Search Results (575)

Although the SARS-CoV-2 pandemic no longer poses a global emergency, the virus continues to diversify and acquire immunoevasive properties. Understanding the molecular pathways that shape SARS-CoV-2 pathogenesis has become essential. In this paper, we summarize the most recent current evidence on how the spike protein structurally evolves, on changes in key non-structural proteins, such as nsp14, and on host factors, such as TMPRSS2 and neuropilin-1. These changes, together, shape viral entry, replication fidelity and interferon antagonism. Given the emerging Omicron variants of SARS-CoV-2, recent articles in the literature, cryo-EM analyses, and artificial intelligence-assisted mutational modeling were analyzed to infer and contextualize mutation-driven mechanisms. It is through these changes that the virus adapts and evolves, such as optimizing angiotensin-converting enzyme binding, modifying antigenic surfaces, and accumulating mutations that affect CD8⁺ T-cell recognition. Multi-omics data studies further support SARS-CoV-2 pathogenesis through convergent evidence linking viral adaptation to host immune and metabolic reprogramming, as occurs in myocarditis, liver injury, and acute kidney injury. By integrating proteomic, transcriptomic, and structural findings, this work presents how the virus persists and dictates disease severity through interferon antagonism (ORF6, ORF9b, and nsp1), adaptive immune evasion, and metabolic rewiring. All these insights underscore the need for next-generation interventions that provide a multidimensional framework for understanding the evolution of SARS-CoV-2 and guiding future antiviral strategies. Full article

Metastasis is still the leading cause of cancer-related death. It happens when disseminated tumor cells (DTCs) successfully navigate a series of steps and adapt to the unique conditions of distant organs. In this review, key molecular and immune mechanisms that shape metastatic spread, long-term survival, and eventual outgrowth are examined, with a focus on how tumor-intrinsic programs interact with extracellular matrix (ECM) remodeling, angiogenesis, and immune regulation. Gene networks that sustain tumor-cell plasticity and invasion are described, including EMT-linked transcription factors such as SNAIL and TWIST, as well as broader transcriptional regulators like SP1. Also, how epigenetic mechanisms, such as EZH2 activity, DNA methylation, chromatin remodeling, and noncoding RNAs, lock in pro-metastatic states and support adaptation under therapeutic pressure. Finally, proteases and matrix-modifying enzymes that physically and biochemically reshape tissues, including MMPs, uPA, cathepsins, LOX/LOXL2, and heparinase, are discussed for their roles in releasing stored growth signals and building permissive niches that enable seeding and colonization. In parallel, immune-evasion strategies that protect circulating and newly seeded tumor cells are discussed, including platelet-mediated shielding, suppressive myeloid populations, checkpoint signaling, and stromal barriers that exclude effector lymphocytes. A major focus is metastatic dormancy, cellular, angiogenic, and immune-mediated, framed as a reversible survival state regulated by stress signaling, adhesion cues, metabolic rewiring, and niche constraints, and as a key determinant of late relapse. Tumor-specific metastatic programs across mesenchymal malignancies (osteosarcoma, chondrosarcoma, and liposarcoma) and selected high-burden cancers (melanoma, hepatocellular carcinoma, glioblastoma, and breast cancer) are highlighted, emphasizing shared principles and divergent organotropisms. Emerging therapeutic strategies that target both the “seed” and the “soil” are also discussed, including immunotherapy combinations, stromal/ECM normalization, chemokine-axis inhibition, epigenetic reprogramming, and liquid-biopsy-enabled minimal residual disease monitoring, to prevent reactivation and improve durable control of metastatic disease. Full article

