Mesenchymal stem cells alleviate TNBS-induced colitis by modulating inflammatory and autoimmune responses

AIM: To investigate the potential therapeutic effects of mesenchymal stem cells (MSCs) in inflammatory bowel disease (IBD), we transplanted MSCs into an experimental model of IBD. METHODS: A rectal enema of trinitrobenzene sulfonic acid (TNBS) (100 mg/kg body weight) was administered to female BALB/c mice. Bone marrow mesenchymal stem cells (BMSCs) were derived from male green fluorescent protein (GFP) transgenic mice and were transplanted intravenously into the experimental animals after disease onset. Clinical activity scores and histological changes were evaluated. GFP and Sex determining region Y gene (SRY ) expression were used for cell tracking. Ki67 positive cells and Lgr5-expressing cells were determined to measure proliferative activity. Inflammatory response was determined by mea-suring the levels of different inflammatory mediators in the colon and serum. The inflammatory cytokines included tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-2 (IL-2), IL-6, IL-17, IL-4, IL-10, and transforming growth factor (TGF-β). Master regulators of Th1 cells (T-box expressed in T cells, T-bet), Th17 cells (retinoid related orphan receptor gamma(t), RORγt), Th2 cells (GATA family of transcription factors 3, GATA3) and regulatory T cells (forkhead box P3, Foxp3) were also determined. RESULTS: Systemic infusion of GFP-BMSCs ameliorated the clinical and histopathologic severity of colitis, including body weight loss, diarrhea and inflammation, and increased survival (P < 0.05). The cell tracking study showed that MSCs homed to the injured colon. MSCs promoted proliferation of intestinal epithelial cells and differentiation of intestinal stem cells (P < 0.01). This therapeutic effect was mainly mediated by downregulation of both Th1-Th17-driven autoimmune and inflammatory responses (IL-2, TNF-α, IFN-γ, T-bet; IL-6, IL-17, RORγt), and by up-regulation of Th2 activities (IL-4, IL-10, GATA-3) (P < 0.05). MSCs also induced activated CD4 + CD25 + Foxp3 + regulatory T cells (TGF-β, IL-10, Foxp3) with a suppressive capacity on Th1-Th17 effecter responses and promoted Th2 differentiation in vivo (P < 0.05). CONCLUSION: MSCs are key regulators of immune and inflammatory responses and may be an attractive candidate for cell-based therapy of IBD.

MicroRNA155 is induced in activated CD4^+ T cells of TNBS-induced colitis in mice

AIM:To investigate the expression of microRNA155(miRNA155)in trinitrobenzene sulphonic acid(TNBS)induced colitis and the relationship between miRNA155 and tumor necrosis factor(TNF)expressions.METHODS:In TNBS colitis mice,miRNA155 and TNF mRNA expressions were measured in colons and CD4 + T cells of draining lymph nodes(LNs).CD4 + T cells were cultured in vitro with or without anti-CD3/CD28 antibody,and the expressions of miRNA155 and TNF mRNA in cells and TNF concentration in culture media were examined.RESULTS:miRNA155 and TNF mRNA expressions in colons and in cells of LNs were significantly increased in TNBS colitis compared with controls.In TNBS colitis,miRNA155 and TNF mRNA expressions in CD4 + T cells of LNs and TNF concentration in CD4 + T cells culture media increased compared with controls.When cultured with anti-CD3/CD28 antibody,miRNA155 and TNF mRNA expressions in CD4 + T cells and TNF concentration in the CD4 + T cells culture media were significantly higher than those cultured without anti-CD3/CD28 antibody.Following analysis using the Pearson's correlation coefficient,miRNA155 expression had a significant positive correlation with either TNF mRNA expression in CD4 + T cells(r=0.860,P<0.05)or TNF concentration in CD4 + T cells culture media(r=0.892,P<0.05).CONCLUSION:miRNA155 is induced in colons and activated CD4 + T cells in TNBS colitis,and the levels of miRNA155 and TNF expressions have a significant positive correlation.

