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The 'New York City Marathon' is one of the world's largest and most influential mass-participation marathons. Although numerous studies have examined performance trends, participation patterns, pacing behavior, environmental influences, and physiological aspects of runners in this event, no review has synthesized the evidence specific to this race. This study aimed to systematically summarize the scientific literature on the 'New York City Marathon'. A systematic search of Scopus, PubMed, Web of Science, Embase, and Cochrane was conducted using terms related to the 'New York City Marathon' to identify studies published up to February 2026. Eligible studies included runners of all ages, sexes, and performance levels, with no restrictions on publication date, topic, or study design. Extracted data included: (1) authors; (2) publication year; (3) study design; (4) sample characteristics; (5) variables assessed; and (6) main findings. Results were synthesized narratively by domain. Seventy-six publications met the inclusion criteria. Participation increased markedly over time, driven primarily by growth among women and age-group runners. While elite and competitive age-group performances improved in recent decades, mean finish times across the entire field increased by ~40 min since the 1970s, reflecting the democratization of marathon running. Ethiopian runners were the youngest and fastest. Peak performance occurred at 29.7 years in women and 34.8 years in men (1-year age intervals), and in the 30-34 and 35-39 age groups, respectively (5-year intervals). Approximately 10 % of runners experienced major injuries during training or the race that prevented starting or finishing. Higher training volumes increased injury risk, with foot, knee, and hip injuries most common, whereas adequate preparation reduced risk. Environmental conditions-particularly temperature-had a stronger influence on race times than course metrics. Performance declined with increasing temperature, especially among slower runners and among men aged 30-64 and women aged 40-64. Runners generally adopted a positive pacing strategy with a final spurt in the last segment (40-42.2 km). The fastest split occurred between 5-10 km and the slowest between 35-40 km, coinciding with the undulating terrain entering Central Park. Older athletes paced more evenly than younger athletes. Men showed a larger decrease in running speed from the fastest to the slowest splits than women (21.1 % vs. 16.7 %). Slower runners exhibited greater early-race deceleration but larger late-race speed increases, whereas faster runners maintained the most even pacing. Participation in the 'New York City Marathon' has grown substantially, driven by increased involvement of women and age-group runners. Although elite performance has improved, overall mean finish times have slowed due to broader participation. Ethiopian runners were the youngest and fastest, with peak performance occurring in the early to mid-30s. Injury prevalence was considerable, particularly with higher training volumes, though adequate preparation mitigated risk. Higher temperatures slowed performance, especially among slower runners. Pacing was predominantly positive, with older athletes pacing more evenly and faster runners showing the smallest performance decline. Future research should explore cardiovascular monitoring technologies-including real-time ECG streaming during the race-and assess the impact of innovations such as carbon-plated "supershoes" on performance and pacing. See also the graphical abstract(Fig. 1).
Sarcopenia, a progressive loss of skeletal muscle mass and strength, leads to frailty, falls, fractures, and delayed recovery following orthopedic surgery. When combined with osteoporosis, it manifests as osteosarcopenia, exacerbating musculoskeletal fragility. Although chronic inflammation, mitochondrial dysfunction, and impaired autophagy are recognized contributors, the integrated regulation of these processes in Asian populations remains unclear. This study aimed to elucidate molecular mediators and signaling pathways connecting inflammation, autophagy, and muscle-bone degeneration using an integrated clinical-transcriptomic approach. Transcriptomic data (GSE226151) comprising vastus lateralis muscle samples from 20 sarcopenic patients and 20 age- and sex-matched healthy Asian controls were analyzed using ExDEGA, with differentially expressed genes (DEGs) defined by |log₂ fold change| ≥ 1 and FDR < 0.05. Functional enrichment via ShinyGO identified key Gene Ontology and KEGG pathways, while STRING-Cytoscape network analysis revealed four hub genes-ADAM8, BECN1, KLF4, and GBP5-with high connectivity (degree >10) enriched in cytokine-cytokine receptor interaction and PI3K-Akt pathways. Gene Set Enrichment Analysis further validated these associations. The expression of these hub genes inversely correlated with skeletal muscle index (r = -0.63 to -0.74; p < 0.01) and grip strength (r = -0.58 to -0.69; p < 0.05). Clinically, sarcopenic individuals exhibited significantly lower BMI, gait speed, and muscle mass (all p < 0.001). Integrating bioinformatics and clinical data identified these four genes as critical mediators linking inflammation, defective autophagy, and musculoskeletal decline in sarcopenia. These findings provide translational insight into the molecular mechanisms underlying osteosarcopenia and suggest potential biomarkers and therapeutic targets to improve diagnosis and treatment in aging-related musculoskeletal disorders. See also the graphical abstract(Fig. 1).
