AIMS:Dysregulated macrophage polarization and persistent inflammation drive post-injury endometrial fibrosis and intrauterine adhesion (IUA), yet non-invasive early strategies remain limited. This study investigated the therapeutic effects and mechanisms of low-intensity pulsed ultrasound (LIPUS)-induced macrophage reprogramming in alleviating endometrial fibrosis and restoring fertility. MATERIALS AND METHODS:Immunoregulatory and anti-fibrotic effects of LIPUS were evaluated by optical coherence tomography, flow cytometry, immunohistochemistry, and immunofluorescence. Integrative transcriptomics of LIPUS-treated tissues and macrophages identified key targets and pathways. Western blotting and RT-qPCR assessed SOCS3/JAK1/STAT3 axis changes. Macrophage-endometrial stromal cell crosstalk was examined via co-culture, and pathway dysregulation was further evaluated in patient tissues. KEY FINDINGS:LIPUS suppresses M1 macrophage polarization and alleviates endometrial fibrosis in a mice model of chemically induced endometrial injury. Integrative transcriptomics identified SOCS3 as a significantly differentially expressed gene upregulated by LIPUS. Validation experiments confirmed that LIPUS upregulates SOCS3 with concomitant JAK1-STAT3 and inhibits pathological M1, while attenuating paracrine-driven transdifferentiation of endometrial stromal cells into myofibroblasts via suppression of the TGF-β/Smad3 cascade. Pharmacological JAK1 inhibition recapitulated LIPUS effects, whereas IL-6 pretreatment partially abrogated them, supporting the involvement of the SOCS3/JAK1/STAT3 pathway. LIPUS also helped ameliorate endometrial structural remodeling and restores fertility. SOCS3 downregulation and STAT3 hyperactivation were confirmed in fibrotic endometrial tissues from patients, supporting the clinical relevance of this pathway as a therapeutic target. SIGNIFICANCE:The study demonstrates that LIPUS reprograms macrophages with involvement of the SOCS3/JAK1/STAT3 axis in association with alleviation of endometrial fibrosis and improve function, offering a potential non-invasive early intervention for IUA.
AIMS:Diabetic cardiomyopathy (DCM) is a major cause of diabetes-associated mortality, with myocardial oxidative stress serving as a pivotal pathological driver of DCM. This study aimed to elucidate the function and mechanism of Src tyrosine kinase in T2DM-associated DCM pathogenesis. MATERIALS AND METHODS:35 DCM and 72 T2DM patients were enrolled for clinical analysis. In vivo db/db mice and in vitro high glucose-treated H9c2 cardiomyocyte models were established. Src tyrosine kinase activity, oxidative stress levels, mitochondrial function, and oxidative phosphorylation (OXPHOS) profiles were examined, with Src inhibitors (PP2, SrcI1) applied for functional validation. KEY FINDINGS:Clinical study elevated serum Src activity was an independent risk factor for DCM. T2DM models presented enhanced Src activation, severe myocardial oxidative stress, aberrant OXPHOS complex activities, and impaired mitochondrial energy metabolism. Pharmacological Src inhibition markedly ameliorated diabetic myocardial oxidative damage, normalized mitochondrial respiratory function, and recovered ATP production. Notably, the two Src inhibitors exerted distinct regulatory effects on serum antioxidant enzymes, with no impact on myocardial antioxidant enzyme activities. SIGNIFICANCE:Collectively, these findings demonstrate that aberrant Src activation contributes to diabetic myocardial oxidative damage and mitochondrial dysfunction. Targeted Src inhibition protects the diabetic myocardium primarily by restoring OXPHOS homeostasis and improving mitochondrial energy metabolism, rather than modulating myocardial antioxidant enzyme systems.
