Search Results (15,101)

Phosphate is emerging as an active mediator of oxidative stress and vascular injury in chronic kidney disease (CKD). This emerging pathophysiological framework, referred to as “Phosphatopathy”, describes the systemic syndrome driven by chronic phosphate overload and characterized by oxidative stress, inflammation, endothelial dysfunction, vascular calcification, cellular senescence, and metabolic imbalance. Beyond being a biochemical marker, phosphate overload triggers NOX-derived reactive oxygen species (ROS), activates Wnt/β-catenin and TGF-β signaling, and disrupts the FGF23–Klotho axis, promoting endothelial dysfunction, vascular calcification, and left ventricular hypertrophy (LVH). These pathways converge with systemic inflammation and energy imbalance, contributing to the malnutrition–inflammation–atherosclerosis (MIA) syndrome. Experimental and clinical data reveal that the phosphate/urinary urea nitrogen (P/UUN) ratio is a sensitive biomarker of inorganic phosphate load, while emerging regulators such as microRNA-125b and calciprotein particles integrate phosphate-driven oxidative and inflammatory responses. Therapeutic strategies targeting phosphate burden—rather than serum phosphate alone—include dietary restriction of inorganic phosphate, non-calcium binders, magnesium and zinc supplementation, and activation of important pathways related to the activation of antioxidant defense such as AMP-activated protein kinase (AMPK) and SIRT1. This integrative framework redefines phosphate as a modifiable upstream trigger of oxidative and metabolic stress in CKD. Controlling phosphate load and redox imbalance emerges as a convergent strategy to prevent vascular calcification, improve arterial stiffness, and reduce cardiovascular risk through personalized, mechanism-based interventions. Full article

Background: Fine particulate matter (PM_2.5) is an established systemic toxicant, yet its association with clinical skin aging remains incompletely characterized. Although pigmentary changes and wrinkles are commonly attributed to ultraviolet exposure, experimental and epidemiologic evidence suggests that long-term PM_2.5 exposure may contribute to extrinsic skin aging through oxidative, inflammatory, and aryl hydrocarbon receptor-mediated pathways. However, human studies specifically quantifying PM_2.5 exposure in relation to validated skin aging outcomes are sparse, and no prior meta-analysis has systematically synthesized this evidence. Objective: To conduct a systematic review and meta-analysis of epidemiologic studies reporting measured or modeled long-term PM_2.5 exposure and extractable quantitative associations with clinical skin aging outcomes. Methods: We performed a comprehensive PRISMA 2020-guided search of PubMed, Embase, Web of Science, and Scopus (inception to 18 November 2025). Eligible studies included human participants, quantified long-term PM_2.5 exposure, validated clinical or imaging-based skin aging outcomes, and extractable effect estimates. Ratio-type effect measures (arithmetic mean ratios, geometric mean ratios, and odds ratios) were transformed to the natural-log scale, standardized to a common exposure contrast of per 10 µg/m³ PM_2.5, and synthesized as generic relative association metrics. Random-effects models with DerSimonian–Laird estimation and Hartung–Knapp adjustment were applied for pigmentary outcomes. VISIA imaging β-coefficients were synthesized narratively. Results: Four epidemiologic cohorts met predefined eligibility criteria. From these, we extracted seven PM_2.5-specific pigmentary effect estimates, one clinically assessed wrinkle estimate, and two VISIA imaging outcomes. The pooled relative association for pigmentary aging corresponded to a ratio of 1.11 per 10 µg/m³ PM_2.5 (95% CI, 0.82–1.50), indicating a directionally positive but statistically imprecise association compatible with both increased and unchanged pigmentary aging. All individual pigmentary estimates were directionally positive. A single cohort reported a 3.2% increase in wrinkle severity per 10 µg/m³ PM_2.5 (ratio 1.032). VISIA imaging showed significant worsening of brown spot severity (+9.5 percentile per 10 µg/m³), while wrinkle percentiles showed a non-significant change. Conclusions: Based on a comprehensive PRISMA-guided search, the available epidemiologic evidence suggests a consistent directionally positive association between long-term PM_2.5 exposure and pigmentary skin aging outcomes, with limited and uncertain evidence for wrinkle-related phenotypes. The current evidence base remains small, heterogeneous, and of low certainty. Accordingly, these findings should be interpreted as hypothesis-generating and underscore the need for larger, longitudinal, and methodologically harmonized studies. (Registration: PROSPERO CRD420251231462) Full article

