Triggers for the Nrf2/ARE Signaling Pathway and Its Nutritional Regulation: Potential Therapeutic Applications of Ulcerative Colitis

Ulcerative colitis (UC), which affects millions of people worldwide, is characterized by extensive colonic injury involving mucosal and submucosal layers of the colon. Nuclear factor E2-related factor 2 (Nrf2) plays a critical role in cellular protection against oxidant-induced stress. Antioxidant response element (ARE) is the binding site recognized by Nrf2 and leads to the expression of phase II detoxifying enzymes and antioxidant proteins. The Nrf2/ARE system is a key factor for preventing and resolving tissue injury and inflammation in disease conditions such as UC. Researchers have proposed that both Keap1-dependent and Keap1-independent cascades contribute positive effects on activation of the Nrf2/ARE pathway. In this review, we summarize the present knowledge on mechanisms controlling the activation process. We will further review nutritional compounds that can modulate activation of the Nrf2/ARE pathway and may be used as potential therapeutic application of UC. These comprehensive data will help us to better understand the Nrf2/ARE signaling pathway and promote its effective application in response to common diseases induced by oxidative stress and inflammation.

707 Principles of Damage Control Surgery in Trauma and Beyond: Experience at A Tertiary Centre

Damage control surgery (DCS) is an abbreviated laparotomy used as a temporising measure in critically unwell patients who have limited physiological reserves to tolerate complex definitive surgeries. The aim of DCS is to address life-threatening haemorrhage and manage abdominal contamination. Following an abbreviated laparotomy, patients are continuously resuscitated in intensive care unit until physiological stability can be maintained for definitive surgeries. The role of DCS in the trauma setting is well-described; however, its principles can also be applied in General Surgery for a variety of indications such as mesenteric ischaemia, uncontrolled haemorrhage, and secondary peritonitis. Judicious selection of the non-trauma patient who will benefit from this strategy is paramount. We present two cases of a polytrauma patient (Patient A), and non-trauma patient with abdominal septic shock (Patient B) who underwent DCS at our tertiary centre. Patient A is a 49-year-old male involved in a road traffic accident who sustained multiple injuries including liver laceration, splenic laceration, and colonic injury. Intra-abdominal packing and repair of serosal tears were performed, with a re-look laparotomy 48 hours later -- no further bleeding or visceral injuries were identified. Patient B is a 51-year-old gentleman who re-presented in septic shock due to infected retroperitoneal collection following a bleeding duodenal ulcer, initially managed radiologically. A T tube was inserted into the duodenum with two abdominal drains at initial DCS. After thorough washout, a feeding jejunostomy was sited at the re-look laparotomy. 30-days mortality is 0% and both patients are under follow-up.

Sishen Pill Regulates Memory T Cells in Mice with Colitis via JAK/STAT 5 Signaling Pathway

Background: Memory T cell (Tm) has a pivotal role as host protection in autoimmune inflammatory diseases via a JAK/STAT signaling pathway. Sishen Pill (SSP) is a classic prescription used to treat chronic ulcerative colitis (UC). However, it is still unclear whether SSP can regulate immune memory function. In this study, we examined the effect of SSP and whether it can regulate immune memory function through a JAK/STAT5 signaling pathway.Methods: Mice were randomly divided into four groups (10 mice per group): Normal group (Normal), health mice without DSS administration; DSS group (DSS), mice with DSS administration; Sishen pill treated (DSS+SSP) group, colitis mice treated with SSP for 7 days; Mesalazine controlled (DSS+5-ASA) group, colitis mice treated with mesalazine for 7 days. The therapeutic effect of SSP was evaluated by macroscopic and microscopic observation; Tm and their subsets were analyzed by flow cytometry; Activation of the JAK/STAT signaling pathway was analyzed using a Western blot.Results: SSP significantly reversed weight loss and colonic injury (colon weight increase and colonic length shortening) caused by 3% dextran sodium sulfate (DSS). Flow cytometry showed that the percentages of CD4+ and CD8+ expressions on central memory T cells were enhanced after SSP treatment, while the CD4+ Tcm, CD4+ mTfh (memory T follicular helper) cells and their subpopulations were also significantly increased. Moreover, SSP inhibited the expression of STAT5 signaling pathway proteins JAK1, PIAS3, STAT5, p-STAT5, BIM, BAX, Caspase-3, and β-casein and promoted the expression of JAK3, PISA1, Bcl-2, and Caveolin-1. Conclusions: SSP can be used to effectively treat DSS-induced colitis by improving the status of immune memory via the JAK/STAT signaling pathway.

