Search Results (3,456)

Mitogen-activated protein kinase kinase kinase 1 (MAP3K1) possesses dual enzymatic functions, i.e., kinase and E3 ubiquitin ligase activities, orchestrating proliferation, survival, apoptosis, DNA damage response, and immune modulation. Recent genomic and mechanistic studies have revealed MAP3K1’s paradoxical, context-dependent roles as both an oncogene and a tumor suppressor. We discuss MAP3K1’s multidomain architecture, featuring an N-terminal RING and PHD domain (E3 ligase activity), a TOG domain (microtubule dynamics), and a C-terminal kinase domain, enabling the integration of c-jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (p38 MAPK), extracellular signal-regulated kinase (ERK), and nuclear factor kappa B (NF-κB) signaling pathways. MAP3K1 functions as a molecular switch balancing survival and apoptosis, with caspase-3 cleavage at Asp878 activating pro-apoptotic JNK/p38 signaling. Genomic analyses across >35 cancer types reveal MAP3K1 alterations at frequencies of <1–14%, highest in breast and endometrial cancers. These alterations show tissue specificity: loss-of-function mutations predominate in hormone receptor-positive breast cancer with a favorable prognosis, whereas gain-of-function mutations in melanoma activate oncogenic ERK signaling. MAP3K1 mutations predict response to mitogen-activated protein kinase kinase (MEK) and phosphoinositide 3-kinase (PI3K) inhibitors, with mutant cancers showing higher MEK inhibitor response than wild-type tumors. Despite substantial progress, critical gaps remain regarding MAP3K1’s E3 ligase substrates, context-dependent activity determinants, and therapeutic strategies. Addressing these through inhibitor development, biomarker validation, and mechanistic studies will accelerate potential clinical translation of MAP3K1 biology. Full article

The Qinghai–Tibet Plateau and surrounding mountain regions form one of the world’s most distinctive freshwater environmental gradients. Schizothoracinae are among the most representative endemic fish lineages in these systems and provide a useful model for studying how drainage history, genome evolution, adaptation, and conservation interact. In this review, we synthesize schizothoracine research within an environment–evolution–conservation framework. We examine how drainage history and connectivity shape divergence and gene exchange, how polyploidy and genome remodeling provide the genomic background for adaptive inference, and how phenotypic and population-genomic evidence can be translated into conservation units and management priorities. Across current studies, cold-associated metabolic remodeling and UV-related DNA damage response and repair emerge as the most recurrent molecular themes, whereas hypoxia-related signals are more context-dependent. We further show that morphology, otolith chemistry, age–growth traits, and population structure can strengthen MU/ESU interpretation when integrated with genomic evidence. Future progress will depend on broader chromosome-level genome coverage, more systematic comparison of structural genomic variation, standardized stressor-linked designs, and denser sampling in geomorphic transition zones and putative hybrid regions. Full article

(1) Background: The search for new polymodal antioxidants to correct oxidative stress of various origins and its consequences remains one of the most pressing and rapidly developing areas of biomedical research. (2) Methods: Hydrogen peroxide and hydroxyl radical detection, induced luminescence assay, ELISA for 8-oxoguanine detection, animal survival, blood cell count, micronucleus test, and PCR were used. (3) Results: 2R,3R-trans-dihydroquercetin (DHQ) was shown to reduce the amount of hydrogen peroxide and hydroxyl radicals formed during water radiolysis, leading to reduced damage to biomolecules. DHQ is a radioprotector, most effective at a dose of 300 mg/kg administered 15 min before radiation exposure. The dose reduction factor is 1.22. DHQ administration reduces the severity of radiation-induced leukopenia and thrombopenia by protecting red bone marrow cells. The mechanism of DHQ’s radioprotective action is fundamentally different from that of classical stress response inducers and is based on the normalization of the target cell transcriptional profile, rather than its hyperstimulation. (4) Conclusions: DHQ’s ability to restore the expression of antioxidant defense, DNA repair, and apoptotic genes to physiological levels under radiation exposure allows it to be considered a promising pharmacological agent for the correction of radiation-induced damage to normal tissues. Full article

