Zhi-Lin Luan

Neurodegenerative diseases (NDDs) are a major public health concern characterized by the progressive loss of neurons, ultimately leading to neuronal death and causing a sustained decline in brain function or physical motor abilities. Major examples include Alzheimer’s disease (AD) and Parkinson’s disease (PD). Currently, NDDs lack effective curative methods, and their pathological process primarily involves misfolded protein aggregation, oxidative stress, and neuroinflammation. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway, as a central hub for cytokine signaling, has recently been found to play a key role in neuroinflammation and immune regulation in NDDs. This review systematically elucidates the core mechanisms of the JAK/STAT pathway in NDDs, including the regulation of microglial and astrocytic reactivity, the impact on blood–brain barrier integrity, and involvement in energy metabolism abnormalities. On this basis, we have reviewed and evaluated various therapeutic strategies targeting this pathway, focusing on small-molecule JAK inhibitors such as baricitinib and tofacitinib, and have analyzed their mechanisms of action, preclinical efficacy, and potential side effects. In addition, this article provides a forward-looking perspective on the future research directions of the JAK/STAT pathway from the perspective of anti-neuroinflammation to promote neuroregeneration therapy, aiming to offer theoretical references and new ideas for the clinical translational research of this pathway.

Introduction: Exercise fatigue can significantly impair physical function, while herbal medicines exhibit broad application prospects in anti-fatigue research. The herbal pair of Smilax glabra Roxb. and Ficus hirta Vahl. (FSP) is well-known for its hepatoprotective, dampness-eliminating, and detoxifying effects. However, its mechanism of action in improving exercise performance remains unclear. Methods: The impact of FSP on exercise performance was assessed through motor behavioral tests and monitoring of energy metabolism in both resting and exercise states. The anti-fatigue effects were evaluated by measuring fatigue-related biochemical markers in serum and urine using biochemical assay kits. Transcriptome sequencing of liver tissues from the animal model was conducted, and differentially expressed genes as well as significantly enriched pathways were identified via GO and KEGG enrichment analyses. Subsequently, a multi-parameter evaluation system was established, and in conjunction with molecular docking technology, two potential key active components in FSP were screened. Finally, their mechanisms of action were further verified using animal and cell-based experiments. Results: This study confirmed that FSP intervention significantly improved exercise performance in mice, accelerated lactate clearance, enhanced energy metabolism, and increased hepatic and muscular glycogen reserves, while alleviating oxidative stress and reducing systemic inflammation levels. Mechanistic investigations demonstrated that FSP activated the expression of adiponectin receptors (AdipoR1 and AdipoR2) in mouse liver, promoting the overexpression of downstream phosphorylated AMPK (p-AMPK) and PGC-1α, thereby regulating mitochondrial function and lipid metabolism. Furthermore, the study identified taxifolin and apigenin as the potential primary active components in FSP responsible for modulating the AdipoRs-AMPK pathway, with evidence of a synergistic effect between these two compounds. Conclusions: FSP regulates mitochondrial function through the AdipoRs-AMPK signaling pathway to exert anti-fatigue effects and enhance exercise performance.

Schizophrenia (SZ) is a severe neuropsychiatric disorder arising from complex interactions between genetic susceptibility and environmental factors. There is growing evidence that immune dysregulation and neuroinflammation are central to its pathogenesis, with the microbiota-gut-brain (MGB) axis playing a critical role. This review synthesizes clinical and preclinical findings to elucidate the relationship between gut microbiota dysbiosis and aberrant inflammatory signaling in the periphery and central nervous system in schizophrenia. We detail how alterations in gut microbiota metabolites, following dysbiosis disrupt blood-brain barrier (BBB) integrity and exacerbate neuroinflammation, ultimately leading to the neuropathology of SZ. The review further explores how gut dysbiosis activates innate immune pathways, including the complement system (e.g., C4) and Toll-like receptors (e.g., TLR4), and examines the bidirectional relationship between cytokine imbalances and gut microbiota. A key focus is placed on the dysregulation of the kynurenine pathway of tryptophan metabolism, which mechanistically links immune activation to neurotransmitter imbalances. Collectively, these findings demonstrate that gut microbiota dysbiosis contributes to the pathophysiology of schizophrenia through multifaceted immune-neuro-endocrine pathways, highlighting the MGB axis as a promising target for novel therapeutic strategies.

Activation of PXR enhances urine concentration, whereas PXR deficiency diminishes this capacity. PXR is coexpressed with AVP in the hypothalamus, where it upregulates AVP transcription to promote renal water reabsorption. These findings reveal a novel role for PXR in regulating urinary concentration and propose its potential as a therapeutic target for water metabolism disorders, such as diabetes insipidus.

Kidney renal clear cell carcinoma (KIRC) is the most common histological subtype of renal cell carcinoma (RCC), characterized by high metastatic potential and mortality, accounting for over 75% of RCC patients worldwide. However, KIRC patients often exhibit poor prognosis due to the absence of effective and sensitive biomarkers for early detection. As a key xenobiotic and endobiotic receptor in humans, the pregnane X receptor (PXR, NR1I2) exerts regulatory functions on various biological signaling pathways—most of which are associated with tumorigenesis. In this study, we aimed to elucidate the role of PXR in KIRC and investigate its underlying mechanisms. Using The Cancer Genome Atlas (TCGA) database and our clinical KIRC samples, we analyzed the expression profile and prognostic value of PXR. Results showed that PXR was significantly upregulated in KIRC tumor tissues, and high PXR levels were associated with poor overall survival in KIRC patients. Further in vitro experiments demonstrated that modulating PXR markedly influenced KIRC cell proliferation, invasion, migration, and metastasis. RNA sequencing revealed that PXR knockdown in KIRC cells perturbed multiple cell signaling pathways. Mechanistic investigations showed that PXR down-regulation promoted the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway and affected the proliferation, apoptosis and invasion of KIRC cells. Our findings indicate that PXR is consistently upregulated in KIRC tissues and correlates with poor patient prognosis, suggesting it could serve as a potential biomarker for the diagnosis and prognosis of KIRC.

