Search Results (7,129)

Neurotropic viruses have evolved sophisticated mechanisms to evade host immune responses within the central nervous system (CNS), enabling viral replication, persistence, latency, and neuropathogenesis while minimizing irreversible neuronal damage. Unlike peripheral tissues, the CNS requires tightly regulated antiviral immunity to balance effective pathogen control with the preservation of neural function. This review examines the diverse yet convergent immune evasion strategies employed by major neurotropic RNA and DNA viruses, including herpes simplex virus (HSV), varicella-zoster virus (VZV), cytomegalovirus (CMV), rabies virus (RABV), flaviviruses, alphaviruses, enteroviruses, and JC virus (JCV). We discuss viral interference with innate immune sensing pathways, including RIG-I-like receptors (RLRs) and cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS–STING) signaling, inhibition of type I interferon induction and Janus kinase–signal transducer and activator of transcription (JAK–STAT) signaling, modulation of interferon-stimulated effector mechanisms, and disruption of antigen presentation and adaptive immune surveillance. The review further highlights the distinct roles of viral latency, long-term persistence, neuronal–glial interactions, and metabolic reprogramming in facilitating prolonged infection within the CNS. Emerging evidence indicates that successful neurotropic viruses rarely achieve immune evasion through complete suppression of host defenses; instead, they fine-tune antiviral responses to preserve host cell viability while preventing viral clearance. Finally, we discuss current knowledge gaps and emphasize the need for advanced human-relevant models, single-cell and spatial multi-omics, and systems-level approaches to better define virus–host interactions within the CNS. A deeper understanding of these integrated immune evasion networks may reveal novel therapeutic strategies that enhance antiviral immunity while limiting neuroinflammation and preserving neurological function. Full article

Sacred lotus (Nelumbo nucifera) is an important aquatic crop whose growth and productivity are severely constrained by environmental stresses. Salicylic Acid (SA), Jasmonic Acid (JA), and Abscisic Acid (ABA) are key plant growth regulators (PGRs) involved in stress responses, but their regulatory mechanisms in lotus remain unclear. In this study, transcriptome sequencing was performed in lotus seedlings treated with exogenous SA, JA, and ABA to characterize hormone-responsive regulatory networks. SA predominantly resulted in transcriptional repression, with responsive genes mainly associated with photosynthesis and ribosome-related pathways, whereas JA and ABA showed similar regulatory patterns with enrichment of hormone signaling and Mitogen-activated protein kinase (MAPK) pathways, but distinct roles in defense regulation and stress adaptation. A total of 607 genes were identified as commonly responsive to the three PGRs and were significantly enriched in cold response, defense response, secondary metabolism, and photosynthesis-related pathways. Protein–protein interaction analysis identified two hub genes encoding light-harvesting chlorophyll a/b-binding proteins, suggesting that the photosynthesis–antenna proteins pathway may represent a convergent regulatory node in hormone-mediated stress responses. This study provides new insights into SA-, JA-, and ABA-mediated stress responses and identifies potential candidate genes for improving stress tolerance in lotus. Full article

Background/Objective: Prediabetes is increasingly recognized as a state of chronic, low-grade inflammation that contributes to early β-cell dysfunction, insulin resistance, and progression to type 2 diabetes (T2D). This review synthesizes mechanistic and clinical evidence to characterize the inflammatory landscape of prediabetes, evaluate the consistency of candidate biomarkers, and assess potential for clinical translation. Methods: We conducted a structured narrative review and assessed 22 studies investigating inflammatory and metabolic biomarkers for prediabetes across experimental animal models, human pancreatic islets, and clinical cohorts. Biomarkers included cytokines, oxidative stress indicators, microRNAs, and immune-cell-associated factors. Studies included cross-sectional, longitudinal, and mechanistic designs. Results: Clinical studies generally reported higher CRP and hsCRP. In several cohorts, IL-6 and other inflammatory mediators were increased in individuals with prediabetes. However, inflammatory responses were not uniform across studies. One study reported elevated IL-10 and IL-4 in addition to hsCRP, while TNF-α and IL-6 were not significantly different. Overall, CRP and hsCRP demonstrated the strongest clinical translational evidence, with findings replicated across multiple cohorts and longitudinal evidence linking higher baseline hsCRP or CRP with increased risk of progression to T2D. Other candidates, including IL-6, TNF-α, adiponectin, SFRP4, oxidative stress markers, and microRNAs, remain promising but have more limited or inconsistent evidence for clinical application. Conclusions: Prediabetes is characterized by a multifaceted inflammatory response involving innate and adaptive immune pathways, altered cytokine and microRNA profiles, oxidative stress, and adipose–pancreatic interactions. Although inflammatory biomarkers may enhance conventional metabolic measures for risk stratification, current evidence does not establish any inflammatory marker as a standalone diagnostic test for prediabetes. Full article