Genotoxic stress, which includes DNA damage and the mis-localization of DNA and RNA, is a defining feature of tauopathies, Alzheimer’s disease, and several other neurodegenerative disorders. Recent findings indicate that activation of the innate immune system in response to genotoxic stress can drive harmful neuroinflammation, compromise neuronal integrity, and promote neurodegeneration. Multiple innate immune sensors of genotoxic stress have recently been discovered, but the contributions of many of these emerging nucleic acid–sensing pathways in neurodegenerative disease pathogenesis remain largely unexplored. Z-DNA binding protein 1 (ZBP1) is one such recently discovered genotoxic stress sensor that has been shown to incite various forms of cell death as well as proinflammatory cytokine production in response to left-handed Z conformations of DNA (Z-DNA) and RNA (Z-RNA). Here, we show that ZBP1 deletion provides protection against tau pathology and neuronal loss in the PS19 mouse model of tauopathy. Moreover, we find that this rescue of tauopathy seen with ZBP1 ablation is associated with dampened activation of microglia and astrocytes. These findings identify ZBP1 as a pivotal genotoxic stress sensor that drives tau pathology, gliosis, and neuronal loss in tauopathy. This work further suggests that targeting ZBP1 may offer a therapeutic strategy to treat tau-mediated neurodegenerative disease. Full article

Radiation-responsive promoters represent a functionally distinct class of transcriptional regulatory elements that translate genotoxic stress signals into quantifiable gene expression outputs. These promoters occupy a unique mechanistic position within the broader radiation biomarker landscape: rather than directly measuring molecular damage products, they report the cellular interpretation of radiation-induced stress through coordinated gene regulatory networks. This review provides a systematic analysis of five major classes of radiation-responsive promoters—microRNA (miRNA) promoters, tRNA-derived small RNA (tsRNA) promoters, acute-phase protein gene promoters, DNA repair gene promoters, and long non-coding RNA (lncRNA) promoters—with emphasis on their regulatory logic, dose-response characteristics, and current evidence for clinical deployment. We further describe four complementary screening strategies: homology-based conservation analysis, functional genomics and transcriptomics, epigenetic modification profiling, and synthetic biology promoter engineering. Applications spanning biosensor development, biological dosimetry, treatment response prediction, and radiation-guided gene therapy are evaluated within a two-track framework that distinguishes biomarker-oriented applications (Track A) from tool-oriented reporter gene systems (Track B). Critical appraisal of current limitations—including insufficient clinical-grade validation, absence of standardized dose-response curves, and reproducibility deficits—is integrated throughout. Future priorities include multi-center prospective validation studies, FAIR-compliant data infrastructure, AI-driven multi-omics integration, and point-of-care detection platforms. Radiation-responsive promoter biology holds significant potential for advancing precision radiotherapy and nuclear emergency medical response, contingent upon systematic closure of the current evidence gap relative to established gold-standard cytogenetic methods. Full article

Poly(ADP-ribose) polymerase inhibitors (PARPi) have reshaped therapy for advanced prostate cancer, yet durable benefit remains concentrated in BRCA1/2-altered tumors, especially BRCA2, and most responders eventually relapse. Here, we frame PARPi response and resistance through a unifying model in which DNA damage response (DDR) rewiring (e.g., homologous recombination repair (HRR) restoration, fork protection, checkpoint tolerance, and altered drug handling) converges with treatment-induced dormancy and quiescent therapy-tolerant residual states that sustain minimal residual disease (MRD) under androgen receptor pathway inhibition (ARPI) and PARP blockade. We synthesize clinical and translational evidence for PARPi monotherapy and PARPi-based combinations across disease states. In first-line metastatic castration-resistant prostate cancer (mCRPC), PARPi plus ARPI consistently prolongs radiographic progression-free survival, with the greatest benefit in HRR-altered tumors, and emerging overall-survival signals in selected subgroups. In later-line settings, monotherapy activity is most robust in BRCA2-mutated disease, whereas non-BRCA HRR alterations show heterogeneous and often modest responses, underscoring the need for biomarkers beyond gene panels. We also discuss combination strategies with DDR-targeting agents, radioligand therapies, and immunotherapy, and summarize ongoing phase III programs in metastatic castration-sensitive prostate cancer (mCSPC). Finally, we outline practical considerations for biomarker-informed patient selection, monitoring, sequencing, and toxicity management, with particular emphasis on intercepting MRD and resistance evolution. Full article