Declining Leydig cell steroidogenesis contributes to late-onset hypogonadism and to age-associated impairment of male reproductive health. Determinants of dysfunction extend beyond chronological aging. This review synthesizes recent experimental and translational evidence on cellular and molecular processes that compromise Leydig cell endocrine output and the interstitial niche that supports spermatogenesis. Evidence spanning environmental endocrine-disrupting chemicals (EDCs), obesity and metabolic dysfunction, and testicular aging is integrated with emphasis on oxidative stress, endoplasmic reticulum stress, mitochondrial dysregulation, apoptosis, disrupted autophagy and mitophagy, and senescence-associated remodeling. Across model systems, toxicant exposure and metabolic stress converge on impaired organelle quality control and altered redox signaling, with downstream loss of steroidogenic capacity and, in some settings, premature senescence within the Leydig compartment. Aging further reshapes the testicular microenvironment through inflammatory shifts and biomechanical remodeling and may erode stem and progenitor Leydig cell homeostasis, thereby constraining regenerative potential. Single-cell transcriptomic atlases advance the field by resolving Leydig cell heterogeneity, nominating subsets that appear more vulnerable to stress and aging, and mapping age-dependent rewiring of interstitial cell-to-cell communication with Sertoli cells, peritubular myoid cells, vascular cells, and immune cells. Many mechanistic insights derive from rodent in vivo studies and in vitro platforms that include immortalized Leydig cell lines, and validation in human tissue and human clinical cohorts remains uneven. Together, these findings frame mechanistically informed opportunities to preserve endogenous androgen production and fertility through exposure mitigation, metabolic optimization, fertility-preserving endocrine stimulation, and strategies that target inflammation, senescence, and regenerative capacity. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a progressive spectrum of metabolic liver injury in which immune activation, metabolic stress, and stromal remodeling evolve in a tightly interdependent manner. Although early disease stages are dominated by metabolic overload, accumulating evidence indicates that immunometabolic rewiring and fibro-inflammatory amplification critically shape the transition toward metabolic dysfunction-associated steatohepatitis (MASH) and advanced fibrosis. This review synthesizes emerging insights into how hepatocyte stress responses, innate and adaptive immune circuits, and extracellular matrix-producing stromal populations interact to form a dynamic, feed-forward network driving disease progression. Particular emphasis is placed on the deterministic role of immune–fibrotic coupling in shaping clinical phenotypes, disease trajectory, and therapeutic responsiveness. Rather than focusing on individual molecular layers, we highlight how integrated clinical, imaging, and biomarker-informed frameworks can capture immune–fibrotic signatures relevant to risk stratification and precision intervention. Building on this systems-level perspective, we outline next-generation therapeutic strategies targeting immunometabolic circuits, cross-organ communication, and multi-system dysfunction. Finally, we discuss how future precision medicine—supported by integrative biomarker profiling and dynamic physiological assessment—may reshape MASLD management and improve long-term hepatic and cardiometabolic outcomes. Full article

Serotonergic signaling is traditionally conceived as a transient, vesicle-mediated process restricted to the synaptic cleft. Here, we propose an expanded model in which serotonin can also be inserted into the plasma membrane of neurons and glial cells, forming a stable, membrane-associated reservoir that prolongs its availability beyond classical synaptic timescales. In this framework, the synapse emerges not as a simple neurotransmitter–receptor interface but as a dynamic, multiscale medium where membrane order, hydration, and quantum-level processes jointly govern information flow. Two temporal “tunnels” appear to regulate serotonin bioavailability: its aggregation in synaptic vesicles during exocytosis, and its cholesterol-dependent insertion into neuronal and glial membranes at the tripartite synapse. Lipid raft microdomains enriched in cholesterol and gangliosides thus act as active regulators of a continuum between transient and constitutive serotonin signaling. This extended serotonergic persistence prompts a reconsideration of current pharmacological models and the action of antidepressants such as fluoxetine, which not only inhibits the serotonin transporter (SERT) but also accumulates in lipid rafts, perturbs raft organization, and alters serotonin–cholesterol equilibria, contributing to SERT-independent effects. Grounded in the recently established fundamental parameters of biological systems, this model invites a broader, quantum-informed rethinking of synaptic transmission. Full article

Phosphatidylserine (PS) externalization is a conserved membrane stress signal that becomes chronically dysregulated in cancer cells and tumor-associated endothelium. In vivo, PS does not exist as a free lipid signal but is presented in specific membrane-associated forms, including apoptotic or stressed cell surfaces, PS-rich extracellular vesicles, and circulating lipid particles. Unlike apoptosis-associated transient PS exposure, malignant PS externalization arises from metabolic rewiring, oxidative stress, epigenetic silencing of flippases, and microenvironmental cues, creating an immunosuppressive interface across the tumor–host boundary. This review synthesizes mechanistic, immunological, and clinical evidence on PS biology, including its roles in tumor immune evasion, extracellular vesicle-mediated systemic suppression, and vascular remodeling. We further summarize the development and evaluation of PS-targeted therapeutic platforms—such as bavituximab, SapC-DOPS/BXQ-350, and PS-directed imaging agents—and highlight their translational potential in combination with radiotherapy, chemotherapy, and checkpoint inhibitors. Chronic PS externalization, as manifested through distinct cellular and vesicular carriers, represents a unifying biomarker of tumor stress, immune suppression, and therapeutic vulnerability, offering a next-generation axis for theragnostic cancer management. Full article

