Xipayi Kui Jie'an (KJA), a type of traditional Uygur medicine (TUM), has shown promising therapeutic effects in Ulcerative colitis (UC). Owing to the complexity of TUM, the pharmacological mechanism of KJA remains vague. Therefore, the identification of complex molecular mechanisms is a major challenge and a new method is urgently needed to address this problem. In this study, we established a feasible pharmacological model based on systems pharmacology to identify potential compounds and targets. We also applied compound-target and target-diseases network analysis to evaluate the action mechanisms. According to the predicted results, 12 active compounds were selected and these compounds were also identified by HPLC-ESI-MS/MS analysis. The main components were tannins, this result is consistent with the prediction. The active compounds interacted with 22 targets. Two targets including PTGS2 and PPARG were demonstrated to be the main targets associated with UC. Systematic analysis of the constructed networks revealed that these targets were mainly involved in NF-κB signaling pathway. Furthermore, KJA could also regulate the CD4 + CD25 + Foxp3 + Treg cells. In conclusion, this systems pharmacology-based approach not only explained that KJA could alleviate the UC by regulating its candidate targets, but also gave new insights into the potential novel therapeutic strategies for UC.

Acute radiation proctitis (ARP) is one of the most common complications of pelvic radiotherapy attributed to radiation exposure. The mechanisms of ARP are related to inflammation, angiogenesis, and so on. In this study we evaluated the effect of dexamethasone (DXM) combined with gentamicin (GM) enema on ARP mice, and explored its possible mechanisms by transcriptome sequencing, western blot and immunohistochemistry. C57BL/6 mice were randomly divided into 3 groups: healthy control group, ARP model group, and DXM + GM enema treatment group. ARP mice were established by using a single 6 MV X-ray dose of 27 Gy pelvic local irradiation. Transcriptome sequencing results showed that 979 genes were co-upregulated and 445 genes were co-downregulated in ARP mice compared to healthy mice. According to gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis, we firstly found that PI3K/AKT/NF-κB/VEGF pathways were mostly correlated with the inflammation-induced angiogenesis in ARP mice. PI3K/AKT pathway leads to the activation of NF-κB, which promotes the transcription of VEGF and Bcl-2. Interestingly, symptoms and pathological changes of ARP mice were ameliorated by DXM + GM enema treatment. DXM + GM enema inhibited inflammation by downregulating NF-κB and upregulating AQP3, as well as inhibited angiogenesis by downregulating VEGF and AQP1 in ARP mice. Moreover, DXM + GM enema induced apoptosis by increasing Bax and suppressing Bcl-2. The novel mechanisms may be related to the downregulation of PI3K/AKT/NF-κB/VEGF pathways.

Fecal microbiota transplant is a promising therapy for ulcerative colitis. Parameters maximizing effectiveness and tolerability are not yet clear, and it is not known how import the transmission of donor microbes to patients is. Here (clinicaltrails.gov: NCT03006809) we have tested the effects of antibiotic pretreatment and compared two modes of maintenance dose delivery, capsules versus enema, in a randomized, pilot, open-label, 2 × 2 factorial design with 22 patients analyzed with mild to moderate UC. Clinically, the treatment was well-tolerated with favorable safety profile. Of patients who received antibiotic pretreatment, 6 of 11 experienced remission after 6 weeks of treatment, versus 2 of 11 non-pretreated patients (log odds ratio: 1.69, 95% confidence interval: -0.25 to 3.62). No significant differences were found between maintenance dosing via capsules versus enema. In exploratory analyses, microbiome turnover at both the species and strain levels was extensive and significantly more pronounced in the pretreated patients. Associations were also revealed between taxonomic turnover and changes in the composition of primary and secondary bile acids. Together these findings suggest that antibiotic pretreatment contributes to microbiome engraftment and possibly clinical effectiveness, and validate longitudinal strain tracking as a powerful way to monitor the dynamics and impact of microbiota transfer.

Stress is a powerful modulator of neuroendocrine, behavioral, and immunological functions. So far, the molecular mechanisms of response to stressors still remain elusive. In the current study, after 10 days of repeated chronic stress (hot-dry environment and electric foot-shock), a murine model of combined-stress (CS) was created in the SPF Wistar rats. Meanwhile, we established an ulcerative-colitis (UC) rat model induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS)/ethanol enema according to previous studies. The blood, hypothalamus, and colon tissues of these rats from CS, normal control (NC), UC and sham (SH) groups, were collected for further investigations. Comparing to the NC group, the serum levels of T3, T4, fT3 and fT4 were obviously decreased in the CS group after chronic stress, indicating that thyroid dysfunction was induced by long-term combined stress. Moreover, the application of RNA-seq and subsequent analyses revealed that neurological disorder and immunosuppression were also caused in the hypothalamus and colon tissues, respectively. Comparing with SH group, besides the induced colon inflammation, thyroid dysfuntion and neurological disorder were also produced in the UC group, suggesting that hypothalamic-pituitary-thyroid (HPT) axis and gastrointestinal system might not function in isolation, but rather, have intricate crosstalks.