The tumor suppressor protein p53, encoded by the TP53 gene, is known as the “Guardian of the Genome”, and alterations in TP53 are common to more than 50% of human cancers. p53 is a critical regulator of cellular responses to several stress conditions, such as DNA damage, oncogene activation, and nutrient starvation. p53 was traditionally described as a single transcription factor; however, now it is recognized as a complex family of isoforms generated through alternative promoter usage, alternative splicing, and alternative initiation of translation. These processes give rise to at least 12 distinct p53 isoforms in humans, including p53α (the canonical full-length isoform), p53β, p53γ, Δ40p53, Δ133p53, and Δ160p53, each with unique structural and functional properties. p53 isoforms differ in the presence or absence of specific and fundamental domains located both at N- and C-terminal ends, determining an altered DNA-binding potential, transcriptional activity, and protein–protein interactions. For instance, Δ133p53 isoforms lack part of the N-terminal domains and can exert dominant-negative effects over full-length p53α or modulate alternative transcriptional programs. Similarly, p53β and p53γ isoforms, which have a unique C-termini, influence cellular senescence. The expression patterns of p53 isoforms are tissue-specific and dynamically regulated under both physiological as well as pathological conditions. Alterations of isoform balance have been involved in tumor progression, metastasis, and therapy resistance. Importantly, specific isoforms can either enhance or limit canonical p53 tumor suppressor functions, thereby contributing to the functional diversity of the p53 network. Overall, the p53 isoform landscape adds a critical layer of complexity to p53 biology. In this review, we summarize the mechanisms underlying the production of p53 isoforms, their functions, and their expression in cancer, with the idea that a better understanding of the differential regulation and functional interplay of p53 isoforms may provide novel biomarkers and therapeutic targets in cancer. Full article

Short-wavelength ultraviolet radiation can impair biological systems by causing DNA damage, oxidative stress, and disruption of photosynthetic processes. Although ultraviolet C (UVC) at 254 nm is widely used as a controlled laboratory stressor, the extent to which trophic condition influences repeated UVC tolerance in phototrophic protists remains unclear. Here, we examined the response of Euglena gracilis grown under photoautotrophic or ethanol-supported mixotrophic conditions and exposed to daily UVC pulses for five days. Cell growth, photosynthetic pigments, intracellular oxidative stress measured by 2′,7′ dichlorodihydrofluorescein diacetate fluorescence, and lipid peroxidation estimated as thiobarbituric acid reactive substances equivalent malondialdehyde were assessed, together with qualitative fluorescence microscopy. Repeated UVC exposure reduced cell density in both trophic conditions, with stronger inhibition under photoautotrophy. Photoautotrophic UVC-treated cultures showed the highest oxidative stress signal, whereas malondialdehyde displayed only a non-significant directional increase. Mixotrophic cultures maintained higher cell density under UVC and showed lower oxidative stress signals than photoautotrophic UVC-treated cultures. Pigment responses also differed between trophic conditions, with increased chlorophyll a and carotenoids per cell under photoautotrophic UVC treatment, while mixotrophic pigment levels remained comparatively stable. These findings show that trophic condition shapes repeated UVC stress responses in E. gracilis and that ethanol-supported mixotrophy is associated with improved physiological robustness under the present experimental conditions. Full article