The success of cancer vaccines relies on the ability of dendritic cells (DCs) to efficiently prime cytotoxic CD8 T cell responses against tumors. However, in solid tumors this process is often undermined by tumor-driven immunosuppression and intrinsic defects in DC activation. Among the signaling pathways implicated in DC dysfunction, β-catenin signaling has emerged as a key regulator of immune tolerance in DCs. In parallel, inhibitory receptors such as PD-L1 and TIM-3 on DCs have been recognized as critical DC-intrinsic brakes on CD8 T cell priming and on responses to immune checkpoint blockade (ICB). Recent work has identified a DC-intrinsic immunoregulatory circuit in which β-catenin activation in DCs—particularly in cross-presenting cDC1s—induces expression of TIM-3, thereby suppressing CD8 T cell cross-priming and limiting anti-tumor CD8 T cell immunity. This β-catenin–TIM-3 axis represents a previously underappreciated layer of negative regulation that may help explain, at least in part, the limited efficacy of many current DC-based cancer vaccines. In this review, we examine how β-catenin activation in DCs, particularly in cDC1s, induces TIM-3 and related inhibitory programs that suppress cross-priming of tumor antigen-specific CD8 T cells and constrain the efficacy of DC-based vaccines. We further discuss how selectively targeting this β-catenin–TIM-3 checkpoint axis—alone or together with PD-L1 and other β-catenin–linked receptors—could restore DC function and inform rational combinations of DC-based vaccination with ICB and other T cell-based immunotherapies. Full article

Sodium–glucose cotransporter 2 inhibitors (SGLT2is) have revolutionized the management of type 2 diabetes mellitus, heart failure, and chronic kidney disease (CKD), providing cardiorenal and metabolic benefits that extend beyond glycemic control. While their clinical efficacy is well established, the underlying molecular mechanisms remain only partially understood. This review focuses on current knowledge of SGLT2 expression and regulation in health and metabolic diseases, as well as transcriptional and epigenetic consequences of pharmacological SGLT2 inhibition. Human and experimental studies demonstrate that SGLT2 expression is confined to proximal tubular cells and regulated by insulin, the renin–angiotensin–aldosterone system, the sympathetic nervous system, oxidative stress, and transcriptional and epigenetic pathways. SGLT2 expression follows a biphasic pattern in metabolic disorder-associated CKD: upregulation in early phases and reduction in advanced stages. Evidence from animal models and single-cell transcriptomic studies indicates that SGLT2is normalize metabolic and inflammatory gene networks. To our knowledge, a recent single-cell RNA sequencing study provides the only currently available human dataset linking SGLT2i therapy with tubular metabolic rewiring and suppression of the energy-sensitive mechanistic target of rapamycin complex 1. Collectively, these findings support a model in which SGLT2 inhibition mitigates metabolic stress by restoring energy homeostasis across multiple nephron segments. Full article

Agricultural systems face mounting pressures from climate change, as rising temperatures, elevated CO₂, and shifting precipitation patterns intensify plant disease outbreaks worldwide. Conventional strategies, such as breeding for resistance, pesticides, and even transgenic approaches, are proving too slow or unsustainable to meet these challenges. Synthetic biology offers a transformative paradigm for reprogramming plant immunity through genetic circuits, RNA-based defences, epigenome engineering, engineered microbiomes, and artificial intelligence (AI). We introduce the concept of synthetic immunity, a unifying framework that extends natural defence layers, PAMP-triggered immunity (PTI), and effector-triggered immunity (ETI). While pests and pathogens continue to undermine global crop productivity, synthetic immunity strategies such as CRISPR-based transcriptional activation, synthetic receptors, and RNA circuit-driven defences offer promising new avenues for enhancing plant resilience. We formalize synthetic immunity as an emerging, integrative concept that unites molecular engineering, regulatory rewiring, epigenetic programming, and microbiome modulation, with AI and computational modelling accelerating their design and climate-smart deployment. This review maps the landscape of synthetic immunity, highlights technological synergies, and outlines a translational roadmap from laboratory design to field application. Responsibly advanced, synthetic immunity represents not only a scientific frontier but also a sustainable foundation for climate-resilient agriculture. Full article

