Acid-induced Colitis In Rats Research Articles

Colon-Targeted Trans-Cinnamic Acid Ameliorates Rat Colitis by Activating GPR109A

We designed colon-targeted trans-cinnamic acid (tCA) and synthesized its conjugates with glutamic acid (tCA-GA) and aspartic acid (tCA-AA). We evaluated the anti-colitic activity of colon-targeted tCA using a dinitrobenzenesulfonic acid-induced rat colitis model. The conjugates lowered the distribution coefficient and Caco-2 cell permeability of tCA and converted to tCA in the cecum, with higher rates and percentages with tCA-GA than with tCA-AA. Following oral gavage, tCA-GA delivered a higher amount of tCA to the cecum and exhibited better anti-colitic effects than tCA and sulfasalazine (SSZ), which is the current treatment for inflammatory bowel disease. In the cellular assay, tCA acted as a full agonist of GPR109A (EC50: 530 µM). The anti-colitic effects of tCA-GA were significantly compromised by the co-administration of the GPR109A antagonist, mepenzolate. Collectively, colon-targeted tCA potentiated the anti-colitic activity of tCA by effectively activating GPR109A in the inflamed colon, enabling tCA to elicit therapeutic superiority over SSZ.

Immunohistochemical characterization of transient receptor potential vanilloid types 2 and 1 in a trinitrobenzene sulfonic acid-induced rat colitis model with visceral hypersensitivity

Transient receptor potential vanilloid type 2 (TRPV2) and type 1 (TRPV1) are originally identified as heat-sensitive TRP channels. We compared the expression patterns of TRPV2 and TRPV1 in the rat distal colon and extrinsic primary afferent neurons, and investigated their roles in visceral hypersensitivity in 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis rats. Both TRPV2 and TRPV1 expressions in the colon, dorsal root ganglion (DRG), and nodose ganglion (NG) were significantly upregulated in the TNBS-induced colitis model. TRPV2 cell bodies co-localized with the intrinsic primary afferent marker NeuN and the inhibitory motor neuronal marker nNOS in the myenteric plexus. TRPV2 expressions were further detected in the resident macrophage marker ED2 in the mucosa. In contrast, no TRPV1-expressing cell bodies were detected in the myenteric plexus. Both TRPV2- and TRPV1-positive cell bodies in the DRG and NG were double-labeled with the neuronal retrograde tracer fluorescent fluorogold. Large- and medium-sized TRPV2-positive neurons were labeled with the A-fiber marker NF200, calcitonin gene-related peptide (CGRP), and substance P (SP) in the DRG while small-sized TRPV1-positive neurons were labeled with the C-fiber markers IB4, CGRP, and SP. TRPV2- and TRPV1-positive NG neurons were labeled with NF200 and IB4. TNBS treatment increased p-ERK1/2-positive cells in TRPV2 and TRPV1 neurons but did not affect the TRPV2 and TRPV1 subpopulations in the DRG and NG. Both TRPV2 and TRPV1 antagonists significantly alleviated visceral hypersensitivity in TNBS-induced colitis model rats. These findings suggest that intrinsic/extrinsic TRPV2- and extrinsic TRPV1-neurons contribute to visceral hypersensitivity in an experimental colitis model.

Coumaric acid ameliorates experimental colitis in rats through attenuation of oxidative stress, inflammatory response and apoptosis.

Due to the high side effects of commonly used drugs and according to the pharmacological properties reported for coumaric acid (CA), this study was designed to determine the impact of CA on acetic acid-induced colitis in rats, considering its possible anti-inflammatory, antioxidant, and anti-apoptotic properties. Forty-eight male Wistar rats were divided into 6 equal groups (n = 8). Colitis was induced by acetic acid intrarectally. CA in three different doses (50, 100, and 150mg/kg) was administrated for 5days. Finally, the macroscopic and histopathological changes in the colon tissue were examined. The expression of inflammatory and apoptotic genes, including NF-κB, TNF-α, INOS, IL-1β, IL-6, TLR4, Caspase-3, Caspase-8, Bax, Bcl-2 was assessed. In addition, changes in the levels of catalase (CAT), superoxide dismutase (SOD), malondialdehyde (MDA), nitrite, and total antioxidant capacity (TAC) were measured in the colon tissue. Colitis led to a decrease in TAC and the activity levels of CAT and SOD and an increase in the expression of inflammatory and apoptotic genes, MDA, and nitrite levels in the colon. Colitis was also associated with edema and severe damage to the epithelium, infiltration of inflammatory cells, and the presence of ulcers and necrosis in the colon tissue. CA significantly improved the inflammation, oxidative stress, apoptosis, and histopathological indices caused by acetic acid-induced colitis on the colon. It is concluded that CA probably exerts its positive effects in the management of colitis, through its anti-inflammatory, antioxidant, and anti-apoptotic properties.