Background/Objectives: Early embryonic arrest during the cleavage stage (days 2–4) accounts for a substantial proportion of developmental failure in in vitro fertilization. This phenomenon remains poorly understood at the molecular level, even in chromosomally normal embryos identified by preimplantation genetic testing. This review aims to redefine cleavage-stage arrest from a passive energy deficit to a checkpoint-regulated endpoint caused by inadequate coordination among metabolism, transcriptome integrity, and stress-response pathways. Methods: We integrate evidence from long-read transcriptomics, metabolomics, epigenetics, and immunobiology relevant to pre-blastocyst development. These data are assembled into a unifying mechanistic framework and a clinically oriented stratification model, together with candidate multimodal readouts for early classification. Results: We propose a three-axis model linking: (i) metabolic–epigenetic insufficiency, including defective histone lactylation and impaired alpha-ketoglutarate-dependent DNA demethylation; (ii) isoform-level abnormalities, including intron retention and retrotransposon activation within a hidden transcriptomic landscape better resolved by long-read sequencing; and (iii) stress-related immune signaling, in which NLRP7 links alternative splicing and DNA-damage-response dysfunction with mitochondrial stress and p53-associated arrest. Within this framework, we distinguish three molecular arrest states: an early transition failure marked by defective maternal-to-embryonic reprogramming and severe splicing disruption; a metabolically quiescent state that may retain a limited rescue window; and a later stress-associated state characterized by senescence-like features, oxidative stress, and broad transcriptomic and genomic instability. Conclusions: Early embryo arrest should no longer be viewed as a nonspecific developmental failure, but as a mechanistically stratifiable condition with distinct metabolic, transcriptomic, and stress-associated trajectories. A diagnostic platform combining fluorescence lifetime imaging microscopy, long-read sequencing, and digital polymerase chain reaction may improve early mechanistic classification, help identify embryos with possible reversibility, and reduce uncertainty in embryo selection during in vitro fertilization. Full article

All living organisms possess a DNA damage response (DDR) that is important for genetic evolution. Cells have developed comprehensive mechanisms for addressing DNA damage, collectively called the DNA damage response and repair. External environmental stress continuously disrupts genomic integrity and triggers various pathological changes. The failure of the DDR network often drives cell carcinogenesis, and its core components not only serve as biological markers for disease monitoring but also represent highly promising molecular targets for targeted therapy. Therefore, there is a high level of interest in exploring DDR-related biomarkers as cutting-edge therapeutic regimens and developing highly sensitive tools for DDR diagnosis. These methods should assess the rate of damage occurrence and distinguish when repair pathways are activated. These kinds of advances are key to preserving genetic stability and detecting and preventing diseases early. Here, we provide a broad summary of recent advances in DDR detection technologies, with a particular focus on the complementarity between different techniques. We have also summarized current technological bottlenecks, future research paradigms, and clinical translation pathways. The insights presented in this review will contribute to the development of multidisciplinary integrated DDR detection technologies, promote the establishment of DDR biomarker detection systems, and provide crucial methodological references for targeted drug development, efficacy evaluation, and resistance mechanism research targeting the DDR pathway. Full article

