-2 ml of 5% diluted AA for 24 h. Ulcerated rats were allocated into the disease group and three treated groups, with SZ (100 mg/kg), GEN (100 mg/kg), and their combination for 14 days, besides the control groups. The anti-colitic efficacy of GEN and/or SZ was evidenced by hindering the AA-induced weight loss, colon edema, and macroscopic scores, besides reduced disease activity index and colon weight/length ratio. Furthermore, treatments attenuated the colon histopathological injury scores, increased the number of goblet cells, and lessened fibrosis. Both treatments reduced the up-regulation of INF-γ/JAK1/STAT1 and INF-γ /TLR-4/ NF-κB signaling pathways and modulated the IRF-1/iNOS/NO and IL-6/JAK2/STAT3/COX-2 pathways and consequently, reduced the levels of TNF-α and IL-1ß. Moreover, both treatments diminished oxidative stress, which appeared by reducing the MPO level and elevating the SOD activity, and hindered apoptosis; proved by the decreased immunohistochemical expression of caspase-3. The current findings offer novel insights into the protective effects of GEN and suggest a superior benefit of combining GEN with SZ, over either drug alone, in the UC management.

Mirabegron alleviates acetic acid-induced colitis in rats: Role of adiponectin and GSTM1/GSH detoxification pathway.

The prevalence of the debilitating chronic disease ulcerative colitis (UC) is increasing significantly. Mirabegron is a selective beta-3 adrenergic receptor (ß-3 AR) agonist used to treat an overactive bladder. Previous reports have demonstrated the antidiarrheal effect of ß-3AR agonists. Therefore, the current study aims to investigate the potential symptomatic effects of mirabegron on an experimental colitis model. The effects of oral administration of mirabegron (10 mg/kg) for seven days on rats receiving intra-rectal acetic acid instillation on the sixth day were examined using adult male Wistar rats. Sulfasalazine was utilized as a reference medication. Gross, microscopic, and biochemical observations of the experimental colitis were performed. The quantity and mucin content of goblet cells were found to have significantly decreased in the colitis group. In the colons of rats administered mirabegron, the number of goblet cells and the optical density of its mucin content increased. Mirabegron's ability to increase adiponectin in serum and decrease glutathione, GSTM1, and catalase in the colon may account for its protective effects. In addition, mirabegron decreased the expression of the proteins caspase-3 and NF-κB p65. It also prevented the activation of their upstream signaling receptors TLR4 and p-AKT by acetic acid administration. In conclusion, mirabegron prevented acetic acid-induced colitis in rats, possibly due to its antioxidant, anti-inflammatory, and antiapoptotic properties.

Acetic acid-induced colitis modulating potential of total crude alkaloidal extract of Picralima nitida seeds in rats.

PURPOSE: The total crude alkaloidal extract of Picralima nitida seeds (PNE) is known to possess anti-inflammatory activity among other therapeutic benefits although its benefits in colitis has not been investigated. The current study therefore seeks to investigate the anti-colitis potential of PNE using acetic acid-induced colitis model in rats. METHODS: Sprague Dawley rats were treated with oral 500 mg/kg sulphasalazine or 30, 100, and 300 mg/kg of PNE daily for 8 days with induction of colitis on the fourth day with acetic acid. Rats were killed 24 h after the last treatment and whole blood was obtained from the jugular vein for hematological analysis and biochemical assays. Colons were extirpated for assessment of macroscopic and histological damage to the colon. RESULTS: Treatment with PNE protected against colonic injury induced with acetic acid by decreasing mucosal ulceration, epithelial erosion, inflammatory cell infiltration, and colonic edema. Thus, PNE preserved mucosal architecture and suppressed goblet cells depletion. Moreover, treatment with PNE was associated with improved hematological parameters and reductions in the expression of serum tumor necrosis factor-alpha, interleukin-1ß, and p38 mitogen-activated protein kinase. Also, PNE treatment exerted antioxidant effects by reducing nitric oxide production and increasing glutathione levels. In addition, PNE inhibited colonic lipid peroxidation by decreasing myeloperoxidase activity and malondialdehyde production. CONCLUSION: It can be concluded that PNE attenuates intestinal oxidative and inflammatory damages following intrarectal acetic acid challenge. Thus, demonstrates potential for use in chronic intestinal inflammatory diseases such as ulcerative colitis.

