Search Results (8,113)

Background and Objectives: The inner ear has traditionally been regarded as an immunoprivileged and anatomically isolated organ. However, growing interest in neuro-lymphatic interactions has raised the hypothesis that glymphatic and lymphatic mechanisms may contribute to auditory pathology and its association with cognitive dysfunction. This systematic review aimed to synthesize current human evidence regarding anatomical, imaging, and clinical correlates of glymphatic mechanisms in the inner ear and audiological pathologies, and to quantitatively evaluate currently available biomarkers. Materials and Methods: A structured search of PubMed, Scopus, and Cochrane databases was performed from inception through March 2026. Eligible studies included human investigations reporting anatomical, histopathological, or MRI-based glymphatic assessments related to inner ear disorders. Risk of bias was assessed using the Newcastle–Ottawa Scale and Joanna Briggs Institute tools. Meta-analysis was conducted for diffusion tensor image analysis along the perivascular space (DTI-ALPS) indices comparing auditory disorders with healthy controls. Results: Six studies met inclusion criteria (five cross-sectional imaging studies and one surgical histopathological case series). Histopathology demonstrated lymphatic capillaries in advanced Ménière disease. MRI studies consistently reported reduced ALPS indices and/or increased choroid plexus volume and enlarged perivascular spaces in tinnitus, congenital sensorineural hearing loss, and age-related hearing loss. Meta-analysis of five studies showed a significant reduction of ALPS index in auditory disorders compared with controls (SMD = −0.73, 95% CI −0.90 to −0.55; p < 0.001), with no heterogeneity. Glymphatic markers were frequently associated with audiological data, cognitive performance and inflammatory biomarkers. Conclusions: Human evidence supports the presence of altered central glymphatic function across diverse auditory phenotypes. Although predominantly based on indirect MRI proxies and cross-sectional data, the meta-analytic findings strengthen the biological plausibility of an auditory–glymphatic interaction. Prospective longitudinal studies are warranted to clarify causality and therapeutic implications. Full article

Background: Emerging evidence has established ferroptosis as a vital factor in the pathogenesis of cardiovascular diseases, especially in septic cardiomyopathy (SCM). Meanwhile, ondansetron (OND), a well-established 5-HT3 receptor antagonist, has gained increasing attention for its pleiotropic effects. However, its potential to modulate ferroptosis in the cardiovascular field remains unexplored. This study aims to fill this gap by exploring the potential of OND as an innovative therapeutic intervention for SCM. Methods: This study utilized both in vitro and in vivo models of septic cardiomyopathy (SCM), which was induced by lipopolysaccharide (LPS) stimulation in neonatal rat cardiomyocytes (NRCMs) and C57BL/6 mice. Through RNA sequencing, as well as molecular and functional assessments—including echocardiography and ferroptosis-related measurements—we revealed the anti-ferroptotic effect of ondansetron (OND). Mechanistically, ATF3 was identified as a pivotal regulator, with its overexpression via AAV9 in vivo and ADV in vitro confirming its role in OND-induced cardioprotection. Results: Ondansetron (OND) showed potent anti-ferroptotic effects in both cellular and murine models of septic cardiomyopathy (SCM). Treatment with OND not only improved cardiac performance but also reduced ferroptotic markers, mitigated lipid peroxidation and iron overload, and bolstered antioxidant defense. Notably, OND administration attenuated oxidative and endoplasmic reticulum (ER) stress while restoring mitochondrial integrity. Mechanistically, the anti-ferroptotic activity of OND was mediated through the HTR3A/ATF3 axis: ATF3 overexpression negated OND’s protective effects, while HTR3A antagonism with VUF10166 recapitulated its benefits. Conversely, HTR3A agonism with PBG attenuated ferroptosis resistance, further implicating this pathway as central to OND’s mechanism. Conclusions: This study demonstrated a novel pharmacological role for ondansetron (OND) in attenuating ferroptosis in septic cardiomyopathy (SCM) via the HTR3A/ATF3 signaling pathway. This finding delineates a novel therapeutic avenue and supports the repurposing of OND beyond its traditional antiemetic use to cardiovascular applications. Full article