Type 1 diabetes mellitus (T1DM) is increasingly recognized as a condition in which psychological processes play an important role in disease management, adaptation, and clinical outcomes. Although research has identified a growing number of relevant psychological constructs, these have largely been investigated independently, limiting understanding of their interactions with behavioral and biological processes. This contribution discusses the principal conceptual gaps that currently constrain theoretical integration and proposes an integrative psychobiological framework in which individual and contextual factors, psychological processes, self-management behaviors, and biological and metabolic dimensions are conceptualized as components of a dynamic and temporally embedded system. The framework emphasizes potentially mediated, moderated, and reciprocal pathways whose relative contribution may vary across individuals, life stages, and the disease trajectory. By providing a structure through which these processes can be jointly operationalized and empirically investigated, this perspective may support more coherent research strategies and help identify individual and evolving assessment and intervention priorities in diabetes care. Full article

Background: Pregnancy involves coordinated immunological adaptations that maintain maternal–fetal tolerance while preserving protection against infections. There is growing evidence that vaginal microbiota-associated metabolites contribute to immune balance, yet their molecular mechanisms remain incompletely understood. Methods: This study used an in silico approach combining absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling, molecular docking, and structural interaction analysis. Eight compounds—five organic acids, two bacteriocins, and hydrogen peroxide—were evaluated against eight immune and inflammatory protein targets relevant to pregnancy. Results: The ADMET predictions revealed favorable pharmacokinetic and safety profiles for small organic acids, particularly butyric and propionic acids. Enterocin-HF yielded the most favorable predicted binding energies across the evaluated targets, particularly TNF-α and NF-κB. Redocking of the COX-2 co-crystallized ligand reproduced the experimental binding pose with an RMSD of 1.21 Å, supporting the ability of the protocol to recover the crystallographic binding mode. Conclusions: Overall, these findings prioritize Enterocin-HF and selected organic acids for subsequent experimental evaluation. However, the predicted interactions should not be interpreted as evidence of functional immunomodulation or therapeutic efficacy. Full article

Glioblastoma is the most aggressive primary tumor of the central nervous system, characterized by high invasiveness, rapid progression, and a poor prognosis despite the current treatment modalities. Molecular stratification, using biomarkers such as IDH1, TERT, and MGMT, is a crucial step in the 2021 WHO classification for improving diagnosis and prognosis. Oxidative stress, a feature of GB, has been identified as an important factor in the initiation, progression, and resistance to treatment. It occurs due to an imbalance between reactive oxygen species generated by mitochondrial metabolism, NADPH oxidases, and exogenous sources such as ionizing radiation and xenobiotics and antioxidant defense. This imbalance leads to DNA damage, genomic instability, and deregulation of signaling pathways involved in cell proliferation, apoptosis, and tumor progression. This review provides an overview of key oxidative stress biomarkers and their dual roles in tumor suppression and progression. It highlights how oxidative stress contributes to treatment responses and resistance to current GB treatments, including redox-adaptive mechanisms such as the Nrf2–Keap1 pathway, which promotes radioresistance. Finally, it discusses the potential of understanding these mechanisms to develop therapeutic strategies that target redox balance and homeostasis, aiming to overcome resistance and improve survival outcomes for glioblastoma patients. Full article

