LncRP11-675F6.3 responds to rapamycin treatment and reduces triglyceride accumulation via interacting with HK1 in hepatocytes by regulating autophagy and VLDL-related proteins.

Long noncoding RNAs (lncRNAs) have been widely proven to be involved in liver lipid homeostasis. Herein, we identify an upregulated lncRNA named lncRP11-675F6.3 in response to rapamycin treatment using a microarray in HepG2 cells. Knockdown of lncRP11-675F6. 3 leads to a significant reduction in apolipoprotein 100 (ApoB100), microsomal triglyceride transfer protein (MTTP), ApoE and ApoC3 with increased cellular triglyceride level and autophagy. Furthermore, we find that ApoB100 is obviously colocalized with GFP-LC3 in autophagosomes when lncRP11-675F6. 3 is knocked down, indicating that elevated triglyceride accumulation likely related to autophagy induces the degradation of ApoB100 and impairs very low-density lipoprotein (VLDL) assembly. We then identify and validate that hexokinase 1 (HK1) acts as the binding protein of lncRP11-675F6.3 and mediates triglyceride regulation and cell autophagy. More importantly, we find that lncRP11-675F6.3 and HK1 attenuate high fat diet induced nonalcoholic fatty liver disease (NAFLD) by regulating VLDL-related proteins and autophagy. In conclusion, this study reveals that lncRP11-675F6.3 is potentially involved in the downstream of mTOR signaling pathway and the regulatory network of hepatic triglyceride metabolism in cooperation with its interacting protein HK1, which may provide a new target for fatty liver disorder treatment.

The U.S. FDA approved cardiovascular drugs from 2011 to 2023: A medicinal chemistry perspective.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide. A total of 28 new molecular entities (NMEs) were approved by the U.S. Food and Drug Administration (FDA) for the treatment of cardiovascular diseases from 2011 to 2023. Approximately 25 % of the medications were sanctioned for the management of diverse vascular disorders. The other major therapeutic areas of focus included antilipemic agents (15 %), blood pressure disease (11 %), heart failure, hyperkalemia, and cardiomyopathy (7-8% each). Among all the approved drugs, there are a total of 22 new chemical entities (NCEs), including inhibitors, agonists, polymers, and inorganic compounds. In addition to NCEs, 6 biological agents (BLAs), including monoclonal antibodies, small interfering RNAs (siRNAs), and antisense oligonucleotides, have also obtained approval for the treatment of cardiovascular diseases. From this perspective, approved NCEs are itemized and discussed based on their disease, targets, chemical classes, major drug metabolites, and biochemical and pharmacological properties. Systematic analysis has been conducted to examine the binding modes of these approved drugs with their targets using cocrystal structure information or docking studies to provide valuable insights for designing next-generation agents. Furthermore, the synthetic approaches employed in the creation of these drug molecules have been emphasized, aiming to inspire the development of novel, efficient, and applicable synthetic methodologies. Generally, the primary objective of this review is to provide a comprehensive examination of the clinical applications, pharmacology, binding modes, and synthetic methodologies employed in small-molecule drugs approved for treating CVD. This will facilitate the development of more potent and innovative therapeutics for effectively managing cardiovascular diseases.

Forkhead box O proteins: steering the course of stem cell fate.

Stem cells are pivotal players in the intricate dance of embryonic development, tissue maintenance, and regeneration. Their behavior is delicately balanced between maintaining their pluripotency and differentiating as needed. Disruptions in this balance can lead to a spectrum of diseases, underscoring the importance of unraveling the complex molecular mechanisms that govern stem cell fate. Forkhead box O (FOXO) proteins, a family of transcription factors, are at the heart of this intricate regulation, influencing a myriad of cellular processes such as survival, metabolism, and DNA repair. Their multifaceted role in steering the destiny of stem cells is evident, as they wield influence over self-renewal, quiescence, and lineage-specific differentiation in both embryonic and adult stem cells. This review delves into the structural and regulatory intricacies of FOXO transcription factors, shedding light on their pivotal roles in shaping the fate of stem cells. By providing insights into the specific functions of FOXO in determining stem cell fate, this review aims to pave the way for targeted interventions that could modulate stem cell behavior and potentially revolutionize the treatment and prevention of diseases.

Advancing Tumor-Targeted Chemo-Immunotherapy: Development of the CAR-M-derived Exosome-Drug Conjugate.

Traditional antibody-drug conjugates (ADCs) mainly suppress tumor growth through either chemotherapy with cytotoxic payloads or immunotherapy with immuno-modulators. However, a single therapeutic modality may limit their exploration. Herein, we developed a new type of drug conjugate termed CAR-EDC (CAR-M-derived exosome-drug conjugate) by using CAR-exosomes from CAR-M cells as the targeting drug carrier that contains a high level of CXCL10. CAR-exosomes could significantly enhance the immunological activation and migratory capacity of T lymphocytes and promote their differentiation into CD8+ T cells. It also increased the proportion of M1 macrophages. The CAR-EDC, covalently loaded with SN-38, was internalized into Raji cells through endocytosis mediated by the CAR molecules. It exerted excellent antitumor activity in vivo by virtue of not only chemotherapy by SN38 but also immunotherapy by CXCL10-mediated antitumor immunity. Generally, this study provides an exosome-drug conjugate system with enhanced antitumor effects over traditional ADCs through the synergism of chemotherapy and immunotherapy.

Impact of diabetes mellitus on outcomes of patients with sepsis: an updated systematic review and meta-analysis.

BACKGROUND: The effect of concurrent diabetes on the outcome of sepsis is not conclusively known. A meta-analysis published in 2017 indicated that diabetes did not influence the mortality of patients with sepsis but increased the risk of acute renal injury. In view of publication of several new studies in recent years, there is a need for updated evidence. METHODS: A systematic search was conducted using the PubMed, Scopus, Embase, and Google Scholar databases. Studies that were done in patients with sepsis, were observational in design- either cohort or case-control or analysed retrospective data were considered for inclusion. Statistical analysis was performed using STATA software. RESULTS: A total of 21 studies were included. The risk of in-hospital mortality (RR 0.98, 95% CI 0.93, 1.04) and mortality at latest follow up i.e., within 90 days of discharge (RR 0.94, 95% CI 0.86, 1.04) among diabetic and non-diabetic subjects was statistically similar. There was an increased risk of in-hospital mortality among those with high blood glucose level at admission (RR 1.45, 95% CI 1.01, 2.09). Among those who were diabetic, the risk of acute renal failure (RR 1.54, 95% CI 1.34, 1.78) was higher than non-diabetics. The risk of respiratory failure, adverse cardiac events, need for additional hospitalization post-discharge and length of hospital stay was similar among diabetics and non-diabetics. CONCLUSIONS: Diabetes is not associated with poor survival outcomes in patients with sepsis but is associated with increased risk of acute renal failure. High blood glucose levels, irrespective of the diabetes status, are associated with increased risk of in-hospital mortality. Findings underscore the need for better evaluation of renal function in diabetic patients with concurrent sepsis.