Influence of laboratory-controlled ethanolic wheatgrass extract on acetic acid-induced changes in biochemical and antioxidant indices in the colitis of Wistar rats

Introduction and Aim: Triticum aestivum (wheatgrass) is a good source of mineral nutrients and antioxidant enzymes. It also acts as a detoxifying agent and helps to revive healthy cells. The present study aimed to assess the effects of acetic acid on biochemical and antioxidant indices in the colitis of Wistar rats using an ethanolic extract derived from the dried shoots of wheatgrass maintained under specified growth conditions.
 
 Materials and Methods: Aqueous and ethanolic extract of wheatgrass was subjected to preliminary phytochemical screening and in-vitro antioxidant activity. Effects of the ethanolic wheatgrass extract were investigated in the acetic acid-induced rat colitis model. Sulphasalazine was used as the standard anti-inflammatory drug. Malondialdehyde (MDA), myeloperoxidase (MPO), total antioxidant capacity (TAC), catalase (CAT), and reduced glutathione (GSH) levels were estimated in the rat blood. Colitis was quantified with a clinical score and colon length/weight index was measured. Histopathological analyses were also performed on the colon tissue of rats.
 
 Results: The presence of phytochemical elements such as saponins, tannins, alkaloids, and terpenes in aqueous and ethanolic wheatgrass extract was discovered. These compounds have the potential to boost antioxidant and anti-inflammatory effects. The ethanolic extract significantly reduced MDA, MPO, and antioxidant levels (TAC, CAT, and GSH) in colon tissue and blood. Biochemical measurements corroborated the conclusions of histopathological investigation.
 
 Conclusion: According to macroscopic, microscopic, histological, and other biochemical studies, ethanolic wheatgrass extract significantly inhibits experimental colitis in rats.

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.

The effect of combining basil seeds and gum Arabic on the healing process of experimental acetic acid-induced ulcerative colitis in rats

Background & aimUlcerative colitis (UC) is a chronic recurrent inflammatory disease of the large intestine and rectum that oxidative stress and severe inflammation are the main features of this disease. Previous studies have shown that separate consumption of basil and gum arabic can reduce inflammation and oxidative stress. The aim of the study was evaluating the effect of treatment with basil seeds given together with gum arabic on healing, inflammation and oxidative stress in the course of experimental colitis in rats. Experimental procedureA total number of 50 male rats were used, randomly assigned to five groups of 10 rats each. Colitis was induced in rats by enemas with 4% solution od acetic acid. Four days after induction of colitis, rats were treated for next 4 days with saline or combination of basil seeds plus gum arabic (1 mg/kg) or sulfasalazine (100 mg/g) rectally. The experiment was terminated after last dose of treatment. Rats without induction of colitis were used as a sham group. ResultsAcetic acid-induced colitis increased the macroscopic and histopathological damage scores of the colon as well as colon levels of MDA(Malondialdehyde), MPO(Myeloperoxidase), TNFα(Tissue necrosis factor α), IL6 (Interleukin 6)and IL17(Interleukin 17) and decreased SOD(Superoxide Dismutase), GPx (Glutathione Peroxidase) and IL10 (Interleukin 10) levels compared with the control group(P < 0.001). Treatment with basil and gum arabic reduced macroscopic and histopathological damage scores (P < 0.01) of the colon, MDA, MPO, TNFα, IL6(P < 0.001) and IL17 (P < 0.01) levels of the colon and increased SOD, GPx and IL10 levels compared to the colitis group (P < 0.01). ConclusionRectal administration of combination of basil seeds plus gum arabic after induction of colitis, exhibits antioxidant and anti-inflammatory effects, and accelerates the healing of the colon in experimental colitis evoked by acetic acid.