Oxymatrine Improves TNBS-induced Colitis in Rats by Inhibiting the Expression of NF-κB p65

Inflammatory bowel disease is thought to be regulated by the balance between Th1 and Th2 cytokines secreted by T cells, and NF-κB p65 also plays a predominant role in the intestinal inflammation. We evaluated the potency of oxymatrine, one of active components of Sophora Root, in inhibiting the immune responses and inflammation in 2,4,6-trinitrobenzene sulfonic acid （TNBS）-induced colitis. The inflammation was markedly ameliorated in the oxymatrine-treated rats. The level of IL-2 was increased and that of IL-10 was decreased in colon tissue in the rat model, which was reversed by the treatment of oxymatrine. Moreover, the elevated expression of NF-κB p65 in colon tissue in the model was also improved by oxymatrine treatment. Our results suggest that oxymatrine might be beneficial for the abnormal immune responses and inflammation by regulating the unbalance of Th1 and Th2 cytokines secretion and inhibiting the expression of NF-κB p65 in colon tissue.

Expression and significance of nuclear factor κB p65 in colon tissues of rats with TNBS-induced colitis

AIM: To investigate the role of NF-κB in the pathogenesis of TNBS-induced colitis in rats. METHODS: Thirty-two healthy adult Sprague-Dawley (SD) rats were randomly divided into four groups of eight each: normal, NS, model Ⅰ, model Ⅱ groups in our study. Rat colitis model was established through 2-,4-,6-trinitrobenzene sulfonic acid (TNBS) enema. At the end of four weeks, the macroscopical and histological changes of the colon were examined and mucosa myeloperoxidase (MPO) activities assayed. NF-κB p65 expression was determined by Western blot assessment in cytoplasmic and nuclear extracts of colon tissue, and the expressions of TNF-α and ICAM-1 protein in colon tissue were examined by immunohistochemistry. The relativities between expression of NF-κB p65 and other parameters were analyzed. RESULTS: TNBS enema resulted in pronounced pathological changes of colonic mucosa in model Ⅱ group (macroscopic and histological injury indices 6.25±1.39 and 6.24±1.04, respectively), which were in accordance with the significantly elevated MPO activity (1.69±0.11). And the nuclear level of NF-κB and expression of TNF-α, ICAM-1 in rats of model II group were higher than that of normal control (9.7±1.96 vs1.7±0.15, 84.09±14.52 vs 16.03±6.21, 77.69±8.09 vs 13.41±4.91 P<0.01), Linear correlation analysis revealed that there were strong correlations between the nuclear level of NF-κB and the tissue positive expression of TNF-α and ICAM-1, MPO activities, macroscopical and histological indices in TNBS-induced colitis, respectively (r= 0.8235, 0.8780, 0.8572, 0.9152, 0.8247; P<0.05). CONCLUSION: NF-κB plays a pivotal role in the pathogenesis of ulcerative colitis, which might account for the up-regulation the expression of TNF-α and ICAM-1.

Therapeutic and prophylactic thalidomide in TNBS-induced colitis: Synergistic effects on TNF-α, IL-12 and VEGF production

AIM： To evaluated the therapeutic and prophylactic effect of thalidomide on 2, 4, 6-trinitrobenzene sulfonic acid （TNBS）-induced colitis. Thalidomide has been reported to downregulate the expression of tumor necrosis factor α （TNF-α）, IL-12, and vascular endothelial growth factor （VEGF）, hallmarks of intestinal inflammation in Crohn＇s disease （CD）. METHODS： Male Wistar rats were divided in five groups of ten animals each. Four groups received a rectal infusion of TNBS in ethanol. The first group was sacrificed 7 d after colitis induction. The second and third groups received either thalidomide or placebo by gavage and were sacrificed at 14 d. The fourth group received thalidomide 6 h before TNBS administration, and was sacrificed 7 d after induction. The fifth group acted as the control group and colitis was not induced. Histological inflammatory scores of the colon were performed and lamina propria CD4＋ T cells, macrophages, and VEGF＋ cells were detected by immunohistochemistry. TNF-α and IL-12 were quantified in the supernatant of organ cultures by ELISA. RESULTS： Significant reduction in the inflammatory score and in the percentage of VEGF＋ cells was observed in the group treated with thalidomide compared with animals not treated with thalidomide. Both TNF-α and IL-12 levels were significantly reduced among TNBS induced colitis animals treated with thalidomide compared with animals that did not receive thalidomide. TNF-α levels were also significantly reduced among the animals receiving thalidomide prophylaxis compared with untreated animals with TNBS-induced colitis. Intestinal levels of TNF-α and IL-12 were significantly correlated with the inflammatory score and the number of VEGF＋ cells. CONCLUSION： Thalidomide significantly attenuates TNBS-induced colitis by inhibiting the intestinal production of TNF-α, IL-12, and VEGF. This effect may support the use of thalidomide as an alternate approach in selected patients with CD.

