Search Results (6,431)

Cardiovascular complications increasingly challenge survivors of urological cancers, given the cardiotoxicity of therapies such as androgen deprivation, vascular endothelial growth factor receptor inhibitors, tyrosine kinase inhibitors, immune checkpoint inhibitors, and chemotherapy. This narrative review addresses the complex crosstalk between urological cancer treatment and cardiovascular disease. It summarizes cardiovascular toxicities linked to major antineoplastic agents, explores underlying mechanisms including metabolic and immune-mediated effects, and proposes strategies for surveillance, diagnosis, and management. Highlighting the need for multidisciplinary collaboration, it outlines future directions for research to optimize cardiovascular outcomes in this high-risk population. The increasing complexity of cardiovascular care in patients with urological malignancies highlights the need for closer collaboration between cardiologists, urologists, and oncologists, with uro-cardio-oncology emerging as an important multidisciplinary field. Full article

Plant specialized metabolites connect genetic programs and environmental responses with ecologically and economically valuable natural products. Their accumulation is rarely constitutive, varying instead with tissue identity, developmental stage, stress exposure, hormone signaling, and cellular storage capacity. This review examines basic helix-loop-helix (bHLH) transcription factors as regulatory switch points in plant specialized metabolism, with emphasis on the jasmonate-JAZ-MYC module. In resting tissues, JAZ repressors constrain MYC/bHLH activity; after wounding, herbivory, pathogen challenge, or elicitation, jasmonoyl-isoleucine triggers COI1-dependent JAZ turnover, releasing MYC factors to bind E-box/G-box motifs, recruit coregulators such as MED25, and activate biosynthetic genes or downstream transcription-factor cascades. Plant lineages have repeatedly adapted this regulatory logic to control terpenoids, alkaloids, phenylpropanoids, flavonoids, glucosinolates, phytoalexins, and related metabolites. Comparative examples include Arabidopsis sesquiterpenes and glucosinolates, Taxus taxanes, Artemisia artemisinin, Catharanthus terpenoid indole alkaloids, Salvia phenolic acids and tanshinones, Ginkgo terpene trilactones, rice diterpenoid phytoalexins, and cotton gossypol. Across these systems, bHLH output depends on dimer choice, promoter grammar, chromatin accessibility, hormone crosstalk, partner transcription factors, and cell-type competence. Six shared principles emerge: signal gating, topology matched to pathway architecture, partner-dependent promoter decoding, spatial competence, feedback rheostats, and evidence-dependent transferability. We further discuss evidence standards, multi-omics-guided factor discovery, miRNA-mediated post-transcriptional control, and engineering strategies for crop defense, food quality, medicinal-metabolite production, and synthetic biology. Unlike pathway- or MYC2-centered surveys, this review organizes the literature within a direct–cascade–hybrid framework that integrates promoter grammar, spatial competence, storage anatomy, and an explicit evidence hierarchy. Full article

The gut–lung axis is one of the bidirectional mucosal communication networks linking intestinal microbiota, microbial metabolites, immune regulation, and respiratory inflammation. This narrative review summarizes mechanistic and translational evidence identified through a structured but non-systematic search. This review focuses on gut-to-lung mechanisms, including immune cell trafficking, epithelial barrier regulation, and the role of gut microbiota and its metabolites. Among these metabolites, short-chain fatty acids (SCFAs), particularly acetate, propionate, and butyrate, are key mediators of interorgan communication and are mainly produced through microbial fermentation of dietary fibers and polysaccharides. Unlike previous reviews, reverse lung-to-gut mechanisms are also discussed, whereby respiratory infection, smoking, and lung injury may disrupt intestinal barrier integrity, alter gut microbiota composition, and promote intestinal immune dysregulation. Among plant-derived interventions, dietary fibers, polysaccharides, and polyphenols appear promising, mainly through SCFA-dependent immune modulation, enrichment of metabolite-producing bacteria, and subsequent suppression of inflammatory pathways. Some compounds may also act through microbiota-independent mechanisms, including direct antioxidant effects, epithelial barrier protection, and inhibition of inflammatory signaling pathways. Overall, SCFA-mediated immune regulation is the best-supported mechanism, whereas lung-to-gut signaling remains less established. Most evidence remains preclinical, highlighting the need for standardized human studies evaluating dose, safety, and clinically meaningful respiratory outcomes. Full article