Transforming growth factor-β (TGF-β) belongs to a family of structurally and functionally related cytokines that play essential roles in embryonic development, tissue homeostasis, and cell fate regulation. Dysregulation of TGF-β signaling contributes to a broad spectrum of diseases, including cancer, fibrosis, and immune disorders. In cancer, TGF-β exhibits a context-dependent dual role, functioning as a tumor suppressor during early stages while promoting invasion, metastasis, escape from immune surveillance, and tumor microenvironment remodeling in advanced-stage cancer through effects on stromal cells, extracellular matrix deposition, and angiogenesis. This functional duality makes therapeutic targeting both attractive and challenging. Although current strategies mainly focus on ligand neutralization or receptor kinase inhibition, accumulating evidence indicates that TGF-β activity is also regulated beyond the receptor level, including receptor trafficking, co-receptor function, nucleocytoplasmic shuttling, indirect pathway modulation, and epigenetic regulation. In this review, we emphasize regulatory mechanisms that can be modulated by existing drugs, clinical candidates, or experimentally tractable compounds, rather than providing an exhaustive overview of the broader regulatory landscape of TGF-β signaling. We further highlight opportunities for drug repurposing and discuss how synergistic combination strategies may improve therapeutic efficacy and overcome resistance in TGF-β-driven cancers, supporting a broader therapeutic framework beyond canonical receptor inhibition. See also the graphical abstract(Fig. 1).
Nitric oxide (NO) is a small, bioactive molecule with diverse physiological functions. It is generated both enzymatically by NO synthases (NOS) and non-enzymatically through the nitrate-nitrite-NO reduction pathway. Recent studies have renewed interest in nitrate-based regulation of NO, highlighting a compartmentalization model of nitrate homeostasis. In this model, excess NO is rapidly oxidized to nitrite, which is then oxidized to nitrate, a more stable species that limits oxidative damage. Nitrate is differentially distributed across tissues, allowing both storage and rapid mobilization to maintain NO availability. Human and animal studies show that nitrate concentrations in skeletal muscle, plasma, and liver are approximately 100, 35, and 10 nmol/g, respectively, corresponding to a skeletal muscle-to-plasma-to-liver ratio of ~3:1:0.3. The large skeletal muscle reservoir and its higher muscle-to-plasma gradient support the release of nitrate into the circulation when needed. In contrast, the liver-to-plasma ratio < 1 suggests active hepatic uptake of circulating nitrate. Together, these findings support a compartmentalized system in which nitrate storage and flux contribute to whole-body NO homeostasis. Understanding this model may have implications for exercise physiology, metabolic regulation, and liver pathophysiology - all conditions in which NO biology plays a critical role. See also the graphical abstract(Fig. 1).