Metabolic dysfunction-associated steatotic liver disease (MASLD), hallmarked by hepatic metabolic disorders and chronic inflammation, is a growing global public health threat with limited approved pharmacological options. Natural cyclodipeptides exhibit favorable metabolic stability and bioactivity profiles, making them ideal molecules for drug discovery in metabolic diseases; however, their roles and mechanisms in MASLD remain poorly defined. Here, we investigated the protective effects of cyclo(Val-Pro) and cyclo(Phe-Phe), two bioactive cyclodipeptides previously identified in hydrolyzed chicken meat extract (HCE), against MASLD. Administration of both cyclodipeptides effectively ameliorated metabolic disturbance and hepatic inflammation in high-fat diet-induced MASLD mice, and mitigated lipopolysaccharide-triggered acute inflammation in a complementary in vivo model. Liver transcriptomic analysis revealed that the two cyclodipeptides significantly modulated the hepatic chemokine signaling pathway in MASLD mice. Mechanistically, both cyclodipeptides reduced hepatic CD11b- and F4/80-associated signals and modulated macrophage-associated pro-inflammatory and anti-inflammatory marker expression in vivo and in vitro. Further validation using molecular docking, target inhibitor intervention, drug affinity responsive target stability, cellular thermal shift assay, site-directed mutagenesis, and gene knockout approaches supported that cyclo(Val-Pro) regulated the expression of macrophage CC chemokine receptor type 2 (CCR2), while cyclo(Phe-Phe) modulated adenylyl cyclase 7 (ADCY7), an upstream chemokine signaling regulator, to block downstream inflammatory cascades. Collectively, our findings support further investigation of these two cyclodipeptides and suggest that CCR2- and ADCY7-associated pathways may contribute to their effects in MASLD.
Breast milk exosomes (ΒΜΕs) are extracellular vesicles of 30-150 nm that have currently attracted research attention due to their protective role in neonatal immune development. Their bioactive cargos, including miRNAs, proteins and lipids, have been shown to facilitate cellular communication and regulate various physiological processes. In the present article, we explore known molecular mechanisms through which ΒΜΕs affect innate and adaptive immunity as well as the integrity of the intestinal epithelial barrier. BMEs can reduce symptoms of inflammatory intestinal diseases, such as necrotizing enterocolitis (NEC) by regulating key signaling pathways, including TLR4/MyD88/NF-κB, MAPK and PI3K/AKT. Their unique characteristics highlight the potential to serve as drug nanocarriers for therapeutic interventions especially in high-risk neonatal inflammatory diseases. Although the clinical application of ΒΜΕs needs to overcome several challenges such as heterogeneity, large-scale isolation and processing of ΒΜΕs, their anti-inflammatory effects are consistent and significant. Future multi-omics analyses for the comprehensive understanding of the molecular mechanisms through which exosomes exert immunomodulation are expected to reveal new opportunities to improve the health of vulnerable neonates.
OBJECTIVE:Sleep deprivation (SD) disrupts female reproductive homeostasis, yet the mechanisms linking chronic sleep loss to premature ovarian insufficiency (POI) remain poorly defined. METHODS:We analyzed sleep patterns and menopause timing in 147,814 UK Biobank women using multivariable logistic regression. We established a chronic SD mouse model and performed integrated multi-omics profiling, including serum proteomics and ovarian RNA sequencing, with pharmacological rescue using the ferroptosis inducer Erastin and inhibitor Ferrostatin-1. RESULTS:Healthier sleep patterns were associated with reduced premature menopause risk (OR = 0.466, 95% CI: 0.263-0.826 for highest vs. lowest score). SD mice showed disrupted estrous cyclicity, elevated FSH, decreased AMH and E2, and accelerated ovarian reserve depletion. Multi-omics analysis revealed systemic inflammation (elevated IL-1α and IL-6) and ovarian enrichment of the IL-17 and ferroptosis pathways. Erastin recapitulated major SD-induced ovarian defects, whereas Ferrostatin-1 partially rescued the phenotype, establishing ferroptosis as a critical mediator. IL-17A and IL-17RA were upregulated and co-localized with ferroptosis markers in the ovarian stroma, nominating IL-17 signaling as a candidate upstream regulator. CONCLUSION:Our findings establish ovarian ferroptosis as a key pathogenic mechanism linking chronic sleep deprivation to POI, and highlight sleep quality as a modifiable factor for preserving ovarian health.