Therapeutic and prophylactic role of vitamin D and curcumin in acetic acid-induced acute ulcerative colitis model.

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-1ß, 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 (p < 0.05). TNF-α and IFN-γ levels decreased and Occludin levels increased in colon tissue of Post-Vit D group compared to colitis group (p < 0.05). IL-1ß, IL-6 and IFN-γ levels were decreased in colon tissue of Post-Cur and Pre-Cur groups (p < 0.05). MPO levels in colon tissue decreased in all treatment groups (p < 0.05). Vitamin D and Curcumin treatment significantly reduced inflammation and restored the normal histoarchitecture of the colon. From the present study findings, we can conclude that Vitamin D and Curcumin protect the colon from acetic acid toxicity with their antioxidant and anti-inflammatory potential.Brief synopsis: In this study; distal colon, distal ileum, jejunum and serum physiopathology in colitis induced by acetic acid and intestinal permeability were investigated. The roles of vitamin D and curcumin in this process were evaluated.

Cotinus coggygria Scop. Attenuates Acetic Acid-Induced Colitis in Rats by Regulation of Inflammatory Mediators.

In traditional medicine, many medicinal plants are used in the treatment of various diseases caused by inflammation. The objective of the present study is to elucidate for the first time the effects of Cotinus coggygria (CC) ethanol extract (CCE) on colonic structure and inflammation of acetic acid-induced ulcerative colitis in rats. Colonic damage was assessed using disease activity index score, enzyme-linked immunosorbent assay, and hematoxylin-eosin staining. Also, in vitro antioxidant activity of CCE was investigated by ABTS methods. Total phytochemical content of CCE was measured spectroscopically. Acetic acid caused colonic damage according to disease activity index and macroscopic scoring. CCE significantly reversed these damages. While the levels of proinflammatory cytokines TNF-alpha, IL-1beta, IL-6, and TGF-1beta increased in tissue with UC, IL-10 level decreased. CCE increased inflammatory cytokine levels to values close to the sham group. At the same time, while markers indicating disease severity such as VEGF, COX-2, PGE2, and 8-OHdG indicated the disease in the colitis group, these values returned to normal with CCE. Histological research results support biochemical analysis. CCE exhibited significant antioxidant against ABTS radical. Also, CCE was found to have a high content of total polyphenolic compounds. These findings provide evidence that CCE might be benefit as a promising novel therapy in the treatment of UC in humans due to high polyphenol content and justify the use of CC in folkloric medicine for treatment of inflamed diseases.

Losartan attenuates acetic acid enema-induced visceral hypersensitivity by inhibiting the ACE1/Ang II/AT1 receptor axis in enteric glial cells.

Enteric glial cells (EGCs) play an important role in visceral hypersensitivity associated with irritable bowel syndrome (IBS). Losartan (Los) is known to reduce pain; however, its function in IBS is unclear. The present study aimed to investigate Los's therapeutic effect on visceral hypersensitivity in IBS rats. Thirty rats were randomly divided into control, acetic acid enema (AA), AA + Los low, medium and high dose groups in vivo. EGCs were treated with lipopolysaccharide (LPS) and Los in vitro. The molecular mechanisms were explored by assessing the expression of EGC activation markers, pain mediators, inflammatory factors and angiotensin-converting enzyme 1(ACE1)/angiotensin II (Ang II)/Ang II type 1 (AT1) receptor axis molecules in colon tissue and EGCs. The results showed that the rats in the AA group showed significantly higher visceral hypersensitivity than the control rats, which was alleviated by different doses of Los. The expression of GFAP, S100ß, substance P (SP), calcitonin gene-related peptide (CGRP), transient receptor potential vanilloid 1 (TRPV1), tumor necrosis factor (TNF), interleukin-1ß (IL-1ß) and interleukin-6 (IL-6) was considerably increased in colonic tissues of AA group rats and LPS-treated EGCs compared with control rats and EGCs, and reduced by Los. In addition, Los reversed ACE1/Ang II/AT1 receptor axis upregulation in AA colon tissues and LPS-treated EGCs. These results show that Los inhibits ACE1/Ang II/AT1 receptor axis upregulation by suppressing EGC activation, resulting in reduced expression of pain mediators and inflammatory factors, thereby alleviating visceral hypersensitivity.