We aimed to investigate the prevalence of true rectocele and obstructed defecation (OD) in patients with pelvic organ prolapse (POP), to investigate the correlation between true rectocele and OD, and to understand the diagnostic value of translabial ultrasound (TLUS) in the diagnosis of true rectocele. The patients who scheduled for POP surgery were enrolled in this study. Patients who had previous reconstructive pelvic surgery or repair of rectocele were excluded. Birmingham Bowel and Urinary symptoms questionnaires and Longo's obstructed defecation syndrome scoring system were used to assess the bowel symptoms of patients. TLUS was used to evaluate anatomical defects. P value <0.05 was considered statistically significant, and confidence intervals were set at 95%. 279 patients were included into this study. The prevalence rate of OD was 43%, and the average value of ODS score was 6.67. 17% patients presented straining at stool, 33% presented incomplete emptying, 13% presented digitations, and 12% required laxatives or enema. The prevalence rate of true rectocele was 23%. Defecation symptoms were significantly correlated with age, levator-ani hiatus, levator-ani muscle injury and true rectocele. Logistic regression showed that true rectocele and increased levator-ani hiatus were independent risk factors of OD. True rectocele was significantly correlated with straining at stool, digitation, incomplete emptying and requirement of laxatives or enema.In POP patients, the prevalence rate of true rectocele and OD was 23% and 43%, respectively. True rectocele was related to OD. TLUS was a valuable approach in anatomical evaluation of POP.

To explore the clinical application value of optical coherence microscopy (OCM) in Hirschsprung's disease. 109 HSCR patients were recuited in a Chinese hospital from January 2018 to July 2021. All the recruited patients underwent barium enema angiography preoperatively and the resected diseased intestinal tubes were evaluated intraoperatively. The OCM and the histopathological examination were performed successively on the surgical specimens, and the OCM images were compared with the relevant tissue sections to characterize different lesions. 10 non-HSCR fetal colorectal tissues at the same period were retained for OCM, the characteristics of which with and without HSCR under OCM imaging were analyzed. In the OCM images of in vitro tissue, it can be clearly observed that the scattering degree of HSCR narrow segment mucosal is high, glands and crypt structures are reduced or even atrophy, and the scattering degree of submucosal and intermuscular is low; In the dilated segment, the low scattering and high scattering are complex, and the muscle layer is obviously hypertrophy and structural disorder. Compared with the pathological findings, the OCM sensitivity, Kappa value, and AUC area reached 92.66%, 0.63, and 0.91, respectively. OCM can quickly and clearly display the structure of all layers of colorectal tissue, which is highly consistent with the corresponding histopathological examination results and has high sensitivity. which will provide a more reliable basis for OCM diagnosis of early HSCR, targeted biopsy and location of operative treatment, and has a certain potential for clinical application.

Topical 5-aminosalicylic acid (5-ASA) and corticosteroids are used frequently in the treatment of active distal ulcerative colitis (UC). Our study aimed to determine the efficacy and safety of different topical drugs used to treat active distal UC. A random-effects model within a Bayesian framework was utilized to compare treatment effects and safety as odds ratios (ORs) with corresponding 95% credible intervals (CrI). The surface under the cumulative ranking area (SUCRA) and median rank (MR) with corresponding 95% CrI were calculated to rank the treatment outcomes. In the induction of clinical and endoscopic remission, most regimens showed significant advantages over placebo except topical budesonide 0.5 mg/d and hydrocortisone 100 mg/d. According to SUCRA and MR values, rectal 5-ASA 1.5 to 2.0 g/d + Beclomethasone dipropionate (BDP) 3 mg/d rendered the highest probability of being the best regimen to achieve clinical and endoscopic remission, followed by the separate use of 5-ASA 4 g/d and BDP 3 mg/d. The occurrence of adverse events was not significantly different between each treatments and placebo. In conclusion, the combined use of topical 5-ASA and BDP proved to be the best choice for active distal UC and further well-designed researches are warranted to assess its efficacy and safety.

Mesenchymal stem cells (MSCs) are a new therapeutic strategy for inflammatory bowel disease (IBD), and their efficacy has been widely recognized. However, there are still some challenges in cell therapy, including stable cell passage, laboratory conditions for cell culture, high-cost burden, and poor transplantation. The conditioned medium (CM) of MSCs is considered be an excellent alternative to cell transplantation, but the paracrine group in MSC-CM is limited in variety and low in concentration, which cannot meet the therapeutic needs of injured tissues and needs to be optimized. Pretreatment with low concentration of hydrogen peroxide (H2O2) can not only protect cells from oxidative damage, but also play a role similar to growth factors and regulate the physiological function of stem cells, to obtain an improved conditioned medium. To determine the optimal protocol for pretreatment of MSCs with H2O2, and to study the efficacy and potential mechanism of MSC-CM pretreated with H2O2 on Dextran Sulfate Sodium (DSS)-induced acute experimental colitis. MSCs were exposed to different concentrations of H2O2, and the optimal H2O2 pretreatment conditions were determined by evaluating their critical cell functional properties. H2O2-pretreated MSC-CM was transplanted into experimental mouse colitis by enema at 2, 4, and 6 days in modeling, and the changes of colonic tissue structure, the levels of inflammation and oxidative stress, the molecular changes of Nrf2/Keap1/ARE axis, and the related indicators of apoptosis in colonic epithelial cells were observed in each group. In vitro, Pretreated MSCs with 25 μM H2O2 significantly enhanced cell proliferation, migration, and survival, but had no effect on apoptosis. In vivo, MSC-CM treatment decreased apoptosis and extracellular matrix deposition, and maintained the mechanical barrier and permeability of colonic epithelial cells in experimental mouse colitis. Mechanistically, H2O2-pretreated MSC-CM against reactive oxygen species (ROS) production and MDA generation, accompanied by increases in components of the enzymatic antioxidant system includes SOD, CAT, GSH-PX, and T-AOC, which is through the up-regulation of the Nrf2, HO-1, and NQO-1 antioxidant genes. Our data confirmed that 25 μM H2O2 pretreated MSC-CM treatment could effectively improve intestinal mucosal repair in experimental colitis, which may be achieved by activating Nrf2/Keap1/ARE pathway.