Background: Diabetes mellitus is frequently associated with complications and comorbidities that often require hospitalization and the use of multiple medications for effective management. However, the simultaneous use of these treatments significantly increases the risk of potential drug–drug interactions (pDDIs). Objectives: This study assessed the prevalence, levels, and associated predictors of pDDIs among hospitalized participants with type 2 diabetes mellitus (T2DM) and evaluated their clinical relevance and implications for monitoring and management. Methods: This retrospective cross-sectional study included 430 inpatients with T2DM at Universitas Indonesia Hospital, Indonesia. Lexicomp^® Lexi-Interact™ software Wolters Kluwer was used to analyze and classify pDDIs based on severity, risk rating, and documentation levels. Additionally, logistic regression analysis was conducted to identify the predictors of pDDIs, and the study assessed the clinical relevance of major pDDIs. Results: Of the total participants, 84.7% (n = 364) experienced pDDIs, with 1642 interactions identified. Moderate interactions accounted for 77.5% (n = 1273), whereas major interactions constituted 12.2% (n = 201). The most common risk rating was category C (77.5%, n = 1187), and the predominant evidence support level was ‘fair’ (64.8%, n = 1064). Multivariate logistic regression analysis showed a significant association between pDDIs and of 7–12 medications used (OR = 30.1; p < 0.001), and hospital stays ≥4 days (OR = 9.7; p = 0.001). Major pDDIs were significantly linked to ≥13 medications (OR = 5.5; p = 0.002), ≥4 days hospitalization (OR = 11.3; p < 0.001), and urinary tract infections (OR = 3.5; p = 0.02). Participants with major pDDIs exhibited hypoglycemia, hyperglycemia, electrolyte imbalances, and reduced therapeutic responses. Conclusions: The findings indicate a high prevalence of pDDIs among participants with T2DM, highlighting the impact of polypharmacy, prolonged hospitalization, and comorbidities. Implementing software-based screening, close monitoring, and targeted interventions are essential to reduce adverse clinical outcomes and enhance patient safety. Full article

Background: Stromal remodeling in the tumor microenvironment contributes to multiple myeloma (MM) progression and drug resistance, but the extracellular mediators that drive these changes remain incompletely defined. Extracellular enolase-1 (ENO1), including membrane-associated and secreted forms, has been implicated in tumor progression; however, its role in cancer-associated fibroblast (CAF)-associated stromal reprogramming in MM is unclear. Methods: The effects of extracellular ENO1 on stromal activation and tumor-supportive functions were examined in MM using MM–bone marrow stromal cell (BMSC) co-cultures, lactate production and viability assays, immunoblotting, cytokine analyses, and a subcutaneous xenograft model of bortezomib (BTZ)-resistant MM in male 6–7-week-old NOD.Cg-Prkdc^scid Il2rg^tm1Vst/Vst (NPG) mice. HuL001, an anti-ENO1 monoclonal antibody, was used to evaluate the therapeutic relevance of extracellular ENO1 targeting. Results: Extracellular ENO1 promoted fibroblast activation protein expression through plasmin-mediated transforming growth factor-β (TGF-β) activation and induced a CAF-associated stromal phenotype marked by enhanced glycolytic activity and increased secretion of tumor-promoting cytokines in MM-BMSC co-cultures. HuL001 suppressed these ENO1-driven effects. HuL001-pretreated stromal cells also exhibited reduced tumor-supportive activity in a BTZ-resistant MM xenograft model. In addition, HuL001 combined with lenalidomide overcame BTZ resistance in MM. Conclusions: Extracellular ENO1 drives CAF-associated stromal reprogramming in the MM microenvironment through the ENO1/plasminogen/plasmin/TGF-β axis. Therapeutic targeting of extracellular ENO1 with HuL001 may disrupt these tumor-supportive stromal activities and help overcome drug resistance in MM. Full article

Diabetic peripheral neuropathy (DPN) is a common and debilitating complication of diabetes mellitus which affects individuals with both type 1 and type 2 diabetes mellitus (T2DM), presenting with sensory loss, pain, and progressive nerve dysfunction. DPN pathogenesis is multifactorial: chronic hyperglycemia activates the polyol, hexosamine, and protein kinase C (PKC) pathways, increases advanced glycation end-products, and drives oxidative stress, mitochondrial dysfunction, inflammation, and impaired neurotrophic signaling. In addition to hyperglycemia-driven mechanisms, dyslipidemia and microvascular insufficiency exacerbate neural ischemia and metabolic stress. Recent mechanistic, animal, and associative human studies further implicate amyloidogenic toxicity, particularly from human islet amyloid polypeptide (hIAPP), as a plausible contributory factor in peripheral nerve degeneration in T2DM, linking protein misfolding and aggregation to axonal damage and demyelination in DPN. Despite increased understanding of these mechanisms, current treatments remain mainly symptomatic. Emerging therapeutic strategies, including antioxidants, anti-inflammatory agents, modulators of mitochondrial function, amyloid oligomer modulators, neurotrophic enhancers, and regenerative approaches such as stem cells and gene-based therapies, offer potential to modify disease progression. The strength of evidence across these methods varies, ranging from mechanistic and animal studies to early human research and, in some cases, randomized clinical trials. Therefore, although several candidates show potential to alter the disease, few have demonstrated consistent benefits on objective measures of nerve structure or function in large clinical trials. This review summarizes the key mechanisms driving DPN in T2DM and highlights promising therapeutic innovations poised for clinical translation. Full article