Alzheimer’s disease (AD) and cancer are both age-related conditions, yet numerous large-scale epidemiological studies have consistently documented an inverse association, with individuals diagnosed with cancer exhibiting a reduced risk of AD and vice versa. Although this relationship has been replicated across diverse populations, its biological basis remains poorly understood. To address this gap, the present study applies a framework that integrates locus-level genetic correlation (rg) with genetically regulated gene expression to clarify the molecular factors contributing to the inverse epidemiological patterns observed between the two diseases. We used the largest available genome-wide association studies (GWAS) (Nmax = 448,150) to quantify local genetic correlations between AD and several age-associated cancers, including breast, prostate, lung, colorectal, melanoma, basal cell carcinoma, bladder, and endometrial cancer. Eight genomic regions showed significant negative local rg, at the 19q13.31–19q13.32 locus demonstrating strong negative correlations across multiple cancers, including breast, prostate, lung, melanoma, and endometrial cancer. To evaluate the contribution of genetically regulated gene expression, we conducted transcriptome-wide association studies (TWAS) using precomputed gene expression weights from cancer tissues (The Cancer Genome Atlas-TCGA), disease-agnostic tissues (Genotype-Tissue Expression-GTEx), and brain tissue (dorsolateral prefrontal cortex-DLPFC). For each AD–cancer pair, we prioritized genes that were nominally significant in both traits (p < 0.05) and exhibited inverse TWAS Z scores. This analysis identified 24 genes with opposite effect directions between AD and at least three cancer types. TWAS signals also aligned with local rg findings at the 19q13.31–19q13.32 region, suggesting that regulatory variation near this locus contributes to shared but opposing genetic effects beyond the canonical APOE signal. Across cancer types, genes inversely associated with AD converged on pathways involved in cell cycle regulation, apoptosis, DNA-damage response, and metabolic processes. These results support the hypothesis that biological mechanisms promoting proliferation and survival in cancer may oppose those contributing to neurodegeneration in AD. Full article

Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus (SLE), characterized by immune system disorders and multiple organ damage. Current clinical treatment of LN requires a complex multi-drug combination, which is often associated with severe side effects and low patient compliance. The aim of this study was to design a self-nanoemulsifying drug delivery system (SNEDDS) co-loading total glucosides of Paeonia (TGP) and dihydroartemisinin (DHA) to increase the solubility of the drug as well as achieve synergistic anti-inflammatory and immunomodulatory effects for LN therapy. Network pharmacology, molecular docking and molecular dynamics simulations were employed to predict the core therapeutic targets and related signaling pathways. The SNEDDS co-loaded with TGP and DHA was optimized via central composite design response surface methodology (CCD-RSM). Its physicochemical properties, particle size and the polydispersity index (PDI) of the optimized formulation were characterized. In vivo therapeutic efficacy was evaluated in MRL/lpr mice by measuring disease-related indicators (urinary protein, serum ANA, and anti-ds-DNA) and inflammatory cytokines (TNF-α, IL-6, and IL-1β). Renal tissue pathology was also examined. All data were analyzed by one-way analysis of variance (ANOVA) with p < 0.05 considered statistically significant. The core therapeutic targets predicted with high relevance were AKT1, MAPK1, MAPK3, and RELA. The optimized SNEDDS achieved a high loading capacity of 16.11 ± 0.43 mg/g for TGP and 12.79 ± 1.33 mg/g for DHA, with a particle size of (25.84 ± 0.30) nm and PDI of (0.07 ± 0.02). In MRL/lpr mice, SNEDDS treatment significantly reduced urinary protein levels (p < 0.01), serum ANA (p < 0.01) and anti-ds-DNA titers (p < 0.01) compared with the model group. Additionally, the levels of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β) were markedly decreased (p < 0.05), and renal tissue damage was alleviated. Conclusions: The SNEDDS co-loaded TGP and DHA is a promising oral nanotherapeutic strategy for LN, offering synergistic anti-inflammatory and immunomodulatory effects. Full article

Yeasts play a vital role in food fermentation processes, where their viability, stress tolerance, and metabolic performance directly influence product quality and process efficiency. Controlling and modulating yeast behavior represents a challenge in the food industry, particularly in non-thermal processing contexts. Ultraviolet (UV) technology has traditionally been applied as a microbial control tool; however, yeast response mechanisms to UV irradiation extend beyond simple inactivation. Depending on wavelength, dose, and treatment conditions, UV exposure can lead to complete inactivation, partial reduction in viability, or induce stable phenotypic changes associated with cellular stress responses and Deoxyribonucleic Acid (DNA) damage processing. This review examines current knowledge on yeast–UV interactions across different food matrices, highlighting how UV treatments influence yeast physiology and functionality. In addition, recent studies suggest that UV-induced genetic alterations, when properly controlled, may contribute to yeast diversification and functional modulation without the use of genetically modified organisms. The review discusses technological opportunities, practical limitations, and future research needs, emphasizing the dual role of UV technology as a tool for yeast control and as a potential driver of functional modulation. Full article