3-Nitropropionic acid (3-NPA) is an irreversible inhibitor of succinate dehydrogenase (SDH; mitochondrial complex II) that is widely used to model mitochondrial metabolic stress. Direct reproductive studies now show that 3-NPA can increase ovarian oxidative stress, granulosa-cell apoptosis, follicular atresia, alter ovarian reserve, impair oocyte maturation, and reduce fertility in experimental models. However, no ovarian study has yet demonstrated the complete succinate–HIF-1α–NLRP3 cascade proposed here. We therefore propose a testable framework in which SDH inhibition causes succinate accumulation and impaired respiratory electron flux, while redox stress provides an additional signal for HIF-1α stabilization and NLRP3 activation. Succinate-mediated inhibition of prolyl hydroxylases provides a mechanistic route to HIF-1α stabilization under normoxic or near-normoxic conditions, whereas NLRP3 activation may integrate mitochondrial danger signals with inflammatory signaling. Importantly, HIF-1α is not intrinsically pathogenic in the ovary: physiological HIF-1α signaling supports angiogenesis, ovulation, granulosa-cell survival, autophagy, and luteal remodeling, whereas persistent or excessive activation may become maladaptive. We further refine the proposed metabolic–inflammatory threshold as a measurable state in which combined succinate/redox burden and inflammasome activation exceed the adaptive capacity of a follicular unit. The model predicts that time-resolved measurements of succinate, SDH activity, HIF-1α stabilization, NLRP3 activation, and follicular outcomes should reveal ordered relationships that can be tested by pharmacological and genetic intervention. This review distinguishes direct ovarian evidence from cross-system mechanistic evidence and identifies the experiments required to establish causality. Full article

Background and Objectives: The main neurodegenerative diseases (NDs)—Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS)—represent a growing global health burden with no available disease-modifying therapies. Curcumin, a polyphenol from Curcuma longa, is a promising candidate owing to its pleiotropic antioxidant, anti-inflammatory, and neuroprotective profile observed mainly in preclinical models, but the poor oral bioavailability (<1%) and negligible BBB penetration (<0.1%) have substantially limited curcumin’s clinical translation. The objective of this work was to critically examine the therapeutic potential of curcumin in NDs, focusing on advanced drug delivery systems (DDSs) designed to overcome its pharmacokinetic barriers. Methods: This is a narrative, non-systematic review of PubMed/MEDLINE, Scopus, and Web of Science. The review is organized around five complementary thematic areas selected to span the full translational pipeline of curcumin in neurodegeneration, from mechanistic rationale to clinical applicability: (1) molecular mechanisms, addressing the pleiotropic activities that justify therapeutic interest; (2) pharmacokinetic barriers, the principal obstacle to clinical translation; (3) the evolution of drug delivery systems (DDSs), documenting the technological strategies developed to overcome these barriers; (4) disease-specific applications, evaluating the available evidence across the four main NDs; and (5) translational limitations, identifying the methodological and regulatory gaps that must be closed to enable clinical implementation. Results: Curcumin exhibits neuroprotective activity in preclinical models of the four NDs analysed, acting on six interconnected mechanisms and the gut–brain axis. Four generations of DDSs have been developed, from phytosomes and clinically used lipid dispersions (Meriva^®, BCM-95^®, Longvida^®, and Theracurmin^®) to fourth-generation systems (biomimetic nanoparticles, MOFs, microneedles, 3D scaffolds, hydrogels, and carbon dots) that substantially increase the bioavailability in preclinical studies. Combination strategies, such as curcumin with resveratrol and dutasteride, show preliminary clinical signals in ALS. However, clinical translation remains limited: over 80% of positive animal findings have not been replicated in humans, formulation characterization is frequently incomplete, and most trials lack CNS-exposure biomarkers. Importantly, most of the reported bioavailability claims are based on total curcumin measurements (parent aglycone plus its inactive Phase II conjugates) rather than the active aglycone alone, a methodological limitation that should be considered when interpreting the magnitude of the bioavailability improvements reported for novel formulations. Conclusions: Curcumin exhibits pleiotropic neuroprotective activity in preclinical models of AD, PD, MS, and ALS, mediated by interconnected antioxidant, anti-inflammatory, anti-amyloidogenic, mitochondrial, and gut–brain axis mechanisms. However, its poor systemic bioavailability (<1%), minimal blood–brain barrier penetration, and extensive first-pass metabolism have limited clinical translation. Advanced drug delivery systems (including lipid-based carriers (liposomes, solid lipid nanoparticles, and nanostructured lipid carriers), polymeric nanoparticles (PLGA and chitosan), and bioinspired vesicles (exosomes)) are essential in order to overcome these barriers. Nevertheless, the formulation heterogeneity, limited long-term safety data, and reliance on preclinical models remain major obstacles; a definitive clinical translation will therefore require well-characterized formulations validated in phase II/III trials with cerebrospinal fluid exposure biomarkers, the pharmacokinetic monitoring of active aglycone (rather than total curcumin including inactive conjugates), and adaptive trial designs in neurological populations. Full article