Background/Objectives: Advanced prostate cancer (PCa) evolves through adaptive mechanisms that sustain tumor growth despite the suppression of androgen receptor (AR) signaling. Accumulating evidence identifies activation of the hepatocyte growth factor (HGF)/MET pathway as a potential driver of PCa progression in advanced disease states characterized by AR-independence and therapeutic resistance. We review the biological and clinical evidence supporting MET as a context-dependent therapeutic target and discuss its implications for patient selection and combination strategies. Methods: A comprehensive narrative review of preclinical, translational, and clinical studies evaluating MET-directed therapies for PCa was performed. Results: Aberrant activation of the HGF–MET axis is frequently driven by autonomous paracrine and autocrine loops that sustain pathway activation during disease progression. MET overexpression is associated with adverse pathological features, increased tumor aggressiveness, bone metastasis, lineage plasticity, and resistance to AR-targeted treatments. Preclinical studies have demonstrated that AR suppression, tumor hypoxia and tumor–microenvironment interactions promote MET upregulation, supporting AR-independent growth and epithelial-to-mesenchymal transition. Clinical trials of MET inhibitors have shown modest activity as monotherapies, with the most consistent biological effects observed in bone-dominant disease. Recent studies indicate greater therapeutic potential when MET inhibition is incorporated into rational combination strategies targeting complementary molecular pathways. Emerging data further indicate that MET activation characterizes a biologically aggressive, AR-low or neuroendocrine-like disease state. These findings support a transition from empiric use of MET inhibitors toward precision, context-driven therapeutic development. Conclusions: MET is not a universal therapeutic target but defines a clinically relevant subset of aggressive, AR-indifferent PCa. Future development should focus on biomarker-guided patient selection and rational combination strategies. Integration of molecular profiling, imaging, and liquid biopsy approaches will be essential to identify patients most likely to benefit from MET-directed interventions. Full article

The conventional classification of multiple sclerosis (MS) into relapsing–remitting, secondary progressive, and primary progressive phenotypes has long guided diagnosis, prognosis, and therapeutic decision-making. However, accumulating evidence indicates that disability accumulation frequently occurs independently of clinical relapses, challenging relapse-centric and phenotype-based models of disease evolution. The concept of progression independent of relapse activity (PIRA) has emerged as a clinically relevant framework capturing this phenomenon across MS phenotypes. In this state-of-the-art narrative review, we propose a spectrum-based reinterpretation of MS, integrating PIRA with concepts of smouldering-associated worsening and neurologic reserve. We highlight the heterogeneity of relapse-independent worsening, distinguishing transient from persistent PIRA, and discuss how ageing-related decline in compensatory capacity contributes to the clinical unmasking of progression over time. Within this framework, secondary progressive MS is redefined as the clinically recognizable accumulation of persistent relapse-independent worsening, while primary progressive MS is conceptualized as early predominance of clinically manifest progression due to limited reserve rather than a distinct disease entity. Finally, we examine diagnostic and therapeutic implications of a spectrum-based model in the contemporary era, emphasizing the limitations of relapse-centric treatment strategies and unmet needs in addressing progression-related biology. By reframing MS as a dynamic continuum shaped by the interaction between ongoing pathology and evolving neurologic reserve, this review aims to support earlier recognition of clinically meaningful progression and to inform more biology-aware approaches to disease monitoring and therapy. Full article