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a five-year survival rate below 10%. Cancer-associated fibroblasts (CAFs) promote epithelial–mesenchymal transition (EMT) and metastasis, yet the specific CAF subtypes and molecular axes driving PDAC progression remain incompletely understood. Here, using multi-omics data from PDAC samples, we identified a malignant ductal subpopulation, termed Ductal-T0, characterized by the highest EMT activity and prominent acquisition of myofibroblastic CAF (myCAF)-like transcriptional programs. Computationally, we predicted that myCAF-secreted THBS2 and FN1 engage the ITGA3/ITGB1/SDC1/SDC4 receptor axes in Ductal-T0 cells, which could activate TNF, NF-κB, TGF-β, and PI3K-AKT-signaling pathways to promote EMT. Pseudotime trajectory and velocity analyses suggested that Ductal-T0 cells exhibited the highest propensity to acquire myCAF-like features among all ductal subpopulations. Survival analysis revealed that an increased proportion of Ductal-T0 cells and elevated abundance of THBS2-ITGA3/ITGB1 and THBS2-SDC1 ligand–receptor pairs were significantly associated with poor prognosis. Spatial transcriptomics further revealed that myCAFs and Ductal-T0 cells co-localized at the tumor margin, which may contribute to reduced immune cell presence via dense extracellular matrix (ECM) barrier formation—a computationally inferred model of EMT-associated immune exclusion and metastatic progression—and identify THBS2 as a promising candidate for future therapeutic investigation to disrupt CAF–tumor crosstalk in PDAC. Full article

Osteosarcopenia combines low bone mass or skeletal fragility with sarcopenia, yet its metabolic biology is commonly assessed using single-time-point measurements. We conducted a structured narrative review of PubMed/MEDLINE, Web of Science Core Collection, Embase and Scopus from inception through 28 June 2026, supplemented by ScienceDirect, Google Scholar and citation chaining. Evidence was classified as direct human osteosarcopenia evidence, indirect human evidence, preclinical evidence or conceptual inference. Here, chronometabolomics denotes time-anchored or repeated metabolomic profiling used to estimate variation in phase, amplitude and pathway coordination in relation to sleep, feeding, activity and endocrine timing. Direct human evidence remains scarce. Component-specific human studies and experimental models suggest, but do not establish, that aging, chronic disease and irregular schedules may alter glucose–insulin, amino-acid, lipid, mitochondrial, redox-inflammatory, mineral-endocrine and microbial rhythms relevant to the bone–muscle unit. Chronometabolomics is therefore an emerging research framework, not a validated diagnostic or therapeutic approach. Daytime light, sleep regularization, protein distribution, time-restricted eating, exercise timing and medication timing remain candidates for controlled trials rather than current clinical recommendations; safety evaluation must address frailty, low body mass index, malnutrition, kidney disease, diabetes, polypharmacy, falls and inadequate protein or calcium intake. Full article

Lung cancer ranks first in both incidence and mortality among all malignancies, and tumor microenvironment (TME)-induced CD8⁺ T cell exhaustion is a critical factor driving immune evasion and compromising the efficacy of immunotherapy. MicroRNAs (miRNAs), as key post-transcriptional regulators, shuttle between lung cancer cells and CD8⁺ T cells via extracellular vesicles (EVs), serving as critical communication hubs that reshape the TME. This review systematically synthesizes recent literature to summarize the regulatory patterns of miRNAs on functions of lung cancer cells and CD8⁺ T cells, and dissect the molecular mechanisms underlying miRNA-mediated bidirectional crosstalk between these two cell types. This review focuses on the dual-pronged immune evasion strategy employed by lung cancer cells to counteract CD8⁺ T cells. On the one hand, lung cancer cells aberrantly express endogenous miRNAs, such as miR-20a, miR-149-5p, and miR-326, to remodel their surface ligands and establish immune camouflage. On the other hand, they actively secrete EVs enriched in specific miRNAs, including miR-7108-3p, miR-651-5p, and miR-24-3p, which directly suppress CD8⁺ T cell function. Furthermore, lung cancer cells secrete additional miRNAs, notably miR-6794-5p, miR-708-5p, and miR-1234-3p, to reprogram other TME components, namely tumor-associated macrophages (TAMs), natural killer (NK) cells, and myeloid-derived suppressor cells (MDSCs). These reprogrammed cells, in turn, indirectly attenuate CD8⁺ T cells through a relay-like mechanism via immunosuppressive cytokines or surface checkpoint molecules produced by these cells. In addition, competing endogenous RNA (ceRNA) networks formed by long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) in lung cancer cells regulate miRNA activity at multiple levels, further impairing the immune effector functions of CD8⁺ T cells. Conversely, activated CD8⁺ T cells also secrete miRNA-containing EVs, which deliver these miRNAs to tumor cells, thereby inhibiting tumor progression. Elucidation of this miRNA-based bidirectional communication network will not only advance our understanding of immune evasion mechanisms in lung cancer but also provide novel insights into cell-free immunotherapeutic approaches based on CD8⁺ T cell-derived vesicles. Full article

