Identification of lipid-modifying drug targets for autoimmune diseases: insights from drug target mendelian randomization.

BACKGROUNDS: A growing body of evidence has highlighted the interactions of lipids metabolism and immune regulation. Nevertheless, there is still a lack of evidence regarding the causality between lipids and autoimmune diseases (ADs), as well as their possibility as drug targets for ADs. OBJECTIVES: This study was conducted to comprehensively understand the casual associations between lipid traits and ADs, and evaluate the therapeutic possibility of lipid-lowering drug targets on ADs. METHODS: Genetic variants for lipid traits and variants encoding targets of various lipid-lowering drugs were derived from Global Lipid Genetics Consortium (GLGC) and verified in Drug Bank. Summary data of ADs were obtained from MRC Integrative Epidemiology Unit (MER-IEU) database and FinnGen consortium, respectively. The causal inferences between lipid traits/genetic agents of lipid-lowering targets and ADs were evaluated by Mendelian randomization (MR), summary data-based MR (SMR), and multivariable MR (MVMR) analyses. Enrichment analysis and protein interaction network were employed to reveal the functional characteristics and biological relevance of potential therapeutic lipid-lowering targets. RESULTS: There was no evidence of causal effects regarding 5 lipid traits and 9 lipid-lowering drug targets on ADs. Genetically proxied 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) inhibition was associated with a reduced risk of rheumatoid arthritis (RA) in both discovery (OR [odds ratio] = 0.45, 95%CI: 0.32, 0.63, P = 6.79 × 10- 06) and replicate datasets (OR = 0.37, 95%CI: 0.23, 0.61, P = 7.81 × 10- 05). SMR analyses supported that genetically proxied HMGCR inhibition had causal effects on RA in whole blood (OR = 0.48, 95%CI: 0.29, 0.82, P = 6.86 × 10- 03) and skeletal muscle sites (OR = 0.75, 95%CI: 0.56, 0.99, P = 4.48 × 10- 02). After controlling for blood pressure, body mass index (BMI), smoking and drinking alchohol, HMGCR suppression showed a direct causal effect on a lower risk of RA (OR = 0.33, 95%CI: 0.40, 0.96, P = 0.042). CONCLUSIONS: Our study reveals causal links of genetically proxied HMGCR inhibition (lipid-lowering drug targets) and HMGCR expression inhibition with a decreased risk of RA, suggesting that HMGCR may serve as candidate drug targets for the treatment and prevention of RA.

Simulated human digestion and fermentation of a high-molecular weight polysaccharide from Lentinula edodes mushroom and protective effects on intestinal barrier.

Lentinula edodes (Shiitake) is an important edible mushroom and polysaccharides are its major constituents with proven health benefits. The study was to investigate the gut bacterial fermentation and subsequent effects on gut barrier function of a glucan-rich polysaccharide, LePS40 precipitated from the mushroom water extract with 40 % (v/v) ethanol. LePS40 consisted of a ß-(1→3)-glucan main chain with substitution in the C-6 position with side chains mainly composed of (1 → 6)-linked ß-Glcp residues, (1 → 6)-linked α-Galp residues and terminal residues of ß-Glcp. LePS40 was found highly resistant to digestive enzymes and gastric acid in simulated human gastrointestinal tract, but highly fermentable during in vitro human fecal fermentation. The fecal fermentation degradation of LePS40 appeared to selectively break the glucoside linkage in view of the dramatic decrease in the glucose molar ratio (12.68 to 1.07). Compared with the prebiotic reference FOS, LePS40 led to much higher levels of butyric, and propionic acid and a lower level of acetic acid. Moreover, LePS40 enhanced the abundance of some beneficial bacterial populations, but decreased the bacteria possibly linked with fatty-liver disease and colorectal cancer. Furthermore, the fecal fermentation products of LePS40 showed a potential protective effect on intestinal barrier function against inflammatory damage in Caco-2/Raw264.7 co-culture model. These findings suggest the potential of LePS40 for improvement of gut health through modulation of gut microbiota.

MicroRNAs as Key Regulators in RA and SLE: Insights into Biological Functions.

MicroRNAs (miRNAs) are non-coding RNA molecules that bind to mRNAs to regulate gene expression. Since changes in miRNA expression levels have been found in a variety of autoimmune illnesses, miRNAs are important in autoimmune diseases. MiRNAs serve not only as pathogenic factors and biomarkers for autoimmune diseases but also as important targets for disease therapeutics. Although miRNA-based treatments are still in the research stage, in-depth investigations into the biological functions of miRNAs have significantly enhanced our understanding of their mechanisms in autoimmune diseases. The purpose of this review is to summarize the biological functions of miRNAs, their roles in rheumatoid arthritis and systemic lupus erythematosus, therapeutic strategies, and challenges.