Fuquan Zhang

Neuroimmune lipidome dysregulation in major depressive disorder: A meta-analysis of peripheral endocannabinoid and n-acylethanolamine signaling.

Major depressive disorder (MDD) is a prevalent psychiatric condition characterized by substantial biological heterogeneity. Evidence suggests that the endocannabinoid system (ECS), which regulates stress responses, emotional processing, and neuroimmune signaling, may contribute to depression pathophysiology. However, clinical studies examining circulating endocannabinoids (eCBs) and N-acylethanolamines (NAEs) in MDD have produced inconsistent findings. We therefore conducted a systematic review and meta-analysis to quantify peripheral alterations in eCBs and NAEs in individuals with MDD. Following PRISMA guidelines, case-control and cross-sectional studies comparing circulating levels of eCBs and NAEs between patients with MDD and healthy controls were identified. Standardized mean differences (SMDs) with 95 % confidence intervals (CIs) were calculated using a random-effects model. Between-study heterogeneity was assessed by using Cochran's Q test and further explored in subgroups analysis. Nine studies, including 514 individuals with MDD and 417 healthy controls, met the inclusion criteria. Patients with MDD exhibited significantly higher circulating levels of anandamide (AEA; SMD = 0.32, 95 % CI: 0.10---0.54, p = 0.005) and palmitoylethanolamide (PEA; SMD = 0.35, 95 % CI: 0.04---0.65, p = 0.03) compared with controls, whereas no significant differences were observed for 2-arachidonoylglycerol (2-AG) or oleoylethanolamide (OEA). Subgroup analyses indicated that the elevation in AEA levels were more pronounced among medicated patients and individuals with psychiatric comorbidities. These findings suggest selective alterations in ECS-related lipid mediators in individuals with MDD and support dysregulation of the ECS-NAE signaling axis in depression. Circulating lipid signaling molecules such as AEA and PEA may represent potential peripheral biomarkers of MDD, although longitudinal and mechanistic studies are needed to clarify the influence of treatment and comorbidities.

Exploring the Causal Role of Circulating Inflammatory Proteins in Multiple Sclerosis: A Mendelian Randomization Study and Druggability Analysis.

INTRODUCTION To evaluate the causal effects of circulating inflammatory proteins on the development of Multiple Sclerosis (MS) and to discover potential therapeutic targets for the disease. METHODS Two-sample Mendelian randomization analysis was used to evaluate causal relationships between levels of 91 inflammatory proteins in serum and the risk of MS. For each circulating protein, genetic variation data were from a genome-wide association study of 14,736 individuals of European ancestry. The MS dataset included 47,429 cases and 68,374 controls. Additional sensitivity, colocalization, functional enrichment, and protein-protein interaction analyses were performed to assess the robustness and biological relevance of the findings. Soluble proteins causally associated with MS were assessed for their therapeutic target potentials using the Drug-Gene Interaction Database. RESULTS The analysis identified 9 circulating inflammatory proteins with nominal evidence of association with MS risk. Among them, CD40 (Odds Ratio [OR]: 0.907) and VEGFA (OR: 0.971) appear protective, while IL1A (OR: 1.139), CD6 (OR: 1.047), TNF (OR: 1.058), LIF-R (OR: 1.052), CCL25 (OR: 1.032), CD244 (OR: 1.057) and CXCL10 (OR: 1.061) were associated with higher risks of MS. After correcting for multiple testing, associations with MS risks remained significant only for CD40. Supportive analyses highlighted immune- and inflammationrelated pathways, particularly cytokine signaling, as mediators of the risks of MS. Six circulating proteins were identified as candidates in an exploratory assessment of druggability. DISCUSSION These results offered new insight into the inflammatory landscape of MS, reinforcing the pathogenic relevance of immune signaling pathways. The robust statistical significance of CD40 highlighted it as a primary candidate for further investigation, while the additional eight proteins provided a foundation for future hypothesis-generating studies. While the findings strengthened the biological plausibility of inflammation-driven disease mechanisms, the presence of nominal significance and potential pleiotropy for certain markers necessitated a cautious interpretation. CONCLUSION Genetic evidence linking inflammatory proteins to MS pathogenesis was uncovered, offering clues for novel therapeutic targets for this condition.

Association between antidepressant use and the risk of type 2 diabetes: a multi-stage Mendelian randomization study.