FKBP38 deletion exacerbates ConA-induced hepatitis by promoting the immune response through the MCP-1/p38 pathway.

Autoimmune hepatitis (AIH) is a chronic liver disease characterized by immune dysregulation and hepatocyte damage. FKBP38, a member of the immunophilin family, has been implicated in immune regulation and the modulation of intracellular signaling pathways; however, its role in AIH pathogenesis remains poorly understood. In this study, we aimed to investigate the effects of hepatic FKBP38 deletion on AIH using a hepatic FKBP38 knockout (LKO) mouse model created via cre-loxP technology. We compared the survival rates, incidence, and severity of AIH in LKO mice with those in control mice. Our findings revealed that hepatic FKBP38 deletion resulted in an unfavorable prognosis in LKO mice with AIH. Specifically, LKO mice exhibited heightened liver inflammation and extensive hepatocyte damage compared to control mice, with a significant decrease in anti-apoptotic proteins and a marked increase in pro-apoptotic proteins. Additionally, transcriptional and translational levels of pro-inflammatory cytokines and chemokines were significantly increased in LKO mice compared to control mice. Immunoblot analysis showed that MCP-1 expression was significantly elevated in LKO mice. Furthermore, the phosphorylation of p38 was increased in LKO mice with AIH, indicating that FKBP38 deletion promotes liver injury in AIH by upregulating p38 phosphorylation and increasing MCP-1 expression. Immune cell profiling demonstrated elevated populations of T, NK, and B cells, suggesting a dysregulated immune response in LKO mice with AIH. Overall, our findings suggest that FKBP38 disruption exacerbates AIH severity by augmenting the immune response by activating the MCP-1/p38 signaling pathway.

ω-3 polyunsaturated fatty acid alleviates systemic lupus erythematosus by suppressing autoimmunity in a murine model.

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune inflammatory disease that damages multiple organs by the production of autoantibodies. Numerous research studies have demonstrated the anti-inflammatory effects of ω-3 polyunsaturated fatty acids (PUFAs). A diet rich in ω-3 PUFAs reduces chronic inflammatory and autoimmune conditions. Herein, we investigated the protective effect of ω-3 PUFAs against autoimmune injury in SLE. In a TMPD-induced mouse model of SLE, supplementation with eicosapentaenoic acid (EPA)-rich (97%) fish oil was found to alleviate systemic autoimmune phenotypes such as ascites, lipogranulomas and serum dsDNA levels. In addition, EPA also significantly improved renal manifestations, reducing proteinuria, glomerulonephritis, and immune complex deposition. Mechanistically, ω-3 PUFAs were shown to modulate the differentiation of B lymphocyte subsets of primary splenic lymphocytes in the spontaneous murine lupus model MRL/MpJ-Faslpr in vitro, specifically that both EPA and DHA suppressed the number of total B cells, B1B2 cells and plasma cells. Concurrently, they were also found to promote the secretion of the anti-inflammatory cytokine IL10, mainly produced by Breg and Treg cells. Thus, nutritional supplementation with ω-3 PUFAs can regulate B cell's differentiation and anti-inflammatory function and strongly prevent autoimmune responses and lupus nephritis. The diets balance between ω-6 and ω-3 PUFAs intake may represent a promising treatment strategy to prevent or delay the onset of SLE.

Therapeutic Potential of ω-3 Polyunsaturated Fatty Acids in Human Autoimmune Diseases.

The recognition of ω-3 polyunsaturated acids (PUFAs) as essential fatty acids to normal growth and health was realized more than 80 years ago. However, the awareness of the long-term nutritional intake of ω-3 PUFAs in lowering the risk of a variety of chronic human diseases has grown exponentially only since the 1980s (1, 2). Despite the overwhelming epidemiological evidence, many attempts of using fish-oil supplementation to intervene human diseases have generated conflicting and often ambiguous outcomes; null or weak supporting conclusions were sometimes derived in the subsequent META analysis. Different dosages, as well as the sources of fish-oil, may have contributed to the conflicting outcomes of intervention carried out at different clinics. However, over the past decade, mounting evidence generated from genetic mouse models and clinical studies has shed new light on the functions and the underlying mechanisms of ω-3 PUFAs and their metabolites in the prevention and treatment of rheumatoid arthritis, systemic lupus erythematosus (SLE), multiple sclerosis, and type 1 diabetes. In this review, we have summarized the current understanding of the effects as well as the underlying mechanisms of ω-3 PUFAs on autoimmune diseases.

HLA-B*07, HLA-DRB1*07, HLA-DRB1*12, and HLA-C*03:02 Strongly Associate With BMI: Data From 1.3 Million Healthy Chinese Adults.

