Zezhi Li

Synaptic communication requires mitochondria to supply ATP and buffer calcium at presynaptic terminals. In bipolar disorder, manic episodes are associated with elevated mood and neural activity, but the underlying cellular mechanisms remain unclear. Here we show that hiPSC-derived cortical neurons from donors with bipolar disorder exhibit increased axonal mitochondrial motility and frequent mitochondrial entry–exit transitions, reducing stable mitochondrial retention at presynaptic terminals. This destabilizes local ATP maintenance and calcium buffering, increasing synaptic variability without altering mean synaptic strength. Knockdown of the bipolar disorder risk gene AKAP11 in mouse neurons reproduced these synaptoenergetic deficits. HiPSC-derived neurons from donors with bipolar disorder exhibited reduced expression of the mitochondrial anchor protein syntaphilin(SNPH), and snph  knockout mice displayed manic-like behavioral phenotypes. Lithium restored presynaptic mitochondrial retention, improved ATP maintenance, rescued synaptic variability, and reversed behavioral phenotypes. These findings support impaired presynaptic mitochondrial retention and activity-induced synaptoenergetic deficits as cellular mechanisms contributing to bipolar disorder.

Background: Cardiovascular vascular disease (CVD) is a leading cause of increased mortality in people with severe mental illness (SMI). This study aims to examine the dose–response and intensity‐specific associations between physical activity (PA) and CVD risk and mortality in people with SMI. Methods: This prospective cohort study was conducted on 6313 participants with SMI with accelerometry data from UK Biobank from February 2013 to November 2021. Moderate‐to‐vigorous PA (MVPA) was categorized into 2 groups (<150 and ≥150 min/week) according to the PA guidelines for adults recommended by the World Health Organization, while total PA and light‐intensity PA were grouped by tertiles. Incident CVD, all‐cause and CVD mortality ascertained by hospital and death registries were primary outcomes. Results: Among 6313 participants (mean age 61.05 years; 33.9% men), 868 developed incident CVD, 233 died from any cause, and 88 died from CVD during a median follow‐up of 7 years. PA was inversely associated with the risk of incident CVD, all‐cause mortality, and CVD mortality. Performing guideline‐recommended MVPA was associated with 18% reduced risk for incident CVD (95% CI, 0.68–0.99), 42% for all‐cause mortality (95% CI, 0.43–0.79), and 49% for CVD mortality (95% CI, 0.31–0.83). A combination of recommended MVPA and moderate light‐intensity PA was associated with the lowest risk, with risk reductions of 24%, 59%, and 78%, respectively. Conclusions: Adequate PA, especially guideline‐recommended MVPA, was associated with a lower risk for incident CVD, all‐cause and CVD mortality among SMI population. Combining recommended MVPA with moderate light‐intensity PA yielded extra benefits.

This review summarizes the potential genes involved in both Parkinson's disease (PD) pathogenesis and colorectal cancer (CRC) carcinogenesis, focusing on the oncogenic mechanisms that may arise from PD gene dysfunctions. By investigating genes such as PRKN , PINK1 , and DJ‐1 , which influence pathways primarily related to oxidative stress, mitophagy, cell cycle regulation, and inflammation, this review provides insight into how PD genes may contribute to CRC tumorigenesis through interactions with gut microbes such as Bacillus subtilis and Clostridium butyricum . This review highlights a mechanistic bridge between neurodegeneration and cancer centered on mitochondrial dysfunction, mitophagy, and inflammation. The convergence of molecular mechanisms and gut microbiota in PD and CRC highlights promising avenues for microbiome‐targeted interventions alongside genetic and molecular approaches to advance novel diagnostic and therapeutic strategies for these two diseases. Importantly, therapeutic strategies should be considered in a holistic manner, as interventions for one disease may influence the course of another, and probiotics represent a unique modality with the potential to confer preventive and therapeutic benefits across both conditions.

Background: Comorbidity of depression and anxiety disorders (DAs) is as high as 50%, and diagnosis remains heavily reliant on subjective symptomatic assessments due to the lack of validated objective biomarkers. Neuroinflammation and oxidative stress are well-recognized core pathophysiological features of DAs. Prostaglandins (PGs), a class of lipid mediators closely linked to neuroinflammation and oxidative stress, have been implicated as key mediators in the pathogenesis of mood and anxiety disorders. S-(PGJ₂)-glutathione, a covalent conjugate of 15d-PGJ₂ and glutathione (GSH), integrates PG-mediated inflammatory signaling and GSH-dependent antioxidant defense, suggesting its potential as a candidate biomarker for DAs. Methods: The case-control study enrolled 77 participants, including 39 patients with comorbid depression and anxiety disorders (DAs) and 38 healthy controls (HCs) matched for gender, age, and body mass index (BMI). The cohort was randomly stratified into training and test sets at a 7:3 ratio. Serum levels of PG-related metabolites were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Univariate and multivariate logistic regression analyses were performed in the training set to identify independent biomarkers. Receiver operating characteristic (ROC) analysis was employed to assess diagnostic performance in the training cohort, test cohort, and overall population, while decision curve analysis (DCA) was used to evaluate clinical utility. Results: A total of 21 PG-related metabolites were detected, of which five were significantly dysregulated in DAs patients and remained significant after FDR correction for multiple testing. Multivariate logistic regression identified S-(PGJ₂)-glutathione as an independent biomarker associated with DAs, both before and after adjustment for confounding factors including education level, systolic blood pressure (SBP), and diastolic blood pressure (DBP). ROC analysis in the total cohort showed that S-(PGJ₂)-glutathione yielded an AUC of 0.949, with a sensitivity of 0.789 and specificity of 0.949. Consistent results were observed in the training and internal test sets. DCA suggested that using S-(PGJ₂)-glutathione for diagnosis may provide a higher net benefit than conventional “Treat All” or “Treat None” strategies over a wide range of threshold probabilities. Conclusion: The PG metabolic pathway is dysregulated in patients with DAs. S-(PGJ₂)-glutathione is significantly downregulated and exhibits favorable preliminary diagnostic efficacy based on internal training and test set validation. Given the relatively small sample size and the absence of external cohort validation, these findings should be interpreted as preliminary.