Circadian rhythms regulate hepatic metabolism and physiological homeostasis, which are essential for organisms to adapt to environmental cycles. Bats are the only mammals capable of sustained powered flight, accompanied by extreme metabolic demands and a nocturnal lifestyle. However, the regulatory mechanisms underlying hepatic circadian rhythms in bats remain poorly understood. Herein, we employed data-independent acquisition (DIA)-based quantitative proteomics to characterize the diurnal dynamics of hepatic proteins in Vespertilio sinensis across four representative physiological states, and further conducted integrative multi-omics analysis combined with transcriptomic data. The results revealed that approximately 5% of hepatic proteins exhibited circadian rhythmicity in V. sinensis, a proportion markedly higher than that of rhythmic transcripts and metabolites. Prominent transcription-protein rhythm decoupling was observed, implying that post-transcriptional regulatory processes may play critical roles in shaping circadian rhythms. Core metabolic pathways displayed temporally dynamic enrichment. The diurnal functional switching of the liver was achieved via stable expression of core proteins and temporal turnover of specific proteins, which efficiently coordinated energy supply, oxidative defense and detoxification metabolism. Trend clustering and functional enrichment analyses suggested that the liver may undergo lysosome-mediated immune repair during the daytime, while exhibiting enriched energy metabolic profiles that potentially support the elevated energy expenditure required for flight at night. This study systematically elucidates the protein regulatory patterns underlying hepatic diurnal rhythms in V. sinensis, and provides molecular clues for exploring extreme energy adaptation and circadian evolutionary scenarios in nocturnal flying mammals. Full article

Cancer remains a major global health challenge, requiring innovative diagnostic and therapeutic strategies. Cell culture models are essential tools in cancer research. While traditional two-dimensional (2D) cultures are widely used because of their accessibility and simplicity, they inadequately represent the tumor microenvironment. This review provides a molecular perspective on the biological differences between 2D and 3D cancer models, emphasizing extracellular matrix signaling, mechanotransduction, metabolic adaptation, tumor heterogeneity, and therapeutic resistance rather than a general comparison of culture systems. It discusses the limitations of 2D models and highlights the advantages of 3D systems, including spheroids and organoids, for more accurately recapitulating the tumor microenvironment and improving the predictive value of anticancer drug testing. This narrative review synthesizes current evidence on the roles of 2D and 3D cell culture methods in oncology. The literature was searched in PubMed, Google Scholar, and Web of Science from 2015 to 2026 using keywords including “2D cell culture,” “3D cell culture,” “spheroids,” “organoids,” and “cancer.” Studies were eligible for inclusion if they addressed cancer research using 2D or 3D cell culture models and provided relevant experimental, preclinical, or translational evidence, particularly regarding tumor microenvironment, extracellular matrix signaling, cellular interactions, therapeutic response, or molecular mechanisms. Studies unrelated to cancer or 2D/3D culture models, duplicate records, and publications lacking relevant primary data were excluded. Study selection was performed by screening titles and abstracts followed by full-text assessment according to the predefined eligibility criteria. Seminal studies were also included when considered relevant to the conceptual framework of the review. Findings were synthesized narratively without quantitative analysis. 2D cultures limit cell–cell and cell–extracellular matrix interactions, reducing the applicability of findings to in vivo conditions. In contrast, 3D cultures better reproduce oxygen and nutrient gradients and cellular interactions, providing a more realistic representation of the tumor microenvironment. Recent advances in 3D systems have improved predictive accuracy for drug screening and personalized medicine. Both 2D and 3D culture methods possess unique strengths and limitations. Used in complementary ways, they can improve the translation of in vitro findings to in vivo and clinical applications, accelerating progress in cancer research and therapeutic development. Full article

