Image1_Sex-specific comparison of clinical characteristics and prognosis in Crohn’s disease: A retrospective cohort study of 611 patients in China.JPEG

Background: Real-world data on the impact of sex on the disease progression and prognosis of Crohn’s disease (CD) from large-scale Chinese cohorts are lacking.Aims: This study aimed to evaluate sex disparities in the clinical characteristics of, disease progression behaviours of and surgery-related risk factors for CD.Methods: A retrospective cohort study comprising 611 patients consecutively diagnosed with CD at Peking Union Medical College Hospital from January 2000 to December 2020 was conducted. Multivariate Cox regression and survival analyses was performed to assess the risk factors for disease progression and CD-related surgery in sex subgroups.Results: Male sex was an independent protective factor against multisystemic extraintestinal manifestations [EIMs] (HR: 0.52, p = 0.03) and a risk factor for intestinal perforation (HR: 1.85, p = 0.01). Male patients had longer EIM-free survival (p = 0.024) and shorter intestinal perforation-free survival (PFS) than females (p = 0.012). Of the 397 patients with the A2 classification, male patients had a higher risk of CD-related surgery (HR: 1.80, p = 0.028) and shorter surgery-free survival (SFS) than female patients (p = 0.04).Conclusion: Sex disparities in disease progression and outcomes of CD were revealed in a single Chinese centre. Male sex was independently associated with worse disease progression and prognosis including multisystemic EIMs and perforation, which suggests the need for individualized management according to risk classification.</p

Dyslipidaemia Is Associated with Severe Disease Activity and Poor Prognosis in Ulcerative Colitis: A Retrospective Cohort Study in China

Background: Clinical data on the correlation of dyslipidaemia with the long-term outcomes of ulcerative colitis (UC) are limited. This study aimed to evaluate the impact of lipid levels on disease activity and prognosis in UC. Methods: The retrospective data of UC patients who had detailed lipid profiles were collected from January 2003 to September 2020. All patients were followed-up to 30 September 2021. The long-term outcomes were UC-related surgery and tumorigenesis. Results: In total, 497 patients were included in the analysis. Compared to patients with normal lipid levels, those with dyslipidaemia commonly presented with more serious disease activity. Low high-density lipoprotein cholesterol (p &lt; 0.05) levels were associated with higher risks of severe disease activity in UC. Regarding the long-term outcomes, patients with persistent dyslipidaemia were at higher risks of UC-related surgery (HR: 3.27, 95% CI: 1.86&ndash;5.75, p &lt; 0.001) and tumorigenesis (HR: 7.92, 95% CI: 3.97&ndash;15.78, p &lt; 0.001) and had shorter surgery- and tumour-free survival (p &lt; 0.001) than patients with transient dyslipidaemia and normal lipid levels. Low levels of high-density lipoprotein cholesterol (p &lt; 0.001) and apolipoprotein A1 (p &lt; 0.05) were associated with higher risks of surgery and tumorigenesis. Conclusion: Persistent dyslipidaemia was associated with a higher risk of serious disease activity and worse long-term outcomes among patients with UC. Lipid patterns should be assessed to improve the management of high-risk patients with UC in the early phase

Peptide MSI‐1 inhibited MCR‐1 and regulated outer membrane vesicles to combat immune evasion of Escherichia coli

Abstract Polymyxin resistance is conferred by MCR‐1 (mobile colistin resistance 1)‐induced lipopolysaccharide (LPS) modification of G− bacteria. However, the peptide MSI‐1 exerts potent antimicrobial activity against mcr‐1‐carrying bacteria. To further investigate the potential role of MCR‐1 in improving bacterial virulence and facilitating immune evasion, and the immunomodulatory effect of peptide MSI‐1, we first explored outer membrane vesicle (OMV) alterations of mcr‐1‐carrying bacteria in the presence and absence of sub‐MIC MSI‐1, and host immune activation during bacterial infection and OMV stimulation. Our results demonstrated that LPS remodelling induced by MCR‐1 negatively affected OMV formation and protein cargo by E. coli. In addition, MCR‐1 diminished LPS‐stimulated pyroptosis but facilitated mitochondrial dysfunction, further aggravating apoptosis in macrophages induced by OMVs of E. coli. Similarly, TLR4‐mediated NF‐κB activation was markedly alleviated once LPS was modified by MCR‐1. However, peptide MSI‐1 at the sub‐MIC level inhibited the expression of MCR‐1, further partly rescuing OMV alteration and attenuation of immune responses in the presence of MCR‐1 during both infection and OMV stimulation, which can be exploited for anti‐infective therapy

BZML, a novel colchicine binding site inhibitor, overcomes multidrug resistance in A549/Taxol cells by inhibiting P-gp function and inducing mitotic catastrophe

Multidrug resistance (MDR) interferes with the efficiency of chemotherapy. Therefore, developing novel anti-cancer agents that can overcome MDR is necessary. Here, we screened a series of colchicine binding site inhibitors (CBSIs) and found that 5-(3, 4, 5-trimethoxybenzoyl)-4-methyl-2-(p-tolyl) imidazol (BZML) displayed potent cytotoxic activity against both A549 and A549/Taxol cells. We further explored the underlying mechanisms and found that BZML caused mitosis phase arrest by inhibiting tubulin polymerization in A549 and A549/Taxol cells. Importantly, BZML was a poor substrate for P-glycoprotein (P-gp) and inhibited P-gp function by decreasing P-gp expression at the protein and mRNA levels. Cell morphology changes and the expression of cycle- or apoptosis-related proteins indicated that BZML mainly drove A549/Taxol cells to die by mitotic catastrophe (MC), a p53-independent apoptotic-like cell death, whereas induced A549 cells to die by apoptosis. Taken together, our data suggest that BZML is a novel colchicine binding site inhibitor and overcomes MDR in A549/Taxol cells by inhibiting P-gp function and inducing MC. Our study also offers a new strategy to solve the problem of apoptosis-resistance. (C) 2017 Elsevier B.V. All rights reserved