Cognitive dysfunction is a common feature of schizophrenia and is crucial to long-term prognosis. Loneliness may be associated with poorer cognitive function, potentially through sleep quality and anxiety, but the pathways underlying these associations remain unclear. In this study, we aimed to explore the relationship between loneliness and cognitive function using a clinical cohort from China and to examine the mediating roles of sleep quality and anxiety. Using cross-sectional data from a Chinese clinical cohort, we recruited 299 patients with schizophrenia who met DSM-5 diagnostic criteria. Participants completed the University of California Los Angeles (UCLA) Loneliness Scale, the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Pittsburgh Sleep Quality Index (PSQI), and the Hamilton Anxiety Rating (HAMA) Scale. We first conducted univariable analyses to identify demographic and clinical correlates of cognitive performance to be included as covariates. To examine the robustness of the findings, we further performed subgroup analyses by age (18-44, 45-59, ≥ 60 years), sex (male/female), and education level (≤ 9 years/ > 9 years). We then tested a serial mediation model of "UCLA → PSQI → HAMA → RBANS" using structural equation modelling while adjusting for the identified covariates. The significance of indirect effects was evaluated using bootstrapping with 5,000 resamples. After adjustment for age, sex, and years of education, the structural equation model showed a good fit (χ²/df = 1.287, CFI = 0.996, RMSEA = 0.031). Path analyses indicated that the association between UCLA scores and RBANS scores was partially explained by significant indirect pathways comprising two components. First, anxiety acted as an independent mediator. Higher UCLA scores were associated with higher HAMA scores (β = 0.135, P < 0.001), which in turn were associated with lower RBANS scores (β = -0.710, P < 0.001). Higher UCLA scores were also associated with higher PSQI scores (β = 0.068, P < 0.001), which were associated with higher HAMA scores (β = 0.283, P < 0.001). Bootstrapping confirmed a significant total indirect effect (effect = -0.109, 95% CI [-0.179, -0.055]). The anxiety-only pathway accounted for 13.7% of the total effect and the sleep-anxiety serial pathway for 2.0%. Subgroup analyses revealed that the anxiety-mediated pathway was significant across most strata, with larger effect sizes in males, older adults (≥ 60 years), and individuals with lower education (≤ 9 years), while the serial pathway was uniquely significant in the 45-59 years age group. These findings indicate that anxiety accounted for a larger proportion of the observed indirect association, whereas the contribution of the sleep-anxiety serial pathway was relatively modest. Nevertheless, given the cross-sectional design, the findings should be interpreted cautiously with respect to causality, and the observed relationships among loneliness, sleep quality, anxiety, and cognitive function may reflect clinically relevant interrelated processes in patients with schizophrenia.

The neurobiological mechanisms underlying the therapeutic effects of meditation therapy in patients with schizophrenia remain poorly understood, therefore, we aim to investigate the relationship between clinical symptoms and the structural changes in brain gray matter in a meditation intervention trial. Han inpatients with schizophrenia admitted to the Shanghai First Civil Affairs Mental Health Centre in 2018 were recruited and randomly assigned to the meditation (Med) or the conventional (CON) treatment group in an eight-months trial. MRI data was collected at the outset, three months, and eight months of treatment. Fifty-eight male subjects completed all evaluations and MRI scans, including 30 in Med and 28 in CON. The findings indicate that meditation can significantly inhibit the extensive regional atrophy of gray matter volume (GMV). A positive correlation was observed between the GMV change rate in the right thalamus and the reduction rate of PANSS positive score (r = 0.3850, p = 0.0028), negative score (r = 0.3789, p = 0.0034) and total score (r = 0.3705, p = 0.0042); The GMV change rate in right insula was positively correlated with PANSS positive score (r = 0.2976, p = 0.0233), negative score (r = 0.3987, p = 0.0019), general score (r = 0.3216, p = 0.0138) and total score (r = 0.3765, p = 0.0035). Additionally, the GMV change rate in the right supplementary motor area was positively correlated with negative scores (r = 0.3633, p = 0.0051). while the right paracentral lobule positively correlated with PANSS general score (r = 0.2791, p = 0.0338). These findings demonstrate the effectiveness of meditation in chronic schizophrenia and suggest it as a promising method for the alleviation of clinical symptoms in schizophrenia.