The Dual Positive Actions of Colonic Release of Ibuprofen in TNBS-Induced Colitis Wistar Rats

Ibuprofen is a relatively safe anti inflammatory drug among other NSAIDs. However, frequent and long-term administration of ibuprofen in conventional oral preparation is still considered for ulceration. As previously reported, the daily administration of the ibuprofen orally for 14 days in rats caused the gastroduodenal ulcer. Several mechanisms have been reported: the suppression of the gastric prostaglandin synthesis and the local irritant effect on epithelium due to the direct contact of drug with mucosal wall. In this work, developed ibuprofen pellet with double coatings aimed to release ibuprofen only when reaching colonic compartment. The results of pharmacokinetic study reported previously suggested that this might be a successful target. Present study described the potential benefits of this formula in exhibiting effective local anti inflammatory action in colon. Male Wistar rats were induced for ulcerative colitis with 2,4,6-trinitrobenzene sulfonic acid. Twenty four hours after induction, treatments were given using either ibuprofen suspension or pellet for 14 days. Ulcerations were observed visually, with gross anatomic and microscopic examinations. Group treated with ibuprofen pellet showed best recovery nearly close to healthy group. Moreover, the group did not develop ulceration in upper part of GIT. Colonic targeted ibuprofen pellet showed most effective local antiinflammatory action and at the same time reduced the ulcer formation in the upper part of GIT.

SPECT-computed tomography in rats with TNBS-induced colitis: A first step toward functional imaging

AIMTo assess the feasibility of SPECT-computed tomography (CT) in rats with trinitrobenzene sulfonic acid (TNBS)-induced acute colitis and confront it with model inflammatory characteristics.METHODSColitis was induced in Sprague-Dawley rats by intrarectal injection of TNBS (n = 10) while controls received vehicle (n = 10). SPECT-CT with intravenous injection of 10 MBq of 67Ga-Citrate was performed at day 2. SPECT-CT criteria were colon wall thickness and maximal wall signal intensity. Laboratory parameters were assessed: colon weight:length ratio, colon cyclooxygenase-2 expression by western blot and histological inflammatory score.RESULTSColon weight/length ratio, colon COX-2 expression and histological inflammatory score were significantly higher in the TNBS group than in the control group (P = 0.0296, P &#x0003c; 0.0001, P = 0.0007 respectively). Pixel max tend to be higher in the TNBS group than in the control group but did not reach statistical significance (P = 0.0662). Maximal thickness is significantly increased in the TNBS group compared to the control group (P = 0.0016) while colon diameter is not (P = 0.1904). Maximal thickness and colon diameter were correlated to colon COX-2 expression (P = 0.0093, P = 0.009 respectively) while pixel max was not (P = 0.22). Maximal thickness was significantly increased when inflammation was histologically observed (P = 0.0043) while pixel max and colon diameter did not (P = 0.2452, P = 0.3541, respectively).CONCLUSIONSPECT-CT is feasible and easily distinguished control from colitic rats.

Vedolizumab serum trough concentrations with and without thiopurines in ulcerative colitis: The prospective VIEWS pharmacokinetics study