Nutritional therapy is an essential component of comprehensive care for cancer patients, playing a vital role in preventing malnutrition, improving treatment tolerance, and maintaining quality of life. In recent years, there has been growing interest in the ketogenic diet as a potential strategy to support cancer therapy. This diet, based on a significant reduction in carbohydrate intake and an increase in fat intake, leads to a state of ketosis that mimics the metabolic changes that occur during starvation. Consequently, the body utilizes ketone bodies as an alternative source of energy. The potential application of the ketogenic diet in oncology stems from the distinct metabolism of cancer cells, which often exhibit an increased demand for glucose. Although the results of preclinical studies suggest a possible anticancer effect of this dietary intervention, clinical evidence remains limited, and its routine use is not currently recommended as a standard of care in oncology. The aim of this study was to analyze the current literature on the use of the ketogenic diet in oncology, with a particular focus on breast cancer. The study assessed the impact of this intervention on metabolic parameters, body composition, and patients’ mental well-being, and analyzed the potential metabolic risks associated with its use. The study discusses the molecular basis of oncogenesis and metabolic adaptation in cancer cells, the mechanisms of action of the ketogenic diet, and the results of preclinical and clinical studies as well as meta-analyses. Importantly, the current evidence base should be interpreted with caution. Most mechanistic evidence supporting ketogenic diet in breast cancer derives from preclinical models, whereas clinical studies remain limited by small sample sizes, short intervention periods, heterogeneous ketogenic diet protocols, substantial attrition, and differences in concomitant anticancer treatment. Therefore, mechanistic plausibility and promising preclinical findings should not be interpreted as evidence of clinical anticancer efficacy. Full article

Understanding the genomic basis of environmental adaptation is essential for the conservation and genetic improvement of domestic camels. In this study, we investigated the population structure, genetic diversity, and genomic variation potentially associated with environmental adaptation of Kazakh dromedary and Bactrian camels using whole-genome sequencing. Whole-genome sequencing data were generated for Kazakh camels (15 dromedaries and 16 Bactrian camels) and integrated with 131 publicly available genomes representing camel populations from the Arabian Peninsula, Iran, Xinjiang, Inner Mongolia, and Mongolian wild camels. Population structure, genetic diversity, and genome-wide selection were evaluated using principal component analysis, ADMIXTURE, nucleotide diversity, linkage disequilibrium, runs of homozygosity, genomic inbreeding (FROH), and selection scans based on F_ST, θπ ratio, and XP-EHH. Population genomic analyses revealed clear differentiation between dromedary and Bactrian camels, whereas Kazakh camel populations exhibited higher nucleotide diversity (θπ = 1.307–1.551 × 10⁻³), and lower genomic inbreeding (median FROH: 0.037–0.056) than Arabian populations. Genome-wide selection analyses identified MC4R as the prominent candidate gene in Kazakh dromedaries and RYR1 as a prominent candidate gene in Kazakh Bactrian camels. Functional enrichment analyses highlighted pathways related to energy metabolism, thermogenesis, calcium signaling, skeletal muscle function, mitochondrial activity, and oxidative stress response. These findings provide new insights into genomic variation potentially associated with environmental adaptation in Kazakh camels and offer valuable genomic resources for future conservation, breeding, and evolutionary studies. Full article

Ammonia nitrogen represents a critical environmental stressor in aquaculture and exerts adverse impacts on the growth, reproduction and survival of shellfish. In the present study, diploid Pacific oysters (Magallana gigas) were exposed to ammonia nitrogen stress for 0, 6, and 48 h. We combined histopathological examination, antioxidant enzyme measurements, transcriptome profiling, and metabolome profiling to characterize time-dependent hepatopancreatic responses. Tissue injury became progressively more severe with prolonged exposure. Superoxide dismutase activity increased throughout the experiment, whereas catalase and glutathione peroxidase activities and malondialdehyde content showed an increase followed by a decrease, with no statistically significant differences in malondialdehyde content among the three time points. Transcriptome data revealed alterations in genes associated with ATP-binding cassette transporters, lysosomal function, endocytosis, and autophagy. Metabolic alterations were mainly associated with nucleotide, purine, pyrimidine, and sphingolipid metabolism. Cross-omics integration linked these molecular shifts to transmembrane transport, glutathione metabolism, sulfur-containing amino acid metabolism, and amino acid biosynthesis. The consistency between transcriptomic and metabolomic signals further highlights the central roles of transport processes, antioxidant defense, and metabolic adjustment under ammonia nitrogen exposure. These findings indicate that diploid Pacific oysters respond to ammonia nitrogen stress through coordinated regulation of oxidative stress responses, transmembrane transport, intracellular degradation and clearance, and metabolic reorganization. These findings provide insights into the adaptive mechanisms of bivalves exposed to ammonia nitrogen stress. Full article