Mesenchymal Stem Cells for the Treatment of Acetic Acid-Induced Ulcerative Colitis in Rats

Background: Ulcerative colitis (UC) is an autoimmune inflammatory bowel disease, characterized by chronic and relapsing inflammation of the intestinal mucosa. Clinical treatments fail to reduce inflammation and induce side effects in nearly 30% of patients. Mesenchymal stem cells (MSCs) are immunomodulatory agents that can encourage tissue repair and regeneration.&#x0D; Aim: To investigate the ability of MSCs to differentiate into enterocytes under the mediation of activin a, fibroblastic growth factor 2, and epidermal growth factors and to study the effect of administering MSCs to rats with acetic acid (AA)-induced UC.&#x0D; Methods: MSCs isolated from the umbilical cord were induced to differentiate into enterocytes. The induced cells were morphologically evaluated by flow cytometry and immunocytochemistry. Forty rats were divided into four groups: control, AA-induced UC, differentiated, and undifferentiated MSC treated groups. The acute UC in rats was induced by 3% AA transrectal administration. Body weight changes, disease activity index (DAI), and histopathological and immunohistochemical CD105 and CD34 staining were recorded. IL-17, IL-10, and TGF- β levels were measured as well.&#x0D; Results: In Both differentiated and undifferentiated MSCs, induced MSCs improved the DAI score and significantly recovered the pathological changes. The favorable effect of MSCs was significantly linked to CD105 overexpression and CD34 low expression. IL-10 and TGF-β levels increased while IL-17 levels decreased.&#x0D; Conclusion: Both differentiated and undifferentiated MSCs showed anti-inflammatory and immunomodulatory effects in our study. Based on our results, MSCs could become potentially useful for regenerative medicine and the clinical treatment of UC.

Evaluation of anti-inflammatory effects of leaf and seed extracts of Plantago major on acetic acid-induced ulcerative colitis in rats

Ethnopharmacological relevancePlantago major (P. major) has traditionally been used in Iranian Persian medicine to treat gastrointestinal ulcers and bleeding. Research objectivesThis study aimed to investigate the anti-inflammatory effects of the leaf and seed extracts of P. major in rats with acetic acid-induced ulcerative colitis (UC). Materials and methodsTo this end, 49 rats were randomly divided into seven groups. UC was induced in all groups but the control (vehicle) group using a single intra-rectal administration of 2 ml of 4% acetic acid. Other groups received daily intraperitoneal (i.p.) injections of the seed extract of P. major (400 mg/kg and 700 mg/kg), the leaf extract of P. major (400 mg/kg and 700 mg/kg), and sulfasalazine (400 mg/kg) for seven consecutive days, respectively. The rats’ rectum was surgically removed and evaluated for macroscopic and microscopic damage. The tissue levels of oxidative stress and inflammatory markers were measured using the ELISA method. ResultsThe high-dose leaf extract significantly decreased ulcer index and histopathologic damage as well as the tissue levels of IL-6, TNF-α, PGE2, IL-1β, MPO, and MDA compared to the damage group. The low-dose leaf extract also significantly reduced the levels of some markers. The seed extract in the two used doses caused a modest decrease in the histopathological damages and ulcer index. ConclusionsP. major leaf extract effectively reduces inflammation and mucosal damage in rats with UC, especially when administered in high doses. P. major seed extract has minimal protective effects on UC.

A validated LC-MS/MS method for the determination of hederasaponin C: Application to pharmacokinetics-pharmacodynamics studies in the therapeutic area of acetic acid-induced ulcerative colitis in rats.