BACKGROUND Ulcerative colitis(UC)is a chronic inflammatory condition requiring continuous treatment and monitoring.There is limited pharmacokinetic data on vedolizumab during maintenance therapy and the effect of thiopurines on vedolizumab trough concentrations is unknown.AIM To investigate the exposure-response relationship of vedolizumab and the impact of thiopurine withdrawal in UC patients who have achieved sustained clinical and endoscopic remission during maintenance therapy.METHODS This is a post-hoc analysis of prospective randomized clinical trial(VIEWS)involving UC patients across 8 centers in Australia from 2018 to 2022.Patients in clinical and endoscopic remission were randomized to continue or withdraw thiopurine while receiving vedolizumab.We evaluated vedolizumab serum trough concentrations,presence of anti-vedolizumab antibodies,and clinical outcomes over 48 weeks to assess exposure-response asso-ciation and impact of thiopurine withdrawal.RESULTS There were 62 UC participants with mean age of 43.4 years and 42%were females.All participants received vedolizumab as maintenance therapy with 67.7%withdrew thiopurine.Vedolizumab serum trough concentrations remained stable over 48 weeks regardless of thiopurine use,with no anti-vedolizumab antibodies detected.Pa-tients with clinical remission had higher trough concentrations at week 48.In quartile analysis,a threshold of>11.3μg/mL was associated with sustained clinical remission,showing a sensitivity of 82.4%,specificity of 60.0%,and an area of receiver operating characteristic of 0.71(95%CI:0.49-0.93).Patients discontinuing thiopurine required higher vedolizumab concentrations for achieving remission.CONCLUSION A positive exposure-response relationship between vedolizumab trough concentrations and UC outcomes suggests that monitoring drug levels may be beneficial.While thiopurine did not influence vedolizumab levels,its with-drawal may necessitate higher vedolizumab trough concentrations to maintain remission.

Ulcerative colitis and bullous pemphigoid:Direct association or a medication side effect:A case report

BACKGROUND Bullous pemphigoid(BP)is an autoimmune blistering skin disorder.It is associated with other autoimmune disorders and the use of certain drugs.We describe a case of BP in a patient with ulcerative colitis(UC)treated with mesalamine.CASE SUMMARY A 38-year-old male patient with UC and a history of multiple flares was maintained on mesalamine with good clinical response.One year after starting mesalamine,he sought medical care following the onset of a severe itchy rash of several weeks’duration with a recent appearance of skin bullae.A biopsy of the skin revealed subepidermal blistering dermatitis with focal eosinophilic spongiosis.Direct immunofluorescence studies revealed linear IgG and C3 immune reactant deposits at the dermoepidermal junction,consistent with the diagnosis of BP.Prednisone therapy alleviated his symptoms.However,tapering prednisone led to re-eruption of the bullae.CONCLUSION BP should be considered when patients with UC develop skin manifestations.Although BP is not one of the extraintestinal manifestations of UC,there may be an association between these two conditions.Whether treatment with mesalamine or other therapeutic agents plays a role in the development of BP remains unclear.

Septic shock due to cytomegalovirus colitis associated with rituximab use:A case report

BACKGROUND Cytomegalovirus(CMV)infections can cause significant morbidity and mortality in immunocompromised individuals.CMV targets dysfunctional lymphocytes.Chronic rituximab(RTX)therapy can cause B-lymphocyte dysfunction,increasing CMV risk.Rarely,CMV infections present with critical illness such as septic shock.CASE SUMMARY A 64-year-old African American woman presented with generalized weakness and non-bloody watery diarrhea of 4-6 weeks duration.She did not have nausea,vomiting or,abdominal pain.She had been on monthly RTX infusions for neuromyelitis optica.She was admitted for septic shock due to pancolitis.Blood investigations suggested pancytopenia and serology detected significantly elevated CMV DNA.Valganciclovir treatment led to disease resolution.CONCLUSION This case illustrates an extremely rare case of CMV colitis associated with RTX use presenting with septic shock.High suspicion for rare opportunistic infections is imperative in individuals with long-term RTX use.

Activation of nuclear factor-kappa B and effects of pyrrolidine dithiocarbamate on TNBS-induced rat colitis