Mancozeb, a polymeric dithiocarbamate complex fungicide with zinc and manganese salts, has the potential to be neurotoxic to humans. Unfortunately, the parent molecule maneb has attracted far too much attention, limiting the available evidence on mancozeb neurotoxicity to preclinical research and non-human cells. We sought to evaluate mancozeb cytotoxicity in neuroblastoma SH-SY5Y cells at lower concentrations than those used for maneb in in vitro investigations in order to quantify its risk for humans. Commercial mancozeb showed concentration- and time-dependent neurotoxicity in the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction test (EC50= 5.9 µM and 1.7 µM at 24 h and 72 h respectively). Using the trypan blue exclusion dye, cell death toll reached around 100% after 24- and 72-hour exposure to mancozeb 1 µM and 0.5 µM respectively. Reactive oxygen species generated by mancozeb, which peaked at 4 µM, could be the cause of cell death. The number and length of neurites were concentration-dependently reduced by mancozeb at sub-µM concentrations, and this was accompanied by changes in cell biomechanical characteristics (stiffness) as determined by atomic force microscopy. The uncertainty factor obtained from our cytotoxic studies, when performing risk assessment of mancozeb, varied from 200 to 2000, which may result in detectable neurotoxicity in humans in accordance with international regulatory agencies recommendations. See also the graphical abstract(Fig. 1).
Extrapulmonary tuberculosis continues to challenge clinicians with its protean manifestations, particularly when involving the gastrointestinal tract. While ileocecal TB is well-characterized, isolated involvement of the liver, stomach, and esophagus, Duodenum remains exceptionally rare and diagnostically elusive. We describe four rare presentations of gastrointestinal tuberculosis from a tertiary care center in India. Case 1 involves hepatic tuberculosis mimicking intrahepatic cholestasis, diagnosed via liver biopsy and special staining. Case 2A details isolated gastric TB presenting with nonspecific dyspepsia, ultimately diagnosed through endoscopic ultrasound-guided FNAC. Case 2B describes esophageal tuberculosis with bronchoesophageal fistula-an exceedingly rare entity-confirmed radiologically and histologically. Case 2C describes a case of duodenal tuberculosis presenting as partial gastric outlet obstruction (GOO). All cases demonstrated clinical and radiological resolution following standard anti-tubercular therapy. These cases posit the diagnostic complexity of gastrointestinal TB when it involves uncommon sites. Heightened clinical suspicion and timely histopathological confirmation remain key to averting morbidity. Early recognition facilitates successful medical management and obviates unnecessary surgical interventions.
PANoptosome (Programmed Necrosis-Apoptosis Optosome) multiprotein complexes mediate the convergence of apoptosis, pyroptosis, and necroptosis. The ability of cells to undergo programmed inflammatory cell death is regulated by the epigenetic control of PANoptotic sensors, adaptors, and effectors, and has pivotal implications for their use in cancer therapies. DNA methylation suppresses the main PANoptotic pathways, such as RIPK3 (Receptor-Interacting Serine/Threonine-Protein Kinase 3), GSDME (Gasdermin E), and CASP8 (Caspase-8) that promote chemoresistance; hypomethylating DNA silencers resume PANoptotic sensitivity. BRD4 (Bromodomain-Containing Protein 4)/p300 (E1A-Associated Protein p300 - Histone Acetyltransferase) -mediated histone acetylation in enhancers (H3K27ac) stimulates ZBP1 (Z-DNA Binding Protein 1), NLRP3 (NOD-Like Receptor Family Pyrin Domain Containing 3), and caspase-8 transcription but inhibits the formation of inflammasomes by HDAC (Histone Deacetylase). PANoptotic regulatory regions become accessible in response to inflammatory signals through the dynamic regulation of accessibility through the SWI/SNF (Switch/Sucrose Non-Fermentable Chromatin Remodeling Complex) and NuRD (Nucleosome Remodeling Complex) and NuRD (Nucleosome Remodeling and Deacetylase Complex) chromatin remodelling complexes. Post-transcriptional regulation is mediated by ncRNAs (ncRNAs) such as miR-223-3p (MicroRNA-223-3p) and lncRNA NEAT1 (Long Non-Coding RNA - Nuclear Enriched Abundant Transcript 1) which converge to regulate the expression of NLRP3, RIPK3, and Gasdermin D (GSDMD). The interaction of DNA methylation, histone modification, and ncRNAs creates quantitative epigenetic thresholds that regulate PANoptotic sensitivity. The rational next step to overcome tumor immunoresistance is epigenetic biomarker stratification in combination with DNA methyltransferase inhibitors (DNMTi), histone deacetylase modulators (HDACi), and PANoptosis agonists, which could help reduce collateral tissue toxicity. See also the graphical abstract(Fig. 1).