Bone and muscle are two strictly linked tissues due both for their nearness but also for their tight coupled activity. Due to the increase of longevity it is important to work on these tissues to guarantee locomotion, thus it is important to identify potential therapeutic target for their health. Thus, together with the classical approaches, new modalities have been identified and in particular those involving nanotechnologies. AIM:to review the role of nanotechnologies in musculoskeletal health. MATERIALS AND METHODS:PubMed search using as keywords nanotechnologies combined with musculoskeletal, bone and muscle. SIGNIFICANCE:the key role of calcium in the nanotechnological approach in bone health, as in this tissue this ion is presented at high percentage, and thanks to its characteristics also bisphosphonates can be assembled with nanoparticle to bind specifically bone. The role of lipid-based nanoparticles for bone and muscle homeostasis is revised. Polymeric nanoparticles are also revised. Positive and toxic effects were also reported. This overview is important for future development in musculoskeletal health.
Epileptogenesis is a multifactorial cascade involving neuroinflammation, glial activation, neuronal hyperexcitability, abnormal synaptic plasticity, and cell death. Understanding the epileptogenic changes is critical for improving therapeutic outcomes. Despite extensive knowledge of inflammatory pathways in epilepsy, the role of signal transducer and activator of transcription 3 (STAT3) remains underexplored. This review synthesizes the current evidence on classical and alternative STAT3 signalling mechanisms in epilepsy. Classical cytokine-driven Janus Kinase (JAK)/STAT3 signalling promotes neuroinflammation and gliosis in epilepsy, whereas non-classical STAT3 functions modulate mitochondrial, epigenetic, and ion-channel/neurotransmitter-receptor homeostasis. Mechanistically, STAT3 promotes neuronal hyperexcitability by repressing gamma-aminobutyric acid (GABAA) receptor α1 subunit expression, thereby disrupting the inhibitory neurotransmission. Additionally, STAT3 links neuroinflammation to ferroptosis via astrocyte chemokine signalling and crosstalk with the mechanistic target of rapamycin (mTOR), Rho-associated coiled-coil containing protein kinase 2 (ROCK2), and nuclear factor erythroid 2-related factor 2 (Nrf2) pathways. Preclinical studies have demonstrated that pharmacological inhibitors, cell-specific genetic deletion, and RNA-based silencing of STAT3 attenuate seizures and preserve GABAergic interneurons. However, clinical translation is constrained by challenges in pathway specificity, blood-brain barrier penetration, and selective modulation of pathological and physiological functions. Altogether, the current review identifies STAT3 as a critical integrator of inflammatory, metabolic, and excitability-related signalling networks that drive epileptogenic remodelling and delineates future directions for mechanism-driven, precision-based, and combinatorial interventions to harness STAT3-directed therapies in epilepsy.