Sodium–glucose cotransporter 2 (SGLT2) inhibitors have substantially reshaped the management of type 2 diabetes mellitus (T2DM), owing not only to their glucose-lowering properties but also to their consistent cardiovascular and renal protective effects. Beyond their initial metabolic indication, these agents have emerged as disease-modifying therapies across a broad spectrum of cardiometabolic and renal conditions. Building on the clinical success of first-generation SGLT2 inhibitors, such as empagliflozin and dapagliflozin, next-generation SGLT2-based therapies have been developed with the aim of refining pharmacological selectivity, optimizing pharmacokinetic profiles, and expanding therapeutic applicability beyond diabetes. These innovations include dual SGLT1/SGLT2 inhibition, alternative dosing strategies, and molecular designs tailored to specific clinical phenotypes, such as heart failure with preserved ejection fraction (HFpEF) and chronic kidney disease (CKD). This narrative review critically evaluates the evolving landscape of next-generation SGLT2 inhibitors, with a focus on structural and pharmacokinetic innovations, transporter selectivity, glucose-independent mechanisms, and emerging clinical implications. A comprehensive literature search was conducted using PubMed/MEDLINE, Scopus, and Web of Science, encompassing publications from inception to March 2025. Eligible sources included randomized clinical trials, observational studies, meta-analyses, and authoritative reviews published in English. Available evidence indicates that, while conventional SGLT2 inhibitors confer robust and reproducible cardiorenal benefits, newer agents may further extend therapeutic potential through incretin-related effects, modulation of extra-renal pathways, and disease-specific cardiac and renal mechanisms. Nevertheless, evidence supporting incremental clinical benefit beyond established SGLT2 inhibitors remains limited and heterogeneous, particularly for recently developed compounds. Overall safety profiles appear broadly consistent within the class, although long-term data for next-generation agents are still evolving. Key limitations of the current evidence base include reliance on emerging or indirect mechanistic data, heterogeneity in study populations and clinical endpoints, and the relative scarcity of large, outcome-driven trials for newer SGLT2-based therapies. Future research should prioritize mechanism-driven clinical trials, precision-oriented patient stratification, and head-to-head comparative studies to more clearly define the role of next-generation SGLT2 inhibitors in cardiovascular, renal, and metabolic disease management. Full article

Microplastics and nanoplastics (<5 mm and <1 μm, respectively) are emerging contaminants now ubiquitous across environmental matrices and increasingly recognized for their impacts on human health. These particles commonly adsorb or contain endocrine-disrupting chemicals—such as bisphenol-A and phthalate additives—that together trigger complex biological responses. This review examines the central role of oxidative stress in mediating the toxicity of microplastics and associated endocrine disruptors across multiple organ systems. We discuss mechanisms including cellular uptake, reactive oxygen species generation, mitochondrial dysfunction, impairment of antioxidant defenses, and activation of key signaling pathways. Organ-specific effects on reproductive health, cardiovascular function, hepatic metabolism, gut barrier integrity, and neurological systems are highlighted. Current evidence strongly supports oxidative stress as a pivotal mechanism linking microplastic exposure to systemic toxicity, underscoring important implications for public health policy and clinical intervention strategies. Full article

Background/Objectives: Multidrug-resistant tuberculosis remains a critical public health challenge in Kazakhstan, yet the genomic determinants contributing to its emergence are still insufficiently understood. Although the quantity of genomic studies from Central Asia and the wider post-Soviet region has increased in recent years, the involvement of DNA repair and genome maintenance pathways in the development of resistance within Kazakhstan has not been comprehensively explored. Methods: In this study, we performed whole-genome analysis of 175 Mycobacterium tuberculosis clinical isolates collected across Kazakhstan between 2010 and 2022 to evaluate the contribution of single-nucleotide polymorphisms in DNA replication, repair, and recombination (3R) genes to the evolution of drug resistance. Results: Alongside well-established resistance mutations in gyrA, we identified recurrent variants in 3R-associated loci (genes involved in DNA replication, repair, and recombination)—including polA, uvrC and ligC—that were enriched among drug-resistant isolates, suggesting a broader role for genome maintenance pathways in facilitating resistance evolution under treatment pressure. Conclusions: These findings provide the first region-specific genomic insights into 3R gene variation in Kazakhstani M. tuberculosis isolates. Full article

