Exploring the mechanism of electroacupuncture at different acupoints on acute colitis rats based on JAK2/STAT3/SOCS1 signaling pathway

Objective:To investigate the mechanism of JAK2/STAT3/SOCS1 signaling pathway in electroacupuncture of different acupoints on acute colitis rats.Methods:36 SPF SD rats were randomly divided into 6 groups,with 6 rats in each group.The rat model of acute colitis was prepared by enema with glacial acetic acid solution.After the model was established,electroacupuncture was given to each acupoint group,with density wave,frequency 2Hz-50 Hz,intensity 2 mA,muscle tremor as the degree 20 min/time,1 time/day,for 3 consecutive days.Observe the general condition of rats;the pathological changes of colonic mucosa in rats were observed by HE method.The contents of serum interleukin-4(IL-4)and interleukin-8(IL-8)were detected by ELISA.Western blot and RT-PCR were used to detect the expression of JAK2,STAT3,SOCS1 protein and mRNA in rat colon tissue.Results:In contrast to the normal group,the overall condition of the model group was worse,the colonic mucosa was severely damaged,even necrotic,and the ulcer surface was obvious.The content of IL-4 in serum was obviously reduced,and the content of IL-8 was obviously go up(P<0.01).The protein content of JAK2,STAT3 and the expression of JAK2,STAT3 mRNA in colon tissue of rats were obviously go up,while the protein content of SOCS1 and the expression of SOCS1 mRNA were obviously reduced(P<0.01).In contrast to the model group,the general condition of rats in each acupoint group was significantly improved,the damage and necrosis of colonic mucosa and ulcer surface were obviously alleviated,the content of IL-4 in serum was obviously go up,and the content of IL-8 was significantly decreased(P<0.01).The protein content of JAK2,STAT3 and the expression of JAK2,STAT3 mRNA in colon tissue of rats were obviously reduced,while the protein content of SOCS1 and the expression of SOCS1 mRNA were obviously go up(P<0.05,P<0.01).Comparison of different acupoint groups,the colonic mucosal injury in the Zusanli group was significantly reduced,the content of serum IL-4 was significantly increased,and the content of IL-8 was significantly decreased(P<0.05,P<0.01).The protein content and mRNA expression of JAK2 and STAT3 in colon tissue were significantly down-regulated,while the protein content and mRNA expression of SOCS1 were significantly go up(P<0.05,P<0.01).Conclusion:Electroacupuncture at each acupoint can improve the damage of colonic mucosa and reduce the inflammatory response.The therapeutic effect of Zusanli(ST36)is better than that of Tianshu(ST25),Dachangshu(BL25)and Shangjuxu(ST37).The mechanism may be related to the regulation of JAK2/STAT3/SOCS1 signaling pathway related proteins and inflammatory cytokines IL-4 and IL-8.

Mucosal healing progression after acute colitis in mice

BACKGROUND Mucosal healing has become a therapeutic goal to achieve stable remission in patients with inflammatory bowel diseases. To achieve this objective, overlapping actions of complex cellular processes, such as migration, proliferation, and differentiation, are required. These events are longitudinally and tightly controlled by numerous factors including a wide range of distinct regulatory proteins. However, the sequence of events associated with colon mucosal repair after colitis and the evolution of the luminal content characteristics during this process have been little studied.AIM To document the evolution of colon mucosal characteristics during mucosal healing using a mouse model with chemically-induced colitis.METHODS C57 BL/6 male mice were given 3.5% dextran sodium sulfate(DSS) in drinking water for 5 d. They were euthanized 2(day 7), 5(day 10), 8(day 13), and 23(day28) d after DSS removal. The colonic luminal environment and epithelial repair processes during the inflammatory flare and colitis resolution were analyzed with reference to a non-DSS treated control group, euthanized at day 0. Epithelial repair events were assessed histo-morphologically in combination with functional permeability tests, expression of key inflammatory and repairing factors, and evaluation of colon mucosa-adherent microbiota composition by 16 S rRNA sequencing.RESULTS The maximal intensity of colitis was concomitant with maximal alterations of intestinal barrier function and histological damage associated with goblet cell depletion in colon mucosa. It was recorded 2 d after termination of the DSStreatment, followed by a progressive return to values similar to those of control mice. Although signs of colitis were severe(inflammatory cell infiltrate, crypt disarray, increased permeability) and associated with colonic luminal alterations(hyperosmolarity, dysbiosis, decrease in short-chain fatty acid content), epithelial healing processes were launched early during the inflammatory flare with increased gene expression of certain key epithelial repair modulators, including transforming growth factor-β, interleukin(Il)-15, Il-22, Il-33, and serum amyloid A. Whereas signs of inflammation progressively diminished, luminal colonic environment alterations and microscopic abnormalities of colon mucosa persisted long after colitis induction.CONCLUSION This study shows that colon repair can be initiated in the context of inflamed mucosa associated with alterations of the luminal environment and highlights the longitudinal involvement of key modulators.