BACKGROUND:Sepsis is associated with an extremely high global mortality rate, primarily due to the lack of effective therapeutic strategies for clearing bacteria from infected tissues. However, the underlying mechanisms by which methylsulfonylmethane (MSM) protects mice against lethal doses of MRSA infection remain incompletely understood. METHODS:RNA sequencing was used to identify transcriptional differences of peritoneal macrophages (PMs). Immunofluorescence, Western blotting, and RT-qPCR were used to assess target protein and RNA levels. Molecular docking, flow cytometry, and pharmacological inhibitors and agonists were employed to characterize MSM targets, cellular functions, and pathway involvement. RESULTS:MSM significantly enhanced macrophage phagocytic activity without altering cell counts in vivo during MRSA infection. Notably, phagocytic molecule mRNA levels were significantly higher in whole blood from sepsis survivors than non-survivors, linking phagocytic capacity to sepsis outcomes. Transcriptomic analysis revealed MSM upregulated genes involved in phagosomes, JAK-STAT signaling, lysosomes, and GTPase-related functions in macrophages. RT-qPCR confirmed increased phagosome/lysosome marker expression, while immunofluorescence showed MSM induced LAMP1+ late endosome formation. Mechanistically, MSM is predicted to interact with PIK3CB, thereby activating PIP3 signaling and subsequently inducing iNOS expression and nitric oxide (NO) production in CD11b+F4/80+ macrophages. The PI3K/mTOR inhibitor dactolisib blocked MSM-induced PIP3 accumulation and iNOS expression, validating the PI3K-PIP3 pathway's critical role. MSM-stimulated NO production was confirmed to mediate intracellular MRSA killing. CONCLUSIONS:MSM alleviates lethal MRSA infection by enhancing macrophage phagocytosis and promoting NO production to eliminate intracellular bacteria. These findings position MSM as a promising therapeutic agent against drug-resistant bacterial infections, offering a novel strategy for managing sepsis.
The gut microbiota plays a fundamental role maintaining homeostasis by regulating neuroglial maturation, immune function, and the production of gut derived metabolites (e.g short chain fatty acids and neurotransmitters), while also preventing pathogen colonization. Disruption of this microbial ecosystem characterized by changes in gut microbiota abundance, decreased production of short chain fatty acids (SCFAs), and more pathobionts is known as gut dysbiosis, which has been linked to progression of a range of pathologies, including both traumatic and non-traumatic spinal cord injuries (SCI). Following SCI, a reduction in beneficial bacterial phylum such as Lachnospiraceae and Firmicutes is commonly observed, leading to decreased SCFA production and altered activation of B and T lymphocytes. These changes contribute to -increased intestinal barrier permeability, dysregulated immunoglobulin A secretion, and an imbalance between inflammatory cytokines and anti-inflammatory cytokines. Such disturbances reflect impaired bidirectional communication between the immune system and the gut microbiota, contributing to disease progression. This review synthesizes current evidence on how gut dysbiosis contributes to immune dysfunction after SCI and highlights emerging research that proposes gut microbiota modulation as a novel, cost-effective, and promising therapeutic strategy. Finally, it discusses the clinical implications of these findings and their translational potential, while identifying key knowledge gaps that should be addressed to facilitate the development of microbiome-targeted interventions aimed at improving neurological recovery and quality of life.
AIMS:Western-style hyperpalatable diets are recognized as biologically active exposures that disturb intestinal homeostasis, yet the molecular changes linking obesogenic nutrition to colonic injury remain insufficiently defined. This study investigated how cafeteria-diet exposure reshapes colonic homeostasis by integrating metabolic alterations, proteomic changes, tissue injury, antioxidant defense, and inflammatory signaling. MATERIALS AND METHODS:Male Wistar rats were fed a standard or cafeteria diet for 12 weeks. Colonic responses were assessed by metabolic profiling, label-free quantitative nLC-MS/MS proteomics, functional enrichment and protein-protein interaction analyses, Western blotting, histopathology, immunofluorescence, and immunohistochemistry. KEY FINDINGS:Cafeteria-diet feeding induced metabolic deterioration, with increased body weight, fasting glucose, body mass index, insulin, leptin, and circulating LPS. Colonic MDA and 4-HNE immunoreactivity were increased, whereas SOD was reduced. Proteomic profiling identified 132 exploratory differentially expressed protein candidates, including 54 upregulated and 78 downregulated proteins. Functional enrichment revealed two signatures: upregulated mitochondrial respiration-related pathways and downregulated desmosome-, cell-cell junction-, and glutathione-related processes. Hub proteins included COX7A2, COX6C, COX5B, COX7, MT-CO1, JUP, PKP1, DSG1, and DSG4. Western blot analysis of colon samples confirmed increased MT-CO1 abundance. These alterations were accompanied by lamina propria inflammation, epithelial necrosis, crypt dilatation, submucosal edema, goblet cell depletion, reduced occludin, claudin-1 and ZO-1, decreased total NRF2 and HO-1, and increased NF-κB p65 expression. Exploratory correlations linked tight junction markers with antioxidant, inflammatory, oxidative, and metabolic parameters. SIGNIFICANCE:These findings define an integrated metabolic, mitochondrial protein, redox, inflammatory, and barrier-related signature associated with cafeteria-diet exposure and identify candidate indicators for future studies of diet-induced colonic injury.