Background: Neonatal myocytes rely predominantly on glycolytic metabolism for survival during hypoxic conditions. During asphyxia, metabolic pathway dysregulation impairs cardiac myocyte contractility. Co-administration of dextrose and insulin may help restore metabolic homeostasis and improve cardiac function. Methods: Following blinded randomization and instrumentation, near-term lambs (138–140 days gestational age) were asphyxiated by umbilical cord occlusion until complete cardiac arrest, followed by 7 min of continued arrest to model severe asphyxia. Return of spontaneous circulation (ROSC) was defined as heart rate ≥ 100 beats per minute (bpm) and diastolic blood pressure ≥ 20 mmHg. Results: The incidence of ROSC was 3/6 in the control group compared to 5/5 in the experimental group receiving dextrose–insulin therapy, although this difference did not reach statistical significance. Conclusions: In this proof-of-concept study using a near-term ovine model of prolonged asphyxial cardiac arrest, dextrose and insulin co-administered with epinephrine were associated with improved ROSC rates although could be an association. Larger studies are needed to confirm these findings and evaluate clinical translation Full article

Oxidative stress arises from an imbalance between reactive oxygen species (ROS) and antioxidant defense mechanisms and disrupts the structural integrity of macromolecules such as lipids, proteins, and DNA. This biochemical imbalance triggers the pathogenesis of cardiovascular and neurodegenerative diseases and leads to lipid oxidation and quality degradation in food systems. Plant-derived bioactive compounds (BACs) such as polyphenols and terpenes develop versatile molecular strategies to mitigate this oxidative damage. In addition to their direct radical scavenging effects, polyphenols stimulate the synthesis of endogenous antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT) by activating the Nrf2–Keap1 signaling pathway. Terpenes, on the other hand, create a specialized protective shield in lipid-based matrices through “chain-breaking” reactions and a “slingshot” mechanism that externally halts the oxidation of γ-terpinene. In food engineering applications, these compounds meet the demand for “clean-label” products by providing alternatives to synthetic antioxidants such as BHA and BHT. Specific terpenes, such as carnosic acid, demonstrate higher performance in inhibiting lipid oxidation compared to their synthetic counterparts. Although BAC use extends the shelf life of products while maintaining color and flavor stability, potential interactions with protein digestibility necessitate dosage management. From a clinical perspective, these compounds suppress inflammatory responses by inhibiting the NF-κB pathway and contribute to the prevention of chronic diseases by modulating the gut microbiota. This review evaluates the capacity of BACs to manage oxidative stress in food preservation technologies and human health through a mechanistic and application-based approach. Full article

Background and Objectives: There are many well-described approaches to symptomatic ventral hernia management; however, there remains a significant patient population with limited options for a durable ventral hernia repair with a reasonable risk of infection and recurrence. Drawing from the orthopedic literature, we changed our approach to this clinical problem and developed a palliative ventral hernioplasty pathway. Materials and Methods: A retrospective review (2017–2019) of patients’ palliative ventral hernioplasty was performed. Results: In total, 43 patients included, with a female preponderance of 24 (58.6%) and a mean age 61.5 ± 11.5 years. The mean BMI was 38.1 kg/m² (IQR: 25.4–62), and 28 patients (65.1%) had a history of prior wound/mesh infection. Urgent repair was performed in 14 patients. Overall polypropylene prosthetic was implanted in 26 patients, and bioprosthetic/absorbable mesh was used in the remaining. The mean surface area of the implanted mesh was 561 cm². The most common wound complications identified were skin separation (30.2%) and seroma formation (48.8%). Hernia recurrence occurred in four (9.3%) patients, with a mean follow-up of 24.1 months (9–37). Three patients had central lightweight mesh rupture and one had a recurrence (bioprosthetic mesh); all were subsequently repaired. Conclusions: Despite the small number of patients, our palliative ventral hernia repair pathway offers durable repair with an acceptable risk of recurrence and mesh infection in patients who would otherwise be considered nonoperative. Full article