Hederasaponin C (HSC), one of the main components of Pulsatilla chinensis, is considered as a potential drug for the treatment of inflammatory bowel disease. In the present research, we developed a pharmacokinetics-pharmacodynamics model to describe the concentration-effect course of drug action following the intraperitoneal injection of HSC in colitis rats. A sensitive UPLC-MS/MS method was established for the the determination of HSC in rat plasma to explore the pharmacokinetics properties. The separation was performed on an Accucore C18 column (2.1 × 100 mm, 2.6 μm) with a flow phase consisting of acetonitrile and 0.1% formic acid water. The assay method was validated and demonstrated good adaptability for application in the pharmacokinetics study. Then the levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) in colon tissues were measured using an ELISA assay. The levels of TNF-α, IL-1β and IL-6 were decreased after HSC administration, suggesting that HSC can significantly improve the level of inflammatory syndrome factor. The pharmacokinetics study showed that the time to peak concentration of HSC was 1 h. The concentration-effect curves showed a hysteresis loop. There was also a hysteresis between the peaked concentration and the maximum effect of HSC. The present study established in vivo pharmacokinetics-pharmacodynamics models and the results showed a great potential of HSC for treating ulcerative colitis.

Canagliflozin-loaded chitosan-hyaluronic acid microspheres modulate AMPK/NF-κB/NLRP3 axis: A new paradigm in the rectal therapy of ulcerative colitis

Ulcerative colitis is an idiopathic disease that is widely incident worldwide. Canagliflozin, antidiabetic agent, exhibited significant anti-inflammatory effects in a variety of animal models. Additionally, hyaluronic acid is considered one of the key players in the tissue regeneration process. It has been proven to modulate inflammation and cellular migration, which are the main phases of wound healing. The combination of hyaluronic acid with chitosan in microsphere fabrication was anticipated to reveal a synergistic muco-adhesiveness potential with additional advantage of the chitosan penetration enhancing effect. The current study aimed to explore the potential of canagliflozin-loaded chitosan-hyaluronic acid microspheres intrarectal administration to mitigate acetic acid-induced colitis in rats. Colon tissues were examined for macroscopic and microscopic pathological changes. ELISA and qRT-PCR techniques were applied for the detection of cytokines involved in the AMPK/NF-κB/NLRP3 axis. Intrarectal administration of this formula alleviated colitis severity, which was reflected by the reduced DAI, MES, colonic weight/length ratio and histopathological scoring values. Interestingly, canagliflozin-loaded chitosan-hyaluronic acid microspheres significantly enhanced AMPK phosphorylation and depressed NF-κB and NLRP3 expression leading to a subsequent reduction in caspase-1 cleavage and the inhibition of several inflammatory cytokines, including IL-1β, and IL-18. Overall, the current study revealed that the protective effects of the formula against acetic acid-induced colitis are primarily mediated via augmenting AMPK phosphorylation and its consequences of NF-κB inactivation. Since canagliflozin is not associated with hypoglycemic effects, clinical application of canagliflozin-loaded chitosan-hyaluronic acid microspheres represent a novel therapeutic option for the treatment of patients with ulcerative colitis.

The emerging coloprotective effect of sildenafil against ulcerative colitis in rats via exerting counterbalance between NF-κB signaling and Nrf-2/HO-1 pathway

The current work explored the influences of time dependent Sildenafil (SILD) administration, and the possible outcomes from its concomitant administration with dexamethasone against acetic acid-induced ulcerative colitis in rats. Rats were assigned into six random groups: diseased group (AA), injected once with 2 ml acetic acid (3%) intrarectally, 2 days before sacrification. SILD + AA, received sildenafil (25 mg/kg, orally) for 6 days starting 3 days pre-injection of AA; SILD-t + AA, received sildenafil (25 mg/kg, orally), starting at time of AA injection and continued for 3 days; DEXA + AA, received dexamethasone (2 mg/kg, i.p.) for 3 days, starting at time of AA injection; SILD-t + DEXA + AA, received sildenafil (25 mg/kg, orally) and dexamethasone (2 mg/kg, i.p.), as mentioned. Sildenafil markedly ameliorated disease activity index (DAI), ulcer scores, colon length shortening and colonic histopathological changes. Mechanistically, Sildenafil markedly attenuated immunoexpression of NF-κB p65/ TNF-α and COX-2, diminished oxidative stress (↓ MDA/NO levels and ↑ GSH level and SOD activity), increased levels of Nrf-2/HO-1, compared to untreated group. Taken together, Sildenafil treatment suppressed acetic acid-induced ulcerative colitis, probably via inhibiting NF-κB/TNF-α signaling dependent of Nrf-2/HO-1 pathway, reducing oxidative stress and attenuating inflammation. Surprisingly, effects of sildenafil were unpromoted in a time dependant manner. Short term treatment with sildenafil was sufficient to exert its coloprotective effect, while longer term pretreatment was only superior among other treatments in the macroscopical changes. Moreover, concurrent administration of sildenafil and dexamethasone had the preference in boosting the antioxidant defense and anti-inflammatory mechanisms, visualized by histopathological/immunohistochemical changes.