A new bioactive compound, methyl linolenate (Methyl-octadeca-9,12,15-trienote), designated as ML, was isolated and purified from Clerodendrum viscosum leaves. Treatment of Ehrlich ascites carcinoma (EAC) cells with ML induced cancer growth inhibition dose-dependently, with a maximum cell growth inhibition of 67 % at a dose of 3.0 mg/kg/day (p<0.001). It also inhibits EAC cell volume and tumor weight and increases the survival time of EAC-bearing mice (25 versus 41 days) (p<0.001). In addition, EAC-bearing control mice exhibited a drastic deterioration of blood parameters, and treatment of EAC-bearing mice with ML prevented the deterioration of hematological parameters compared to untreated EAC-bearing mice. Also, ML abrogates angiogenesis by inhibiting the development of new blood vessels in the peritoneum of EAC-bearing mice. ML-treated cells exhibited apoptotic features such as condensed, fragmented nuclear material and cell membrane damage. Expression of pro-apoptotic genes such as p53, Bax, Caspase 3, and Caspase 9 was upregulated, whereas anti-apoptotic gene Bcl2 was downregulated in ML-treated EAC cells, which indicates the induction of intrinsic mitochondrial apoptosis of EAC cells. However, as it is a novel anticancer compound showing an antineoplastic effect, inhibiting angiogenesis, and inducing apoptosis in mouse models, thus, using other cellular models and more preclinical and clinical research is essential for further development. See also the graphical abstract(Fig. 1).
MAGEB16 (Melanoma-associated antigen B16) is an X-linked cancer-testis antigen belonging to the MAGE-B family, whose expression is tightly regulated by a promoter DNA-methylation switch that restricts transcription primarily to the male germ line under normal physiological conditions. In addition to its established roles in spermatogenesis and oncogenesis, emerging functional, epigenomic, and genetic evidence points to MAGEB16 as an epigenetically sensitive modifier of early developmental programs implicated in neurodevelopmental disorders such as Autism Spectrum Disorder (ASD). In this study, we performed an integrative analysis combining MAGEB16's chromosomal context, molecular interaction networks, and methylation-dependent regulatory features, alongside experimental depletion datasets from pluripotent stem cells, perinatal cord-blood methylome data from ASD cohorts, peripheral transcriptomics linked to neuropsychiatric risk and recently reported genetic variant associations. Our synthesis identifies underlying evidence indicating that MAGEB16 participates in epigenetically regulated lineage specification processes during early embryonic development. We propose a unified model in which MAGEB16 acts as a dosage- and timing-dependent regulator of early lineage commitment. Disruption of its epigenetic control, particularly during X-chromosome-enriched developmental periods, may influence neurodevelopmental pathways toward ASD-associated phenotypes. These findings position MAGEB16 as a candidate epigenetic-susceptibility factor linking germline-restricted regulatory changes, that could influence early brain development and increase the risk for neurodevelopmental conditions. See also the graphical abstract(Fig. 1).
Ischemic disorders are one of the prime causes of mortality and disability among various individuals across the globe. Although drug treatment/percutaneous coronary interventions may recanalize the obstructed blood vessels, yet reperfusion therapy may aggravate tissue damage and result in ischemia-reperfusion injury. Eugenol, a phenolic monoterpenoid (4-allyl-2-methoxyphenol), has been used extensively in various preclinical studies as an antioxidant compound that ameliorates ischemia-reperfusion injury in several organs, including the heart, brain, kidney, and intestine. This protective effect of eugenol is attributed to its ability to influence various several key signaling pathways. These include the AMPK-mTOR-P70S6K (AMP-activated protein kinase-mammalian target of rapamycin-p70 ribosomal S6 kinase) pathway, AMPK/GSK3β (Glycogen synthase kinase-3 beta) axis, PI3K/Akt (phoshatidylinositol-3 kinase/ protein kinase B) signaling, which help to mitigate oxidative damage and inflammation. It also modulates the activity of the Nrf2 transcription factor, ACE, and the apoptotic pathway, affects histone acetylation, and alters the expression of HMGN1, PPP2Ca, and CD151 genes, demonstrating its wide-ranging therapeutic effects. In this review, we will discuss the preclinical evidences and potential mechanisms of action of eugenol-dependent protective benefits against ischemia-reperfusion injury. See also the graphical abstract(Fig. 1).