AIM: To explore the changes of nuclear factor-kappa B (NF-κB) DNA-binding activity, the expression of intercellular adhesion molecule-1(ICAM-1) regulated by IMF-κB at various times and to evaluate the effects of pyrrolidine dithiocarbamate (PDTC) on trinitrobenzene sulfonic acid (TNBS)-induced rat colitis. METHODS: TNBS of 0.6 mL was mixed with ethanol of 0.3 mL solution and instilled into the lumen of the rat colon. The rat models were divided into 6 groups, which were killed at 24 h, 3, 7,14, and 21 d after enema. Colonic inflammation and damage were assessed by macroscopical and histological criteria. Activity of NF-κB DNA-binding was analyzed by electrophoresis mobility shift assays (EMSA). Expression of ICAM-1 was detected by in situ hybridization (ISH) and immunohistochemistry (IH). Then various doses of PDTC were injected into rat abdomen 30 min before enema with TNBS/ethanol as pretreatment. The rats were killed 4 h after enema and the colonic inflammation, myeloperoxidase (MPO) activity, malondialdehyde (MDA) level, and DNA-binding activity of NF-κB were assessed. Finally, PDTC was injected intraperitoneally after colitis was induced. Changes of morphology were assayed. RESULTS: During the first week, hyperemia, hemorrhage, edema and ulceration of the colonic mucosa appeared with predominant infiltration of leukocytes. Neutrophils, macrophages, lymphocytes infiltrated in mucosa and submucosa 14 d later. Fibroblasts and granuloma-like structures were also obviously seen. The binding activity of NF-κB began to increase at 24 h time point and reached a peak at 14 d, then decreased but still was higher than control group at 21 d (P<0.01). Levels of ICAM-1 mRNA and protein significantly elevated at 24 h and the peak was at 21 d. Pretreatment with PDTC could attenuate the development of inflammation but not by reducing NF-KB activity. This attenuation of inflammation had a positive relationship with the dose of PDTC. PDTC at the dose of 100 mg/kg had no therapeutic effect after colitis was induced. CONCLUSION: NF-κB activation is an important event that may be involved in acute and chronic inflammation development and may contribute to self-protection against early inflammation damage. NF-κB also regulates ICAM-1 expression during colonic inflammation. Pretreatment of PDTC may attenuate the inflammation development. But PDTC has no therapeutic effect after the colitis is induced.

BLT1 in dendritic cells promotes Th1/Th17 differentiation and its deficiency ameliorates TNBS-induced colitis

Leukotriene B4(LTB4)synthesis is enhanced in the colonic mucosa in patients with inflammatory bowel disease(IBD).BLT1,a highaffinity receptor for LTB4,exhibits no effect on the progression of dextran sodium sulfate(DSS)-induced colitis,which mostly relies on innate immunity.Here,we reported that BLT1 regulates trinitrobenzene sulfonic acid(TNBS)-induced colitis,which reflects CD4+T-cell-dependent adaptive immune mechanisms of IBD.We found that BLT1 signaling enhanced the progression of colitis through controlling the production of proinflammatory cytokines by dendritic cells(DCs)and modulating the differentiation of Th1 and Th17.BLT1−/−mice displayed an alleviated severity of TNBS-induced colitis with reduced body weight loss and infiltrating cells in the lamina propria.BLT1 deficiency in DCs led to reduced production of proinflammatory cytokines,including IL-6,TNF-α,and IL-12,and these results were further confirmed via treatment with a BLT1 antagonist.The impaired cytokine production by BLT1−/−DCs subsequently led to reduced Th1 and Th17 differentiation both in vitro and in vivo.We further performed a conditional DC reconstitution experiment to assess whether BLT1 in DCs plays a major role in regulating the pathogenesis of TNBS-induced colitis,and the results indicate that BLT1 deficiency in DCs also significantly reduces disease severity.The mechanistic study demonstrated that BLT1-regulated proinflammatory cytokine production through the Gαiβγsubunit-phospholipase Cβ(PLCβ)-PKC pathway.Notably,we found that treatment with the BLT1 antagonist also reduced the production of proinflammatory cytokines by human peripheral blood DCs.Our findings reveal the critical role of BLT1 in regulating adaptive immunity and TNBS-induced colitis,which further supports BLT1 as a potential drug target for adaptive immunity-mediated IBD.

Role of nitric oxide in the impairment of circular muscle contractility of distended, uninflamed mid-colon in TNBS-induced acute distal colitis in rats

