Can visceral adipose tissue and skeletal muscle predict recurrence of newly diagnosed Crohn's disease in different treatments.

BACKGROUND AND AIMS: It is crucial to manage the recurrence of Crohn's disease (CD). This study is aimed to explore whether visceral adipose tissue (VAT) and skeletal muscle (SM) are associated with the recurrence of CD upon different treatments. METHODS: All patients with a definite diagnosis of CD were retrospectively divided into three groups according to distinct treatment regimens: 5-amino salicylic acid group (Group A), steroids + azathioprine (Group B) and biologics (Group C). The pretreatment computerized tomography (CT) images and clinical data were collected. The VAT area, mesenteric fat index (MFI), the ratio of VAT area to fat mass (VAT area/FM) were assessed. The primary end point was the recurrence of CD within 1 year of follow-up. RESULTS: A total of 171 CD patients were enrolled, including 57 (33.33%) patients in Group A, 70 (40.94%) patients in Group B and 44 (25.73%) patients in Group C. Patients with 1-year recurrence had higher MFI (P = 0.011) and VAT area/FM (P = 0.000). ROC curve demonstrated that patients with the ratio of VAT area/FM and MFI higher than 0.578 and 1.394 tended to have recurrence with the AUC of 0.707 and 0.709. Similar results could be observed in Group A & B but not in Group C. CONCLUSIONS: High VAT area/FM and MFI are related to recurrence within 1 year for newly diagnosed CD patients treated by 5-amino salicylic or azathioprine + steroids rather than biologics. We could not observe any radiological data associated with the recurrence of CD patients under biological treatment.

Phosphoproteomics Reveals Novel Insights into the Pathogenesis and Identifies New Therapeutic Kinase Targets of Ulcerative Colitis.

BACKGROUND: Ulcerative colitis (UC) is a chronic recurrent inflammatory disease with unclear etiology. Currently, safe and effective treatment options for UC remain to be developed. Kinases, which catalyze the phosphorylation of substrates, have emerged as promising therapeutic targets for inflammatory diseases. We clarified the kinase activity profile and phosphorylation network in UC and aimed to reveal new pathogenic mechanisms and potential therapeutic targets. METHODS: We first performed the phosphoproteomic analysis of rectal tissues from UC patients and healthy individuals. Further bioinformatic analyses revealed the remodeling of key kinases and signaling pathways. Then, we conducted a screening of kinases to identify new potential therapeutic targets through in vivo and in vitro experiments. RESULTS: Phosphoproteomics revealed a drastic remodeling of signaling pathways in UC, such as pathways related to tight junction, adhesion junction, and necroptosis. Additionally, the activity of kinases such as CDK2, CLK1 and AURKB were significantly changed. Additional screening of these kinases identified CDK2 as a potential therapeutic target for UC, as inhibiting CDK2 effectively alleviated dextran sulfate sodium-induced colitis in mice. Further research revealed that suppressing CDK2 remarkably inhibited RIPK1, RIPK3, and MLKL phosphorylation, as well as MLKL oligomerization, thereby inhibiting epithelial necroptosis and protecting the intestinal barrier. CONCLUSIONS: Our research deepened the understanding of UC pathogenesis through the lens of phosphorylation. Moreover, we identified CDK2 as a new potential therapeutic target for UC, revealing a novel role for CDK2 in necroptosis.

We conducted phosphoproteomics of rectal tissues from ulcerative colitis patients and healthy individuals. The results revealed a drastic remodeling of signaling pathways and identified CDK2 as a potential therapeutic target for ulcerative colitis. Inhibiting CDK2 effectively protected the intestinal barrier by suppressing epithelial necroptosis, and thereby alleviated dextran sulfate sodium­induced colitis.

Microcystin-LR Induces and Aggravates Colitis through NLRP3 Inflammasome-Mediated Pyroptosis in Mice.