Neuroprotective effects of methyl jasmonate in male Wistar rats exposed to delayed acetic acid-induced ulcerative colitis: involvement of antioxidant status, GFAP, and IBA-1 immunoreactivities.

Neurobehavioral deficits have been severally reported as a comorbid outcome in inflammatory bowel diseases (IBDs). This study evaluated neurological changes in the experimental model of IBDs, as well potential protective effects of methyl jasmonate (MJ). The study used the acetic acid model of colitis and thereafter delayed the healing process by the administration of indomethacin (Indo) (2 mg/kg, SC). Thirty male Wistar rats (120-160 g) were divided into 5 groups (n = 6). Control, Colitis, Colitis + Indo, MJ (50 mg/kg, IP) + Colitis and MJ + Colitis + Indo. Colitis was induced by intrarectal administration of 2 mL, 4% acetic acid. Neurobehavioral studies were carried out to assess memory function, depression, and anxiety on day 7 of post-colitis induction. Animals were thereafter sacrificed to collect the brain tissues for routine histology, immunoreactivity of GFAP and IBA-1, and biochemical assays. Neurobehavioral tests showed anxiety, depression, and memory deficits, especially in the Colitis + Indo group which were accompanied by increased IBA-1 and GFAP count. MJ reversed these effects and reduced GFAP count in the hippocampus and amygdala as well as IBA-1 count in the hippocampus, amygdala, and cortex. Histological observations of these areas showed no significant histopathological changes across all groups. GPx and CAT levels were significantly reduced, while MPO was significantly increased in colitis and Colitis+indo groups when compared with control, which was attenuated in groups administered with MJ. These findings tuggest that MJ possesses neuroprotective, anti-oxidant, and neuron-regeneration properties. Therefore, it could be considered as a potential treatment for behavioral deficits associated with ulcerative colitis.

A Chemically Induced Experimental Colitis Model with a Simple Combination of Acetic Acid and Trinitrobenzene Sulphonic Acid.

BACKGROUND: It was aimed to induce a new experimental colitis model by using acetic acid and trinitrobenzene sulphonic acid together and to investigate the severity of inflammation biochemically and histopathologically in comparison with other models. METHODS: Fifty-six Wistar albino male rats were randomly divided into 4 groups as control, acetic acid, trinitrobenzene sulphonic acid, and combined groups, and the animals were sacrificed following the induction of colitis on the third day and on the seventh day. The serum amyloid A and myeloperoxidase were tested in plasma samples, and the tumor necrosis factor-alpha, interleukin 33, and ST2 were assayed in colon tissue samples with enzyme-linked immunosorbent assay in addition to histopathological examination. RESULTS: There were statistically significant differences between the combined and the control groups both on the third day and on the seventh day in all parameters. There was no difference between the acetic acid group on the seventh day and the control groups in biochemical parameters. CONCLUSIONS: The acetic acid model forms acute colitis. The combined model is found to be more successful in forming inflammation when compared to other models.

Integrated Metabolomics and Network Pharmacology to Decipher the Latent Mechanisms of Protopanaxatriol against Acetic Acid-Induced Gastric Ulcer.