Diabetic neuropathy (DN) is a prevalent microvascular complication of diabetes mellitus, characterized by hyperalgesia and allodynia that severely impair quality of life. Current treatment approaches do not provide adequate relief, largely due to the multifactorial nature of disease pathogenesis. Growing evidence indicates that dysregulation of multiple ion channel families is a central mechanism underlying sensory neuron hyperexcitability and chronic pain in DN. This review comprehensively discusses the roles of major ion channel families, including voltage-gated sodium (Naᵥ), calcium (Caᵥ), and potassium (Kᵥ) channels, transient receptor potential (TRP) channels, purinergic receptors (P2X/P2Y), and mechanosensitive PIEZO (PIEZO 1 and PIEZO 2) channels, in sensory transmission and pain modulation. Their dysregulation, induced by chronic hyperglycemia and oxidative stress, promotes ectopic firing, altered calcium homeostasis, and glial activation, sustaining nociceptive hypersensitivity. The review further evaluates current and emerging ion channel-targeted therapeutic approaches, highlighting mechanistic insights, translational challenges, and future research directions. Recent research highlights multi-target and combination strategies, such as Naᵥ1.8 inhibition with KCNQ activation or concurrent blockade of TRPV1 and P2X3, as promising avenues offering synergistic analgesic benefits and disease-modifying potential. Advances in nanocarrier-based delivery, gene modulation, and patient-specific electrophysiological profiling further enhance translational prospects. Ultimately, the therapeutic landscape of PDN is shifting from single-channel blockade toward integrated approaches that modulate excitability, inflammation, and metabolic stress concurrently. Ion channels thus represent not only crucial mediators of PDN pathophysiology but also versatile therapeutic targets whose selective and combinatorial modulation may transform the management of diabetic neuropathic pain. See also the graphical abstract(Fig. 1).
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On September 22, 2025, the United States government announced that the Food and Drug Administration (FDA) would modify paracetamol (acetaminophen) labelling to warn of possible associations with autism, advising pregnant individuals to avoid the medication. This contradicts professional medical consensus and high-quality evidence, replicating communication failures of the 1998 MMR-autism controversy that caused vaccine hesitancy, disease outbreaks, and trust erosion. This narrative review synthesized epidemiological evidence on paracetamol safety in pregnancy, analyzed the September 2025 announcement through the measles, mumps, and rubella (MMR)-autism crisis lens, and proposed an evidence-based communication framework. We searched PubMed, Embase, Web of Science, and Google Scholar, supplemented with governmental statements, professional responses, and media analysis. The two highest-quality sibling-control studies (Swedish: 2.5 million; Japanese: 200,000 children) reported no causal associations between prenatal paracetamol exposure and neurodevelopmental outcomes after controlling genetic and familial confounding. Conversely, untreated maternal fever and pain carry established risks including neural tube defects, preterm birth, and maternal morbidity. The governmental announcement employed inflammatory categorical warnings contradicting FDA's nuanced advisory and scientific consensus. Professional organizations immediately issued strong rebuttals. This replicates MMR failures: governmental statements contradicting evidence, false media balance, and public confusion. The September 2025 announcement represents failure to apply MMR lessons. Healthcare providers must employ evidence-based shared decision-making emphasizing sibling-controlled studies show no causal relationship while untreated conditions carry established harms. The Precautionary Communication Principle provides framework for transparent uncertainty discussion without disproportionate alarm or undermining evidence-based medicine trust. See also the graphical abstract(Fig. 1).