OBJECTIVE:To explore melanocortin-4 receptor (MC4R) and uncoupling protein 1 (UCP1) expression and function in autoimmune uveitis (AU) and their regulation of retinal pigment epithelium (RPE) autophagy/pyroptosis, for therapies. METHODS:EAU was induced in female C57BL/6 J mice; eyeballs underwent transcriptome sequencing. Bioinformatics and protein-protein interaction (PPI) network screened differentially expressed genes (DEGs) and core targets. Retinal damage was assessed by hematoxylin and eosin (H&E); cytokines and autophagy/pyroptosis markers by enzyme-linked immunosorbent assay (ELISA), terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), and immunofluorescence. In vitro, ARPE-19 cells were lipopolysaccharide (LPS)-stimulated to establish an inflammatory model; cell death/autophagy were evaluated by flow cytometry and monodansylcadaverine (MDC). RNA immunoprecipitation (RIP), co-immunoprecipitation (Co-IP), actinomycin D assays verified the interaction between MC4R and UCP1 and their effect on mRNA stability; small interfering RNA (siRNA) rescue experiments in vivo, in vitro confirmed that UCP1 mediates AU pathology via MC4R. RESULTS:A total of 161 DEGs were identified, with MC4R and UCP1 hub genes aberrantly expressed in EAU tissues and LPS-treated cells. MC4R knockdown reduced clinical scores and inflammatory cell infiltration, and inhibited RPE autophagy/pyroptosis. UCP1 did not directly bind MC4R but indirectly regulated MC4R mRNA stability, downregulating MC4R protein expression. UCP1 knockdown exacerbated pathological retinal damage and RPE autophagy/pyroptosis, reversed by MC4R knockdown. CONCLUSION:Systemic MC4R modulation attenuates retinal inflammatory and histopathological damage in AU, associated with RPE autophagy-pyroptosis activation. UCP1 downregulates MC4R via indirect post-transcriptional regulation of mRNA stability, reversing these processes, offering new insights into the immunometabolic regulatory mechanisms underlying ocular autoimmune diseases.
Atherosclerosis is characterized by pathological vascular smooth muscle cell (VSMC) proliferation and metabolic dysregulation, yet the underlying mechanisms remain incompletely understood. Here, we identified receptor expression enhancer protein 5 (REEP5) as a potential regulator of VSMC proliferation in atherosclerosis by analyzing single-cell RNA sequencing datasets from human atherosclerotic coronary arteries and aortic tissues. REEP5 expression was markedly reduced in proliferative SMCs. In human aortic VSMCs, apelin-13 downregulated REEP5 in a time- and concentration-dependent manner. The REEP5 downregulation was associated with disrupted endoplasmic reticulum architecture, increased endoplasmic reticulum vacuolization, and impaired mitochondria-associated membrane coupling. Moreover, apelin-13 elevated mitochondrial reactive oxygen species, reduced mitochondrial membrane potential, and decreased mitochondrial Ca2+ levels, indicating mitochondrial dysfunction. Functionally, apelin-13 promoted a metabolic shift toward glycolysis, as evidenced by increased glucose consumption, lactate production, glycolytic enzyme expression and activity, and extracellular acidification rate, together with reduced oxidative phosphorylation and decreased oxygen consumption rate in vitro. REEP5 overexpression largely reversed these alterations and inhibited apelin-13-induced VSMC proliferation. Inhibition of glycolysis similarly attenuated the pro-proliferative effect of apelin-13. In ApoE-/- mice, REEP5 overexpression alleviated apelin-13-induced exacerbation of atherosclerosis, reduced lesion burden, ameliorated dyslipidemia, and reduced glycolytic marker expression in plaques. Collectively, these findings suggested that apelin-13 may promote VSMC proliferation and atherosclerotic progression, at least in part, by downregulating REEP5 and disrupting mitochondria-associated membrane coupling, thereby contributing to a glycolytic metabolic shift in VSMCs. Targeting the REEP5/mitochondria-associated membrane coupling axis may be a potential therapeutic target for atherosclerosis.
