Search Results (9,070)

Skin aging is a complex, multifactorial process driven by intrinsic biological mechanisms and environmental exposures, resulting in progressive functional and structural decline. Chronological age does not adequately capture this variability, highlighting the need for molecular biomarkers that reflect biological aging. In this context, transcriptomic aging clocks have emerged as a promising approach, as gene-expression profiles provide a dynamic representation of cellular and tissue states. This narrative review is based on a targeted literature search in PubMed and IEEE Xplore and focuses on transcriptomic aging clocks in human skin, with emphasis on gene-expression signatures, key biological pathways, and computational modeling strategies. These models consistently capture coordinated alterations in processes such as cellular senescence, DNA damage response, inflammation, and extracellular matrix remodeling. Representative transcriptomic frameworks, including models such as SkinAGE, illustrate the ability of gene-expression-based approaches to quantify biologically meaningful and dynamic aging states in the skin. Advances in machine-learning approaches, including deep learning and pathway-guided models, are critically evaluated, alongside the role of explainable artificial intelligence in enhancing model transparency and biological interpretability. Future developments are expected to integrate multi-omics data and digital twin frameworks, enabling the transition from static biomarkers toward dynamic, predictive, and personalized models of skin aging Full article

Proteasome inhibitors (PIs) are central to multiple myeloma (MM) therapy; however, resistance remains a major clinical challenge, particularly in relapsed/refractory disease. To identify functional mediators of carfilzomib (CFZ) resistance, we performed complementary gain-of-function CRISPR activation and pharmacological screening approaches. These unbiased strategies converged on the E3 ubiquitin ligase MDM2 as a modulator of PI response. MDM2 transactivation enhanced MM cell survival and accelerated recovery following CFZ exposure, supporting a causal role in proteotoxic stress tolerance. Pharmacologic inhibition of MDM2 with NVP-CGM097 synergized with CFZ across multiple PI-sensitive and PI-resistant MM cell lines, irrespective of TP53 status. Mechanistically, MDM2 inhibition induced p21 upregulation, cell-cycle arrest, and reduced c-MYC expression, accompanied by impaired activation of DNA damage response mediators. Genetic silencing of MDM2 phenocopied these effects and increased CFZ sensitivity. Importantly, the combination retained efficacy in MM–stromal co-culture models and in primary patient samples, including cases harboring del(17p), while sparing normal peripheral blood mononuclear cells. Collectively, these findings identify MDM2 as a functional driver of PI resistance and support combined MDM2 and proteasome inhibition as a rational therapeutic strategy in MM, including TP53-deficient contexts. Full article

The overexpression of hypoxia-inducible factor-1α (HIF-1α) suppresses STING signaling and modulates lipid metabolism in tumor cells, leading to abnormal lipid droplet (LD) accumulation. Herein, we constructed a manganese dioxide (MnO₂)-based nanomotor (HMIP@A). HMIP@A depletes intracellular hydrogen peroxide (H₂O₂) and glutathione (GSH) to generate oxygen (O₂), reactive oxygen species (ROS), and manganese (Mn²⁺). A dual strategy of “oxygen supplementation” and “small-molecule inhibition” synergistically downregulates HIF-1α, thereby suppressing LD biogenesis. This process sensitizes tumor cells to ROS, leading to severe DNA damage. Released Mn²⁺ and damaged DNA synergistically activate the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. In vitro, HMIP@A markedly increases ROS production, lipid peroxidation (LPO), and DNA damage, thereby inducing tumor cell death, immunogenic cell death (ICD), and dendritic cell (DC) maturation. Furthermore, HMIP@A exhibits excellent penetration in tumor spheroids. Overall, this study provides a theoretical basis for the design of nanomedicines through a strategy integrating metabolic intervention, oxidative damage sensitization, and immune activation. Full article