The advent of cancer immunotherapy opened a transformative era in oncology, shifting the focus from targeting mutated genes through precision oncology to harnessing the body’s immune system via agnostic therapies. This paradigm has demonstrated that a deeper understanding of the tumor immune microenvironment (TIME) can transcend the challenges posed by cancer’s genetic diversity and evolutionary dynamics. In the case of thyroid cancer, progress in immunotherapy has been comparatively slow. Much of the current research still centers on the genetic landscape of thyroid tumors rather than on comprehensive exploration of their TIME. The TIME, composed of immune cells such as macrophages, lymphocytes, natural killer cells, and mast cells, along with a network of signaling molecules, evolves alongside tumor growth and metastasis. It both influences and is influenced by genetic alterations, metabolic conditions, and therapeutic interventions. This dynamic crosstalk defines the clinical and biological heterogeneity of thyroid cancers; from the aggressive anaplastic thyroid carcinoma (ATC) to the more indolent papillary thyroid carcinoma (PTC). Mapping the spatial and temporal changes within the TIME offers the opportunity to design therapies that counter immune evasion and enhance treatment response. As understanding of the tumor microenvironment deepens, thyroid cancer therapy is undergoing a major shift; from strategies aimed merely at genetic mutations to integrated, combinational approaches incorporating personalized immunotherapy. Building on recent findings, which detail immune cell composition and therapeutic implications in thyroid malignancies, this review expands on the molecular and cellular mechanisms shaping the microenvironment. We highlight how oncogenic signaling, stromal remodeling, and metabolic reprogramming coordinate to influence tumor immunity, and we explore emerging strategies that aim to reengineer the tumor microenvironment for improved therapeutic outcomes. Full article

Cardiac senescence is not an isolated organ decline but a systemic consequence driven by pathological crosstalk between the heart and its peripheral metabolic organs. In this review, we discard the traditional organ–centric perspective and construct an integrated framework around multi-organ crosstalk axes, including the epicardial adipose tissue–heart axis, the skeletal muscle–heart axis, the gut–heart axis, and the kidney–heart axis. For each axis, we dissect the local molecular mediators—inflammatory cytokines, lipotoxic metabolites, microbiota-derived compounds such as trimethylamine N-oxide (TMAO), renin-angiotensin-aldosterone system (RAAS) effectors, and extracellular vesicle (EV) cargoes—and illustrate how they converge onto common pathways of oxidative stress, impaired autophagy, and cellular senescence. Importantly, we emphasize that these signals do not operate in isolation; they act synergistically through the circulation, converting local organ dysfunction into systemic cardiac aging via convergence onto shared senescence pathways. By redefining aging as a potentially modifiable multi-organ crosstalk, we propose emerging nodal points—senolytics, myokine mimetics, gut microbiota modulation, RAAS/sodium–glucose cotransporter 2 (SGLT2) inhibitors, and integrated lifestyle strategies—to block pathological crosstalk and delay cardiovascular aging. This framework shifts the research focus from isolated organs to systemic multi-organ crosstalk, providing new insights into cardiometabolic aging. Full article

Histone deacetylases (HDACs) are key epigenetic enzymes governing lysine deacetylation. This modification is tightly coupled to cellular redox homeostasis and antioxidant signaling in plants. Plant HDACs are grouped into three subfamilies: RPD3/HDA1, SIR2, and plant-specific HD2. HDACs target both histone residues (e.g., H3K9 and H4K5) and a broad set of non-histone substrates (e.g., transcription factors and metabolic enzymes). Via coordinated chromatin remodeling and non-histone protein modification, HDACs integrate phytohormone signals, reactive oxygen species (ROS) bursts and NAD⁺ metabolic fluctuations to orchestrate plant abiotic stress responses, balancing antioxidant defense, redox equilibrium and normal growth. This review systematically sorts the divergent stress-response traits, substrate preferences and bidirectional regulatory logic of the three HDAC subfamilies; integrates chromatin-dependent and transcription factor-centered transcriptional branches; and summarizes crosstalk rules between HDAC-mediated deacetylation and other epigenetic marks. We further hierarchically clarify current research bottlenecks spanning basic mechanism dissection, multi-crop validation and field breeding transformation and propose targeted stratified research directions. We further construct a complete regulatory cascade linking environmental stimuli, ROS/ABA/NAD⁺ signals, HDAC activity and downstream antioxidant/stress gene expression, filling gaps in previous reviews that overlook redox-dependent HDAC functions. This mechanistic framework delivers integrated epigenetic and redox theoretical references for breeding stress-tolerant crops with reinforced antioxidant capacity. Full article

