Irinotecan (CPT-11) is a widely utilized topoisomerase I inhibitor in the treatment of colorectal cancer and other malignant tumors. However, severe and even life-threatening dose-limiting toxicity-delayed diarrhea affects the clinical application of CPT-11. The standard treatment for CPT-11-induced delayed diarrhea is prompt use of loperamide (LPA), however LPA can also cause constipation, diarrhea and even intestinal obstruction and has a high failure rate. Carboxylesterase 2 (CES2) is the main enzyme in the intestinal transformation of CPT-11, which can convert CPT-11 into toxic metabolite SN-38 and produce intestinal toxicity. Inhibiting CES2 activity can block the hydrolysis process of CPT-11 in the intestine and reduce SN-38 accumulation. Additionally, Farnesoid X receptor (FXR) agonists have anti-inflammatory, anti-secretory, and protective functions on intestinal barrier integrity that could potentially alleviate diarrhea. In this study, we investigated for the first time the anti-delayed diarrhea effect of FXR agonists, and the first time identified LE-77 as a potent dual modulator that activates FXR and inhibits CES2 through high-throughput screening. In the CPT-11-induced delayed diarrhea model, LE-77 demonstrated a dual modulator mechanism by activating FXR and inhibiting CES2, thereby reducing the accumulation of SN-38 in the intestine, alleviating intestinal inflammation, preserving intestinal mucosal integrity, and ultimately alleviating delayed diarrhea.

2024-11-01·Social Psychiatry and Psychiatric Epidemiology

Replacement of sedentary behavior with various physical activities and the risk of incident depression: a prospective analysis of accelerator-measured and self-reported UK Biobank data

Article

作者: Zhu, Jia-Hui ; Jia, Cun-Xian ; Liu, Bao-Peng ; Shen, Zhen-Zhen

PURPOSETo examine the dose‒response relationships of sedentary behavior (SB) and physical activities (PAs) with depression, and to explore the effects of replacing SB with PAs on depression risk.METHODSThe study used data from UK Biobank aged 37 to 73 years. Light physical activity (LPA), moderate-to-vigorous activity (MVPA), sleep duration, and total sedentary behavior (TSB) were measured by accelerometers. Self-reported SB was also adopted when daily screen-sedentary behavior time (SSB) and leisure-sedentary behavior time (LSB) were the focus. Incident depression was obtained from the part of mental and behavioral disorders in the "first occurrence fields" of UK Biobank. A Cox proportional hazard model and isotemporal substitution model were performed to explore the associations of LPA, MVPA, TSB, LSB, SSB, and sleep on depression and the effects of replacing SB time with equal PA time.RESULTSHighest levels of MVPA (HR = 0.58, 95%CI: 0.50-0.68) were associated with decreased depression risk compared with the lowest level (Q1). Longer SSB time (HR = 1.18, 95%CI: 1.06-1.32), LSB time (HR = 1.19, 95%CI: 1.07-1.32), and TSB time (HR = 1.17, 95%CI: 1.00-1.38) could increase depression risk significantly. Replacing 1h/day TSB, SSB, and LSB with MVPA brought the greatest risk reductions [31% (HR = 0.69, 95%CI: 0.62-0.77), 30% (HR = 0.70, 95%CI: 0.65-0.77), and 29% (HR = 0.71, 95%CI: 0.65-0.77)]. Under the same conditions, the effects of LPA replacement were also significant, but weaker than those of MVPA. Subgroup analyses showed that replacing 1h/d TSB with LPA could significantly decrease the depression risk for the females, but not for the males.CONCLUSIONLarge benefits for reducing the risk of incident depression could be attained by replacing a period of TSB, SSB, or LSB with equal PA time, especially for MVPA. Regular PA and less SB were recommended for improving mental health.

2024-09-11·Journal of Agricultural and Food Chemistry

The Function and Mechanism of Laminaripentaose Prepared from Curdlan for the Amelioration of the Cognitive Dysfunctions in Obese Mice

Article

作者: Xu, Yuncong ; Mao, Xiangzhao ; Jiang, Zhengqiang ; Yan, Qiaojuan ; Yang, Shaoqing ; Li, Yanxiao

Functional oligosaccharides induce specific alterations in gut microbiota, potentially providing physiological benefits. However, the effects of laminaripentaose (LPA) on metabolic syndrome and the mechanism underlying it have not been intensively investigated yet. This study aimed to determine the effects of LPA on obesity and obesity-induced cognition impairment in mice. C57BL/6N mice fed with a high-fat diet received an LPA treatment for 12 weeks. An antibiotic intervention was further applied to evaluate the effects of the gut microbiota on cognitive functions. LPA treatment (500 mg/kg) reduced the weight gain by 32.4%. Furthermore, LPA improved memory functions and reduced hippocampal insulin resistance and neuronal injury. LPA markedly reduced systemic low-grade inflammation and intestinal barrier injury. Moreover, LPA increased gut beneficial bacteria, and Butyricimonas and Bifidobacterium were increased by 94.0 and 422.7%, respectively, accompanied by increased fecal short-chain fatty acids. Interestingly, antibiotic cocktail treatment abrogated the beneficial effects of LPA on cognition, which further suggests that LPA may attenuate obesity-induced cognition impairment via the gut-brain axis. Our findings provide the first evidence for the potential of dietary LPA to prevent obesity and obesity-associated complications.

100 项与 LPA siRNA(赛诺菲) 相关的药物交易

登录后查看更多信息