Brucellosis, acting as a typical chronic zoonotic disease, is caused by the invasion of Brucella into the human body. Outer membrane protein 25 (Omp25), specifically localized on the Brucella membrane, is the main virulence factor of Brucella and participates in multiple links of the damage process. Omp25c, a porin protein of Brucella, is a paralog of Omp25 with high sequence identity. NADH dehydrogenase [ubiquinone] complex I assembly factor 2 (Ndufaf2) has a key function in cell energy metabolism, particularly in the formation and activity of the mitochondrial respiratory chain. Loss of Ndufaf2 results in oxidative stress and mitochondrial DNA (mtDNA) deletion. However, the functional relationship between Omp25c and Ndufaf2, the underlying mechanism of the proteins, remains unclear. In this work, we purified the Omp25c and Ndufaf2proteins. Our data revealed that Omp25c directly interacts with Ndufaf2, as determined using Biacore analysis. In addition, assays revealed that Ompa2c reshapes the host cell’s redox environment by decreasing the oxidized nicotinamide adenine dinucleotide/reduced nicotinamide adenine dinucleotide (NAD⁺/NADH) ratioand adenosine triphosphate (ATP) production, whereas Ndufaf2 exerts an opposing regulatory effect; Co-expression results further revealed an antagonistic relationship between the two during metabolic processes. These findings provide a new perspective for elucidating the mechanisms of mitochondrial functional regulation in Brucella–host interactions and lay the theoretical and experimental foundation for drug development targeting metabolic interventions to eliminate intracellular pathogens. Full article

Background: Tuberculosis (TB) remains a major global health challenge, highlighting the urgent need for more effective vaccines. This study aimed to develop an artificial intelligence-guided epitope prediction and prioritization pipeline to identify immunodominant peptides from Mycobacterium tuberculosis (Mtb) and to evaluate the immunogenicity and protective efficacy of the resulting vaccine candidates. Methods: An AI-guided framework was used to predict and prioritize immunodominant Mtb epitopes, leading to the generation of 72 recombinant immunogens. Among these, RI-13, RI-20, and RI-31 were selected as the leading candidates. Their protective efficacy was assessed in a zebrafish TB infection model and in BALB/c mice following DNA vaccination. Humoral and cellular immune responses were further evaluated in C57BL/6 mice. Results: RI-13, RI-20, and RI-31 markedly reduced infection-associated pathology and lowered bacterial burden by up to 1.5 log₁₀ in the zebrafish TB infection model, outperforming benchmark antigen combinations, including the Ag85A plus ESAT6/CFP10 cocktail used in the phase III vaccine candidate GamTBvac. In BALB/c mice, DNA vaccination with each construct reduced pulmonary mycobacterial burden by approximately 0.3 log₁₀ and alleviated lung tissue damage. In addition, all three candidates elicited robust humoral and cellular immune responses, with RI-13 showing the strongest overall immunogenicity and inducing a balanced Th1, Th2, and Th17 response profile in C57BL/6 mice. Conclusions: These findings identify RI-13, derived from Rv1174c, as a promising next-generation TB vaccine candidate. More broadly, this study supports the utility of an AI-guided framework for the rational design and preclinical prioritization of novel TB immunogens. Full article