AIMS:While primarily known for its critical role in glucose metabolism, the glucagon-like peptide-1 receptor (GLP-1R) is increasingly recognized for its significant involvement in tissue repair and regeneration. This study comprehensively investigates how the natural compounds, quercetin and lupeol, regulate GLP-1R expression, protein stability, and subsequent downstream signaling pathways in keratinocytes. MATERIALS AND METHODS:Cells were treated with quercetin or lupeol. GLP-1R expression was analyzed at both mRNA and protein levels. Promoter regulation was evaluated by luciferase assays, site-directed mutagenesis, and chromatin immunoprecipitation. Molecular docking, molecular dynamics (MD) simulations, and cycloheximide chase assays evaluated GLP-1R interactions and stability. Downstream signaling and wound-healing markers were examined by Western blotting. KEY FINDINGS:Quercetin and lupeol significantly increased GLP-1R expression and protein stability through complementary mechanisms. Quercetin enhanced GLP-1R transcription via GATA6-dependent promoter activation, leading to ERK-mediated β-catenin phosphorylation and increased expression of COL1A1, COL4A1, and MMP9, indicating enhanced extracellular matrix remodeling. In contrast, lupeol predominantly promoted a proliferative response by markedly increasing Cyclin D1 together with COL4A1 expression. Molecular docking and MD simulation predicted quercetin binding to GLP-1R residues Ser31 and Leu32 and lupeol binding to Leu32, consistent with cycloheximide chase assays demonstrating delayed GLP-1R degradation. SIGNIFICANCE:These findings identify quercetin and lupeol as natural modulators of GLP-1R that enhance receptor availability through distinct transcriptional and post-translational mechanisms. By activating ERK-dependent regenerative signaling, quercetin primarily promotes matrix remodeling, whereas lupeol supports cellular proliferation, highlighting their therapeutic potential for modulating GLP-1R-mediated tissue repair.
The Popeye domain-containing protein 1 (Popdc1, also known as Bves) is a transmembrane protein whose dysfunction is closely associated with various diseases. Clinical studies have identified that mutations in the bves gene predispose individuals to limb-girdle muscular dystrophy. However, a marked reduction in Bves protein expression has been observed in patients with heart failure, highlighting a critical unresolved challenge in understanding its role in disease pathogenesis. In this study, we discovered that bves deficiency drives cardiac contractile dysfunction, thereby revealing a novel mechanism underlying heart failure pathogenesis. The study found that bves knockout led to cardiac contractile dysfunction in zebrafish during both embryonic and adult stages, with a significant reduction in ejection fraction. Twelve-month-old bves knockout zebrafish exhibited ventricular dilation, increased cardiomyocyte size but significantly decreased cell numbers, and aggravated fibrosis of atrioventricular valves. Transmission electron microscopy revealed widened Z-lines and shortened I-bands in myocardial fibers of the bves knockout group. Collectively, these findings provide compelling evidence that bves knockout induces heart damage. Transcriptome analysis showed disrupted expression of ATP synthesis-related genes and activation of the mitochondrial autophagy pathway following bves knockout. In bves knockout zebrafish, myocardial mitochondria exhibited abnormal structure and impaired oxidative respiratory function, with upregulated expression levels of a series of protein complexes in the mitochondrial electron transport chain. These studies have for the first time established that myocardial mitochondrial structural/functional damage caused by bves deficiency may be associated with the pathogenesis of heart failure, providing a new perspective for the occurrence and development of heart failure.