Resistance to mTOR inhibition is mediated by multiple adaptive mechanisms, including feedback activation of the PI3K/AKT/mTOR pathway, autophagic adaptation, metabolic reprogramming, immune evasion, tumor heterogeneity, and microenvironmental crosstalk. Recent research has also elucidated the crucial role of RNA modifications, particularly m6A methylation, and the regulatory impact of non-coding RNAs in facilitating tumor adaptation to mTOR blockade. Accordingly, novel therapeutic approaches are emerging. The combination of PI3K/AKT/mTOR inhibitors with immune checkpoint blockades represents a promising strategy for overcoming therapeutic resistance. Additionally, next-generation mTOR inhibitors and synthetic lethality strategies are being tailored to target specific tumor profiles. Furthermore, advancements in multi-omics technologies and AI-powered predictive models are transforming personalized cancer treatment. This comprehensive review delves into the molecular intricacies of mTOR inhibitor resistance and explores innovative strategies aimed at enhancing therapeutic outcomes and improving patient responses. Full article

Influenza A virus (IAV) remains a major threat to global public health because of its capacity for antigenic drift, reassortment, zoonotic transmission, and pandemic emergence. Viral transcription and genome replication are carried out by the influenza virus RNA-dependent RNA polymerase (FluPol), a heterotrimeric complex composed of polymerase basic protein 1 (PB1), polymerase basic protein 2 (PB2), and polymerase acidic protein (PA), which functions together with nucleoprotein (NP) within viral ribonucleoprotein complexes (vRNPs). FluPol activity is regulated not only by viral determinants and host cofactors but also by diverse post-translational modifications. Among these, ubiquitination has emerged as a particularly versatile regulatory mechanism because it can control protein stability, polymerase assembly, subunit interactions, conformational dynamics, NP–RNA interactions, and innate immune signaling. Depending on the modified substrate, ubiquitin linkage type, acceptor residue, and responsible E3 ligase or deubiquitinase, ubiquitination may either restrict IAV replication or be exploited by the virus to enhance polymerase function and vRNP activity. This review summarizes recent advances in ubiquitination-mediated regulation of FluPol and NP, focusing on the responsible E3 ubiquitin ligases, deubiquitinases, ubiquitination sites, ubiquitin-chain types, and host restriction mechanisms. We further discuss the crosstalk between ubiquitination and other post-translational modifications, highlight unresolved mechanistic questions, and evaluate the therapeutic potential and challenges of targeting ubiquitin-dependent pathways for antiviral intervention. Collectively, this review provides a conceptual framework for understanding how ubiquitination shapes IAV replication and identifies E3 ligases and DUBs as potential targets for host-directed antiviral strategies. Full article

Obesity is associated with chronic adipose dysfunction characterized by oxidative stress, inflammation, senescence, and fibrosis, which can promote tumor progression. In prostate cancer, periprostatic adipose tissue may directly influence the prostate microenvironment. Radiation therapy is widely used in prostate cancer, but radiation-induced adipose dysfunction in obesity and its impact on the prostate microenvironment remain poorly understood. In the present study, we investigated the impact of obese and irradiated obese adipose microenvironments on prostate stromal remodeling, as well as the activation of prostate fibroblasts mediating prostate cancer progression. We utilized a high-fat diet obesity model with localized adipose irradiation in animal and in vitro studies using obese and irradiated obese adipocytes. Prostates from obese and irradiated obese mice exhibited epithelial hyperplasia, increased stromal activation markers, oxidative damage, and senescence. Interestingly, radiation maintained the obesity-induced pathological behavior in the prostate, rather than elevating it. The conditioned media from obese and irradiated obese adipocytes induced stromal activation markers, senescence, extracellular H₂O₂ production, pro-survival signaling, and inflammation. Notably, the only significant changes observed with the addition of radiation to obesity were enhancement of fibrosis-associated features and infiltration of CD4⁺ T cells. Functionally, prostate myofibroblasts or senescent fibroblasts promoted prostate cancer migration and induced epithelial-to-mesenchymal transition and elevated pro-tumorigenic pathways. Cytokine profiling identified elevated levels of CXCL10 and CXCL11 from myofibroblasts, and pharmacological inhibition of CXCR3 significantly reduced prostate cancer migration, implicating this signaling axis in activated fibroblast-driven tumor-promoting crosstalk. Collectively, these findings demonstrate obesity-associated adipose dysfunction reprograms the prostate microenvironment toward a pro-tumorigenic state, while radiation sustains rather than markedly amplifies these pathological changes, identifying obese adipose-stromal crosstalk and the CXCL10/CXCL11-CXCR3 axis as potential therapeutic targets to inhibit prostate cancer progression. Full article