Background/Objectives: Aflatoxin B1 (AFB1) contamination of maize and peanut is influenced by fungal responses to environmental and food-matrix cues, but the transcriptional coordination of redox adaptation, lipid metabolism, and aflatoxin biosynthesis remains unresolved. This study examined whether an expression-defined redox–lipid state is associated with high relative aflatoxin biosynthetic activity in Aspergillus flavus. Methods: A cross-dataset secondary analysis integrated 18 analytical datasets (247 samples) derived from eight public source records spanning defined-medium, maize, and peanut systems. Harmonized expression profiles were used to derive an aflatoxin biosynthetic activity score (ABAS), oxidative-stress adaptation score (OSAS), and lipid metabolic reprogramming score (LMRS). ABAS is an expression-derived relative score, not a direct measure of biosynthetic flux or accumulated toxin. Dataset-aware mixed-effects models evaluated the OSAS–ABAS association and the linear OSAS × LMRS interaction. Results: ABAS correlated with matched AFB1 measurements in 54 samples (Pearson $r=0.734$, $p=2.70\times {10}^{-10}$). The quadratic OSAS term was negative ($\beta =-0.434$, 95% CI $-0.502$ to $-0.366$; $p<0.001$), with maximum predicted ABAS near 0.81 SD on the pooled within-dataset-standardized OSAS scale. Separately, the linear OSAS × LMRS interaction was positive ($\beta =0.284$, 95% CI 0.198–0.370; $p<0.001$), and the high-OSAS/high-LMRS quadrant had the greatest adjusted mean ABAS (0.789, 95% CI 0.661–0.917). Candidate prioritization recovered established regulators and nominated redox- and lipid-associated nodes. Conclusions: The findings identify an associative transcriptional signature across heterogeneous food-relevant conditions and provide focused hypotheses for prospective validation using direct toxin, redox, lipid, flux, and functional measurements. Full article

Groundcover chrysanthemums exhibit inherently poor low-temperature adaptability, making them highly vulnerable to cold stress and thereby constraining their large-scale regional cultivation. Interspecific hybridization was conducted between diploid Chrysanthemum lavandulifolium (Fisch. ex Trautv.) Makino (pollen donor) and hexaploid cultivar Chrysanthemum × morifolium Ramat., cv. ‘Yannong Qiujin’ (seed parent) to generate cold-tolerant groundcover chrysanthemum germplasm. Comprehensive physiological profiling and integrated multi-omics analyses were performed on both parental plants and their hybrid progeny to identify candidate molecular pathways associated with cold adaptation in ploidy-divergent Chrysanthemum hybrids. Hybrid progeny exhibited significantly lower semi-lethal temperature (LT₅₀), malondialdehyde (MDA) content, and relative electrical conductivity compared with the female parent, indicating heterosis-mediated enhancement of cellular membrane integrity. Integrated transcriptomic and metabolomic profiling identified significant enrichment of glycerophospholipid metabolism in the hybrid progeny. Upregulated expression of glycerol-3-phosphate acyltransferase (GPAT) and lysophosphatidic acid acyltransferase (LPAAT) genes promoted substantial accumulation of lysophosphatidic acid (LPA) and phosphatidic acid (PA). We found that higher expression levels of GPAT and LPAAT were positively associated with increased accumulation of LPA and PA. PA further contributes to phosphatidylcholine (PC) synthesis, potentially improving plasma-membrane permeability and sustaining plasma membrane integrity under chilling stress. Meanwhile, transcript abundance of the inducer of CBF expression (ICE), cold-regulated (COR) genes were markedly elevated. This study identifies candidate molecular pathways underlying cold adaptation in hybrid progeny derived from ploidy-divergent Chrysanthemum, thereby providing a robust theoretical foundation for breeding novel cold-tolerant chrysanthemum cultivars. Full article