The circadian system, primarily governed by the suprachiasmatic nucleus of the hypothalamus, consists of a central clock and peripheral clocks distributed across various body tissues. Clock genes generate a 24-h oscillatory cycle via a transcription-translation feedback loop (TTFL). Emerging evidence has identified circadian rhythm disruption as a significant contributor to the risk of metabolic disorders. With aging, the function of circadian rhythms declines, leading to metabolic dysfunction in multiple organs. This article reviews the molecular mechanisms underlying circadian rhythm disruption during aging, with a focus on telomere homeostasis, SIRT1-mediated epigenetic regulation, and the NAD⁺ metabolic pathway, and systematically analyzes the characteristics of rhythm imbalance in different metabolic organs. A comprehensive understanding of the correlation between circadian rhythms and aging is essential for developing strategies to combat aging and metabolic diseases.

Wnt/β-catenin is a signaling pathway associated with embryonic development, organ formation, cancer, and fibrosis. Its activation can repair kidney damage during acute kidney injury (AKI) and accelerate the occurrence of renal fibrosis after chronic kidney disease (CKD). Interestingly, p53 has also been found as a key modulator in AKI and CKD in recent years. Meantime, some studies have found crosstalk between Wnt/β-catenin signaling pathways and p53, but more evidence is required on whether they have synergistic effects in renal disease progression. This article reviews the role and therapeutic targets of Wnt/β-catenin and p53 in AKI and CKD and proposes for the first time that Wnt/β-catenin and p53 have a synergistic effect in the treatment of renal injury.

Purpose: The aim of this study was to investigate the effect of blood flow restriction (BFR) combined with low-intensity resistance training (RT) on cardiovascular risk factors in obese individuals.Methods: Twenty-six male obese college students were recruited and randomly assigned to a control group (CON, n = 8), a low-intensity RT group (RT, n = 9), and a combined BFR training and low-intensity RT group (BFRT, n = 9).Results: The subjects in BFRT group showed significant reductions in body fat percentage and waist-to-hip ratio and a significant increase in lean mass and muscle mass; the peak torque, peak power, and endurance ratio of knee extensors and elbow flexors were significantly upregulated; the root mean square (RMS) for the medial femoral muscle, lateral femoral muscle and biceps significantly increased; the diastolic blood pressure (DBP) showed a significant decrease. The BFRT group also showed significant up-regulations in RMS of the difference between the adjacent R-R intervals (RMSSD), high-frequency power (HF) of parasympathetic modulatory capacity, the standard deviation of R-R intervals (SDNN) of overall heart rate variability (HRV) changes and low-frequency power (LF) of predominantly sympathetic activity. In addition, glycated hemoglobin (HbA1C), insulin resistance index (HOMA-IR) and fasting blood glucose (FBG) were all significantly downregulated in BFRT group. In parallel, low-density lipoprotein (LDL-C) significantly reduced while high-density lipoprotein (HDL-C) significantly increased in BFRT group.Conclusion: BFR combined with low-intensity RT training effectively improved body composition index, increased muscle mass, improved neuromuscular activation, enhanced muscle strength and endurance, which in turn improved abnormal glucolipid metabolism and enhanced cardiac autonomic regulation.

Objective Schizophrenia is a complex and devastating psychiatric disorder with a strong genetic background. However, much uncertainty still exists about the role of genetic susceptibility in the pathophysiology of schizophrenia. TEA domain transcription factor 1 (TEAD1) is a transcription factor associated with neurodevelopment and has modulating effects on various nervous system diseases. In the current study, we performed a case–control association study in a Northeast Chinese Han population to explore the characteristics of pathogenic TEAD1 polymorphisms and potential association with schizophrenia.Methods We recruited a total of 721 schizophrenia patients and 1,195 healthy controls in this study. The 9 single nucleotide polymorphisms (SNPs) in the gene region of TEAD1 were selected and genotyped.Results The genetic association analyses showed that five SNPs (rs12289262, rs6485989, rs4415740, rs7113256, and rs1866709) were significantly different between schizophrenia patients and healthy controls in allele or/and genotype frequencies. After Bonferroni correction, the association of three SNPs (rs4415740, rs7113256, and rs1866709) with schizophrenia were still evident. Haplotype analysis revealed that two strong linkage disequilibrium blocks (rs6485989-rs4415740-rs7113256 and rs16911710-rs12364619-rs1866709) were globally associated with schizophrenia. Four haplotypes (C-C-C and T-T-T, rs6485989-rs4415740-rs7113256; G-T-A and G-T-G, rs16911710-rs12364619-rs1866709) were significantly different between schizophrenia patients and healthy controls.Conclusion The current findings indicated that the human TEAD1 gene has a genetic association with schizophrenia in the Chinese Han population and may act as a susceptibility gene for schizophrenia.