Gastric ulcer (GU) is a peptic disease with high morbidity and mortality rates affecting approximately 4% of the population throughout the world. Current therapies for GU are limited by the high relapse incidence and side effects. Therefore, novel effective antiulcer drugs are urgently needed. Ginsenosides have shown good anti-GU effects, and the major intestinal bacterial metabolite of ginsenosides, protopanaxatriol (PPT), is believed to be the active component. In this study, we evaluated the anti-GU effect of PPT in rats in an acetic acid-induced GU model. High (H-PPT) and medium (M-PPT) doses of PPT (20.0 and 10.0 mg/mg/day) significantly reduced the ulcer area and the ET-1, IL-6, EGF, SOD, MDA and TNF-α levels in serum were regulated by PPT in a dose-dependent manner. We also investigated the mechanisms of anti-GU activity of PPT based on metabolomics coupled with network pharmacology strategy. The result was that 16 biomarkers, 3 targets and 3 metabolomic pathways were identified as playing a vital role in the treatment of GU with PPT and were further validated by molecular docking. In this study, we have demonstrated that the integrated analysis of metabolomics and network pharmacology is an effective strategy for deciphering the complicated mechanisms of natural compounds.

Anxiolytic and anti-colitis effects of Moringa oleifera leaf-aqueous extract on acetic acid-induced colon inflammation in rat.

Moringa oleifera decoction is believed to alleviate gastrointestinal tract diseases. This study investigated antioxidant and anxiolytic activities of its leaves aqueous extract on acetic acid-induced colitis in rats. Rats (36) were randomly divided into six groups and received (20 days) distilled water, 10 mL/kg; Moringa oleifera leaf-aqueous extract (25, 50, and 100 mg/kg) or Loperamide (5 mg/kg). On days 1, 8, 17, and 20, behavioral parameters were evaluated. Colitis was induced (day 15, except in normal group) through acetic acid (4%, 1 mL) intra-rectal administration. After sacrifice (day 21), lesion number, weight/length ratio of the colon were recorded. Oxidative stress biomarkers were evaluated. On day 20, Moringa oleifera (100 mg/kg) reduced the number of head dipping and the duration in opened arms, respectively 2.00 ± 0.37 and 5.00 ± 0.37 s against 14.50 ± 0.72 and 2.17 ± 0.48 s in the control. It decreased colon weight/length ratio: 112.29 ± 9.46 against 185.93 ± 5.28 mg/cm in the control; malondialdehyde level (P < 0.01) and nitric oxide concentration (P < 0.001), in the brain: respectively 25.60 ± 0.60 and 36.34 ± 1.19 against 34.00 ± 0.33 and 46.17 ± 3.25 µmol/mg of tissue in the control. In the serum, the extract (50 mg/kg) significantly (P < 0.05) increased the catalase activity (0.10 ± 0.00 against 0.03 ± 0.00 µmol/mg of protein in the negative control group). At 100 mg/kg, it increased (P < 0.001) reduced glutathione concentration to 5.07 ± 0.31 against 3.26 ± 0.08 µmol/mg of protein in the negative control group. The improvement on colitis pathophysiology, the antioxidant and the anxiolytic effects noted therefore suggest that Moringa oleifera can be a potential source of drugs alleviating anxiety and oxidative stress associated to ulcerative colitis.

"Theranekron: A Novel Anti-inflammatory Candidate for Acetic Acid-Induced Colonic Inflammation in Rats".

BACKGROUND: Inflammatory bowel disease (IBD) is characterized with chronic inflammation of gastrointestinal track. In the pathogenesis of IBD, inflammation is the main mechanism. Induction of inflammation triggers the oxidative stress that subsequently leading to apoptosis. Considering the all pathological mechanisms, many therapeutic agents have been used for IBD but because of serious side effects there is still a need for new therapeutic drugs. In this study, we aim to evaluate the possible protective effects of Theranekron (TH) on acetic acid (AA)- induced colonic damage and to describe the probable effect mechanisms of TH. MATERIALS AND RESULTS: Fourty female adult Wistar albino rats were divided into 5 groups. Following 24 h fasting, colitis was induced by rectal instillation of AA. In TH group, a single dose of subcutaneous 0.2 ml TH was used. In treatment groups, 0.2 ml TH single dose or 100 mg/kg sulfasalazine (SS) for 7 days were used after colitis induction. Normal salin was used for all applications in control group. Histopathologically hemorrhage, edema and inflammatory reactions were seen in AA group. TH and SS decreased the severity of lesions. Nuclear factor kappa B, Serum amyloid A, C-reactive protein, Growth-related oncogene, and Osteopontin expressions were markedly increased in AA group and TH markedly reduced these expressions. In Western analysis, decreased NF-kB and caspase-3 levels were observed with TH. Oxidative markers did not changed significantly. CONCLUSIONS: TH has a prominent anti-inflammatory effect on AA-induced colonic inflammation via NF-kB signaling whereas antiapoptic effects seem to be independent from this pathway.