AIM： To evaluate the role of nitric oxide （NO） in the motor disorders of the dilated uninflamed mid-colon （DUMC） from trinitrobenzene sulfonic acid （TNBS）-induced acute distal colitis in rats. METHODS： Colitis was induced in male Sprague-Dawley rats by a single intracolonic administration of TNBS. Control rats received an enema of 0.9% saline. The rats were killed 48 h after TNBS or saline administration. Macroscopic and histologic lesions of the colon were evaluated. Myeloperoxidase （MPO） and nitric oxide synthase （NOS） activity were measured on the colonic tissue. In TNBS rats, we evaluated spontaneous and evoked contractile activity in circular muscle strips derived from DUMC in comparison to the same colonic segment of control rats, both in the presence and in the absence of a non-selective NOS isoforms inhibitor N-nitro-L- arginine （L-NNA）. Pharmacological characterization of electric field stimulation （EFS）-evoked contractile responses was also performed. RESULTS： In TNBS rats, the distal colon showed severe histological lesions and a high MPO activity, while the DUMC exhibited normal histology and MPO activity. Constitutive NOS activity was similar in TNBS and control rats, whereas inducible NOS activity was significantly increased only in the injured distal colon of TNBS rats. Isometrically recorded mechanical activity of circular muscle strips from DUMC of TNBS rats showed a marked reduction of the force and frequency of spontaneous contractions compared to controls, as well as of the contractile responses to a contracting stimulus. In the presence of L-NNA, the contractile activity and responses displayed a significantly greater enhancement compared to controls. The pharmacological characterization of EFS contractile responses showed that a cooperative-like interaction between cholinergic muscarinic and tachyldnergic neurokinin 1 and 2 receptors mediated transmission in DUMC of TNBS rats vs a simple additive interaction in controls. CONCLUSION： The results of this study show that, during TNBS-induced acute distal colitis, circular muscle intrinsic contractile mechanisms and possible enteric neural excitatory activity are inhibited in the distended uninflamed mid-colon. Suppression of NO synthesis markedly improves spontaneous and evokes muscle contractions, in spite of any evident change in local NO activity. 2005 The WJG Press and Elsevier Inc. All rights reserved

Real-world efficacy and safety of tofacitinib treatment in Asian patients with ulcerative colitis

BACKGROUND Real-world data on tofacitinib(TOF)covering a period of more than 1 year for a sufficient number of Asian patients with ulcerative colitis(UC)are scarce.AIM To investigate the long-term efficacy and safety of TOF treatment for UC,including clinical issues.METHODS We performed a retrospective single-center observational analysis of 111 UC patients administered TOF at Hyogo Medical University as a tertiary inflammatory bowel disease center.All consecutive UC patients who received TOF between May 2018 and February 2020 were enrolled.Patients were followed up until August 2020.The primary outcome was the clinical response rate at week 8.Secondary outcomes included clinical remission at week 8,cumulative persistence rate of TOF administration,colectomy-free survival,relapse after tapering of TOF and predictors of clinical response at week 8 and week 48.RESULTS The clinical response and remission rates were 66.3%and 50.5%at week 8,and 47.1%and 43.5%at week 48,respectively.The overall cumulative clinical remission rate was 61.7%at week 48 and history of anti-tumor necrosis factor-alpha(TNF-α)agents use had no influence(P=0.25).The cumulative TOF persistence rate at week 48 was significantly lower in patients without clinical remission than in those with remission at week 8(30.9%vs 88.1%;P<0.001).Baseline partial Mayo Score was significantly lower in responders vs non-responders at week 8(odds ratio:0.61,95%confidence interval:0.45-0.82,P=0.001).Relapse occurred in 45.7%of patients after TOF tapering,and 85.7%of patients responded within 4 wk after re-increase.All 6 patients with herpes zoster(HZ)developed the infection after achieving remission by TOF.CONCLUSION TOF was more effective in UC patients with mild activity at baseline and its efficacy was not affected by previous treatment with anti-TNF-αagents.Most relapsed patients responded again after re-increase of TOF and nearly half relapsed after tapering off TOF.Special attention is needed for tapering and HZ.

Emerging role of exosomes in ulcerative colitis: Targeting NOD-like receptor family pyrin domain containing 3 inflammasome

Ulcerative colitis(UC)is a chronic recurrent inflammatory bowel disease.Despite ongoing advances in our understanding of UC,its pathogenesis is yet unelu-cidated,underscoring the urgent need for novel treatment strategies for patients with UC.Exosomes are nanoscale membrane particles that mediate intercellular communication by carrying various bioactive molecules,such as proteins,RNAs,DNA,and metabolites.The NOD-like receptor family pyrin domain containing 3(NLRP3)inflammasome is a cytosolic tripartite protein complex whose activation induces the maturation and secretion of proinflammatory cytokines interleukin-1β(IL-1β)and IL-18,triggering the inflammatory response to a pathogenic agent or injury.Growing evidence suggests that exosomes are new modulators of the NLRP3 inflammasome,with vital roles in the pathological process of UC.Here,recent evidence is reviewed on the role of exosomes and NLRP3 inflammasome in UC.First,the dual role of exosomes on NLRP3 inflammasome and the effect of NLRP3 inflammasome on exosome secretion are summarized.Finally,an outlook on the directions of exosome-NLRP3 inflammasome crosstalk research in the context of UC is proposed and areas of further research on this topic are high-lighted.