Background: Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality despite major advances in diagnostics and therapies. The prognosis remains poor, mostly due to late-stage presentation and molecular heterogeneity. Epidermal growth factor receptor (EGFR) mutations are common drivers of NSCLC. The development of EGFR tyrosine kinase inhibitors (TKIs) has significantly improved outcomes in patients with EGFR mutations. Variant allele frequency (VAF) is a quantitative genomic measure representing the proportion of sequencing reads harboring a given mutation. In NSCLC tissue, the EGFR mutation VAF reflects tumor clonality and intratumoral heterogeneity, and accumulating evidence suggests an association between EGFR VAF and response to EGFR-targeted TKIs. Methods: To address the limited synthesis of data on the relevance of EGFR mutation VAF in NSCLC, we conducted a narrative review of the literature using PubMed/MEDLINE and Embase databases and current clinical guidelines, synthesizing available evidence on EGFR VAF, including its biological, molecular, and therapeutic implications in EGFR-mutated disease. The review was structured in accordance with the SANRA (Scale for the Assessment of Narrative Review Articles) checklist. Results: EGFR VAF and on-treatment VAF dynamics are consistently associated with treatment response, progression-free survival, and overall survival in osimertinib-treated NSCLC. Baseline VAF enables risk stratification, early clearance kinetics predict durable benefit, and longitudinal VAF monitoring facilitates early detection of resistance. Importantly, the prognostic implications of VAF differ fundamentally between tissue-based and plasma-based measurements: high tissue VAF reflects clonal homogeneity and predicts favorable TKI response, whereas high plasma VAF indicates elevated tumor burden and is associated with inferior outcomes. In the second-line setting, the T790M/activating mutation ratio serves as a surrogate for resistance clonality and independently predicts osimertinib efficacy. Conclusions: EGFR VAF represents a promising dynamic molecular biomarker for treatment monitoring and precision decision-making in EGFR-mutated NSCLC. Full article

Trauma-induced heterotopic ossification (tHO) is characterized by aberrant ectopic bone formation in soft tissue following high-energy trauma, affecting >60% of combat-related amputees and >50% of major burn patients. Current prophylactic strategies (including NSAIDs, bisphosphonates, and low-dose radiation) lack mechanistic specificity, carry significant side effects, and surgical excision carries a 27% recurrence rate. This review reframes tHO pathogenesis through the neural–immune axis, arguing that ectopic bone formation is a downstream consequence of dysregulated neuroimmune signaling rather than a primary osteogenic event. Following trauma, nociceptor activation drives nociception-induced neural inflammation (NINI), releasing substance P (SP) and calcitonin gene-related peptide (CGRP), which disrupts the blood–nerve barrier, mobilizes neural crest-derived progenitor cells, and, alongside BMP-2/SMAD1/5/8 signaling and M1-polarized macrophage activation, establishes a permissive osteogenic microenvironment. A BMP-2/CGRP positive feedback loop sustains aberrant osteogenesis, converging on osteogenic transcription factors Runx2, SOX5/6/9, and Osterix. Dysregulated noncoding RNAs represent promising pre-radiographic biomarkers. This neural–immune framework motivates mechanism-based therapeutic strategies targeting CGRP (fremanezumab, erenumab), SP/NK1 signaling (aprepitant), and macrophage polarization (metformin, palovarotene, rapamycin), with multi-node combination approaches tailored to the temporal stages of tHO offering the most promise for precision prophylaxis. Full article

Hidradenitis suppurativa (HS) is a chronic inflammatory dermatosis characterized by recurrent nodules, abscesses, and sinus tract formation in intertriginous skin. Although HS is increasingly recognized as an autoinflammatory condition rather than a classical infection, antimicrobial therapies remain central to disease management, implicating a potential role for the cutaneous microbiome in disease activity. Recent advances in culture-independent sequencing techniques have enabled more detailed characterization of microbial communities in HS, revealing consistent alterations in microbial composition and diversity. Compared with healthy skin, HS lesions exhibit reduced microbial diversity, depletion of commensal organisms such as Cutibacterium acnes, and enrichment of anaerobic bacteria including Prevotella, Porphyromonas, and Finegoldia. These alterations are more pronounced in chronic, tunnel-forming disease and are frequently associated with biofilm formation, which may contribute to treatment resistance and persistent inflammation. Microbiome changes have also been observed beyond overtly lesional skin, suggesting a broader field effect. Evidence regarding extracutaneous microbial compartments, particularly the gut microbiome, remains limited and heterogeneous, while methodological variability in sampling, sequencing, and treatment exposure continues to complicate cross-study comparisons. Emerging data further suggest that immune-targeted therapies, including biologic and small-molecule agents, may indirectly influence microbial community structure through modulation of the inflammatory milieu. Collectively, the available evidence supports cutaneous dysbiosis as a characteristic feature of HS that may potentially interact bidirectionally with immune dysfunction. Future longitudinal, multi-omic studies integrated with clinical phenotyping will be critical to clarify causal relationships and to determine whether microbiome modulation can be leveraged to improve therapeutic outcomes in HS. Full article