Myrica salicifolia Hochst. ex A. Rich. suppress acetic acid-induced ulcerative colitis in rats by reducing TNF-alpha and interleukin-6, oxidative stress parameters and improving mucosal protection.

Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) with rising prevalence in developing countries, and limited success of current therapies, natural products have immense potential for therapy due to their "disease modifying and side-effect neutralizing" potential. Myrica salicifolia is traditionally used for gastrointestinal diseases and have reported antiinflammatory activities, but its use in IBD has not yet been studied. Therefore, in the present study, the effects of the root extract of M. salicifolia (Ms.Cr) were investigated using the acetic acid-induced UC model in rats. For 6 days, the rats were given either vehicle (10 mL/kg), lower (200 mg/kg), and higher (400 mg/kg) doses of Ms.Cr, or the positive control drug (prednisolone; 2 mg/kg) orally. A single dosage of 5% acetic acid (1.0 mL) was administered intrarectally to rats on day 6 to induce UC. Disease activity index (DAI), histological observations, the biochemical parameters related to oxidative stress, and specific cytokines such as interleukin-6 (IL-6) and the tumor necrosis factor-α (TNF-α) were determined to assess the effect of Ms.Cr. In comparison to the AA-induced colitis rats, Ms.Cr's pretreatment significantly decreased DAI, colonic ulceration, and inflammatory score. Total glutathione levels and catalase activity were considerably recovered in the colitis group treated with Ms.Cr, whereas enhanced lipid peroxidation in colon tissues was significantly decreased. Moreover, Ms.Cr pretreatment also caused inhibition of the activation of IL-6 and TNF-α in the colonic tissues of respective groups. Based on these findings, Ms.Cr might be developed to treat UC in the future.

Fingolimod ameliorates acetic acid-induced ulcerative colitis: An insight into its modulatory impact on pro/anti-inflammatory cytokines and AKT/mTOR signalling.

BACKGROUND: Because of the approved immunomodulatory activities of fingolimod, the current study aimed at studying the curative potential of fingolimod against experimentally induced ulcerative colitis (UC) via modulating pro/anti-inflammatory cytokines release and AKT/mTOR signalling. METHODS: UC was induced in rats by intracolonic instillation of acetic acid. Fingo (0.5 mg/kg/day, p.o.) was given for 8 consecutive days that started 48 h after UC induction. RESULTS: Fingolimod increased body weight growth rate and colon body/weight and colon weight/length indices compared to the UC group. Fingolimod significantly decreased clinical evaluation score and macroscopic score compared to the UC group. The curative potential of fingolimod was further confirmed by histopathological examination revealing marked attenuation of mucosal injury and inflammatory cells infiltration. Fingolimod significantly decreased colon malondialdehyde content and increased colon glutathione contents compared to the UC group. Fingolimod also significantly decreased the expressions of pro-inflammatory cytokines interleukin-9 and T-helper 17 along with increasing the expression of anti-inflammatory interleukin-10 and transforming growth factor-ß compared to the UC group. In addition, fingolimod decreased the expressions of AKT and mTOR compared to the UC group. CONCLUSION: Fingolimod attenuated acetic acid-induced UC through its immunomodulatory effect by shifting the balance to favour anti-inflammatory cytokine production rather than pro-inflammatory cytokines and modulating the AKT/mTOR signalling.

Sodium Selenite Modulates IDO1/Kynurenine, TLR4, NF-κB and Bcl2/Bax Pathway and Mitigates Acetic Acid-Induced Colitis in Rat.