Upadacitinib for refractory ulcerative colitis with primary nonresponse to infliximab and vedolizumab:A case report

BACKGROUND Many patients with ulcerative colitis(UC)do not respond well to,or tolerate conventional and biological therapies.There is currently no consensus on the treatment of refractory UC.Studies have demonstrated that the selective Janus kinase 1 inhibitor upadacitinib,a small-molecule drug,is effective and safe for treating UC.However,no studies have revealed that upadacitinib is effective in treating refractory UC with primary nonresponse to infliximab and vedolizumab.CASE SUMMARY We report the case of a 44-year-old male patient with a chief complaint of bloody diarrhoea with mucus and pus,in addition to dizziness.The patient had recurrent disease after receiving mesalazine,prednisone,azathioprine,infliximab and vedolizumab over four years.Based on the endoscopic findings and pathological biopsy,the patient was diagnosed with refractory UC.In particular,the patient showed primary nonresponse to infliximab and vedolizumab.Based on the patient’s history and recurrent disease,we decided to administer upadacitinib.During hospitalisation,the patient was received upadacitinib under our guidance.Eight weeks after the initiation of upadacitinib treatment,the patient’s symptoms and endoscopic findings improved significantly.No notable adverse reactions have been reported to date.CONCLUSION Our case report suggests that upadacitinib may represent a valuable strategy for treating refractory UC with primary nonresponse.

Are we ready to use new endoscopic scores for ulcerative colitis?

For ulcerative colitis(UC),the variability in inflammatory activity along the colon poses a challenge in management.The focus on achieving endoscopic healing in UC is evident,where the UC Endoscopic Index of Severity and Mayo Endoscopic Subscore are commonly used for evaluation.However,these indices primarily consider the most severely affected region.Liu et al recent study validates the Toronto Inflammatory Bowel Disease Global Endoscopic Reporting(TIGER)score offering a comprehensive assessment of inflammatory activity across diverse segments of the colon and rectum and a reliable index correlating strongly with UC Endoscopic Index of Severity and moderately with Mayo Endoscopic Subscore(MES).Despite recommendation,certain aspects warrant further invest-igation.Fecal calprotectin,an intermediate target,correlates with TIGER and should be explored.Determining TIGER scores defining endoscopic remission and response,evaluating agreement with histological activity,and assessing inter-endoscopist agreement for TIGER require scrutiny.Exploring the correlation between TIGER and intestinal ultrasound,akin to MES,adds value.

Five commonly used traditional Chinese medicine formulas in the treatment of ulcerative colitis:A network meta-analysis

BACKGROUND Currently,traditional Chinese medicine(TCM)formulas are commonly being used as adjunctive therapy for ulcerative colitis in China.Network meta-analysis,a quantitative and comprehensive analytical method,can systematically compare the effects of different adjunctive treatment options for ulcerative colitis,providing scientific evidence for clinical decision-making.AIM To evaluate the clinical efficacy and safety of commonly used TCM for the treatment of ulcerative colitis(UC)in clinical practice through a network metaanalysis.METHODS Clinical randomized controlled trials of these TCM formulas used for the adjuvant treatment of UC were searched from the establishment of the databases to July 1,2022.Studies that met the inclusion criteria were screened and evaluated for literature quality and risk of bias according to the Cochrane 5.1 standard.The methodological quality of the studies was assessed using ReviewManager(RevMan)5.4,and a funnel plot was constructed to test for publication bias.ADDIS 1.16 statistical software was used to perform statistical analysis of the treatment measures and derive the network relationship and ranking diagrams of the various intervention measures.RESULTS A total of 64 randomized controlled trials involving 5456 patients with UC were included in this study.The adjuvant treatment of UC using five TCM formulations was able to improve the clinical outcome of the patients.Adjuvant treatment with Baitouweng decoction(BTWT)showed a significant effect[mean difference=36.22,95%confidence interval(CI):7.63 to 65.76].For the reduction of tumor necrosis factor in patients with UC,adjunctive therapy with BTWT(mean difference=−9.55,95%CI:−17.89 to−1.41),Shenlingbaizhu powder[SLBZS;odds ratio(OR)=0.19,95%CI:0.08 to 0.39],and Shaoyao decoction(OR=−23.02,95%CI:−33.64 to−13.14)was effective.Shaoyao decoction was more effective than BTWT(OR=0.12,95%CI:0.03 to 0.39),SLBZS(OR=0.19,95%CI:0.08 to 0.39),and Xi Lei powder(OR=0.34,95%CI:0.13 to 0.81)in reducing tumor necrosis factor and the recurrence rate of UC.CONCLUSION TCM combined with mesalazine is more effective than mesalazine alone in the treatment of UC.