Strong associations between HLA alleles and infectious and autoimmune diseases are well established. Although obesity is also associated with these diseases, the relationship between HLA and obesity has not been systematically investigated in a large cohort. In the current study, we analyzed the association of HLA alleles with BMI using data from 1.3 million healthy adult donors from the Chinese Marrow Donor Program (CMDP). We found 23 HLA alleles, including 12 low-resolution and 11 high-resolution alleles, were significantly associated with BMI after correction for multiple testing. Alleles associated with high BMI were enriched in haplotypes that were common in both Chinese and European populations, whereas the alleles associated with low BMI were enriched in haplotypes common only in Asians. Alleles B*07, DRB1*07, DRB1*12, and C*03:02 provided the strongest associations with BMI (P = 6.89 × 10-10, 1.32 × 10-9, 1.52 × 10-9, and 4.45 × 10-8, respectively), where B*07 and DRB1*07 also had evidence for sex-specific effects (Pheterogeneity = 0.0067 and 0.00058, respectively). These results, which identify associations between alleles of HLA-B, DRB1, and C with BMI in Chinese young adults, implicate a novel biological connection between HLA alleles and obesity.

ω-3 polyunsaturated fatty acids ameliorate type 1 diabetes and autoimmunity.

Despite the benefit of insulin, blockade of autoimmune attack and regeneration of pancreatic islets are ultimate goals for the complete cure of type 1 diabetes (T1D). Long-term consumption of ω-3 polyunsaturated fatty acids (PUFAs) is known to suppress inflammatory processes, making these fatty acids candidates for the prevention and amelioration of autoimmune diseases. Here, we explored the preventative and therapeutic effects of ω-3 PUFAs on T1D. In NOD mice, dietary intervention with ω-3 PUFAs sharply reduced the incidence of T1D, modulated the differentiation of Th cells and Tregs, and decreased the levels of IFN-γ, IL-17, IL-6, and TNF-α. ω-3 PUFAs exerted similar effects on the differentiation of CD4+ T cells isolated from human peripheral blood mononuclear cells. The regulation of CD4+ T cell differentiation was mediated at least in part through ω-3 PUFA eicosanoid derivatives and by mTOR complex 1 (mTORC1) inhibition. Importantly, therapeutic intervention in NOD mice through nutritional supplementation or lentivirus-mediated expression of an ω-3 fatty acid desaturase, mfat-1, normalized blood glucose and insulin levels for at least 182 days, blocked the development of autoimmunity, prevented lymphocyte infiltration into regenerated islets, and sharply elevated the expression of the ß cell markers pancreatic and duodenal homeobox 1 (Pdx1) and paired box 4 (Pax4). The findings suggest that ω-3 PUFAs could potentially serve as a therapeutic modality for T1D.

Elevation of ω-3 Polyunsaturated Fatty Acids Attenuates PTEN-deficiency Induced Endometrial Cancer Development through Regulation of COX-2 and PGE2 Production.

Endometrial cancer is one of the most common gynecologic malignancies. Phosphatase and tensin homologue (PTEN)-mutation is frequently identified in endometrial cancer patients. Although high dietary intake of ω-3 polyunsaturated fatty acids (PUFAs) has been associated with reduced risk of endometrial cancer, the underlying mechanisms is still unknown. To this end, we evaluated the impact of ω-3 PUFAs using several endometrial cancer cellular and animal models. While ~27% and 40% of heterozygotic PTEN mutant mice developed endometrial cancer and atypical complex hyperplasia, respectively, none of the PTEN(+/-) mice developed cancer when we overexpressed an mfat-1 transgene, which allowed endogenous production of ω-3 PUFAs. Fish oil-enriched diet or expression of mfat-1 transgene significantly inhibited the growth of xenograft tumor derived from RL95-2 cells bearing a PTEN null mutation. At cellular level, ω-3 PUFAs treatment decreased the viability of RL95-2 cells, AKT phosphorylation, and cyclin D1 expression. These molecular events are primarily mediated through reduction of cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) production. Exogenous PGE2 treatment completely blunted the impact of ω-3 PUFAs on endometrial cancer. Thus, we revealed the direct inhibitory effects of ω-3 PUFAs on endometrial cancer development and the underlying mechanisms involving reduction of COX-2 and PGE2.

A potential new therapeutic system for glaucoma: solid lipid nanoparticles containing methazolamide.

Methazolamide (MTA) is an antiglaucoma drug; however, there are many side effects of its systemic administration with insufficient ocular therapeutic concentrations. The aim of this study was to formulate MTA-loaded solid lipid nanoparticles (SLNs) and evaluate the potential of SLNs as a new therapeutic system for glaucoma. SLNs were prepared by a modified emulsion-solvent evaporation method and their physicochemical characteristics were evaluated. The pharmacodynamics was investigated by determining the percentage decrease in intraocular pressure. The ocular irritation was studied by Draize test. Despite a burst release of SLNs, the pharmacodynamic experiment indicated that MTA-SLNs had higher therapeutic efficacy, later occurrence of maximum action, and more prolonged effect than drug solution and commercial product. Formulation of MTA-SLNs would be a potential delivery carrier for ocular delivery, with the advantages of a more intensive treatment for glaucoma, lower in doses and better patient compliance compared to the conventional eye drops.