Olmesartan medoxomil self-microemulsifying drug delivery system reverses apoptosis and improves cell adhesion in trinitrobenzene sulfonic acid-induced colitis in rats

Olmesartan medoxomil (OM) is an angiotensin receptor blocker. This study aimed to investigate the effects of OM self-microemulsifying drug delivery system (OMS) in trinitrobenzene sulfonic acid (TNBS)-induced acute colitis in rats. Besides two control groups, five TNBS-colitic-treated groups (n = 8) were given orally sulfasalazine (100 mg/kg/day), low and high doses of OM (3.0 and 10.0 mg/kg/day) (OML and OMH) and of OMS (OMSL and OMSH) for seven days. A colitis activity score was calculated. The colon was examined macroscopically. Colonic levels of myeloperoxidase, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), malondialdehyde, and reduced glutathione were measured. Plasma and colonic olmesartan levels were measured. Colonic sections were subjected to hematoxylin and eosin staining and immunohistochemical staining for E-cadherin, caspase-3, and matrix metalloproteinase-9 (MMP-9). Protein expression of E-cadherin, Bcl-2 associated X protein (Bax), and B-cell lymphoma 2 (Bcl-2), and cleaved caspase-3 by Western blot was done. TNBS-colitic rats showed increased colonic myeloperoxidase, TNF-α, IL-6, and malondialdehyde, decreased colonic glutathione, histopathological, immunohistochemical, and protein expression alterations. OMS, compared with OM, dose-dependently achieved higher colonic free olmesartan concentration, showed better anti-inflammatory, antioxidant, and anti-apoptotic effects, improved intestinal barrier, and decreased mucolytic activity. OMS more effectively up-regulated the reduced Bcl-2, Bcl-2/Bax ratio, and E-cadherin expression, and down-regulated the overexpressed Bax, cleaved caspase-3, and MMP-9. OMSL exerted effects comparable to OMH. Sulfasalazine exerted maximal colonic protective effects and almost completely reversed colonic damage, and OMSH showed nearly similar effects with non-significant differences in-between or compared with the normal control group. In conclusion, OMS could be a potential additive treatment for Crohn's disease colitis.

Protective Effect of Nanoparticles of Oleoresin of Pistacia atlantica var. mutica Against Acetic Acid-Induced Ulcerative Colitis in Rats

Dying Various therapeutic activities of Pistacia atlantica var. mutica such as hypoglycemic, antioxidant and anti-inflam matory activity were shown by several studies. Regarding these therapeutic activities, and due to advantages of nanoparticles for drug delivery systems, the anti-colitic effects of P. atlantica var. mutica oleoresin nanoparticles were studied in acetic acid-induced ulcerative colitis in rats. Nanoparticles were synthesized by using ethanol and acetone as solvent. Nano precipitation method was also used for nanoparticles synthesis. P. atlantica oleoresin was orally administered to acetic acid-induced colitis rats at the doses of 50, 100 and 200 mg/kg. Then rats were killed and their colons were dissected away for histopathological and macroscopic tests. Statistical results showed homogeneity and uniformity in size and size distribution of fabricated nanoparticles. Proposed models for size and size distribution of nanoparticles were also adequate (P value &lt; 0.05). All doses of nanoparticles of P. atlantica oleoresin significantly reduced macroscopic damage score. The microscopic study also showed anti-colitic activities of P. atlantica oleoresin nanoparticles. Administration of 200 mg/kg of fabricated nanoparticles showed better anti-inflammatory and healing effects compared to other doses. Our results showed that nanoparticles of P. atlantica var. mutica oleoresin might be an effective agent to treat ulcerative colitis disease, due to the therapeutic activities of the plant and desirable properties of fabricated nanoparticles. Therefore, nanoparticles of P. atlantica var. mutica oleoresin might provide an alternative drug for colonic inflammation.