While distinguishing between collis and caput patterns in cervical dystonia (CD) has clear clinical and therapeutic relevance, the effects of botulinum toxin type A (BoNT-A) on segmental spinal excitability and inhibitory function in caput-pattern CD have not been previously investigated. This study aimed to advance understanding of the effects of BoNT-A and its broader neurophysiological impact in cervical dystonia, particularly in the caput subtype. The study utilised non-invasive neurophysiological methods to assess F-wave and cutaneous silent period (CSP or CuSP) parameters in 21 CD patients with caput motor patterns at waning and peak response phases of BoNT-A therapy. Significant prolongation of Fmin latency, increased F–M interlatency, reduced F-wave amplitude, and a marked increase in CSP duration and onset latencies were observed following BoNT-A administration, indicating that BoNT-A not only reduces spinal motoneuron excitability and strengthens spinal inhibitory processes, but also highlights its capacity to modulate central sensorimotor pathways beyond local chemodenervation. Together, the observed changes in CSP support its use as a potential biomarker for nervous system effects of BoNT-A in dystonia; however, further validation in controlled studies is warranted. Full article

Background: Type 2 diabetes mellitus (T2DM) is a global epidemic in which gut microbiota dysbiosis contributes to impaired glucose homeostasis and chronic inflammation. Intermittent fasting (IF) and probiotic supplementation have independently demonstrated glycemic benefits in T2DM, largely through microbiota remodeling. This narrative review synthesizes evidence up to October 2025 to clarify the microbiota-dependent mechanisms of IF and probiotics, and to evaluate the biological plausibility and preliminary clinical data for their combined application in T2DM management. Methods: We conducted a comprehensive literature review of preclinical and clinical studies (PubMed, Embase, Web of Science, and Cochrane Library) examining IF regimens (primarily time-restricted feeding and 5:2 protocols) and multi-strain probiotics containing Lactobacillus and Bifidobacterium species in T2DM or relevant models. Mechanistic pathways, microbial compositional shifts, and metabolic outcomes were qualitatively synthesized, with emphasis on overlapping signaling (short-chain fatty acids, bile acids, GLP-1, and barrier function). Results: IF consistently increases Akkermansia muciniphila and, variably, Faecalibacterium prausnitzii abundance, restores microbial circadian rhythmicity, and enhances SCFA and secondary bile acid production. Multi-strain probiotics modestly reduce HbA1c (–0.3% to –0.6%) and fasting glucose, outperforming single-strain preparations. Both interventions converge on reduced endotoxaemia and improved intestinal integrity. Preclinical models indicate potential synergy, whereas the only direct human trial to date showed neutral results. Conclusions: IF and probiotics engage overlapping microbiota-mediated pathways, supporting their combined use as an adjunctive strategy in T2DM. Adequately powered randomized trials incorporating deep metagenomics, metabolomics, and hard clinical endpoints are now required to confirm additive or synergistic efficacy. Full article

(1) Background: Cutaneous secondary malignant neoplasms are a growing survivorship burden after pediatric cancers and hematopoietic stem cell transplantation (HSCT), yet skin-focused surveillance remains inconsistently implemented. (2) Objective: To synthesize current molecular dermatology insights relevant to prevention, early detection, and treatment of basal cell carcinoma (BCC) in high-risk survivors, while anchoring the discussion in a detailed case of multiple BCCs after childhood acute lymphoblastic leukemia and HSCT. (3) Methods: Narrative review integrating clinical, dermoscopic, molecular, and translational data from recent high-impact studies; case retained in full. (4) Results: Radiation exposure (especially total body irradiation), prior immunosuppression, and persistent immune dysregulation synergize with ultraviolet mutagenesis to create a “field cancerization” state characterized by Hedgehog-pathway activation (Patched1/Smoothened), impaired Deoxyribonucleic Acid damage response, and stromal remodeling. Dermoscopy, when embedded in routine whole-body examinations, markedly improves accuracy for keratinocyte cancers. Chemoprevention (e.g., nicotinamide) and targeted therapies (hedgehog inhibitors; Programmed Death-1 blockade) represent key translational levers for care innovation. (5) Conclusions: Integrating structured dermatologic surveillance with molecularly informed prevention and therapy should be standard in survivorship pathways for hematopoietic stem cell transplantation/Radiotherapy-exposed patients. Full article