Background: Aging brains are shaped by a persistent dialogue between declining neurogenesis and rising neuroinflammation. Neural stem cells progressively lose regenerative capacity, while microglia and astrocytes shift toward maladaptive states that erode synaptic plasticity and cognition. This convergence defines inflammaging, a slow yet relentless process that undermines resilience. However, the field remains hampered by critical gaps: incomplete mapping of microglial heterogeneity, poorly understood epigenetic scars from inflammasome signaling, lack of longitudinal data, unclear niche-specific immune mechanisms, and uncertain cross-species relevance. This review addresses these pressing barriers, aiming to transform fragmented insights into actionable strategies. Summary: I chart how neurogenesis and neuroinflammation operate in continuous dialogue, identify five major knowledge gaps, and evaluate strategies to reprogram this interaction. Approaches include longitudinal imaging, niche-focused immunomodulation, glial subtype reprogramming, brain-penetrant inflammasome inhibitors, and CRISPR-based epigenetic editing. Each strategy is mapped against translational potential, short-term feasibility, and long-term vision, with emphasis on how mechanistic precision can guide clinical innovation. Conclusions: Here I highlight that neurogenic potential is not entirely lost with age but may be preserved or restored by tuning immune and epigenetic environments. This review proposes a roadmap for reshaping the aging brain’s fate, offering mechanistically grounded strategies to delay cognitive decline. Beyond neurology, the work underscores a broader principle: by integrating cellular plasticity with immune modulation, science edges closer to re-engineering resilience across the lifespan. Full article

Background: Thoracic aortic aneurysm (TAA) is driven by complex molecular mechanisms beyond size thresholds, yet the role of cyclic nucleotide metabolism remains unclear. Phosphodiesterases (PDEs), which hydrolyze cAMP and cGMP in compartmentalized microdomains, act as key regulators of vascular integrity and remodeling. Methods: We performed a hypothesis-driven, transcriptomic analysis of 20 PDE isoforms using the GSE26155 dataset (43 TAA vs. 43 controls). Raw microarray data underwent background correction, log2 transformation, and false-discovery adjustment. Differential expression, logistic regression, receiver-operating characteristic (ROC) curves, calibration testing, correlation analysis, and interactome/enrichment mapping were conducted. Results: Thirteen PDE isoforms were significantly dysregulated in TAA. Upregulated transcripts included PDE10A, PDE2A, PDE4B, PDE7A, and PDE8A, whereas PDE1A/B/C, PDE3B, PDE5A, PDE6C, and PDE8B were downregulated. PDE10A achieved excellent discrimination for TAA (AUC = 0.838), while other isoforms demonstrated fair discriminatory ability. Correlation architecture revealed coordinated regulation between PDE subfamilies, including inverse relationships between PDE2A and PDE8B (r = −0.68). Interactome analysis highlighted dense connections with cyclic nucleotide and purinergic signaling hubs, enriched in vascular tone, NO–cGMP–PKG, and junctional assembly pathways. Integrating these findings with epigenetic and junctional frameworks suggests that PDE dysregulation promotes endothelial barrier fragility and maladaptive smooth-muscle remodeling. Conclusions: Family-wide PDE dysregulation characterizes human TAA, with PDE10A emerging as a central transcriptomic signature. Altered cAMP/cGMP microdomain signaling aligns with junctional failure and epigenetic control, supporting the potential of PDE isoforms as biomarkers and therapeutic targets. These results provide experimental evidence that cyclic nucleotide hydrolysis is re-wired in TAA, supporting PDE10A as a novel biomarker and therapeutic target that bridges molecular dysregulation with clinical risk stratification in thoracic aortic disease. Full article

Advanced prostate cancer, particularly castration-resistant disease, remains challenging to treat due to intratumoral heterogeneity, immune exclusion, and a suppressive tumor microenvironment. Within this ecosystem, cancer-associated fibroblasts shape tumor–stroma communication, but their marked heterogeneity and plasticity complicate classification and make indiscriminate fibroblast depletion potentially ineffective or even harmful. This review summarizes recent progress in fibroblast origins, functional subtypes, and fibroblast-driven mechanisms that promote tumor progression and therapy resistance, as well as emerging therapeutic opportunities in prostate cancer. We conducted a structured literature search of PubMed, ScienceDirect, and major publisher platforms (including Nature and SpringerLink) from database inception to 15 February 2025, supplemented by targeted manual screening of reference lists. Evidence from single-cell/spatial-omics and mechanistic studies indicates that prostate tumors contain multiple fibroblast programs that occupy distinct niches yet can interconvert. Across these studies, it was found that these fibroblasts contribute to immune suppression, extracellular matrix remodeling and stromal barrier formation, angiogenesis, and metabolic support, collectively limiting drug penetration and reinforcing immune evasion; therapeutic pressure can further rewire fibroblast states and resistance-associated signaling. Overall, the literature supports a shift toward function- and subtype-directed intervention rather than “one-size-fits-all” targeting, with promising directions including precision targeting and reversible reprogramming, rational combination strategies, and localized delivery approaches that reduce stromal barriers while preserving tissue homeostasis in high-risk and treatment-refractory prostate cancer. Full article