Older adults with acute severe ulcerative colitis have similar steroid non-response and colectomy rates as younger adults

BACKGROUND There is paucity of data on outcomes of acute severe ulcerative colitis(ASUC)in older adults(≥60 years of age).AIM To assess steroid non-response rates during the index admission for ASUC in older adults.Secondary outcomes were response to medical rescue therapy and colectomy rates;at index admission,3 and 12 mo.METHODS This retrospective multicentre cohort study included ASUC admissions who received intravenous steroids between January 2013 and July 2020 at two tertiary hospitals.Electronic medical records were reviewed to collect clinical,biochemical,and endoscopic data.A modified Poisson regression model was used for analysis.RESULTS Of 226 ASUC episodes,45(19.9%)occurred in patients≥60 years of age.Steroid non-response rates were comparable in older adults and patients<60 years of age[19(42.2%)vs 85(47%),P=0.618],crude risk ratio(RR)=0.89[95%confidence interval(CI):0.61-1.30],adjusted RR=0.99(0.44-2.21).Rates of response to medical rescue therapy in older adults was comparable to the younger cohort[76.5%vs 85.7%,P=0.46,crude RR=0.89(0.67-1.17)].Index admission colectomy[13.3%vs 10.5%,P=0.598,crude RR=1.27(0.53-2.99),adjusted RR=1.43(0.34-6.06)],colectomy at 3 mo[20%vs 16.6%,P=0.66,crude RR=1.18(0.61-2.3),adjusted RR=1.31(0.32-0.53)]and colectomy at 12 mo[20%vs 23.2%,P=0.682,crude RR=0.85(0.45-1.57),adjusted RR=1.21(0.29-4.97)],were similar between the two groups.CONCLUSION In older adults with ASUC,the steroid non-response rate,response to medical rescue therapy,and colectomy rate at index admission,3 and 12 mo is similar to patients less than 60 years of age.

Treatment of acute severe ulcerative colitis using accelerated infliximab regimen based on infliximab trough level:A case report

BACKGROUND Acute severe ulcerative colitis (ASUC) is a complication of ulcerative colitisassociated with high levels of circulating tumor necrosis factor alpha, due to theintense inflammation and faster stool clearance of anti-tumor necrosis factordrugs. Dose-intensified infliximab treatment can be beneficial and is associatedwith lower rates of colectomy. The aim of the study was to present a case of apatient with ASUC and megacolon, treated with hydrocortisone and acceleratedscheme of infliximab that was monitored by drug trough level.CASE SUMMARYA 22-year-old female patient diagnosed with ulcerative colitis, presented withdiarrhea, rectal bleeding, abdominal pain, vomiting, and distended abdomen.During investigation, a positive toxin for Clostridium difficile and colonic dilatationof 7 cm consistent with megacolon were observed. She was treated with oralvancomycin for pseudomembranous colitis and intravenous hydrocortisone forsevere colitis, which led to the resolution of megacolon. Due to the persistentsevere colitis symptoms, infliximab 5 mg/kg was prescribed, monitored by drugtrough level (8.8 μg/mL) and fecal calprotectin of 921 μg/g (< 30 μg/g). Based onthe low infliximab trough level after one week from the first infliximab dose, thepatient received a second infusion at week 1, consistent with the acceleratedregimen (infusions at weeks 0, 1, 2 and 6). We achieved a positive clinical andendoscopic response after 6 mo of therapy, without the need for a colectomy.CONCLUSIONInfliximab accelerated infusions can be beneficial in ASUC unresponsive to thetreatment with intravenous corticosteroids. Longitudinal studies are necessary todefine the best therapeutic drug monitoring and treatment regimen for thesepatients.

Predictive factors for a severe clinical course in ulcerative colitis: Results from population-based studies

Ulcerative colitis(UC)is characterized by chronic inflammation of the large bowel in genetically suscep-tible individuals exposed to environmental risk factors.The disease course can be difficult to predict,with symptoms ranging from mild to severe.There is no generally accepted definition of severe UC,and no single outcome is sufficient to classify a disease course as severe.There are several outcomes indicating a severe disease course,including progression of the disease’s extension,a high relapse rate,the development of acute severe colitis,colectomy,the occurrence of colorectal cancer and UC-related mortality.When evaluating a patient’s prognosis,it is helpful to do so in relation to these outcomes.Using these outcomes also makes it easier to isolate factors predictive of severe disease.The aims of this article are to evaluate different disease outcomes and to present predictive factors for these outcomes.

Development and validation of novel models for the prediction of intravenous corticosteroid resistance in acute severe ulcerative colitis using logistic regression and machine learning

Background The early prediction of intravenous corticosteroid(IVCS)resistance in acute severe ulcerative colitis(ASUC)patients remains an unresolved challenge.This study aims to construct and validate a model that accurately predicts IVCS resistance.Methods A retrospective cohort was established,with consecutive inclusion of patients who met the diagnosis criteria of ASUC and received IVCS during index hospitalization in Peking Union Medical College Hospital between March 2012 and January 2020.The primary outcome was IVCS resistance.Classification models,including logistic regression and machine learning-based models,were constructed.External validation was conducted in an independent cohort from Shengjing Hospital of China Medical University.Results A total of 129 patients were included in the derivation cohort.During index hospitalization,102(79.1%)patients responded to IVCS and 27(20.9%)failed;18(14.0%)patients underwent colectomy in 3 months;6 received cyclosporin as rescue therapy,and 2 eventually escalated to colectomy;5 succeeded with infliximab as rescue therapy.The Ulcerative Colitis Endoscopic Index of Severity(UCEIS)and C-reactive protein(CRP)level at Day 3 are independent predictors of IVCS resistance.The areas under the receiver-operating characteristic curves(AUROCs)of the logistic regression,decision tree,random forest,and extreme-gradient boosting models were 0.873(95%confidence interval[CI],0.704–1.000),0.648(95%CI,0.463–0.833),0.650(95%CI,0.441–0.859),and 0.604(95%CI,0.416–0.792),respectively.The logistic regression model achieved the highest AUROC value of 0.703(95%CI,0.473–0.934)in the external validation.Conclusions In patients with ASUC,UCEIS and CRP levels at Day 3 of IVCS treatment appeared to allow the prompt prediction of likely IVCS resistance.We found no evidence of better performance of machine learning-based models in IVCS resistance prediction in ASUC.A nomogrambased on the logistic regression model might aid in the management of ASUC patients.