BACKGROUND/AIMS: Colitis is a main presentation of inflammatory bowel disease (IBD) and yet, has no definitive cure. Currently, corticosteroids, anti-tumor necrosis factor (anti-TNF) agents and 5-aminosalicylic acid derivatives are prescribed for management of colitis. Except their failure rate, they are not always tolerated because of their severe adverse effects. Additive formulas with fewer adverse effects may improve the treatment of colitis. METHODS: In this study, colitis was induced with intra-rectal injection of three concentrations of acetic acid (4, 6 and 8 v/v). Each group received sodium selenite (0.5 mg/kg) or saline, gavaged on days 0 and 1 for treatment. Two days after induction of colitis, rats were sacrificed and the end part of their colons were resected for macroscopic and microscopic evaluation and molecular measurement. RESULTS: Sodium selenite improved macroscopic and microscopic view of the colon, decreased cryptitis, crypt abscess and inflammatory cells infiltration and partly maintained mucosal structure. Sodium selenite markedly reduced tissue levels of malondialdehyde (MDA), TNF-α and interferon γ (INF-γ) and decreased myeloperoxidase (MPO) activity. Treatment with sodium selenite also significantly downregulated IL17, IL22, indoleamine 2,3-dioxygenase (IDO1), and kynurenine levels. Western blotting revealed that sodium selenite prevented apoptosis by increasing bcl2/Bax ratio. Furthermore, our findings showed that sodium selenite significantly downregulated the upstream inflammatory molecules such as nuclear factor kappa B (NF-κB) and toll-like receptor 4 (TLR4) in colitis. CONCLUSION: These findings show that sodium selenite alleviates inflammatory response and oxidative stress and protects against colitis.

Effects of hydro-ethanolic extract of leaves of Maesa lanceolata (Mursinaceae) on acetic acid-induced ulcerative colitis in rats.

Ulcerative colitis is a form of inflammatory bowel disease that is characterized by acute and chronic inflammation. The aim of this work was to evaluate the efficacy of hydroethanolic extract of Maesa lanceolata leaves on acetic acid-induced colitis in rats. Colitis was induced by rectal administration of 1 mL of acetic acid (4%) in 25 male rats except the normal control group which received distilled water after 18 h of fasting followed by Ketamine (50 mg/kg)/Valium (10 mg/kg) anesthesia. Five hours later, the normal control and the negative control received distilled water, the positive control received prednisolone (5 mg/kg) and the three test groups received extract at 100, 200 and 400 mg/kg bw for eight days. During treatment, rectal temperature, the number and quality of the stools, and changes in body weight were assessed. At the end of the treatment, the animals were sacrificed, blood, colon, liver and spleen were collected for evaluation of hematological, inflammatory, antioxidant and histological parameters. Rectal temperature and the number of diarrheal, mucus and bloody stools were significantly reduced (P < 0.01) during treatment in the test and positive control groups with an increase in body weight change. The extract significantly (P < 0.01) reduced myeloperoxidase, TNF-α, interleukin 6, NO and MDA levels and significantly (P < 0.01) increased SOD levels, of GSH and catalase activity in the colon and blood. This extract also increased (P < 0.01) levels of red blood cells, hemoglobin, hematocrit, total white blood cells and blood platelets, prevented leukocyte infiltration in the liver and colon.

Nerolidol, a sesquiterpene, attenuates oxidative stress and inflammation in acetic acid-induced colitis in rats.