Background: Chronic stress is a major risk factor for cognitive decline and blood–brain barrier (BBB) disruption, yet the underlying molecular mechanisms remain elusive. This study aimed to investigate the specific role of the metabolic intermediate homocysteine (Hcy) in chronic stress-induced BBB dysfunction and cognitive impairment. Methods: We utilized a male Sprague-Dawley rat model of chronic unpredictable mild stress (CUMS) and administered vitamin B complex to lower Hcy levels in vivo. Regional Hcy accumulation, BBB permeability, and cognitive behaviors were assessed. In vitro, primary rat brain microvascular endothelial cells (BMECs) were exposed to Hcy to evaluate barrier-forming function, transcriptomic alterations, DNA methylation patterns, Cav1.2 expression, and reactive oxygen species (ROS) production. Results: CUMS selectively induced BBB hyperpermeability and significant Hcy accumulation predominantly within the rat hippocampus, which correlated intimately with cognitive deficits. Lowering Hcy levels via vitamin B supplementation successfully restored hippocampal BBB integrity and alleviated cognitive impairment. In addition, elevated Hcy severely impaired the barrier function of BMECs. Mechanistically, Hcy reduced global DNA methylation in BMECs and specifically induced targeted DNA hypomethylation at the intro region of Cacna1c. This epigenetic shift caused the transcriptional derepression and overexpression of the Cav1.2 calcium channel. Upregulated Cav1.2 subsequently triggered a robust ROS burst, leading to tight junction degradation. Conclusions: Our findings unveil a novel metabolic–epigenetic axis where Hcy-driven Cacna1c hypomethylation directly disrupts BMECs function to dismantle the hippocampal BBB. Lowering Hcy or targeting this Hcy-Cav1.2 pathway establishes a promising therapeutic strategy for mitigating stress-related neurovascular damage and cognitive disorders. Full article

Cadmium (Cd) is a typical heavy metal pollutant in aquatic environments. It enters fish through the gills, digestive tract, and body surface, and accumulates mainly in the liver and kidneys, with species- and tissue-specific distribution. Cadmium triggers apoptosis by inducing oxidative stress, calcium imbalance, and DNA damage. These signals are integrated and amplified by the mitogen-activated protein kinase (MAPK), nuclear factor kappa B (NF-κB), phosphatidylinositol 3-kinase (PI3K)/AKT, and nuclear factor erythroid 2-related factor 2 (Nrf2) pathways, ultimately activating three downstream apoptotic execution pathways: the death receptor, mitochondrial, and endoplasmic reticulum stress pathways. These three pathways form an interactive network through molecular nodes such as BH3 interacting domain death agonist (Bid), Ca²⁺, c-Jun N-terminal kinase (JNK), and C/EBP homologous protein (CHOP), synergistically amplifying the apoptotic effect, with the mitochondrial pathway playing a central role. Cadmium-induced apoptosis is dose-dependent: low concentrations activate protective responses, whereas high concentrations strongly promote apoptosis. Current research gaps remain regarding dynamic pathway crosstalk, chronic low-dose effects, species differences, and fish-specific apoptotic molecules (e.g., caspase-12 homologs). Future studies should focus on constructing multidimensional response maps, clarifying pathway activation thresholds and interaction contributions, and developing composite protective strategies based on Nrf2 activators, metal chelators, and antioxidants, thereby promoting translation into ecological risk assessment and aquaculture pollution control. Full article

Myostatin is associated with inflammatory processes; however, its renal expression and impact on mitochondrial homeostasis during chronic kidney disease (CKD) remain poorly defined. This study investigated whether omega-3 fatty acids (FAs) modulate renal myostatin and mitochondrial integrity under uremic conditions using both in vivo and in vitro models. In rats with adenine-induced CKD, omega-3 FA supplementation attenuated the increase in renal myostatin expression. Uremia was associated with impaired mitochondrial homeostasis, evidenced by decreased peroxisome proliferator-activated receptor gamma coactivator-1 alpha levels and increased dynamin-related protein 1 levels, alongside the upregulation of mitophagy and inflammatory markers. Furthermore, mitochondrial structural damage and reduced mitochondrial DNA (mtDNA) content were observed in uremic kidneys. Omega-3 FA treatment partially reversed these alterations, restored mtDNA levels, and preserved mitochondrial cristae integrity. In vitro, HK-2 cells treated with indoxyl sulfate exhibited increases in myostatin expression and mitochondrial impairment, which were mitigated by eicosapentaenoic acid, docosahexaenoic acid, or their combination. These findings suggest that omega-3 FAs exert protective effects against uremia-induced renal injury by suppressing myostatin and preserving mitochondrial homeostasis, specifically by modulating biogenesis, dynamics, and structural integrity. Consequently, omega-3 FAs may serve as a potential therapeutic strategy with which to preserve mitochondrial homeostasis in patients with CKD. Full article