Exploring the autophagy-related pathogenesis of active ulcerative colitis

BACKGROUND The pathogenesis of ulcerative colitis(UC)is complex,and recent therapeutic advances remain unable to fully alleviate the condition.AIM To inform the development of novel UC treatments,bioinformatics was used to explore the autophagy-related pathogenesis associated with the active phase of UC.METHODS The GEO database was searched for UC-related datasets that included healthy controls who met the screening criteria.Differential analysis was conducted to obtain differentially expressed genes(DEGs).Au-tophagy-related targets were collected and intersected with the DEGs to identiy differentially expressed autophagy-related genes(DEARGs)associated with active UC.DEARGs were then subjected to KEGG,GO,and DisGeNET disease enrichment analyses using R software.Differential analysis of immune infiltrating cells was performed using the CiberSort algorithm.The least absolute shrinkage and selection operator algorithm and protein-protein interaction network were used to narrow down the DEARGs,and the top five targets in the Dgree ranking were designated as core targets.RESULTS A total of 4822 DEGs were obtained,of which 58 were classified as DEARGs.SERPINA1,BAG3,HSPA5,CASP1,and CX3CL1 were identified as core targets.GO enrichment analysis revealed that DEARGs were primarily enriched in processes related to autophagy regulation and macroautophagy.KEGG enrichment analysis showed that DEARGs were predominantly associated with NOD-like receptor signaling and other signaling pathways.Disease enrichment analysis indicated that DEARGs were significantly linked to diseases such as malignant glioma and middle cerebral artery occlusion.Immune infiltration analysis demonstrated a higher presence of immune cells like activated memory CD4 T cells and follicular helper T cells in active UC patients than in healthy controls.CONCLUSION Autophagy is closely related to the active phase of UC and the potential targets obtained from the analysis in this study may provide new insight into the treatment of active UC patients.

Congestive ischemic colitis successfully treated with antiinflammatory therapy: A case report

BACKGROUND Congestive ischemic colitis is a rare subtype of ischemic colitis with an unknown pathophysiology.Excluding conservative management,such as fasting,no established treatment exists;therefore,surgical intervention should be considered in some cases if symptoms worsen.Current literature suggests that anti-inflam-matory agents may effectively treat congestive ischemic colitis.CASE SUMMARY We present the case of a 68-year-old female patient who underwent laparoscopic left hemicolectomy for transverse colon cancer 3 years ago.Postoperatively,follow-up included an annual colonoscopy and abdominal computed tomography(CT)at a local clinic.However,progressive erythema and edema of the sigmoid colon were observed 1 year postoperatively.Upon admission to our hospital,she complained of abdominal pain and diarrhea.Abdominal CT showed thickening of the sigmoid colon walls,and colonoscopy revealed erythema,edema,and multiple ulcers with exudate in the sigmoid colon.CT angiography showed engorgement of the sigmoid vasa recta without any vascular abnormalities.The diagnosis was congestive ischemic colitis,and we treated the patient with anti-inflammatory agents.After 2 mo of glucocorticoid therapy(20 mg once daily)and 7 mo of 5-aminosalicylate therapy(1 g twice daily),the ulcers completely healed.She has not experienced any recurrence for 2 years.CONCLUSION Anti-inflammatory therapy,specifically glucocorticoids and 5-aminosalicylate,has demonstrated promising efficacy and introduces potential novel treatment options for congestive ischemic colitis.