Renqing Zhao

Objectives: Obesity disrupts adipose and systemic immune–metabolic homeostasis, yet the molecular mechanisms through which exercise restores abnormal tissue function remain incompletely defined. This study aimed to screen cross-tissue candidate genes associated with exercise-mediated correction of obesity-related transcriptional disorders via multi-tissue transcriptome profiling and bioinformatic gene prioritization. Methods: Transcriptomic datasets of mouse visceral white adipose, subcutaneous white adipose and skeletal muscle were downloaded from the public GEO database, covering normal control, high-fat induced obese and post-exercise intervention groups. R programming was applied to complete differential analysis, GO/KEGG enrichment, PPI network, LASSO and GSEA; independent human adipose datasets from GEO validated candidate genes. Results: Exercise reversed obesity-triggered transcriptional changes in adipose tissues. Exercise-responsive genes concentrated on immune inflammation, lipid and energy metabolism. Key hub genes for tissue remodeling were screened, and depot-specific pathway regulation was verified by GSEA. CCL2 showed consistent expression trends across mouse and human adipose data. Conclusions: This study identifies distinct tissue-specific transcriptional responses to exercise: visceral adipose mainly achieves reversal of obesity-induced inflammatory dysregulation, subcutaneous adipose undergoes combined immune–inflammatory and metabolic reprogramming, while skeletal muscle presents only energy-metabolism adaptive remodeling without obvious reversal of obese gene disorders. Immune–metabolic pathways dominate exercise-induced restoration in adipose tissues. Integrated network screening and cross-species validation identified CCL2 as a conserved candidate associated with exercise-responsive immune–metabolic pathways, providing valuable molecular candidates for further anti-obesity research.

Alzheimer’s disease (AD), the most prevalent form of dementia, is characterized by progressive memory impairment and cognitive dysfunction. The neuropathological hallmarks of this neurodegenerative disorder encompass two principal pathological features: extracellular deposition of amyloid- β (Aβ) plaques due to abnormal protein aggregation, and intracellular accumulation of neurofibrillary tangles (NFTs) caused by hyperphosphorylation of tau proteins (p-Tau). These pathological changes induce synaptic loss and neuronal apoptosis, which leads to impaired neuroplasticity and progressive deterioration of cognitive function. Autophagy, a critical mechanism in the central nervous system (CNS) responsible for clearing misfolded protein aggregates and damaged organelles, plays a pivotal role in maintaining neuronal homeostasis and synaptic plasticity. However, AD is associated with autophagy impairment, resulting in the accumulation of toxic protein aggregates and damaged organelles. These pathological changes disrupt protein homeostasis, thereby exacerbating neurodegenerative processes. Currently, AD therapeutic strategies remain limited. Emerging evidence indicates that exercise intervention mitigates cognitive decline and enhances synaptic plasticity, potentially through reducing Aβ deposition and pathological phosphorylation of tau proteins. However, the precise mechanisms through which these interventions act remain to be fully elucidated. Recent studies have shown that exercise can promote autophagosome formation, fusion, and lysosomal hydrolytic function, thereby ameliorating the pathological progression of AD. Despite these promising findings, the precise molecular targets and underlying signaling mechanisms through which exercise modulates autophagy in AD remain to be fully elucidated. The purpose of this study is to establish innovative therapeutic targets while identifying mechanistically actionable pharmacological targets to advance therapeutic development against AD pathogenesis.

Recent advances in single-cell RNA sequencing (scRNA-seq) have substantially deepened our understanding of adult hippocampal neurogenesis (AHN), enabling the detection of neural stem cells, progenitors, and immature neurons in postmortem human brain tissue and revealing how these populations are altered in neurological disease. Additionally, scRNA-seq enables the identification of disease-specific cell subtypes and distinct gene expression signatures associated with neurological disorders, many of which are linked to alterations in AHN and cognitive function. Such cellular- and molecular-level insights into neurological disease mechanisms provide a strong foundation for the development of targeted therapeutic strategies. Indeed, scRNA-seq has also emerged as a powerful tool in drug discovery and development across multiple disease areas, including cancer, cardiovascular disorders, and neurological conditions. In this review, we offer a comprehensive and integrative perspective on the cellular and molecular landscape of human hippocampal neurogenesis, the pathological mechanisms underlying neurological disorders, and their implications for therapeutic development.