Micronutrient malnutrition persists as a global health burden, while conventional biofortification approaches suffer from low efficiency and environmental trade-offs. This study aimed to develop and evaluate a foliar-applied selenium–zinc nanocomposite (Nano-ZSe, a mixture of zinc ionic fertilizer and nano selenium) for synergistic Se/Zn co-biofortification in Brassica chinensis L., using a controlled pot experiment that integrated physiological, metabolic, molecular, and rhizosphere analyses. Application of Nano-ZSe at 0.18 mg·kg⁻¹ (Based on soil weight) not only increased shoot biomass by 28.4% but also elevated Se and Zn concentrations in edible tissues by 7.00- and 1.66-fold (within the safe limits established for human consumption), respectively, compared to the control. Mechanistically, Nano-ZSe reprogrammed the ascorbate-glutathione redox system and redirected carbon flux through the tricarboxylic acid cycle, suppressing acetyl-CoA biosynthesis and reducing abscisic acid accumulation. This metabolic rewiring promoted stomatal opening, thereby enhancing foliar nutrient uptake. Simultaneously, Nano-ZSe triggered the coordinated upregulation of BcSultr1;1 (a sulfate/selenium transporter) and BcZIP4 (a Zn²⁺ transporter), enabling synchronized translocation and the tissue-level co-accumulation of Se and Zn. Beyond plant physiology, Nano-ZSe improved soil physicochemical properties, enriched rhizosphere microbial diversity, and increased crop yield and economic returns. Collectively, this work demonstrates that nano-enabled dual-nutrient delivery systems can bridge nutritional and agronomic objectives through integrated physiological, molecular, and rhizosphere-mediated mechanisms, offering a scalable and environmentally sustainable pathway toward functional food production and the mitigation of hidden hunger. Full article

Adipose tissue is far more than a passive reservoir for surplus energy: it is an active metabolic and endocrine organ that senses nutrient availability and orchestrates systemic energy balance. When caloric intake chronically exceeds expenditure, adipocytes become engorged with lipids and exposed to metabolic, mechanical, and hypoxic stress. To adapt, they initiate a fibro-inflammatory response that may be protective in the short term. As this response becomes chronic, adipocytes lose their metabolic flexibility, acquire a maladaptive fibro-inflammatory phenotype, and contribute to the cascade of inflammation, insulin resistance, and metabolic disease that characterizes obesity. In this review, we dissect the cellular and molecular cues that trigger fibro-inflammation, from nutrient excess and mitochondrial stress to hypoxia and immunometabolic rewiring, and highlight how these processes reshape adipocyte identity and tissue homeostasis. Full article

Mammalian oocyte maturation is a metabolically demanding process relying on lipid metabolism that supplies energy, structural substrates, and signaling mediators. However, a comprehensive cross-species understanding of the dynamic requirement for lipids during this process remains elusive, hindering the optimization of assisted reproductive technologies. Utilizing an integrated single-cell transcriptomic and targeted lipidomic approach, we mapped the metabolic landscape of bovine oocyte maturation. Our analysis uncovered a global transcriptional downregulation, with 3259 genes suppressed during the transition from the germinal vesicle (GV) to the metaphase II (MII) stage. This was particularly apparent in lipid catabolism pathways (e.g., for ACAA1), while mitochondrial energy production genes (ATP6) were upregulated. Lipidomics indicated a selective depletion of saturated fatty acids (SFAs; e.g., C16:0, C18:0) in MII oocytes, while monounsaturated (MUFAs) and polyunsaturated fatty acids (PUFAs) were preferentially retained. Integrated network analysis specified hexadecanoic acid (C16:0) as a central metabolic hub, which rewires its interactions from biosynthetic genes (FASN, ELOVL6) in GV oocytes to degradative enzymes (ACADVL, HADH) in MII oocytes. Expanding to a cross-species transcriptomic atlas, we identified a core set of 59 lipid metabolism genes conserved across bovine, mouse, and human oocytes. Despite this conservation, we discovered stark species-specific regulatory strategies: bovine and human oocytes significantly downregulated fatty acid degradation and elongation post-maturation, whereas murine oocytes maintain pathway activity, upregulating key regulators like Acsl3. Our work unveils an evolutionarily conserved core lipid metabolic program in mammalian oocytes that is adaptively tuned to meet species-specific physiological demands. Bovine and human oocytes prioritize catabolic flexibility, using SFAs for energy, while mouse oocytes maintain their anabolic capacity for membrane biosynthesis. These findings provide a transformative resource for the field, offering biomarkers for oocyte quality and a rationale for enhancing species-tailored lipid formulations to develop in vitro maturation systems and amend reproductive outcomes in both agriculture and medicine. Full article