Zhijian Rao

Exercise is a pivotal non-pharmacological intervention for enhancing overall health, with a key underlying mechanism being the induction of adaptive angiogenesis across multiple organ systems. This narrative review discusses recent advances in exercise-induced angiogenesis, with a particular focus on its tissue- and organ-specific manifestations and underlying molecular mechanisms. The available evidence indicates that exercise integrates diverse signals—including mechanical stress, metabolic shifts, and hypoxic or ischemic stress—to upregulate key angiogenic factors, such as vascular endothelial growth factor (VEGF), angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2), and to activate conserved signaling pathways including hypoxia-inducible factor-1α (HIF-1α), phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), and endothelial nitric oxide synthase (eNOS), thereby driving angiogenesis. This process exhibits tissue specificity: in skeletal muscle, it primarily enhances oxygen transport and metabolic efficiency; in bone, it couples with osteogenesis to maintain structural integrity; in the brain, it supports neuroplasticity and cognitive function; in the heart, it improves myocardial perfusion via angiogenesis and collateral remodeling (arteriogenesis); and in adipose tissue, it ameliorates the metabolic microenvironment. Furthermore, the mode and intensity of exercise, along with individual differences (such as age and health status), significantly influence the magnitude of its angiogenic effects. Accordingly, this review highlights the proposed role of exercise-induced angiogenesis in a range of conditions—including cardiovascular disease, sarcopenia, osteoporosis, neurodegenerative disorders, and metabolic syndrome—and we treat these relationships as potential mechanisms that require further validation rather than established therapeutic pathways. In the future, research should aim to define optimal exercise parameters, elucidate deeper molecular mechanisms, and investigate the translational potential of these insights for personalized clinical interventions.

Ginkgetin (GK) is a naturally occurring biflavonoid predominantly isolated from Ginkgo biloba and has attracted increasing attention because of its broad pharmacological activities. Structurally, GK belongs to the 3′-8″-linked biflavone subclass, which distinguishes it from other biflavonoids like amentoflavone (the parent compound of this subclass) and its monomeric counterparts such as apigenin. This unique C-C linked dimeric architecture confers distinct molecular planarity and lipophilicity, contributing to its enhanced membrane permeability and multitarget engagement capabilities. GK has been shown to exert pleiotropic biological effects in preclinical studies, including anti-inflammatory, antioxidant, antifibrotic, anticancer, neuroprotective, cardioprotective, metabolic regulatory and antibacterial activities. Mechanistically, preclinical evidence indicates that GK functions as a multitarget modulator of key signaling pathways involved in oxidative stress, inflammation, cell death and tissue remodeling, such as nuclear factor erythroid 2–related factor 2/heme oxygenase-1 (Nrf2/HO-1), nuclear factor kappa-B(NF-κB), Janus kinase/signal transducer and activator of transcription(JAK/STAT), mitogen-activated protein kinases(MAPKs), AMP-activated protein kinase/mechanistic target of rapamycin(AMPK/mTOR), phosphoinositide 3-kinase/protein kinase B(PI3K/Akt) and cyclic GMP-AMP synthase–stimulator of interferon genes(cGAS–STING). Notably, GK has been observed to display context-dependent regulation of cell fate decisions, including apoptosis, autophagy and ferroptosis, thereby enabling the selective elimination of pathological cells while preserving normal tissue function. Preclinical studies further demonstrate that GK exhibits therapeutic potential across diverse disease systems, including cancer, metabolic disorders, cardiovascular diseases, neurological disorders and musculoskeletal diseases. In addition, emerging evidence highlights its antibacterial and antivirulence properties through the inhibition of biofilm formation and quorum sensing. It is crucial to note, however, that this promising profile is predominantly derived from preclinical studies, and clinical evidence in humans remains to be established. Despite these promising findings, the clinical translation of GK remains limited by challenges related to pharmacokinetics, bioavailability and druggability. This review systematically summarizes the chemical characteristics, pharmacological activities and molecular mechanisms of GK, with an emphasis on its multitarget actions and therapeutic potential across disease systems, and discusses current limitations and future perspectives to facilitate the rational development of GK-based interventions.

Microplastics (MPs) are pervasive environmental contaminants with significant bioaccumulation potential, posing a growing threat to global health through multi-organ toxicity. This review systematically synthesizes current knowledge on MPs-induced organ-specific damage and its systemic health implications. We detail the accumulation of MPs in major organ systems, including the liver, brain, lungs, kidneys, intestines, heart, and reproductive organs. Furthermore, we emphasize the critical role of inter-organ communication in amplifying toxicity, such as gut-liver axis-mediated hepatotoxicity and gut-brain axis-driven neurotoxicity. Emerging evidence on the transgenerational adverse effects of parental MPs exposure is also discussed. The core cellular and molecular mechanisms across these organs are examined, with a particular focus on oxidative stress, inflammatory activation, mitochondrial dysfunction, and programmed cell death. This review is distinct in its integrative approach, offering a novel perspective by synthesizing organ-specific pathologies with cross-organ communication networks and transgenerational effects, thereby providing a more holistic understanding of MPs’ systemic toxicity. Collectively, this review elucidates the exposure-organ damage correlation, analyzes the underlying pathogenic mechanisms, and aims to provide a scientific foundation for public health risk assessment and informed environmental policy formulation.