Sinapic Acid Ameliorates Acetic Acid-Induced Ulcerative Colitis in Rats by Suppressing Inflammation, Oxidative Stress, and Apoptosis.

Background: Ulcerative colitis (UC) is a long-term condition which results in inflammation and ulcers of the colon and rectum. The key indications of active disease are abdominal pain and diarrhea mixed with blood. Aims: We explore the underlying colon protective mechanism of sinapic acid (SA) against acetic acid (AA) induced ulcerative colitis in rats. The implications of inflammation, oxidative stress, and apoptosis are studied. Methodology: Twenty-four rats were distributed into four categories, normal control (NC), ulcerative colitis (UC), ulcerative Colitis with SA 40 mg/kg (SA 40 mg/kg + AA), and ulcerative colitis with prednisolone (PRDL 10 mg/kg + AA), and were pretreated orally with saline, saline and SA (40 mg/kg/day) or PRDL (10 mg/kg/day) respectively, for 7 days. UC was prompted by trans-rectal administration of 4% AA on the 5th day, colon tissues were surgically removed for gross morphology and histological inspection, oxidative stress, and inflammatory markers and immunoblot analysis of Bax, caspase-3, and Bcl-2. Results: Macroscopic and histological inspection demonstrated that both SA 40 mg/kg and PRDL (10 mg/kg/day) significantly ameliorates colonic injuries. In addition, both pretreatments significantly ameliorates AA-induced UC, oxidative stress, as indicated by suppressed malondialdehyde (MDA), nitric oxide (NO) levels and restoring antioxidant/oxidant balance as indicated by catalase and glutathione levels, suppressed inflammation via inhibiting cytokines TNF-α, IL-6, inflammatory markers MPO, PGE2, COX-2 and NF-κB and inhibiting the protein expression of Bax and caspase-3 apoptotic protein and increasing the anti-apoptotic protein, Bcl-2 thereby inhibiting apoptosis. Conclusion: Sinapic acid significantly ameliorates AA induced UC in rats by suppressing inflammation, oxidative stress, and apoptosis in colonic tissues which exhibits its potential for the management of UC.

Carbocisteine as a Modulator of Nrf2/HO-1 and NFκB Interplay in Rats: New Inspiration for the Revival of an Old Drug for Treating Ulcerative Colitis.

Ulcerative colitis (UC), an inflammatory bowel disease, is a chronic condition of a multifaceted pathophysiology. The incidence of UC is increasing internationally. The current therapies for UC lack relative effectiveness and are associated with adverse effects. Therefore, novel therapeutic options should be developed. It has been well documented that modulating the Nrf2/NFκB is a promising therapeutic target in inflammation. Carbocisteine is a mucoregulatory medication and its efficacy in COPD was found to be more closely related to its antioxidant and anti-inflammatory properties. Carbocisteine has not yet been examined for the management of UC. Hence, our approach was to investigate the potential coloprotective role of carbocisteine in acetic acid-induced colitis in rats. Our results revealed that carbocisteine improved colon histology and macroscopic features and subdued the disease activity as well. Additionally, carbocisteine attenuated colon shortening and augmented colon antioxidant defense mechanisms via upregulating catalase and HO-1 enzymes. The myeloperoxidase activity was suppressed indicating inhibition of the neutrophil infiltration and activation. Consistent with these findings, carbocisteine boosted Nrf2 expression along with NFκB inactivation. Consequently, carbocisteine downregulated the proinflammatory cytokines IL-6 and TNF-α and upregulated the anti-inflammatory cytokine IL-10. Concomitant to these protective roles, carbocisteine displayed anti-apoptotic properties as revealed by the reduction in the Bax: BCL-2 ratio. In conclusion, carbocisteine inhibited oxidative stress, inflammatory response, and apoptosis in acetic acid-induced UC by modulating the Nrf2/HO-1 and NFκB interplay in rats. Therefore, the current study provides a potential basis for repurposing a safe and a commonly used mucoregulator for the treatment of UC.

