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Recent studies have shown that human and experimental alcohol-related liver disease (ALD) is robustly associated with dysregulation of bile acid homeostasis, which may in turn modulate disease severity. Pharmacological agents targeting bile acid metabolism and signaling may be potential therapeutics for ALD.
The potential beneficial effects of a gut-restricted apical sodium-dependent bile acid transporter (ASBT) inhibitor were studied in a chronic-plus-binge ALD mouse model.
Blocking intestinal bile acid reabsorption by the gut-restricted ASBT inhibitor GSK2330672 attenuated hepatic steatosis and liver injury in a chronic-plus-binge ALD mouse model. Alcohol feeding is associated with intestinal bile acid accumulation but paradoxically impaired ileal farnesoid×receptor (FXR) function, and repressed hepatic cholesterol 7α-hydrolase (CYP7A1) expression despite decreased hepatic small heterodimer partner (SHP) and ileal fibroblast growth factor 15 (FGF15) expression. ASBT inhibitor treatment decreased intestinal bile acid accumulation and increased hepatic CYP7A1 expression, but further decreased ileal FXR activity. Alcohol feeding induces serum bile acid concentration that strongly correlates with a liver injury marker. However, alcohol-induced serum bile acid elevation is not due to intrahepatic bile acid accumulation but is strongly and positively associated with hepatic multidrug resistance-associated protein 3 (MRP4) and MRP4 induction but poorly associated with sodium-taurocholate cotransporting peptide (NTCP) expression. ASBT inhibitor treatment decreases serum bile acid concentration without affecting hepatocyte basolateral bile acid uptake and efflux transporters.
ASBT inhibitor treatment corrects alcohol-induced bile acid dysregulation and attenuates liver injury in experimental ALD.
ASBT inhibitor treatment corrects alcohol-induced bile acid dysregulation and attenuates liver injury in experimental ALD.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) genetic polymorphisms play a significant role in cholesterol homeostasis. Therefore, we aimed to investigate the association of PCSK9 genetic variations NM_174936.3c.137G>T (R46L, rs11591147) and NM_174936.3c.1120G>T (D374Y, rs137852912), as well as promoter DNA methylation status, with mRNA expression and circulating serum protein levels in coronary artery disease (CAD) patients.
The present study includes 300 CAD cases and 300 controls from South India. Biochemical assays were performed using commercially available kits. PCSK9 rs11591147 and rs137852912 polymorphisms were analyzed by the polymerase chain reaction (PCR)-restriction fragment length polymorphism method, whereas promoter DNA methylation status and gene expression were determined using methylation specific PCR and quantitative PCR respectively.
The genotypic distribution of PCSK9 rs11591147 revealed that individuals with the TT-genotype and T-allele have a reduced risk for CAD. Fuon may open avenues for novel treatment possibilities targeting PCSK9 for CAD management.
In conclusion, the present study indicates that the PCSK9 gene expression and circulating serum protein levels are not only associated with rs11591147 genotype, but also with promoter DNA methylation. Furthermore, the findings with respect to both single nucleotide polymorphism and promoter DNA methylation may open avenues for novel treatment possibilities targeting PCSK9 for CAD management.Rivaroxaban is an anticoagulant (orally active direct Xa inhibitor) considered to reduce the risk of stroke and systemic embolism and treat deep vein thrombosis, pulmonary embolism, and other cardiovascular complications. Bioanalytical methods for rivaroxaban quantification in plasma are necessary for application in pharmacokinetic studies, as well as in drug therapeutic monitoring. In this work, we developed and validated a sensitive bioanalytical method using LC-MS/MS for rivaroxaban quantification in human plasma using an one-step liquid-liquid extraction. The linear concentration range was 1-600 ng/mL. The bioanalytical method was also applied to pharmacokinetic studies in healthy volunteers under fasting and fed conditions. MHY1485 The results demonstrated that the method is rapid, sensitive, and adequate for application in pharmacokinetic studies.
In myasthenia gravis (MG) therapy, achieving Myasthenia Gravis Foundation of America minimal manifestation (MM) or better status is proposed as a desirable target. However, this level of control is often not achieved and clinical factors affecting prognosis remain unclear.
Participants were 104 consecutive patients with MG who visited Osaka Medical College Hospital. We retrospectively assessed the association of clinical and laboratory features at baseline with prognosis. Eighty patients who achieved MM or better status were classified as the good outcome group and the remaining 24 patients were classified as the poor outcome group.
The rate of dysphagia at baseline was significantly higher in the poor outcome group than in the good outcome group (P=.002). The levels of serum total protein and albumin at baseline were both significantly lower in the poor outcome group than in the good outcome group (P=.036 and P=.014, respectively). In addition, Controlling Nutritional Status scores at baseline were significantly higher in the poor outcome group than in the good outcome group (P=.043). Multivariate analysis using a Cox proportional hazards model showed that dysphagia (hazard ratio [HR], 6.92; 95% confidence interval [CI], 1.49-40.31) and hypoalbuminemia (HR, 2.57; 95% CI, 1.04-6.57) at baseline were risk factors that predicted prognosis.
These findings suggest that dysphagia and hypoalbuminemia at baseline are associated with outcomes and are predictive risk factors for poorer outcomes in patients with MG.
These findings suggest that dysphagia and hypoalbuminemia at baseline are associated with outcomes and are predictive risk factors for poorer outcomes in patients with MG.Paraspeckles are constructed by NEAT1_2 architectural long noncoding RNAs. Their characteristic cylindrical shapes, with highly ordered internal organization, distinguish them from typical liquid-liquid phase-separated condensates. We experimentally and theoretically investigated how the shape and organization of paraspeckles are determined. We identified the NEAT1_2 RNA domains responsible for shell localization of the NEAT1_2 ends, which determine the characteristic internal organization. Using the soft matter physics, we then applied a theoretical framework to understand the principles that determine NEAT1_2 organization as well as shape, number, and size of paraspeckles. By treating paraspeckles as amphipathic block copolymer micelles, we could explain and predict the experimentally observed behaviors of paraspeckles upon NEAT1_2 domain deletions or transcriptional modulation. Thus, we propose that paraspeckles are block copolymer micelles assembled through a type of microphase separation, micellization. This work provides an experiment-based theoretical framework for the concept that ribonucleoprotein complexes (RNPs) can act as block copolymers to form RNA-scaffolding biomolecular condensates with optimal sizes and structures in cells.