Exercise-induced fatigue involves oxidative stress and metabolic dysregulation. While the anti-aging protein α-Klotho regulates metabolism and oxidative stress, its role in exercise fatigue is unexplored. This study investigated whether α-Klotho supplementation mitigates cumulative exercise-induced fatigue and elucidated the underlying tissue-specific mechanisms. Male C57BL/6J mice were divided into three groups (n = 10 per group), the control group, fatigue treated with saline, or α-Klotho (0.2 mg/kg, i.p. daily) group. Fatigue was induced by a 6-day exhaustive swimming protocol (5% body weight load). Tissues were collected 24h post-final exercise. Assessments included daily exhaustion time, grip strength, serum creatine kinase (CK), urea nitrogen (BUN), oxidative stress markers (H₂O₂, MDA, SOD, GSH/GSSG), tissue glycogen, and pathway protein expression (Western blot). α-Klotho supplementation prevented exercise-induced weight loss and restored grip strength. While exhaustive exercise markedly increased serum CK and BUN levels, α-Klotho selectively normalized CK without effecting serum BUN. α-Klotho attenuated oxidative damage by reducing hydrogen peroxide levels while enhancing antioxidant capacity, accompanied by activation of the NRF2/HO-1 pathway and further upregulation of PGC-1α. Notably, α-Klotho induced striking hepatic glycogen supercompensation through activation of the AKT/GS signaling pathway and upregulation of GLUT4, whereas muscle glycogen levels remained unchanged. In conclusion, α-Klotho ameliorates cumulative exercise-induced fatigue through dual recovery-phase mechanisms: NRF2/HO-1-mediated antioxidant protection in skeletal muscle and AKT/GS-triggered hepatic glycogen supercompensation, thereby facilitating oxidative stress resolution and enhancing energy reserve restoration.

Decreased skeletal muscle mass and function are a serious complication of long-term diabetes, often leading to numerous adverse outcomes. The primary pathological features of diabetic sarcopenia include muscle fiber atrophy and interstitial fibrosis. Although resistance exercise (RE) has been reported to mitigate skeletal muscle atrophy in type 2 diabetes mellitus (T2DM), the underlying mechanisms remain unclear. Fibroblast growth factor 21 (FGF21), an exercise-induced cytokine, has been shown to protect against skeletal muscle atrophy at elevated levels. In this study, a T2DM mouse model was established through 12 weeks of high-fat diet feeding and intraperitoneal injection of streptozotocin (STZ) to investigate the effect and mechanism of RE on skeletal muscle atrophy in T2DM mice. Our results demonstrated that 8 weeks of RE significantly decreased body weight, fat mass, triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), fasting blood glucose (FBG), and serum insulin levels in T2DM mice. RE also improved lean mass, glucose tolerance (IPGTT), and insulin tolerance (ITT). Additionally, RE increased skeletal muscle mass cross-sectional area (CSA) while attenuating fibrosis and inflammatory responses in skeletal muscle. Notably, RE upregulated FGF21 expression and activated the PI3K/Akt signaling pathway in diabetic skeletal muscle. RE promoted the phosphorylation of mTOR, 4EBP1, and p70S6K while suppressing the expression of the atrophy-related E3 ubiquitin ligases MuRF1 and MAFbx/Atrogin-1. Furthermore, RE inhibited lipid synthesis and enhanced both lipid oxidation and glucose utilization in skeletal muscle of T2DM mice. RE also improved mitochondrial biogenesis and dynamics in skeletal muscle of T2DM mice. In summary, 8 weeks of RE alleviated skeletal muscle atrophy in T2DM mice via activation of the FGF21/PI3K/Akt signaling pathway, which enhanced protein synthesis, improved glycolipid metabolism and mitochondrial quality control, and attenuated fibrosis and inflammation.

Fibrosis represents a terminal pathological manifestation encountered in numerous chronic diseases. The process involves the persistent infiltration of inflammatory cells, the transdifferentiation of fibroblasts into myofibroblasts, and the excessive deposition of extracellular matrix (ECM) within damaged tissues, all of which are characteristic features of organ fibrosis. Extensive documentation exists on fibrosis occurrence in vital organs such as the liver, heart, lungs, kidneys, and skeletal muscles, elucidating its underlying pathological mechanisms. Regular exercise is known to confer health benefits through its anti-inflammatory, antioxidant, and anti-aging effects. Notably, exercise exerts anti-fibrotic effects by modulating multiple pathways, including transforming growth factor-β1/small mother decapentaplegic protein (TGF-β1/Samd), Wnt/β-catenin, nuclear factor kappa-B (NF-kB), reactive oxygen species (ROS), microRNAs (miR-126, miR-29a, miR-101a), and exerkine (FGF21, irisin, FSTL1, and CHI3L1). Therefore, this paper aims to review the specific role and molecular mechanisms of exercise as a potential intervention to ameliorate organ fibrosis.