Inflammatory bowel disease (IBD) is a chronic, lifelong gastrointestinal disease, characterized by periods of activity and remission. The etiology of IBD is closely related to environmental factors. Previous studies have shown that the cyanotoxin microcystin-LR (MC-LR) causes intestinal damage, even IBD. To explore MC-LR's effects and potential mechanisms on IBD occurrence and development, we used dextran-sulfate sodium gavage (DSS) and MC-LR together for the first time in mice. There were four groups of mice: (A) mice given PBS gavage (control, CT); (B) mice given 3% DSS gavage (DSS); (C) mice given 200 µg/kg MC-LR gavage (MC-LR); and (D) mice given 3% DSS + 200 µg/kg MC-LR gavage (DSS + MC-LR). Compared with the CT group, the MC-LR group and the DSS group demonstrated more severe colitis results, which presented as higher weight loss, an increased Disease Activity Index (DAI) score, shorter colon length, a higher degree of tissue structural damage, more apoptotic cells, and greater pro-inflammatory cytokines. Similarly, the DSS + MC-LR group showed more severe colitis compared with the DSS group. Subsequent experiments confirmed that MC-LR or DSS increased the expression of pyroptosis-related proteins mediated by the nucleotide-binding domain-like receptor protein 3 (NLRP3). Likewise, compared with the DSS group, the DSS + MC-LR group expressed these proteins at a higher level. In conclusion, our research is the first to show that MC-LR may induce colitis, and even IBD, through NLRP3 inflammasome-mediated pyroptosis, and it could aggravate DSS-induced colitis in the same way.

A pyroptosis-related gene signature for prognosis and immune microenvironment of pancreatic cancer.

Pancreatic cancer is one of the most lethal tumors owing to its unspecific symptoms during the early stage and multiple treatment resistances. Pyroptosis, a newly discovered gasdermin-mediated cell death, facilitates anti- or pro-tumor effects in a variety of cancers, whereas the impact of pyroptosis in pancreatic cancer remains unclear. Therefore, we downloaded RNA expression and clinic data from the TCGA-PAAD cohort and were surprised to find that most pyroptosis-related genes (PRGs) are not only overexpressed in tumor tissue but also strongly associated with overall survival. For their remarkable prognostic value, cox regression analysis and lasso regression were used to establish a five-gene signature. All patients were divided into low- and high-risk groups based on the media value of the risk score, and we discovered that low-risk patients had better outcomes in both the testing and validation cohorts using time receiver operating characteristic (ROC), nomograms, survival, and decision analysis. More importantly, a higher somatic mutation burden and less immune cell infiltration were found in the high-risk group. Following that, we predicted tumor response to chemotherapy and immunotherapy in both low- and high-risk groups, which suggests patients with low risk were more likely to respond to both immunotherapy and chemotherapy. To summarize, our study established an effective model that can help clinicians better predict patients' drug responses and outcomes, and we also present basic evidence for future pyroptosis related studies in pancreatic cancer.

C646 Protects Against DSS-Induced Colitis Model by Targeting NLRP3 Inflammasome.

Numerous pieces of evidence have identified that the NLRP3 inflammasome plays a pivotal role in the development and pathogenesis of colitis. Targeting the NLRP3 inflammasome represents a potential therapeutic treatment. Our previous studies have suggested that acetylation of NLRP3 is indispensable to NLRP3 inflammasome activation, and some acetyltransferase inhibitors could suppress the NLRP3 inflammasome activation. Here, we identified that C646, an inhibitor of histone acetyltransferase p300, exerts anti-inflammatory effects in DSS-induced colitis mice by targeting the NLRP3 inflammasome. Mechanistically, C646 not only inhibits NF-κB activation, leading to the decreased expression of pro-inflammatory cytokines (IL-1ß, IL-6, and TNF-α) and NLRP3, but also suppresses the NLRP3 inflammasome assembly by disrupting the interaction between NLRP3 and ASC. In addition, C646 attenuated the LPS-induced acute systemic inflammation model. Thus, our results demonstrate the ability of C646 to suppress the NLRP3 inflammasome activity and its potential application in the treatment of inflammatory bowel disease.

Functional Characterization of TMEM127 Variants Reveals Novel Insights into Its Membrane Topology and Trafficking.