This study aims to develop effective screening tools for cognitive impairment by integrating optimised speech classification features with various machine learning models. A total of 65 patients diagnosed with early-stage Mild Cognitive Impairment (MCI) and 55 healthy controls (HCs) were included. Audio data were collected through a picture description task and processed using the Python-based Librosa library for speech feature extraction. Three machine learning models were constructed: the Random Forest (RF) and Support Vector Machine (SVM) models utilised speech classification features optimised via the Sequential Forward Selection (SFS) algorithm, while the Extreme Gradient Boosting (XGBoost) model was trained on preprocessed speech data. After parameter tuning, the Librosa library successfully extracted 41 speech classification features from all participants. The application of the SFS optimisation strategy and the use of preprocessed data significantly improved identification accuracy. The SVM model achieved an accuracy of 0.825 (AUC: 0.91), the RF model reached 0.88 (AUC: 0.86), and the XGBoost model attained 0.92 (AUC: 0.91). These results suggest that speech-based machine learning models markedly improve the accuracy of distinguishing MCI patients from healthy older adults, providing reliable support for early cognitive deficit identification.

Although exercise is known to exert anti-inflammatory effects in neurodegenerative diseases, its specific impact and underlying mechanisms in Parkinson’s disease (PD) remain poorly understood. This study explores the effects of exercise on microglia-mediated neuroinflammation and apoptosis in a PD model, focusing on the role of irisin signaling in mediating these effects. Using a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model, we found that a 10-week treadmill exercise regimen significantly enhanced motor function, reduced dopaminergic neuron loss, attenuated neuronal apoptosis, and alleviated neuroinflammation. Exercise also shifted microglia from a pro-inflammatory to an anti-inflammatory phenotype. Notably, levels of irisin, phosphorylated AMP-activated protein kinase (p-AMPK), and sirtuin 1 (Sirt1), which were decreased in the PD brain, were significantly increased following exercise. These beneficial effects were abolished by blocking the irisin receptor with cyclic arginine–glycine–aspartic acid–tyrosine–lysine (cycloRGDyk). Our results indicate that exercise promotes neuroprotection in PD by modulating microglial activation and the AMPK/Sirt1 pathway through irisin signaling, offering new insights into exercise-based therapeutic approaches for PD.

Persistent microglial inflammation is a detrimental contributor to the progression of Parkinson disease (PD) pathology and related issues such as impaired adult hippocampal neurogenesis (AHN) and cognition. We conducted a 10‐week exercise program with MPTP‐treated mice to determine whether neuroinflammation can be addressed by aerobic exercise and elucidate its underlying regulatory mechanisms. Ten weeks of exercise significantly reduced PD‐related pathology and enhanced AHN and memory. These changes were linked to a reduction in neuronal apoptosis, microglial inflammation, and NLRP3 inflammasome activation. In cultured microglia, fibril α‐synuclein reduced FNDC5/irisin protein levels and induced NLRP3 inflammasome formation and IL‐1β production, which could be diminished by recombinant irisin treatment. Interestingly, “runner serum” isolated from exercising rodents enhanced FNDC5/irisin expression and reduced NLRP3 inflammasome components and IL‐1β secretion in α‐synuclein‐treated microglia. These effects could be diminished by blocking irisin signaling with cyclo RGDyk or NLRP3 agonist, nigericin sodium salt. Exercise‐induced neuroprotective effects were weakened by treatment of MPTP‐treated mice with cyclo RGDyk. In contrast, systematic administration of irisin partially replicated the beneficial effects of exercise on PD pathology, AHN, and memory function. As a nonpharmacological strategy, aerobic exercise effectively addresses PD pathology and preserves adult neurogenesis and cognition by mitigating microglial inflammation via mediating irisin/NLRP3 inflammasome pathways.