Exercise is a recognized non-pharmacological treatment for improving glucose homeostasis in type 2 diabetes (T2DM), with resistance exercise (RE) showing promising results. However, the mechanism of RE improving T2DM has not been clarified. This study aims to investigate the effects of RE on glucose and lipid metabolism, insulin signaling, and mitochondrial function in T2DM mice, with a focus on the regulatory role of miR-30d-5p. Our results confirmed that RE significantly improved fasting blood glucose, IPGTT, and ITT in T2DM mice. Enhanced expression of IRS-1, p-PI3K, and p-Akt indicated improved insulin signaling. RE improved glycolipid metabolism, as well as mitochondrial biogenesis and dynamics in skeletal muscle of T2DM mice. We also found that miR-30d-5p was upregulated in T2DM, and was downregulated after RE. Additionally, in vitro, over-expression of miR-30d-5p significantly increased lipid deposition, and reduced glucose uptake and mitochondrial biogenesis. These observations were reversed after transfection with the miR-30d-5p inhibitor. Mechanistically, miR-30d-5p regulates glycolipid metabolism in skeletal muscle by directly targeting SIRT1, which affects the expression of PGC-1α, thereby influencing mitochondrial function and glycolipid metabolism. Taken together, RE effectively improves glucose and lipid metabolism and mitochondrial function in T2DM mice, partly through regulating the miR-30d-5p/SIRT1/PGC-1α axis. miR-30d-5p could serve as a potential therapeutic target for T2DM management.

OBJECTIVES: In light of the rise in the global aging population, this study investigated the potential of the oxidative balance score (OBS) as an indicator of phenotypic age acceleration (PhenoAgeAccel) to better understand and potentially slow down aging.METHODS: Utilizing data from the National Health and Nutrition Examination Survey collected between 2001 and 2010, including 13,142 United States adults (48.7% female and 51.2% male) aged 20 and above, OBS and PhenoAgeAccel were calculated. Weighted generalized linear regression models were employed to explore the associations between OBS and PhenoAgeAccel, including a sex-specific analysis.RESULTS: The OBS demonstrated significant variability across various demographic and health-related factors. There was a clear negative correlation observed between the higher OBS quartiles and PhenoAgeAccel, which presented sex-specific results: the negative association between OBS and PhenoAgeAccel was more pronounced in male than in female. An analysis using restricted cubic splines revealed no significant non-linear relationships. Interaction effects were noted solely in the context of sex and hyperlipidemia.CONCLUSIONS: A higher OBS was significantly associated with a slower aging process, as measured by lower PhenoAgeAccel. These findings underscore the importance of OBS as a biomarker in the study of aging and point to sex and hyperlipidemia as variables that may affect this association. Additional research is required to confirm these results and to investigate the biological underpinnings of this relationship.

This study aimed to examine the relationship between daily total intake of water (DTIW) and handgrip strength (HGS) among US adults and to explore the impact of water intake on muscle function and health, providing a reference for public health policies and health education. Using the data from the National Health and Nutrition Examination Survey (NHANES) 2011–2014, a cross-sectional survey design was adopted to analyze 5427 adults (48.37% female and 51.63% male) aged 20 years and above. DTIW was assessed using two non-consecutive 24 h dietary recall interviews, and the HGS level was measured using a Takei Dynamometer. Weighted generalized linear regression models and restricted cubic spline plots were used to analyze the linear and nonlinear associations between DTIW and HGS level and to conduct a gender subgroup analysis and an interaction effect test. The results showed that there were significant differences in HGS and other characteristics among different quartile groups of DTIW (p < 0.05). There was a significant nonlinear trend (exhibiting an inverted U-curve) between DTIW and HGS (p for nonlinear = 0.0044), with a cut-off point of 2663 g/day. Gender subgroup analysis showed that the nonlinear trend (exhibiting an inverted U-curve) was significant only in males (p for nonlinear = 0.0016), with a cut-off point of 2595 g/day. None of the stratified variables had an interaction effect on the association between DTIW and HGS (p for interaction > 0.05). In conclusion, this study found a nonlinear association between DTIW and HGS levels, as well as a gender difference. This finding provides new clues and directions for exploring the mechanism of the impact of DTIW on muscle function and health and also provides new evidence and suggestions for adults to adjust their water intake reasonably.