The developing central nervous system (CNS) relies on tightly regulated metabolic substrates, including glucose, lactate, and ketone bodies (KBs), to energy demands, brain maturation and neural circuit formation. Disruptions in substrate flow availability during early life can lead to long-lasting brain functional and structural impairments. Among these substrates, KBs serve as a critical alternative fuel during the neonatal period, sustaining cerebral energy demands under conditions of limited glucose availability and metabolic stress. Mounting evidence highlights pronounced sex-specific differences in brain development and vulnerability to injury, with males showing increased susceptibility to neurodevelopmental disorders, whereas females exhibit greater metabolic flexibility during hypoglycemia and oxidative stress. Despite this, most neuroscience and metabolic research remains male-focused, limiting our understanding of female-specific cerebral metabolic adaptations. This review examines KB metabolism across major neural cell types (astrocytes, neurons, oligodendrocytes and microglia) during neurodevelopment, with a particular focus on sex-specific differences in substrate utilization, metabolic signaling and cellular resilience. Understanding these distinctions is critical, as even subtle energetic impairments during early brain development may contribute to neurological disorders with sex-biased prevalence. Addressing this gap may ultimately facilitate the development of more precise, sex-specific therapeutic strategies for neurodevelopmental disorders.
AIMS:High-protein diets stimulate muscle anabolism and influence gut microbiota composition, while resistance training improves neuromuscular function and metabolic health. We investigated whether dietary protein acts as the primary driver of physiological and microbial adaptations, and whether resistance training provides additional benefits. MATERIALS AND METHODS:Twenty-four male C57BL/6 mice were randomly assigned to four groups (n = 6 per group): normal control (NC), high-protein diet (HPD), normal diet with exercise (NC + EX), and high-protein diet with exercise (HPD + EX). The HPD provided 60% of total energy from protein. Resistance training consisted of progressive ladder-climbing performed three times per week for eight weeks. Physical performance was evaluated by grip strength, weight-holding capacity, rotarod performance, and functional strength performance. Gut microbiota was analyzed using 16S rRNA sequencing, and blood and tissue samples were collected for biochemical and histological analyses. KEY FINDINGS:Compared with NC, the HPD + EX group exhibited significantly enhanced physical performance, and reduced mesenteric fat mass and adipocyte size (p < 0.05). HPD alone decreased gut microbial richness, whereas the HPD + EX group did not differ significantly from the HPD group in microbial richness or overall microbiota composition. LEfSe analysis identified higher relative abundances of selected genera, including Lactobacillus and Faecalibaculum, in the HPD + EX group than in the HPD group. SIGNIFICANCE:These findings identify dietary protein as a key determinant of physiological and gut microbial adaptations, while resistance training primarily improves physical performance and may influence selected microbial taxa without restoring or stabilizing the overall microbial community. Together, these findings suggest that dietary protein and resistance training may play distinct and complementary roles in host metabolic regulation and physical function.
Kidney diseases, mainly chronic kidney diseases and acute kidney injury, impose a heavy burden on global health care systems. However, traditional kidney-centric therapies, such as dialysis and renal transplantation, face limitations in terms of availability, efficiency and long-term sustainability. Kidney diseases are being increasingly recognized as systemic disorders orchestrated through dynamic interorgan communication. In addition to the kidney itself, multiple organs, such as the gut, liver, and heart, as well as the endocrine and nervous systems, interact to regulate renal function. This cross-talk involves metabolic signals, endocrine mediators, and neural pathways that collectively contribute to the modulation of kidney disease progression. The interactions among these pathways reveal novel therapeutic targets to alleviate kidney injury. However, causal links and organ-specific roles require further mechanistic investigation. This review highlights the need for a multisystem perspective in both the basic research and clinical management of kidney diseases, providing novel insights for the future development of effective, novel therapies targeting extrarenal organs to treat kidney diseases.