Saxitoxin (STX), produced by certain harmful algal bloom (HAB) species, bioaccumulates through the food chain and can cause paralytic toxicity in humans, potentially resulting in fatal outcomes. To date, STX detection has primarily been conducted under laboratory-controlled conditions, and the availability of a gold-standard method for the proactive monitoring and prevention of HAB-induced secondary damage remains limited. Therefore, the present study introduces an electrochemical-based biosensor that is capable of early monitoring of STX in HAB-occurred environments. The conserved region of sxtA4, a nucleic acid precursor that is essential for STX biosynthesis, is immobilized on the sensing membrane surface in a sandwich structure. In this process, target detection is recognized as an electrochemical signal by a methylene blue-labeled detection probe, and the reliability of biosensing is supplemented by an electrochemical trend that is opposite to DNA binding. The application of an alternating current electrochemical flow technique achieves more sensitive detection at attomolar levels and rapid measurement within 10 min than a conventional DNA biosensor based on hybridization. In addition, the designed biosensing structure selectively detects STX-synthesizing and non-synthesizing dinoflagellates significantly. The proposed platform can utilize the identification of STX-induced secondary damage of HAB and provide insight into a field-ready biosensor based on its characterization and detection performance. Full article

The valorization of agri-food by-products aligns with circular economy principles and offers sustainable sources of bioactive compounds. This study investigated the peels of the purple-fleshed Solanum tuberosum L. cv. Vitelotte Noire (VN), cultivated in Sardinia, as a potential resource for nutraceutical antioxidants. Extracts were obtained using solvents of different polarities (water, 80% and 96% ethanol) and characterized. Phytochemical screening revealed high concentrations of total phenolics, flavonoids, and anthocyanins, with the 96% ethanolic extract showing superior anthocyanin content. Antioxidant capacity, assessed via ORAC-PYR, TEAC-ABTS, and DPPH assays, was highest in the alcoholic extracts. Furthermore, all extracts showed protective effects in an in vitro model of AAPH-induced oxidative DNA damage, as indicated by the preservation of plasmid supercoiling. Untargeted LC-QTOF-MS analysis detailed a rich metabolomic profile, including organic acids, amino acids, and vitamins. The findings confirm VN peel as a potent, sustainable source of antioxidants, supporting its valorization for developing high-added-value nutraceutical and functional food ingredients, while reducing waste disposal costs and environmental impact. Full article

Manganese (Mn) is an essential trace element crucial for antioxidant defense, metabolism, and neuronal function, yet both deficiency and excess may induce oxidative stress and organ-specific damage. This study investigated the effects of dietary manganese exclusion and replacement of standard MnCO₃ with Mn₂O₃ nanoparticles on redox status and oxidative damage in rats. Twenty-four male Wistar rats were divided into three groups: control (K) receiving 65 mg/kg Mn as MnCO₃, manganese-deficient (B), and nanoparticle-supplemented (N) receiving 65 mg/kg Mn as Mn₂O₃ nanoparticles. After 12 weeks, tissues were analyzed for oxidative stress markers and antioxidant enzyme activities. Manganese deficiency resulted in decreased plasma SOD activity, increased lipid peroxidation, and severe oxidative–nitrosative damage in the brain and jejunum, despite hepatic compensatory mechanisms. Mn₂O₃ nanoparticle supplementation enhanced hepatic and renal antioxidant capacity, reducing oxidative damage in these organs. However, nanoparticles induced pronounced neurotoxicity, characterized by GSH depletion, elevated DNA damage (8-OHdG), protein nitration (3-NT), and caspase activation in brain tissue. These findings demonstrate that while Mn₂O₃ nanoparticles offer improved bioavailability and hepatorenal benefits, they pose significant neurotoxic risks, necessitating caution in dietary supplementation strategies. Full article