Glioblastoma is currently an incurable disease despite the development of a wide variety of therapeutic approaches, from surgical methods to immunotherapy. In current clinical practice, treatment typically involves a combination of existing methods, often comprising three stages: tumor resection, radiotherapy, and chemotherapy. Modern research offers improved chemotherapy strategies, as well as combinations of chemotherapy with immunotherapy. However, the efficacy of these therapies is profoundly influenced by factors such as tumor and peritumoral heterogeneity, alongside complex molecular signaling pathways. Optimizing glioma treatment requires a rigorous mechanistic understanding of individual approaches and their synergistic effects. This review comprehensively details current glioblastoma therapeutic strategies and critically evaluates key reference models for assessing combination therapy efficacy and their inherent limitations. A deeper understanding of these mechanisms and models will refine the investigation of observed therapeutic effects and accelerate the translation of promising in vitro approaches to effective clinical management of malignant gliomas. Full article

Metabolomics research in schizophrenia has revealed consistent alterations across multiple biochemical domains, including energy metabolism, lipid composition, amino acid pathways, and oxidative stress regulation. The most reproducible findings include the dysregulation of the tryptophan–kynurenine pathway, disturbances in arginine/nitric oxide metabolism, alterations in phospholipid and sphingolipid profiles, reduced glutathione (GSH) in the brain, and elevated lactate levels, suggesting mitochondrial dysfunction. Antipsychotic treatment itself modifies a wide range of metabolites, complicating biomarker discovery. Although no single biomarker has yet achieved clinical utility, systematic reviews and Mendelian randomization studies provide evidence for validated biomarker panels and potential causal links between peripheral metabolite signatures and schizophrenia risk. The aim of this study is to characterize metabolic changes in patients diagnosed with schizophrenia, where each group received different non-invasive therapeutic methods and was compared to patients continuing standard pharmacotherapy without modification. The study results show that schizophrenia is associated with systemic metabolic disturbances affecting energy, amino acid, lipid, and redox pathways. Further development of research in this area requires comprehensive and long-term studies integrated with modern imaging and analytical techniques. Full article

The Sprouty (SPRY) proteins are evolutionarily conserved modulators of growth factor-induced signaling pathways. The four different SPRY isoforms (SPRY1-4) are implicated in different types of cancer, acting as oncogenes or tumor suppressors depending on the SPRY isoform and the malignancy. Despite being tumor suppressors in many types of cancer, SPRY1 is an oncogene in rhabdomyosarcoma, SPRY2 in colorectal cancer, and SPRY4 in gastric cancer. In this review, we summarize the current literature about the functions of SPRY1-4 in glioblastoma (GB) and neuroblastoma (NB). To further delineate the effects of SPRY1-4 in the tumorigenesis of the nervous system, we analyzed the association of SPRY1-4 with the overall and event/progression-free survival of patients with pediatric and adult glioma, GB, and NB using public datasets. Together, there is evidence that SPRY1 and -2 are oncogenes in GB, whereas the role of SPRY3 and -4 in GB is not well defined. In NB, SPRY2 acts as a tumor suppressor, whereas the effects of SPRY1, -3, and -4 in NB have not been investigated so far, although the survival analysis revealed increased survival of NB patients with low SPRY3 levels in different datasets. Thus, this review demonstrates the requirement for further studies about the functions of the SPRY proteins in tumors of the nervous system to define their clinical relevance as potential therapeutic targets in the future. Full article

Acetaminophen (paracetamol) is one of the most widely used analgesic and antipyretic drugs worldwide, yet its potential impact on hormonal balance and the risk of hormone-dependent cancers remains unclear. This study aimed to integrate epidemiological and bioinformatic evidence to assess the association between acetaminophen use and the risk of sex hormone–related cancers. A systematic review of preclinical and human studies was complemented by in silico analyses of acetaminophen’s molecular targets and their involvement in cancer-related pathways. Epidemiological data indicate that, although experimental studies suggest possible hormonal and reproductive effects, most population-based studies do not support an increased cancer risk, and some even suggest a potential protective effect. Bioinformatic analyses identified genes and pathways associated with ovarian and prostate cancers that may be modulated by acetaminophen, as well as possible links with breast cancer through drug metabolism–related genes. These findings reveal a shared molecular network that may underlie the observed epidemiological patterns. This integrative analysis underscores the need for further basic and clinical research to elucidate acetaminophen’s role in hormone-related carcinogenesis and to inform its safe therapeutic use. Full article