Nuclear factor kappa B (NF-κB) signaling plays a central role in inflammation, immunity, cell survival, and cancer progression. Its constitutive activation is frequently observed in breast cancer, contributing to tumor growth, treatment resistance, and metastasis. MicroRNAs (miRNAs) are key post-transcriptional regulators of gene expression and may modulate NF-κB signaling in a subtype-specific or -independent manner. The aim of the study was to identify miRNAs that may potentially regulate the activity of genes associated with NF-κB signaling across five molecular subtypes of breast cancer in Polish women. Tumor and matched normal tissue samples were collected from 405 patients with five breast cancer subtypes: luminal A (n = 130), HER2-negative luminal B (n = 100), HER2-positive luminal B (n = 96), non-luminal HER2-positive (n = 36), and triple-negative breast cancer (TNBC, n = 43). Expression profile of selected NF-κB-related genes were evaluated using mRNA microarrays and RT-qPCR. Protein levels were assessed by ELISA. Candidate regulatory miRNAs were identified via miRNA microarrays and validated using the miRDB database. A consistent upregulation of MAP3K7, TAB2, TNFAIP3, CSNK2A1, BCL2L1, XIAP, CXCL2, and PLAU was observed across all subtypes, suggesting activation of canonical NF-κB signaling. Downregulation of specific miRNAs, miR-1297 and miR-30a (targeting MAP3K7), miR-134 (TAB2), miR-125b (TNFAIP3), and miR-4329 (XIAP), may contribute to this deregulation. For CSNK2A1, BCL2L1, CXCL2, and PLAU, no regulatory miRNAs meeting our criteria were identified. Our study reveals a subtype-independent activation of the canonical NF-κB signaling pathway in breast cancer, underpinned by consistent upregulation of key components (at both the transcript and protein levels. Dysregulation of specific miRNAs likely contributes to this altered gene expression. These findings suggest the presence of a common NF-κB-driven oncogenic program across molecular subtypes, with potential implications for developing miRNA-based therapeutic strategies targeting inflammation, survival signaling, and treatment resistance in breast cancer. Full article

Tympanosclerosis is a chronic middle ear disorder characterized by fibrosis, hyalinization, and calcification of the tympanic membrane and ossicles, which often results in conductive hearing loss. The objective of this systematic review was to synthesize current evidence on molecular pathways and genetic susceptibility factors contributing to the development of this condition. PubMed, Embase, Web of Science, and Google Scholar were searched up to December 2024. Eligible studies were original peer-reviewed articles in English investigating gene expression, genetic polymorphisms, or molecular signaling pathways in human or animal models. Risk of bias was assessed using standardized tools, and results were synthesized narratively due to heterogeneity. Twenty-five studies were included from 1815 screened records. Reported findings implicated inflammatory cytokines, such as TNF-α and IL-6, oxidative stress-related enzymes, including CAT, and iNOS, and bone remodeling pathways involving Wnt signaling, TGF-β1, and osteopontin. Polymorphisms in TLR4, NOS2 and NAT2 were associated with increased susceptibility or severity. Evidence remains limited but highlights potential biomarkers and therapeutic targets. Full article

Ferroptosis is a form of regulated cell death driven by iron-dependent phospholipid peroxidation and has emerged as a key mechanism of neuronal injury across a broad spectrum of neurological disorders. MicroRNAs (miRNAs), which function primarily as post-transcriptional regulators of gene expression, are increasingly recognized as important modulators of the regulatory networks governing ferroptosis and as potential therapeutic targets in these conditions. In this review, we synthesize current advances in miRNA-mediated regulation of ferroptosis in neurological disorders. We first outline the core molecular pathways governing ferroptosis, with particular emphasis on antioxidant defense, lipid peroxidation, and iron metabolism. We then integrate evidence from ischemic stroke, intracerebral hemorrhage, epilepsy, toxic encephalopathy, spinal cord injury, Parkinson’s disease, and Alzheimer’s disease, to illustrate how disease-specific miRNA regulatory axes shape ferroptotic vulnerability and its pathological consequences in distinct neurological settings. Importantly, we highlight exosome-based strategies targeting ferroptosis-related miRNA networks as a promising therapeutic approach for neurological disorders, with demonstrated neuroprotective and functional benefits in preclinical studies. Collectively, current evidence supports miRNA-mediated regulation of ferroptosis as an important mechanistic framework and a promising therapeutic target in neurological disorders. Full article