Background: Terahertz (THz) waves exhibit both photon-like and electron-like properties, showing emerging potential in biomedical applications. Cutaneous squamous cell carcinoma (CSCC) is one of the most common skin tumors. Studies have reported that THz waves can induce apoptosis in cancer cells or ablate tumor tissues. Our previous studies also confirmed that 0.1 THz radiation could significantly promote apoptosis in cutaneous melanoma cells, while it had no apparent effect on fibroblast viability, proliferation, migration, and apoptosis. However, the effects of 0.1 THz radiation on CSCC cells have not yet been explored. Furthermore, there remains a lack of investigation into the structural and functional effects on fibroblasts. Therefore, it is necessary to conduct a systematic study to evaluate the influence of 0.1 THz radiation on both CSCC cells and fibroblasts in order to better understand its potential therapeutic applications in the treatment of skin cancer. Purpose: This study aims to explore the biological effects of 0.1 THz radiation on SCC-7 cells and to uncover the molecular mechanisms underlying THz-induced apoptosis, as well as its potential effect on L-929 cells. Methods: Cell viability was evaluated through the CCK-8 assay, while cell cycle distribution was analyzed with the DNA content detection kit. Wound healing assays were performed to assess cell migration, and Annexin V-FITC staining was used to detect apoptosis. Caspase-3 activity was measured using the caspase-3 activity assay kit. Cell morphology was observed using the Atomic Force Microscope (AFM) and the Transmission Electron Microscopy (TEM). Alterations in membrane potential were detected with the M09 membrane potential probe kit, and intracellular Ca²⁺ levels were quantified using the Fluo-8 AM fluorescent probe. Mitochondrial permeability transition pore (mPTP) opening was assessed with the MPTP detection kit, mitochondrial membrane potential changes were measured using the JC-1 probe kit, and cellular ATP levels were measured with the enhanced ATP assay kit. Subsequently, proteomic analysis was performed. Intracellular reactive oxygen species (ROS) levels were quantified with the ROS detection kit, and cytochrome c (Cyt c) release was quantified using the mouse Cyt c ELISA kit. Apoptosis-inducing factor (AIF) expression was analyzed at both mRNA and protein levels by quantitative real-time PCR (qPCR) and Western blot. AIF expression in CSCC tissues was further evaluated based on the GSE42677 and GSE45164 databases. Finally, cyclosporin A (CsA) was used to inhibit mPTP, and in combination with the iMAC inhibitor, the Aifm1 expression and Cyt c release were examined. Results: Our results showed that THz waves significantly disrupted the membrane integrity of SCC-7 cells and induced mitochondrial structural and functional damage. This resulted in a significant increase in ROS levels and the activation of mPTP and the mitochondrial apoptosis channel (MAC). THz radiation promoted the release of Cyt c and AIF from mitochondria, triggering a noncanonical caspase-3-dependent apoptosis pathway. Notably, L-929 cells did not show significant phenotypic or apoptotic changes under the same irradiation conditions. Bioinformatics analysis of the Gene Expression Omnibus (GEO) database revealed that AIF expression was significantly altered in CSCC tissues compared to normal skin tissues. Conclusions: These findings indicated that 0.1 THz radiation effectively induced apoptosis in SCC-7 cells by triggering mitochondrial dysfunction and ROS generation, which led to the release of AIF. Furthermore, the dysregulation of AIF in CSCC tissues suggested its potential as a promising biomarker. These results provided important molecular insights into the therapeutic potential of THz radiation, particularly for the treatment of cutaneous squamous cell carcinoma. Full article