Targeting oxidative stress and inflammation by novel dietary compounds of natural origin convincingly appears to be one of the most important therapeutic strategies to keep inflammatory bowel diseases (IBD) such as ulcerative colitis disease in remission. It is imperative to investigate naturally occuring plant-derived dietary phytochemicals that are receiving attention for their therapeutic benefits to overcome the debilitating conditions of IBD. In the present study, the effect of nerolidol (NRD), a monocyclic sesquiterpene found in German Chamomile tea, was investigated in acetic acid-induced colitis model in Wistar rats. NRD was orally administered at a dose of 50 mg/kg/day either for 3 days before or 30 min after induction of IBD for 7 days, after intrarectal administration of acetic acid. The body weight, macroscopic, and microscopic analyses of the colon in different experimental groups were observed on days 0, 2, 4, and 7. Acetic acid caused significant reduction in body weight and induced macroscopic and microscopic ulcer along with a significant decline of antioxidants, concomitant to increased malondialdehyde (MDA), a marker of lipid peroxidation, and myeloperoxidase (MPO) activity, a marker of neutrophil activation. Treatment with NRD significantly improved IBD-induced reduction in body weight, improved histology, inhibited MDA formation, and restored antioxidants along with reduced MPO activity. Acetic acid also induced the release of pro-inflammatory cytokines and increased calprotectin, released by neutrophils under inflammatory conditions. NRD treatment significantly reduced calprotectin and pro-inflammatory cytokines. NRD treatment showed potential to improve disease activity and inhibit oxidative stress, lipid peroxidation, and inflammation along with histological preservation of the colon tissues.

Regulation of IL-6/STAT-3/Wnt axis by nifuroxazide dampens colon ulcer in acetic acid-induced ulcerative colitis model: Novel mechanistic insight.

AIM: Ulcerative colitis (UC) is a common intestinal problem characterized by the diffusion of colon inflammation and immunity dysregulation. Nifuroxazide, a potent STAT-3 inhibitor, exhibits diverse pharmacological properties. The present study aimed to elucidate a novel anti-colitis mechanism of nifuroxazide against the acetic acid-induced UC model. METHODS: Rats were grouped into control (received vehicle), UC (2 ml of 5% acetic acid by intrarectal infusion), UC plus sulfasalazine (100 mg/kg/day, P.O.), UC plus nifuroxazide (25 mg/kg/day, P.O.), and UC plus nifuroxazide (50 mg/kg/day, P.O.) and lasted for 6 days. RESULTS: The present study revealed that nifuroxazide significantly reduced UC measures, hematological changes, and histological alteration. In addition, treatment with nifuroxazide significantly down-regulated serum CRP as well as the colonic expressions of MPO, IL-6, TNF-α, TLR-4, NF-κB-p65, JAK1, STAT-3, DKK1 in a dose-dependent manner. Besides, our results showed that the colonic Wnt expression was up-regulated with nifuroxazide treatment. In a dose-dependent manner, nifuroxazide markedly alleviated acetic acid-induced cellular infiltration and improved ulcer healing by increasing intestinal epithelial cell regeneration. SIGNIFICANCE: Our results collectively indicate that nifuroxazide is an effective anti-colitis agent through regulation of colon inflammation and proliferation via modulation IL-6/STAT-3/Wnt signaling pathway.

An investigation of the anti-inflammatory effects of gabapentin on acetic acid-induced colitis in rats.

Inflammatory bowel disease (IBD) is considered a chronic inflammatory gastrointestinal disease with treatment options which exhibit low efficacies and lead to considerable side effects. Hence, the challenge to alleviate IBD complications is remained to be resolved. The purpose of this study is evaluating anti-inflammatory impacts of gabapentin on acetic acid-induced colitis in rats. Colitis was induced by the instillation of 2 mL of 3% acetic acid solution into rat's colons. Rats were randomly allocated into six groups including normal group, colitis control group, gabapentin-treated groups (25, 50, and 100 mg/kg; i.p.), and dexamethasone-treated group (1 mg/kg; i.p.). Based on the macroscopic assessment besides histological and biochemical findings [myeloperoxidase (MPO), pro-inflammatory cytokines], the efficacy of gabapentin was investigated. Gabapentin (50 and 100 mg/kg), and dexamethasone considerably reduced macroscopic and microscopic colonic lesions induced by acetic acid in rats in comparison with colitis control group. These results were confirmed by reduced levels of MPO activity and colonic concentrations of interleukin-6, interleukin-1 beta, and tumor necrosis factor-alpha, in inflamed colon tissue. Our data demonstrated that gabapentin exerts profitable impacts in experimental colitis that might be ascribed to its anti-inflammatory features and thus can be a potential therapeutic agent for IBD treatment.