Primary Anastamosis Versus Colostomy in Patients with Penetrating Colonic Injuries

Objective: The aim of this study is to determine the outcomes among primary anastomosis versus colostomy in patients with penetrating colonic injuries. Study Design: Comparative Study Place and Duration: Study was conducted at surgical department of Mardan Medical complex, Mardan and Bakhtawar Amin Medical & Dental College, Multan for duration of one year from January, 2020 to January 2021 Methods: 70 patients were presented in this study. Patients were aged between 18-75 years. Patients details demographics age, sex and body mass index were recorded after taking informed written consent. Patients penetrating colonic injuries were admitted in emergency ward. Patients were equally (n=35) divided into 2-groups, A and B. For abdominal surgery, group A received primary anastomosis and group B received colostomy. Post-operatively outcomes and complications among both groups were identified. SPSS 22.0 version was used to analyze the data. Results: Mean age of the patients was 29.48 ± 16.4 years with mean BMI 23.16 ± 08.13 kg/m2. Total 50 (71.43%) were males and 20 (28.57%) were females. Fire arm injured 55 (78.6%) was the most common cause of colonic injury followed by stab wound 10 (14.3%) among both groups. Small gut 28 (40%) was the most common organ injured followed by liver 13 (18.6%). Mean hospital stay in primary group was 7.45 ± 7.6 days while in colostomy group hospital stay was 9.54 ± 5.9 days. Postoperatively complications were lower in group A, wound infection found in 9 (25.71%) patients while in group B it was 11 (31.43%). Rate of mortality in primary group was 2 (5.71%) while in colostomy group was 4 (11.43%). Conclusion: We concluded in this study that primary anastomosis was effective because of less hospital stay and less post-operatively complications as compared to colostomy. Mortality rate was higher observed in colostomy group as compared to primary. Keywords: Colostomy, Primary anastomy, Colonic Injuries

Critical role of interferons in gastrointestinal injury repair

The etiology of ulcerative colitis is poorly understood and is likely to involve perturbation of the complex interactions between the mucosal immune system and the commensal bacteria of the gut, with cytokines acting as important cross-regulators. Here we use IFN receptor-deficient mice in a dextran sulfate sodium (DSS) model of acute intestinal injury to study the contributions of type I and III interferons (IFN) to the initiation, progression and resolution of acute colitis. We find that mice lacking both types of IFN receptors exhibit enhanced barrier destruction, extensive loss of goblet cells and diminished proliferation of epithelial cells in the colon following DSS-induced damage. Impaired mucosal healing in double IFN receptor-deficient mice is driven by decreased amphiregulin expression, which IFN signaling can up-regulate in either the epithelial or hematopoietic compartment. Together, these data underscore the pleiotropic functions of IFNs and demonstrate that these critical antiviral cytokines also support epithelial regeneration following acute colonic injury.

Gastrin/CCK2R alleviates mucus barrier loss via β-arrestin1/NF-κBp65 signaling in ulcerative colitis

Background and Purpose: The defective colonic mucus barrier is a feature of ulcerative colitis (UC) that enables increased bacterial contact with the epithelium, which triggers mucosal damage, and gastrin has been reported to be able to promote healing through the cholecystokinin 2 receptor (CCK2R) signaling to increase epithelial regeneration and protect against colonic injury. However, the role of gastrin in UC remains unclear. Experimental Approach: Colonic samples from human sections and mouse models using β-arrestin1 wild-type (β-arr1-WT) and β-arrestin1 knockout (β-arr1-KO) littermates, intestinal epithelial cells specific NF-κBp65 deletion (NF-κBp65) and wild-type (NF-κBp65) mice were analyzed. The mucosal injury, goblet cells status, MUC2 expression and bacteria penetration/colonisation were examined, and the effect of gastrin in colitis was also investigated. Key Results: We demonstrate that mucus barrier loss and bacterial colonisation of the crypts were observed in colitis, and exogenous gastrin could restore the mucus barrier, reduce bacterial colonisation of the colonic crypts and alleviate colitis via CCK2R. Furthermore, targeting CCK2R by YF476, β-arrestin1 (β-arr1) deletion or intestinal epithelial NF-κBp65 deficiency breached gastrin-mediated mucus barrier restoration and mucosal protection in colitis. Conclusion and Implications: These data demonstrate that gastrin alleviates mucus barrier loss and bacterial colonisation of the colonic crypts via CCK2R/β-arr1/NF-κBp65 signaling in colitis, and this network may be a potential therapeutic target for UC.