As an alternative to perfluorooctane sulfonate (PFOS), 6:2 fluorotelomer sulfonic acid (6:2 FTSA) has been increasingly produced and detected in aquatic environments, yet its toxicological effects in fish remain incompletely characterized. In this study, adult female zebrafish were exposed for 30 days to solvent control (CK), 50 μg/L PFOS (P50), 50 μg/L 6:2 FTSA (F50), and 500 μg/L 6:2 FTSA (F500), respectively. Histopathological analysis revealed that both compounds induced hepatic injury, with the most severe damage observed in the F500 group. Hepatic transcriptomic analysis identified 645, 191, and 85 differentially expressed genes (DEGs) in the P50, F50, and F500 groups versus CK, respectively. Functional enrichment analysis further demonstrated distinct toxic profiles: PFOS at 50 μg/L primarily disrupted pathways related to the cell cycle, DNA replication, and reproduction. In contrast, 50 μg/L 6:2 FTSA predominantly activated PPAR-mediated lipid metabolism pathways, consistent with a “metabolic toxicity” phenotype. Notably, at 500 μg/L, 6:2 FTSA induced the most severe injury accompanied by a distinct transcriptomic signature—characterized by fewer DEGs but a pronounced enrichment of endoplasmic reticulum stress pathways—suggestive of a shift from metabolic perturbation to overwhelming cellular stress. Biochemical analysis confirmed a significant increase in malondialdehyde (MDA) only in the F50 group, supporting oxidative stress-mediated metabolic toxicity. Collectively, these findings demonstrate that 6:2 FTSA is not a safe alternative to PFOS but exhibits a dose-dependent and multifaceted toxicological profile, with high-dose effects indicative of acute cellular stress. This study underscores the need for case-specific, dose-range inclusive risk assessment of emerging PFAS alternatives. Full article

The objective of this study was to compare the protective effects of native and nanostructured quercetin on the initiation of oxidative stress in human keratinocytes exposed to tert-butyl hydroperoxide (tBHP). Quercetin was encapsulated within gelatin-based nanocontainers, forming nanoparticles with diameters ranging from 140 to 180 nm. Two formulations were prepared: uncoated gelatin nanoparticles (NP1) and gelatin nanoparticles coated with a shell composed of dextran sulfate and a chitosan–dextran copolymer (NP2). Cell viability was assessed using PrestoBlue™ reagent. Apoptotic and necrotic cell populations were identified via flow cytometry using an Annexin V-FITC/PI staining kit. DNA damage was evaluated using the comet assay. The results demonstrate that gelatin nanoparticles effectively encapsulate quercetin, and the nanostructured form enables its application in aqueous suspensions without compromising its antioxidant, gene-protective, and cytoprotective effects under conditions of cellular oxidative stress. These findings suggest that gelatin nanoparticles are suitable carriers for quercetin, owing to their high aqueous solubility, which may improve its potential for oral or topical delivery. Full article

There has been an immense concern in the healthcare industry about the globally raising rate of cardiovascular disease (CVD). As per recent WHO reports, CVD is the leading cause of disability, hospitalization and premature death. Studies indicate that oxidative stress negatively impacts the heart and vascular system, which could potentially lead to myocardial infarction, hypertension, cardiomyopathies, atherosclerosis and diabetic heart failure, highlighting its significance as a prognostic indicator in cardiovascular conditions. Nowadays, many common experimental assays are used for in-vitro and in-vivo evaluation of oxidative stress and its negative effects on the cardiovascular system. This review aims to serve as a comprehensive guide for researchers seeking to evaluate the impact of oxidative stress on DNA damage in CVD utilizing standardized methods published by leading institutions. To achieve this, we analyzed 208 relevant articles from prominent databases such as Scopus, PubMed, ScienceDirect, etc., summarizing experimental validation of oxidative stress measurements from 1955 to the present. Oxidative stress-induced DNA damage is a key driver of cardiovascular disease progression, yet experimental approaches to study it remains highly variable. This review systematically summarizes established in-vitro and in-vivo models, oxidative stress inducers, and analytical assays used in cardiovascular research. By integrating mechanistic insights with standardized methodologies, it provides a practical framework to guide model selection, improve reproducibility, and enhance translational relevance. This work serves as a concise reference for researchers investigating redox biology, cardiovascular pathology, and antioxidant-based therapeutic strategies. Full article