Lactiplantibacillus plantarum attenuates 2,4,6-trinitrobenzenesulfonic acid-induced ulcerative colitis in rats by regulating the inflammatory response, T helper 17 immune response, and intestinal permeability

Lactiplantibacillus plantarum attenuates 2,4,6-trinitrobenzenesulfonic acid-induced ulcerative colitis in rats by regulating the inflammatory response, T helper 17 immune response, and intestinal permeability

Morus macroura Miq. Fruit extract protects against acetic acid-induced ulcerative colitis in rats: Novel mechanistic insights on its impact on miRNA-223 and on the TNFα/NFκB/NLRP3 inflammatory axis

Nod-like receptor pyrin domain-1 containing 3 (NLRP3) inflammasome/tumor necrosis factor alpha (TNFα)/nuclear factor kappa B (NFκB) inflammatory pathway is known to be involved in the pathogenesis of ulcerative colitis (UC). Inversely, miRNA-223 can exert counter-regulatory effect on NLRP3 expression. The mulberry tree (Morus macroura) fruit is attaining increased importance for its antioxidant and anti-inflammatory activity in addition to its high safety profile. Accordingly, we attempted to explore the possible protective effect of mulberry fruit extract (MFE) in acetic acid (AA)-induced UC rat model. Phytochemical constituents of MFE were characterized using high performance liquid chromatography coupled to mass spectrometry (HPLC-MS). In the in vivo study, three doses of MFE were orally given for seven days before intra-rectal induction of UC by AA on day eight. Screening study revealed that MFE (300 mg/kg) significantly reduced macroscopic and microscopic UC scores. Biochemically, MFE ameliorated oxidative stress, levels of TNFR1, NLRP3, p-NFκB p65, TNFα, IL-1β, and IL-18, caspase-1 activity, but enhanced miRNA-223 expression. In conclusion, our study provided a novel protective impact for MFE against UC, in which miRNA-223 and TNFα/NFκB/NLRP3 pathway are involved. These results provide a promising step that might encourage further investigations of MFE as a protective agent in UC patients.

Lycopodium Mitigates Oxidative Stress and Inflammation in the Colonic Mucosa of Acetic Acid-Induced Colitis in Rats.

Inflammatory bowel diseases (IBDs) such as ulcerative colitis (UC) and Crohn’s disease (CD) are diseases of the gastrointestinal system involving genetic and environmental factors attributed to oxidative stress and inflammation. Targeting oxidative stress and inflammation by novel dietary compounds of natural origin convincingly appears to be one of the important therapeutic strategies to keep the disease in remission. As there is no permanent cure for IBD except for chronic long-term treatment or surgery, it is therefore imperative to investigate plant-based agents that are receiving attention for their therapeutic benefits to overcome the debilitating clinical conditions of IBD. Lycopodium (LYCO), a plant of tropical and subtropical origin and known by numerous names such as ground pine, club moss, or devil’s claw, has been popularly used for centuries in traditional medicine including Chinese and Indian medicines. In the present study, the effect of LYCO has been investigated in an acetic acid (AA)-induced colitis model in Wistar rats. LYCO was orally administered at the dose of 50 mg/kg/day either 3 days before or 30 min after the induction of IBD and continued for 7 days by intrarectal administration of AA. The changes in body weight and macroscopic and microscopic analysis of the colon of rats of different experimental groups were observed on days 0, 2, 4, and 7. The levels of myeloperoxidase (MPO), reduced glutathione (GSH), and malondialdehyde (MDA) were measured. AA caused a significant reduction in body weight and increased macroscopic and microscopic ulcer scores along with a significant decline in antioxidant enzymes, superoxide dismutase (SOD), and catalase and antioxidant substrate, glutathione (GSH). There was a concomitant increased formation of malondialdehyde (MDA), a marker of lipid peroxidation, and raised myeloperoxidase (MPO) activity, a marker of neutrophil activation. Treatment with LYCO significantly improved IBD-induced reduction in body weight, improved histology, inhibited MDA formation, and restored antioxidants along with reduced MPO activity. AA also caused the release of proinflammatory cytokines such as interleukin-1β (IL-1β) and interleukin-23 (IL-23). Furthermore, AA also increased the levels of calprotectin, a protein released by neutrophils under inflammatory conditions of the gastrointestinal tract. LYCO treatment significantly reduced the release of calprotectin and proinflammatory cytokines. The results demonstrate that LYCO treatment has the potential to improve disease activity by inhibiting oxidative stress, lipid peroxidation, and inflammation along with histological preservation of colonic tissues.