Growing evidence indicates that myocardial infarction (MI) is the clinical manifestation of heterogeneous plaque substrates with distinct molecular, cellular, and biomechanical mechanisms. Acute coronary thrombosis (ACT) most commonly arises from plaque rupture (PR), plaque erosion (PE), and calcified nodules (CNs), each associated with different inflammatory profiles, thrombus composition, clinical presentation, and prognosis. This comprehensive review provides a clinician-oriented synthesis of the pathophysiological mechanisms underlying these three principal plaque phenotypes and discusses their implications for the contemporary management of acute coronary syndromes (ACS). We examine the molecular and cellular determinants of plaque instability and highlight how systemic factors such as plaque burden, impaired healing responses, and myocardial jeopardy modulate clinical risk. The role of intracoronary and non-invasive imaging is discussed primarily as a tool to elucidate plaque biology with direct clinical relevance rather than merely as a procedural guide. Building on these insights, we propose a conceptual framework for integrating plaque biology into clinical decision-making across the acute phase, secondary prevention, and long-term follow-up. In particular, recognizing the biological heterogeneity of plaque substrates may support more personalized therapeutic strategies, enabling clinicians to tailor pharmacological and interventional approaches according to the underlying plaque phenotype and patient-specific risk profile. Finally, we briefly address emerging perspectives, including the potential role of artificial intelligence (AI) in refining plaque characterization, risk stratification, and precision cardiovascular prevention. Overall, recognition of PR, PE, and CNs as biologically distinct entities supports a shift toward mechanism-informed and personalized management of MI, aligning advances in plaque biology with the principles of precision cardiovascular medicine. Full article

Prediabetes is increasingly recognized as a risk factor for sarcopenia, driven by chronic low-grade inflammation, insulin resistance, and impaired anabolic signaling. Nutritional interventions containing whey protein, hydroxymethylbutyrate (HMB), glucosamine, and micronutrients may offer a multi-target strategy to counteract muscle deterioration. This study aimed to evaluate the efficacy of HiLo Platinum™ supplementation in attenuating muscle strength decline in a prediabetic rat model, with integrated analysis of metabolic biomarkers and gut microbiome profiles. A randomized preclinical trial was conducted using male Sprague Dawley rats assigned to four groups: normal diet (ND), prediabetic control induced by cholesterol- and fat-enriched diet with fructose (CFEDF), and two treatment groups receiving low-dose (0.63 g/kg BW) or high-dose (1.26 g/kg BW) HiLo Platinum™. The intervention lasted six weeks. Muscle strength was assessed via a four-limb grip strength test (reverse hang time and holding impulse). Biomarkers related to inflammation, mitochondrial function, and anabolic signaling (TNF-α, IL-10, PGC-1α, IGF-1, SIRT-1, AMPK, mTOR, and myostatin), lipid profile, and blood glucose were analyzed. Gut microbiome composition and diversity were evaluated using taxonomic profiling and multivariate analyses. HiLo Platinum™ supplementation significantly improved muscle strength, evidenced by increased reverse hang time and holding impulse (p < 0.001). Both doses reduced blood glucose and improved lipid profiles, including increased HDL and decreased LDL, triglycerides, and total cholesterol. Anti-inflammatory effects were observed with reduced TNF-α and elevated IL-10 levels. Mitochondrial and metabolic regulators (PGC-1α, SIRT-1, AMPK) and anabolic mediators (IGF-1) were significantly upregulated, while mTOR levels decreased. Gut microbiome analysis revealed increased genus richness (Chao1 index) and distinct microbial shifts associated with improved metabolic and inflammatory markers. HiLo Platinum™ effectively mitigates prediabetes-induced muscle strength decline through integrated modulation of inflammatory pathways, mitochondrial function, metabolic homeostasis, and gut microbiome composition. These findings support its potential as a nutritional therapeutic strategy for preventing sarcopenia in prediabetic conditions, although further studies are needed to evaluate long-term effects and implications on muscle hypertrophy. Full article