Hepatocyte leukotriene B4 receptor 1 promotes NAFLD development in obesity.

BACKGROUND AND AIMS: NAFLD is the most prevalent chronic liver disease worldwide and has emerged as a serious public health issue with no approved treatment. The development of NAFLD is strongly associated with hepatic lipid content, and patients with NAFLD have significantly higher rates of hepatic de novo lipogenesis (DNL) than lean individuals. Leukotriene B4 (LTB4), a metabolite of arachidonic acid, is dramatically increased in obesity and plays important role in proinflammatory cytokine production and insulin resistance. But the role of liver LTB4/LTB4 receptor 1 (Ltb4r1) in lipid metabolism is unclear. APPROACH AND RESULTS: Hepatocyte-specific knockout (HKO) of Ltb4r1 improved hepatic steatosis and systemic insulin resistance in both diet-induced and genetically induced obese mice. The mRNA level of key enzymes involved in DNL and fatty acid esterification decreased in Ltb4r1 HKO obese mice. LTB4/Ltb4r1 directly promoted lipogenesis in HepG2 cells and primary hepatocytes. Mechanically, LTB4/Ltb4r1 promoted lipogenesis by activating the cAMP-protein kinase A (PKA)-inositol-requiring enzyme 1α (IRE1α)-spliced X-box-binding protein 1 (XBP1s) axis in hepatocytes, which in turn promoted the expression of lipogenesis genes regulated by XBP1s. In addition, Ltb4r1 suppression through the Ltb4r1 inhibitor or lentivirus-short hairpin RNA delivery alleviated the fatty liver phenotype in obese mice. CONCLUSIONS: LTB4/Ltb4r1 promotes hepatocyte lipogenesis directly by activating PKA-IRE1α-XBP1s to promote lipogenic gene expression. Inhibition of hepatocyte Ltb4r1 improved hepatic steatosis and insulin resistance. Ltb4r1 is a potential therapeutic target for NAFLD.

Discovery of potent glycogen synthase kinase 3/cholinesterase inhibitors with neuroprotection as potential therapeutic agent for Alzheimer's disease.

In the present work, a novel series of pyridinethiazole bearing benzylpiperidine hybrids were designed and synthesized as dual-target inhibitors of GSK-3ß/AChE. Among them, GD29 was the most promising candidate, with an IC50 value of 0.3 µM for hAChE and an IC50 value of 0.003 µM for hGSK-3ß, respectively. The compounds exhibited good drug-like properties with optimal inhibitory enzyme activities. Moreover, GD29 showed anti-inflammatory properties at micromolar concentrations and displayed interesting neuroprotective profiles in an in vitro model of oxidative stress-induced neuronal death. Notably, the compounds also exhibited good permeability across the blood-brain-barrier (BBB) both in vitro. Central cholinomimetic activity was confirmed using a scopolamine-induced cognition impairment model in Institute of Cancer Research (ICR) mice upon oral administration. The current work identified optimized compounds and explored the therapeutic potential of glycogen synthase kinase 3/cholinesterase inhibition for the treatment of AD.

Acceptance of Advance Care Planning Among Young Adults in Shijiazhuang, China: A Mixed-Methods Study.

Context: In the event of accidental trauma, incurable disease and public health emergencies, young adults are unable to participate in their own medical decisions, family members face the huge decision-making pressure and medical resources of the society were unevenly distributed. Objective: The purposes of this study is to investigate the Advanced Care Planning (ACP) acceptance and examine its influencing factors using sequential explanatory mixed methods in order to provide a basis for the formulation of later interventions. Methods: A cross-sectional study of young adults (N = 785) and 12 other young adults from two other communities were investigated from January 2021 to February 2022. Descriptive statistics and multiple linear regressions were conducted. Content analysis was performed on the qualitative data. Results: The primary factors that contributed to the acceptance of ACP were the natural acceptance of death, being female, having a high level of education, having a loved one diagnosed with a chronic disease, and having heard of ACP. Among young adults, the acceptance of ACP may be impeded by a fear of the unknown nature of death, a poor understanding of ACP, and family-led decision-making. Discussion: Our study found that 77.1% had not heard of ACP before participating in the study and showed potential to accept ACP-related interventions. The study highlighted the importance of implementing regular young adult education courses, promoting routine ACP knowledge, individualized education, discussing family member's disease experiences, conducting family meetings, and identifying young adult responsibilities and roles in implement ACP for young adults in China.