Insufficient early vascularization remains a major limitation for the successful integration of implanted dermal substitutes. To overcome this challenge, nanofat has recently been introduced as a promising fat derivative for implant seeding. The present study investigated whether short-term ex vivo pretreatment with the hypoxia-mimetic agent deferoxamine (DFO) can further enhance the in vivo vascularization capacity of nanofat. Nanofat from green fluorescent protein (GFP)+ donor mice was pretreated for 1 h with DFO (1 mM) or vehicle and subsequently seeded onto collagen-glycosaminoglycan-based dermal substitutes, which were implanted into dorsal skinfold chambers of syngeneic GFP- recipient mice. Implant vascularization, microhemodynamics, tissue integration and inflammatory response were assessed over a 14-day period using intravital fluorescence microscopy, histology and immunohistochemistry. Dermal substitutes seeded with DFO-pretreated nanofat exhibited a faster and more extensive vascularization, as evidenced by a significantly higher functional microvessel density in both implant border and center zones when compared to controls. Most blood-perfused microvessels originated from the GFP+ DFO-pretreated nanofat. The improved vascularization was associated with reduced leukocyte-endothelial cell interactions in peri-implant venules as well as a decreased implant infiltration by macrophages and neutrophils, indicating an attenuation of the early innate inflammatory response. Moreover, DFO pretreatment promoted the tissue integration of the implants and regenerative extracellular matrix remodeling, as evidenced by increased collagen III deposition. These findings demonstrate that short-term ex vivo DFO pretreatment effectively primes nanofat to enhance microvascular network formation and suppress inflammation, resulting in an accelerated and improved engraftment of nanofat-seeded dermal substitutes. See also the graphical abstract(Fig. 1).
The presence of leptin resistance is a key barrier to the successful management of obesity. The most recent study has focused on pharmacological drugs that are associated with inflammation and endoplasmic reticulum stress, as well as inhibitors of negative regulators, including PTP1B, SOCS3, and HDAC6, and substances that affect the mTOR and cAMP/Epac/Rap1 signaling pathways. Having an understanding that leptin resistance is caused by defective leptin signaling pathways, such as a disruption in the JAK-STAT pathway or an increase in the expression of SOCS3, shows the difficulty of restoring sensitivity. The physiological implications of leptin resistance extend beyond the regulation of metabolism and can influence the cardiovascular system, the liver (NAFLD/MASLD), the immunological system, the inflammatory system, reproductive health and the neuroendocrine system. The fact that leptin has metabolic impacts on various systems highlights the importance of taking an integrated strategy to treatment procedures. Within the context of metabolic and extra-metabolic leptin resistance, this review provides a summary of recent literature evidence pertaining to the restoration of leptin responsiveness. Also, we include a discussion regarding pharmacologic strategies, systemic implications, and future directions. See also the graphical abstract(Fig. 1).
Type 2 diabetes mellitus (T2DM) is increasingly recognized as a major risk factor for Alzheimer's disease (AD), with mounting evidence highlighting shared pathophysiological mechanisms. This review explores the intricate biological and molecular links between these two chronic disorders. Key overlapping pathways include impaired insulin signaling, chronic inflammation, oxidative stress, mitochondrial dysfunction, amyloid-beta (Aβ) accumulation, tau hyperphosphorylation, and the formation of advanced glycation end-products (AGEs). Disruption of insulin signaling in the brain contributes to synaptic loss and neurodegeneration, while systemic metabolic disturbances aggravate blood-brain barrier dysfunction and neurovascular damage. Emerging studies also underscore the role of antidiabetic treatments, especially newer agents targeting the gut-brain axis, in modulating AD progression. The review further examines preclinical models, clinical observations, and the development of biomarkers to improve early detection and intervention. Despite growing insights, challenges remain in translating mechanistic knowledge into effective therapies. A multidisciplinary approach integrating metabolic control and neuroprotective strategies is essential for addressing the comorbid burden of T2DM and AD. See also the graphical abstract(Fig. 1).