Anticolitic activity of prodigiosin loaded with selenium nanoparticles on acetic acid-induced colitis in rats.

Ulcerative colitis (UC) is a chronic autoimmune inflammatory disease associated with extensive mucosal damage. Prodigiosins (PGs) are natural bacterial pigments with well-known antioxidant and immunosuppressive properties. In the current study, we examined the possible protective effect of PGs loaded with selenium nanoparticles (PGs-SeNPs) against acetic acid (AcOH)-induced UC in rats. Thirty-five rats were separated into five equal groups with seven animals/group: control, UC, PGs (300mg/kg), sodium selenite (Na2SeO3, 2mg/kg), PGs-SeNPs (0.5mg/kg), and 5-aminosalicylates (5-ASA, 200mg/kg). Interestingly, PGs-SeNPs administration lessened colon inflammation and mucosal damage as indicated by inhibiting inflammatory markers upon AcOH injection. Furthermore, PGs-SeNPs improved the colonic antioxidant capacity and prevented oxidative insults as evidenced by the upregulation of Nrf2- and its downstream antioxidants along with the decreased pro-oxidants [reactive oxygen species (ROS), carbonyl protein, malondialdehyde (MDA), inducible nitric oxide synthase (iNOS), and nitric oxide (NO] in the colon tissue. Furthermore, PGs-SeNPs protected intestinal cell loss through blockade apoptotic cascade by decreasing pro-apoptotic proteins [Bcl-2-associated X protein (Bax) and caspase-3] and increasing anti-apoptotic protein, B cell lymphoma 2 (Bcl2). Collectively, PGs-SeNPs could be used as an alternative anti-colitic option due to their strong anti-inflammatory, antioxidant, and anti-apoptotic activities.

Dapsone Azo-Linked with Two Mesalazine Moieties Is a “Me-Better” Alternative to Sulfasalazine

Dapsone (DpS) is an antimicrobial and antiprotozoal agent, especially used to treat leprosy. The drug shares a similar mode of action with sulfonamides. Additionally, it possesses anti-inflammatory activity, useful for treating autoimmune diseases. Here, we developed a “me-better” alternative to sulfasalazine (SSZ), a colon-specific prodrug of mesalazine (5-ASA) used as an anti-inflammatory bowel diseases drug; DpS azo-linked with two molecules of 5-ASA (AS-DpS-AS) was designed and synthesized, and its colon specificity and anti-colitic activity were evaluated. AS-DpS-AS was converted to DpS and the two molecules of 5-ASA (up to approximately 87% conversion) within 24 h after incubation in the cecal contents. Compared to SSZ, AS-DpS-AS showed greater efficiency in colonic drug delivery following oral gavage. Simultaneously, AS-DpS-AS substantially limited the systemic absorption of DpS. In a dinitrobenzene sulfonic acid-induced rat colitis model, oral AS-DpS-AS elicited better efficacy against rat colitis than oral SSZ. Moreover, intracolonic treatment with DpS and/or 5-ASA clearly showed that combined treatment with DpS and 5-ASA was more effective against rat colitis than the single treatment with either DpS or 5-ASA. These results suggest that AS-DpS-AS may be a “me-better” drug of SSZ with higher therapeutic efficacy, owing to the combined anti-colitic effects of 5-ASA and DpS.