CONTEXT: TMEM127 is a poorly known tumor suppressor gene associated with pheochromocytomas, paragangliomas, and renal carcinomas. Our incomplete understanding of TMEM127 function has limited our ability to predict variant pathogenicity. PURPOSE: To better understand the function of the transmembrane protein TMEM127 we undertook cellular and molecular evaluation of patient-derived germline variants. DESIGN: Subcellular localization and steady-state levels of tumor-associated, transiently expressed TMEM127 variants were compared to the wild-type protein using immunofluorescence and immunoblot analysis, respectively, in cells genetically modified to lack endogenous TMEM127. Membrane topology and endocytic mechanisms were also assessed. RESULTS: We identified 3 subgroups of mutations and determined that 71% of the variants studied are pathogenic or likely pathogenic through loss of membrane-binding ability, stability, and/or internalization capability. Investigation into an N-terminal cluster of missense variants uncovered a previously unrecognized transmembrane domain, indicating that TMEM127 is a 4- transmembrane, not a 3-transmembrane domain-containing protein. Additionally, a C-terminal variant with predominant plasma membrane localization revealed an atypical, extended acidic, dileucine-based motif required for TMEM127 internalization through clathrin-mediated endocytosis. CONCLUSION: We characterized the functional deficits of several germline TMEM127 variants and identified novel structure-function features of TMEM127. These findings will assist in determining pathogenicity of TMEM127 variants and will help guide future studies investigating the cellular role of TMEM127.

Changes of second-time mothers and their infants under the universal two-child policy in Changsha, China.

BACKGROUND: China announced the implementation of the universal two-child policy in Oct, 2015; every couple was allowed to have two children. However, its influences on maternal well-being and infants' outcomes are still to be discovered. OBJECTIVES: To detect influences of the universal two-child policy. To provide information for maternal health care under the new policy. STUDY DESIGN: This study enrolled 859 and 1230 women who delivered their second child (hereafter second-time mothers) before and after the policy's implementation, respectively, and the data included maternal demographic characteristics, gestational complications, delivery mode and infants' outcomes. RESULTS: After the policy's implementation, the proportion of second-time mothers with advanced age increased significantly. The advanced gestational age is well acknowledged to correlate with higher risk during the pregnancy, both for pregnant women and their babies. However, in our study, the incidence of hypertensive disorders in pregnancy, placenta previa and postpartum haemorrhage decreased significantly after the introduction of the policy and no differences were noted in other gestational complications. Moreover, the hospitalization time was shortened, and caesarean delivery was chosen less frequently. As for the infants, foetal distress exhibited an alleviation and the incidence of premature labour and low birth weight decreased as well. CONCLUSIONS: Even though the age of second-time mothers increased after the introduction of the universal two-child policy, their general gestational health condition improved and their infants also exhibited a better outcome, which might be attributed to the improvement of China's maternal medical care system.

The tumor suppressor TMEM127 regulates insulin sensitivity in a tissue-specific manner.

Understanding the molecular components of insulin signaling is relevant to effectively manage insulin resistance. We investigated the phenotype of the TMEM127 tumor suppressor gene deficiency in vivo. Whole-body Tmem127 knockout mice have decreased adiposity and maintain insulin sensitivity, low hepatic fat deposition and peripheral glucose clearance after a high-fat diet. Liver-specific and adipose-specific Tmem127 deletion partially overlap global Tmem127 loss: liver Tmem127 promotes hepatic gluconeogenesis and inhibits peripheral glucose uptake, while adipose Tmem127 downregulates adipogenesis and hepatic glucose production. mTORC2 is activated in TMEM127-deficient hepatocytes suggesting that it interacts with TMEM127 to control insulin sensitivity. Murine hepatic Tmem127 expression is increased in insulin-resistant states and is reversed by diet or the insulin sensitizer pioglitazone. Importantly, human liver TMEM127 expression correlates with steatohepatitis and insulin resistance. Our results suggest that besides tumor suppression activities, TMEM127 is a nutrient-sensing component of glucose/lipid homeostasis and may be a target in insulin resistance.