LRH-1/NR5A2 is a member of the NR5A subfamily of nuclear receptors, acting as a crucial transcription factor involved in diverse biological processes. Although LRH-1 has been extensively studied in vitro and in vivo, in relation to its role in embryonic development and differentiation and in adult tissue processes, such as cholesterol, glucose, and ethanol metabolism, current knowledge about its function in immunity is very limited. This review, therefore, presents the most recent knowledge regarding NR5A2 regulation and LRH-1 function, including the wide spectrum of its target genes. In addition to LRH-1 regulating steroidogenesis in tissues such as the ovaries, testes, pancreas, and breast adipocytes, it is also key in driving glucocorticoid production in intestine, where its immunomodulatory activity is undoubtedly important in maintaining gut homeostasis and countering inflammation. Likewise, LRH-1 also appears to be crucial to the enterohepatic circulation, regulating hepatic bile acid synthesis and secretion, and intestinal transport/reabsorption. Our review also highlights fundamental roles for LRH-1 in macrophage polarization and in T cell homeostasis, revealing a major role in Th2 immune responses. Although no studies to date have explored the association of LRH-1 with respect to B-lymphocyte biology, we highlight the need for understanding its wider role in the immune system and its interplay with tissues and organs in health and disease.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterised by motor neuron loss and protein aggregation, commonly driven by mutations in superoxide dismutase 1 (Sod1). Recent evidence implicates gut microbiota-derived metabolites, such as butyrate, in modulating neurodegeneration, but the underlying mechanisms remain unclear. Here, we demonstrate that sodium butyrate (NaB), a histone deacetylase inhibitor and microbial metabolite, ameliorates ALS-related phenotypes in C. elegans and mammalian cell models expressing mutant isoforms of Sod1 linked to ALS. NaB treatment prevented Sod1 aggregation and restored motor function and axonal integrity in transgenic worms overexpressing Sod1G85R. Mechanistically, NaB recapitulated the effects of the pan-HDAC inhibitor trichostatin A, suggesting HDAC inhibition as key to reducing Sod1 aggregation and its downstream effects. Application of NaB or the HDAC inhibitor valproic acid also prevented aggregation of Sod1A4V, Sod1G85R or Sod1G37R in transfected human neuroblastoma cells. These findings support a conserved neuroprotective role for NaB and HDAC inhibitors via their antiaggregation activity. Our findings also verify C. elegans and neuroblastoma cell lines as excellent research tools to explore the mechanisms underlying the antiaggregation action of NaB and HDAC inhibitors, as well as their potential for future therapeutic development.
Clear cell renal cell carcinoma (ccRCC) remains poorly understood at the genetic level. In this study, 12 GEO microarray datasets were combined, and meta-analysis and multiparameter gene prioritization were used to reveal candidate diagnostic biomarkers. Improved preprocessing and analysis were used to identify differentially expressed genes (DEGs), which led to 4651 DEGs enriched in metabolic pathways, immune response, and kidney development. Key transcription factors (TFs), including ZNF692, ZNF395, and ZNF582, were identified. Utilizing WGCNA, 21 hub genes were identified, and diagnostic potential was determined via ROC analysis. Seventeen of the genes with AUC > 0.7 were validated as diagnostic hub genes, including ALDH2, ACADM, KIF11, and PTPRC. Nine of these genes showed significant prognostic relevance. The current work identifies key biomarkers that can enhance ccRCC diagnosis and guide future therapy.
siRNA is a versatile tool with practical applications in various fields, such as fundamental research, therapeutic development, and plant genetics. A few siRNA therapeutics have been FDA-approved, such as Onpattro (patisiran) and Leqvio (inclisiran) to treat hereditary transthyretin amyloidosis and primary hypercholesterolemia, respectively. In addition, several others are currently in clinical trials, highlighting the potential of siRNA-based treatment for undruggable targets. siRNA is a double-stranded RNA molecule that has the potential to inhibit gene expression by degrading target mRNA. The siRNA sequence must be precisely designed for effective gene knockdown and to minimize off-target effects. Strategies for designing siRNA to achieve optimal efficacy are presented in this review. We emphasize approaches that promote effective gene knockdown by siRNA. These approaches include preventing off-target RNAi and ensuring incorporation of the intended guide/antisense strand into RISC for targeted gene knockdown. This review also discusses the assessment of siRNA efficacy in vitro and the design of appropriate nonsilencing controls. Furthermore, the challenges of in vivo applications are identified, and strategies to overcome these challenges, such as siRNA delivery methods, biodistribution, and immunotoxicity prevention, are highlighted. Lastly, nucleotide chemical modifications to the ribose sugar and phosphodiester bonds and their effects on siRNA stability, activity, and interaction with the RISC complex are discussed. Overall, this review serves as a guide for well-designed and rigorously tested siRNA sequences, starting from initial in silico design to the application of siRNA for research or development of siRNA-based therapeutics.
Background: Lactic acid bacteria (LAB) are extensively used in the preservation of fruits and vegetables due to their ability to inhibit spoilage organisms and pathogenic bacteria. The fermentation process mediated by LAB not only extends the shelf life of produce but also enhances its nutritional and sensory properties. Objective: This study is aimed at reviewing the mechanisms through which LAB preserve fruits and vegetables, evaluating the benefits of their application, and highlighting recent advances in this field. Methods: A comprehensive literature review was conducted, focusing on the various preservative mechanisms of LAB, including acid production, bacteriocin secretion, competition for nutrients, and exopolysaccharide production. The impact of LAB on the shelf life, safety, nutritional value, and sensory attributes of fruits and vegetables was assessed through an analysis of recent scientific studies and case examples. Results: LAB extends the shelf life of fruits and vegetables primarily through the production of lactic acid, which lowers the pH and inhibits the growth of spoilage organisms and pathogens. The secretion of bacteriocins by LAB provides additional antimicrobial activity. Competition for nutrients further suppresses unwanted microbial growth. Exopolysaccharides produced by LAB can improve texture and form protective biofilms. Notable examples of LAB application include the fermentation of cabbage into sauerkraut, the production of kimchi, and the pickling of cucumbers. Advances in biotechnology have led to the development of optimized LAB strains and starter cultures, enhancing the efficacy of preservation processes. Conclusion: LAB are highly effective in preserving fruits and vegetables through multiple mechanisms, offering significant benefits in terms of extended shelf life, improved safety, enhanced nutritional value, and better sensory qualities. Ongoing research and technological advancements are expected to further improve the application of LAB in food preservation, making it a more efficient and widespread practice.