Mitochondrial dysfunction plays a crucial role in the pathogenesis of Parkinson’s disease (PD), yet therapeutic strategies targeting mitochondrial function remain limited. Exercise has shown neuroprotective benefits in PD, but the underlying mechanisms are not fully understood. This study aimed to investigate how exercise affects MPTP-induced excessive apoptosis, mitochondrial fission, and mitochondrial function in PD mice, with a focus on the Irisin/AMPK/SIRT1 pathway. Thirty-two male C57BL/6 J mice, aged 7–8 weeks, were randomly assigned to control (n = 8) and experimental groups (n = 24). Mice in the experimental groups were administered intraperitoneal injections of MPTP to induce the PD model. Subsequently, the experimental mice were divided into three groups (8 mice in each group): the sedentary group (PD), the group subjected to 10 weeks of treadmill exercise (PDEX), and the group receiving both treadmill exercise and Irisin antagonist injections (EXRG). Upon completion of the 10-week intervention, behavioral assessments were performed. Following this, the mice were euthanized to collect brain samples and subjected to immunohistochemistry, immunofluorescence, ELISA, citrate synthase assay, and Western blot analyses. MPTP-treated mice exhibited significant motor dysfunction and dopaminergic neuron loss in the nigrostriatal regions, which were alleviated after a 10-week exercise intervention. Exercise significantly reduced MPTP-induced neuronal apoptosis, as evidenced by decreased cellular debris and abnormal nuclear morphology, increased Bcl-2 protein levels, and decreased BAX expression. Furthermore, exercise mitigated abnormal mitochondrial fission in PD mice and improved mitochondrial function-related markers. This was reflected by reduced immunohistochemical signals and protein expression levels of Drp1, Fis1, and MFF, as well as increased citrate synthase activity and elevated expression levels of COX-I and COX-IV. In the substantia nigra of PD mice, the expression levels of Irisin, p-AMPK, and SIRT1 were reduced but were notably elevated after the 10-week exercise intervention. However, chronic treatment with Cyclo RGDyk to block Irisin signaling potentially counteracted the exercise-induced increases in p-AMPK and Sirt1 expression. Moreover, blocking the Irisin signaling pathway reversed the beneficial effects of exercise on mitochondrial fission, mitochondrial function, and neuronal apoptosis. Exercise is an effective approach for alleviating PD pathology by reducing excessive mitochondrial fission, dysregulated mitochondrial respiration and metabolism, and neuronal loss. The neuroprotective effects of exercise are achieved, in part, by regulating the Irisin/AMPK/SIRT1 signaling pathway. This study underscores the potential of targeting Irisin signaling as a therapeutic strategy of exercise to enhance mitochondrial function and promote neuronal survival in PD.

Neuroinflammation is a major feature of type 2 diabetic mellitus (T2DM), adversely affecting hippocampal neurogenesis. However, the precise mechanism is not fully understood, and therapeutic approaches are currently lacking. Therefore, we determined the effects of exercise on neuroinflammation and hippocampal neurogenesis in T2DM mice, with a specific focus on understanding the role of the irisin and related cascade pathways in modulating the beneficial effects of exercise in these processes. Ten-week exercise significantly decreased T2DM-induced inflammation levels and markedly promoted hippocampal neurogenesis and memory function. However, these positive effects were reversed by 10 weeks of treatment with cyclo RGDyk, an inhibitor of irisin receptor signaling. Additionally, exercise helped reduce the M1 phenotype polarization of hippocampal microglia in diabetic mice; this effect could be reversed with cyclo RGDyk treatment. Moreover, exercise markedly increased the levels of fibronectin type III domain-containing protein 5 (FNDC5)/irisin protein while decreasing the expression of Toll-like receptor 4 (TLR4), myeloid differential protein-88 (MyD88), and nuclear factor kappa-B (NF-κB) in the hippocampus of T2DM mice. However, blocking irisin receptor signaling counteracted the down-regulation of TLR4/MyD88/NF-κB in diabetic mice undergoing exercise intervention. Conclusively, exercise appears to be effective in reducing neuroinflammation and enhancing hippocampal neurogenesis and memory in diabetes mice. The positive effects are involved in the participation of the irisin/TLR4/MyD88/NF-κB signaling pathway, highlighting the potential of exercise in the management of diabetic-induced cognitive decline.