Gencheng Han

Major depressive disorder (MDD) is a leading cause of disability and disease burden worldwide, and increasing attention has been paid to the role of immune dysregulation in MDD pathogenesis. However, the key cellular subsets, hub molecules, and their regulatory mechanisms have not yet been fully elucidated. This study investigated the roles of Sigma-1 receptor (Sigma-1R) and CD36 in myeloid cells, exploring their potential as targets for modulating peripheral inflammation in MDD. We performed a random-effects meta-analysis of five public PBMC transcriptomic cohorts (n = 1388) and analyzed a public PBMC scRNA-seq dataset (MDD, n = 8; HC, n = 8) to characterize cell-type specific expression patterns. CRS mouse experiments and complementary in vitro assays were conducted to examine Sigma-1R regulation of CD36 and the role of the E3 ligase TRIM28, using pharmacological agonism (Hypidone hydrochloride, YL-0919 or SA4503) and antagonism (BD-1047), flow cytometry, cytokine measurements, co-immunoprecipitation, and ubiquitination/proteasome-degradation assays. The meta-analysis estimated a small, non-significant pooled difference in CD36 expression in bulk PBMC between the MDD and HC groups (SMD = 0.043, 95% CI -0.144 to 0.231). PBMC scRNA-seq revealed CD36 upregulation mainly in myeloid cells, accompanied by alterations in inflammatory genes and pathways. In CRS mice, myeloid CD36 levels increased in the liver and spleen, whereas Sigma-1R activation reduced CD36, lowered IL-6 and TNF-α, and improved depression-like behaviors. Mechanistically, Sigma-1R interacted with CD36 and promoted K48-linked ubiquitination and proteasome-dependent degradation. TRIM28 was identified as the E3 ubiquitin ligase mediating Sigma-1R-induced CD36 K48-linked ubiquitination, with K469 and K472 serving as critical ubiquitination sites. Knockdown of Sigma-1R in cells attenuated CD36 K48-linked ubiquitination. In vivo, pharmacological blockade with BD-1047 attenuated CD36 downregulation and associated effects, supporting Sigma-1R involvement. Our study identifies the myeloid Sigma-1R-CD36 axis in MDD and demonstrates that Sigma-1R promotes CD36 proteasome-dependent degradation via TRIM28-dependent K48-linked ubiquitination. This pathway suggests that CD36 in peripheral myeloid subsets may serve as a measurable immune indicator and supports Sigma-1R-CD36 modulation as a potential therapeutic strategy to mitigate inflammation-associated depressive phenotypes.

Introduction: Music has been widely used for disease intervention, while the underlying mechanisms remain to be determined. This study explored whether our novel music combination, which is composed of four pieces of music, can promote neuroimmune homeostasis and then relieve stress. Methods: Fifty-five participants were enrolled in the study, and they underwent three separate music therapy sessions or periods of rest. Saliva and blood samples were collected, cognitive task testing was conducted, and electrocardiographic (ECG) data were recorded. Results: The results showed that our new music combination increased the heart rate variability (HRV) index [RMSSD, PNN20, PNN50, and high-frequency (HF)/NU] while decreasing LF/NU, which suggested restoration of balance between the sympathetic and parasympathetic activity and relieved stress. In addition, participants in the music group had lower Balloon Analogue Risk Task (BART) test results and higher Multiple Object Tracking (MOT) task test results, suggesting increased attention and stress relief. Music therapy also increased the IgA while decreasing cortisol concentrations. Discussion: This study reveals that our novel music combination may relieve stress by promoting neuroimmune homeostasis, which sheds new light on the mechanisms of music therapy and suggests new approaches for intervention.

Exercise has been shown to alleviate depressive symptoms and enhance bodily functions. However, the precise mechanisms underlying its antidepressant effects remain incompletely understood. In this study, we observed that treadmill exercise may exert antidepressant effects in a chronic restraint stress (CRS) mouse model by modulating the proinflammatory Growth Differentiation Factor 15 (GDF15)‐extracellular signal‐regulated kinase (ERK) signaling pathway. Treadmill exercise improved cognitive behaviors in CRS mice and alleviated neuroinflammation, as evidenced by decreased expression of TNF‐α, IL‐1β, IL‐6, and attenuated microglia activation. Intriguingly, we found that treadmill exercise inhibited the expression of GDF15, a biomarker associated with many immune disorders, which is increased following CRS. Mechanistically, treadmill exercise may attenuate neuroinflammation by suppressing GDF15‐induced ERK activation. We thus identified a novel mechanism by which treadmill exercise attenuates depression. Modulation of the GDF15‐ERK pathway may have therapeutic implications for depression.

Objective T cell immunoglobulin and mucin domain-containing molecule 3 (Tim-3), a critical regulator of innate and adaptive immune responses, has been considered as a promising new target for immunotherapy. Based on an existing laboratory murine-derived anti-human Tim-3 antibody, this study aims to employ computer-aided molecular design to construct a mammalian cell-displayed antibody library targeting human Tim-3 and to screen for antibodies with optimized function. Methods The parental Tim-3 sequence was designed and optimized via a computer-assisted molecular model construction platform and mammalian cell-displayed antibody library technology. The plasmid library encoding the Tim-3-targeted mammalian antibody library was obtained by molecular biology techniques including Overlap PCR, vector cleavage, enzyme ligation and transformation. Novel antibody sequences were identified through sequencing alignment, followed by ELISA-based screening to isolate high-expression and high-affinity candidates. The function of the optimized antibody was further verified by in vitro assays (RT-PCR and CCK-8). Results Utilizing computer-aided design platform, five key amino acid substitutions were designed and introduced into the light and heavy chains of the parental murine-derived anti-human Tim-3 antibody. Three mutant light chains (L-1, L-2 and L-3) and heavy chains (H-1, H-2 and H-3) were successfully generated by Overlap PCR. Subsequent ligation into vectors and transformation into TOP10 electrocompetent cells yielded a plasmid library with substantial sequence diversity. Sequence analysis and purification of new antibodies resulted in the identification of an antibody with higher affinity, named No.1. RT-PCR showed that after blockade with antibody No.1, transcription levels of IFN-β, TNF-α, IL-1β and IL-6 were significantly upregulated in the macrophage cell line RAW264.7 cells and microglia cell line BV2 cells, and a similar upregulation was observed in levels of IL-2 and IFN-γ in Jurkat^Tim-3-high cells. In these assays, antibody No.1 exhibited greater blocking efficacy than the parental Tim-3 antibody. CCK-8 assays demonstrated that antibody No.1 promoted Jurkat^Tim-3-high cells proliferation more effectively than the parental Tim-3 antibody. Conclusion A novel humanized Tim-3 antibody (No.1) with enhanced affinity and capacity to upregulate multiple cytokine expressions in both human and murine cell lines was obtained via a computer-aided molecular design platform and mammalian cell antibody display library technology.

Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders and is characterized by memory loss and cognitive decline. The amyloid cascade hypothesis posits that the pathogenesis of AD is initiated by the oligomerization and accumulation of toxic amyloid-β (Aβ) peptides within the brain. The aspartic protease γ-secretase, which catalyzes the final step in the cellular production of Aβ peptides, has been identified as a potential target for anti-amyloid intervention strategies. This target has attracted increasing attention in recent years, and novel small molecules have been developed as selective γ-secretase inhibitors and γ-secretase modulators. This review aims to discuss the role of γ-secretase protein hydrolysis activity in the pathogenesis of AD and to review the molecular mechanisms and prospects for the future development of strategies that target γ-secretase to intervene in AD development, which is expected to provide new ideas for the treatment of AD.