BACKGROUND
Myasthenia gravis (MG) is an autoimmune neuromuscular disorder in which immune dysregulation and altered T-cell homeostasis contribute to pathogenic autoantibody production. Jianpi Yiqi Busui Formula (JPYQBSF) is used as an adjunctive traditional Chinese medicine, but its immunometabolic mechanisms remain incompletely defined.
PURPOSE
To evaluate the clinical and preclinical effects of JPYQBSF and to examine whether gut microbiota remodeling and the regulatory T-cell (Treg) LDHA-lactate-H3K18la-PD-1 axis are associated with its immunomodulatory activity.
STUDY DESIGN
An exploratory prospective clinical cohort, an experimental autoimmune myasthenia gravis (EAMG) rat model, and multi-omics and mechanistic experiments were integrated.
METHODS
Thirty-one anti-acetylcholine receptor antibody-positive MG patients receiving stable conventional therapy were assessed before and after 24 weeks of adjunctive JPYQBSF, with 31 age- and sex-matched healthy participants as a reference group. EAMG rats underwent functional, electrophysiological, immunological, 16S rRNA, serum metabolomic, and TMT-proteomic analyses. Fecal microbiota transplantation, human Treg-cell experiments, pharmacological LDH inhibition, LDHA knockdown, ChIP-qPCR, CUT&Tag, and reporter assays were used to interrogate candidate pathways.
RESULTS
In the clinical cohort, adjunctive JPYQBSF was associated with lower AChR-Ab levels and partial normalization of inflammatory and immunoregulatory markers; the uncontrolled design precludes attribution of these changes to JPYQBSF alone. In EAMG rats, JPYQBSF improved motor and electrophysiological outcomes, reduced inflammatory mediators, and shifted the Treg/Th17 balance. Microbiome, metabolomic, and proteomic analyses identified treatment-associated community and metabolic changes, including aromatic lactic-acid derivatives and LDHA. In cultured Tregs, JPYQBSF exposure increased LDHA expression, lactate, H3K18la enrichment near the PDCD1 promoter, and PD-1 expression. Oxamate and LDHA knockdown attenuated several of these changes, whereas healthy-donor FMT partially reproduced selected immunometabolic effects.
CONCLUSION
The findings support a coordinated model in which gut microbiota remodeling and LDHA-dependent Treg immunometabolic changes contribute to the effects of JPYQBSF. They do not establish a direct linear causal pathway from specific microbial metabolites to H3K18 lactylation, PD-1 regulation, or independent clinical efficacy.
Yibin Zhang, Qinan Lu, Lei Wu et al.· Phytomedicine· 0 citations
Background In Alzheimer’s disease (AD), neurovascular unit and blood–brain barrier (BBB) abnormalities are assessed using biologically distinct readouts, often across separate cohorts, complicating interpretation across clinical stages and biomarker domains. Methods We searched major databases (inception to February 7, 2026) for human observational studies quantifying cerebrospinal fluid (CSF) soluble platelet-derived growth factor receptor-β (sPDGFRβ), dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) Ktrans, or the CSF/serum albumin quotient (QAlb) in cognitively normal (CN), mild cognitive impairment (MCI), and AD dementia groups. Primary contrasts were MCI versus CN, AD dementia versus CN, and AD dementia versus MCI. Outcomes were analyzed separately using standardized mean differences (SMDs) in random-effects models with restricted maximum-likelihood estimation and Hartung–Knapp adjustment. Sensitivity analyses incorporated amyloid/AT (N)-informed biologic anchoring and evidence-tier restrictions where possible. Results We included 24 cross-sectional studies (3,644 participants). Compared to CN, MCI showed higher CSF sPDGFRβ (SMD 0.38, 95% CI 0.03–0.73) and DCE-MRI Ktrans (SMD 0.91, 95% CI 0.09–1.73; highly heterogeneous and based on five studies), whereas the difference for QAlb was smaller (SMD 0.19, 95% CI 0.01–0.37). Stricter etiologic restriction weakened the robustness of MCI-stage estimates, particularly for early AD-specific inferences in cohorts without consistent biomarker confirmation. Tier 1-only pooling was not feasible because biomarker-confirmed MCI-stage evidence was sparse. AD dementia versus CN comparisons showed higher values across all readouts: CSF sPDGFRβ (SMD 0.43, 95% CI 0.12–0.73), Ktrans (SMD 0.90, 95% CI 0.56–1.25; based on four studies), and QAlb (SMD 0.28, 95% CI 0.10–0.45). AD dementia versus MCI comparisons showed no significant pooled differences for CSF sPDGFRβ or QAlb; Ktrans pooling was precluded by insufficient data. Conclusion Pericyte- and BBB-related readouts showed readout-specific, cross-sectional detectability patterns across the AD clinical continuum. Ktrans findings should be considered preliminary because of the small evidence base, and MCI-stage estimates remain limited by etiologic uncertainty. Overall, CSF sPDGFRβ, DCE-MRI Ktrans, and QAlb appear related but non-interchangeable, and the present cross-sectional evidence should not be interpreted as demonstrating temporal priority, within-person progression, or head-to-head biomarker superiority. Systematic review registration PROSPERO, CRD420251142518.
Wenchuan Wang, Hanying Xu, Tong Wu et al.· Frontiers in Aging Neuroscie...· 0 citations
A “cellular state–pathological network–therapeutic window” framework is proposed and the roles of microglia in amyloid-β plaque seeding and compaction, NLRP3 inflammasome activation, mitochondrial DNA–cGAS–STING signaling, complement-mediated synaptic engulfment, and bidirectional microglia–tau feedback are systematically discussed.
Lian-Jing Xu, Ying Zhang, Li Jiang et al.· Frontiers in Cellular Neuros...· 0 citations