Background/Objectives: The NLRP3 inflammasome–Caspase-1–IL-1β pyroptotic axis participates in peripheral inflammatory responses, yet its function in peripheral–central neuroimmune crosstalk underlying endometriosis (EM)-associated pain remains unclear. This study aimed to clarify whether NLRP3-mediated pyroptosis establishes a brain–lesion neuroimmune axis connecting ectopic lesion inflammation with central neuroimmune remodeling and to explore the therapeutic mechanism of transcranial direct current stimulation (tDCS). Methods: An EM rat model was established to detect NLRP3 pathway expression in ectopic lesions and anterior cingulate cortex (ACC), together with central nervous system pathological alterations. Animals received tDCS intervention to evaluate inflammatory, neuropathological and pain behavioral changes. The closed-loop brain–lesion regulatory circuit was further interpreted. In a clinical cohort including 40 EM patients, pain and quality-of-life scores were compared between active and sham tDCS groups. Results: NLRP3, Caspase-1 and IL-1β were upregulated in ectopic lesions and ACC of EM rats, accompanied by ACC mitochondrial injury, microglial activation and thalamic demyelination. tDCS inhibited pyroptosis-related molecules, decreased systemic proinflammatory cytokines, improved central pathological lesions and relieved pain hypersensitivity. Mechanically, top-down descending pain inhibitory pathways, vagal cholinergic anti-inflammatory pathway and the HPA axis jointly mediate therapeutic effects, whereas circulating cytokines and visceral afferents transmit peripheral inflammatory signals to the brain. Clinical data demonstrated that active tDCS effectively alleviated EM-related pain and improved patients’ quality of life. Conclusions: NLRP3-mediated pyroptosis acts as a key mediator linking peripheral and central neuroimmune communication. Targeting this pathway via tDCS interrupts the inflammation–pain vicious cycle through multiple neuroregulatory pathways and remodels the central neuroimmune microenvironment in endometriosis. Full article

Colorectal cancer (CRC) is a major cause of cancer morbidity and mortality worldwide, and metabolic reprogramming is increasingly recognized as an important feature of its progression. Among these changes, fatty acid metabolism (FAM) has drawn growing attention because it supports energy supply, membrane synthesis, redox balance, and stress adaptation in tumor cells. CRC cells can increase fatty acid uptake, activate de novo synthesis, adjust fatty acid oxidation (FAO), and alter lipid droplet (LD) dynamics according to metabolic demand. These processes are strongly influenced by the hypoxic tumor microenvironment. Under hypoxic conditions, signaling pathways centered on hypoxia-inducible factors (HIFs) reshape lipid uptake, synthesis, oxidation, and storage, allowing CRC cells to maintain survival and adapt to limited oxygen and nutrient availability. Increasing evidence suggests that this metabolic shift is closely linked to invasion, metastasis, stem-like behavior, and resistance to therapy. In this review, we provide an integrated overview of the hypoxia–FAM axis in CRC. We first summarize the major steps of FAM reprogramming, then highlight how hypoxia reshapes these processes through HIF-dependent and related pathways. We also discuss FAM crosstalk with stromal and immune cells, experimental models, and metabolic heterogeneity between primary CRC and liver metastases. Finally, we discuss therapeutic strategies targeting FAM and hypoxia-associated signaling in CRC. Full article

Snakebite envenomation causes severe tissue damage, often resulting in permanent disability with long-term complications like amputations and organ dysfunction. Current antivenoms, which are antibody-based, have lower tissue penetrability and limited efficacy in minimizing the local effects, highlighting the need for adjunct therapies. Emerging evidence indicates that venom-induced pathology is not restricted to direct cytotoxicity and necrosis; rather, it also involves multiple interconnected Regulated Cell Death (RCD) pathways, but their mechanistic interplay and therapeutic implications remain poorly understood. This review examines how venom toxins induce a cellular stress response characterized by oxidative stress, membrane disruption, and calcium overload, leading to the activation of interconnected regulated cell death (RCD) pathways, including apoptosis, ferroptosis, and pyroptosis, together with autophagy and mitophagy, which primarily function as cellular stress responses that modulate these forms of regulated cell death. We further discuss the crosstalk between these RCD pathways and emerging therapeutic approaches targeting these mechanisms. Understanding these interconnected RCD pathways may facilitate the development of adjunct therapies that complement antivenom, reduce snakebite-induced morbidity, and improve clinical outcomes. Full article