Hypoxia-inducible factor (HIF) is recognized as a key transcription factor via regulating a variety of molecular responses to hypoxia, although the details are still unclear. In this study, based on bioinformatics analysis, the expression of the HIF-1α gene in T. castaneum (TcHIF-1α) under hypoxic treatments was determined. After TcHIF-1α knockdown by injecting dsRNA, larval mortality, the expression levels of oxidative stress-related genes, and enzymatic activities were measured; DNA damage was also evaluated through single cell gel electrophoresis. The result indicated that TcHIF-1α is highly conserved in structure. TcHIF-1α exhibited distinct temporal patterns, with a peak after 72 h of exposure to 2% O₂. Following TcHIF-1α knockdown, a significant increase in larval mortality (17.44 ± 5.91%) and moderate DNA damage level was found. This might be accompanied by ROS accumulation, lipid peroxidation (LPO), and suppression of antioxidant enzymatic activities. The expression of genes involved in ROS synthesis (e.g., NOX) was significantly upregulated, whereas genes responsible for mitigating oxidative stress (e.g., OGG1, XRCC1, PARP1, SOD1a) were markedly downregulated. These findings elucidate the critical role of HIF-1α in insect hypoxia adaptation by regulating the antioxidative stress, highlighting its potential as a promising target for developing novel pest control strategies. Full article

Background: The combination of conventional drugs and inhibitors of signaling molecules is an effective strategy to increase cancer treatment efficacy and reduce drug doses to protect against their cytotoxic effects. Our research has shown the cisplatin concentration-dependent shift in the role of MAP kinase JNK from antiapoptotic to proapoptotic in non-small cell lung cancer A549 cells. Cell death/survival signaling molecules, tumor suppressor p53 and pro-survival protein kinase AKT were detected to be differently regulated by JNK inhibition at low vs. high cisplatin concentrations. Here, we further investigated the phenomenon and potential mechanisms of combined JNK inhibition and cisplatin treatment. Methods: Cell death in vitro was evaluated by MTT and Western blot assays after combined cisplatin and specific inhibitor treatment; two-way ANOVA was used for analysis. Results: JNK is differently involved in determining cellular sensitivity to different DNA-damaging drugs. There is no universal cell death induction mechanism originating from DNA damage through the involvement of JNK. The outcome of JNK inhibition also depends on the cell type. We found that there is an unusual reciprocal interaction between p53 and AKT in cisplatin-treated A549 cells, where p53 inhibits AKT, while AKT activates p53. In the case of cisplatin + JNK inhibitor SP600125, DNA damage and reactive oxygen species (ROS) contribute to cell death regulation in different ways. ROS exert opposite roles on cell fate-determining molecules p53 and AKT, and ROS act on p53 and AKT in opposite directions at low vs. high concentrations of cisplatin, combined or not with JNK inhibition. The differentially activated p53 in response to ROS (at low versus high concentrations of cisplatin, combined with JNK inhibitor) may be a molecular switch in the role of JNK from antiapoptotic to neutral/proapoptotic, and an executor of cell death. ROS is a possible threshold regulator that, together with an as-yet-unidentified factor, can differentially regulate p53. As a result, AKT phosphorylation and function are altered. The findings emphasize the importance of assessing the role of drug concentration when combining them with JNK inhibition when monitoring therapeutic efficacy and toxicity issues in personalized cancer treatment. Full article