The dynamic field of radiopharmaceuticals is currently experiencing an explosion of growth due in part to excitement over the emerging field of theranostics (therapy and diagnostics). Radiopharmaceuticals use physiological targeting methods to deliver radionuclides with medically relevant decay properties to disease biomarkers for diagnosis and treatment, offering opportunities for early disease imaging and radiation therapy treatment in disease pathologies that are inoperable or refractory to other forms of radiotherapy. Sustaining this rapidly growing field depends heavily on the continued design and production of novel, effective radiopharmaceuticals. Effective therapeutic radiopharmaceuticals cause complex and varied cellular responses, and to choose radionuclides that maximize therapeutic response, researchers must understand radiation biology. Cellular radiation response depends heavily on factors including linear energy transfer (LET), dose, dose rate, targeted location, direct or indirect energy deposition mechanisms, the broader cellular matrix, cellular stress signaling pathways, and endogenous radiation protection mechanisms. Because of the extensive application of low-LET external beam radiation on clinical cancer treatments, biological responses to low-LET form the basis of radiation biology and are generally considered transferable to high-LET radiopharmaceuticals. However, increased focus on high-LET, radiopharmaceutical therapy-specific radiation biology is motivated by differences between low- and high-LET radiation, external beam versus radiopharmaceutical therapy-induced biological response, and the observed varied clinical responses to radiopharmaceutical therapies. This review article summarizes historical understanding of low- and high-LET radiation responses within cells, with emphasis on radiopharmaceutical-specific responses when available, and discusses current gaps in understanding in the radiation biology of radiotheranostic pharmaceuticals.
Terrestrial ecosystems serve as a major carbon (C) sink, but the increasing frequency and intensity of drought threaten the C sink and ecological communities. A comprehensive understanding of the change in ecosystem productivity due to the direct effect versus the legacy effect of drought is still lacking. We quantify the magnitude change in terrestrial gross primary production (GPP) globally due to both direct and long-term legacy effects. We find that the direct effect causes significant GPP decreases in magnitude of -5.94% [-13.40%, -3.21%] per year, while the legacy effect-induced GPP change is weaker and non-significant at a global scale. Drought legacy effects, however, are detectable in dry sub-humid regions. The direct effect-induced change is highly correlated with that of the legacy effect, and rooting depth is a key driver for both. These findings demonstrate the current resilience of global ecosystems to drought but underscore the long-term vulnerability of dryland ecosystems.
Tumor oxygenation is a key determinant of cancer biology and treatment response, correlating with angiogenesis, recurrence, and malignant progression. Hypoxia is a defining feature of glioblastoma (GBM) and adult diffuse gliomas, generating low-oxygen niches that promote invasion, stem-like states, immune suppression, and resistance to radiotherapy and temozolomide, contributing to poor outcomes. Measuring tissue partial pressure of oxygen (pO2) and mapping its spatial heterogeneity can, therefore, inform mechanistic understanding and therapeutic development, including hypoxia-activated prodrugs, hypoxia-responsive gene therapy, and optimized radiotherapy planning. Although direct pO2 assessment is challenging, invasive probes and multimodal imaging can characterize regional hypoxia pre-operatively, support patient stratification, monitor treatment effects, and improve outcome prediction. This review summarizes oxygen dynamics in GBM; analyzes causes of hypoxia (rapid growth outpacing supply, diffusion-limited hypoxia, and abnormal/chaotic vasculature); compares methods to quantify oxygenation from direct measurements to noninvasive imaging surrogates; and evaluates preclinical and clinical strategies that target hypoxia to enhance standard therapy, including barriers to translation. We further integrate oxygenation with cell signaling and redox biology: oxygen gradients are transduced via hypoxia-inducible factor programs and redox-sensitive pathways (NRF2/KEAP1, NOX-derived ROS, nitric oxide/S-nitrosylation, and sulfur metabolic routes), shaping mesenchymal-like transitions and cell-death programs such as ferroptosis. Framing oxygenation as both a microenvironmental and redox-signaling variable positions oxygen imaging as an entry point to biomarker-guided therapies that exploit oxidative vulnerabilities.
Respiratory syncytial virus (RSV) remains a major cause of severe acute respiratory infections across the life course, particularly in infants, older adults, and immunocompromised individuals. For decades, clinical management relied almost exclusively on supportive care, while ribavirin, the only licensed antiviral, offered limited therapeutic benefit. The recent introduction of prefusion F (pre-F)-based vaccines and long-acting monoclonal antibodies has reshaped RSV prevention and represents the most significant advance since the discovery of the virus. Nevertheless, effective pharmacological treatment of established infection continues to be an unmet need, and the burden of RSV-associated hospitalizations and mortality persists worldwide. This review critically synthesizes current and emerging RSV therapeutic strategies from a pharmacological and translational perspective, integrating approved interventions with emerging antiviral pipelines. Licensed vaccines and monoclonal antibodies have demonstrated high efficacy in preventing lower respiratory tract disease; however, their impact is constrained by limited access and uptake, as well as the absence of complementary direct-acting antivirals (DAAs). Investigational agents targeting the fusion protein and the N/L replication complex have shown potent antiviral activity, but clinical trials have highlighted challenges related to the timing of administration, host immunity, and resistance selection. Advances in structural biology, air-liquid interface models, high-throughput screening, and artificial intelligence are accelerating the identification of new molecular targets and host-directed strategies. Overall, RSV control will require an integrated therapeutic framework in which vaccines and monoclonal antibodies prevent severe disease, while early-administered DAAs and resistance-aware combination strategies treat established infection and reduce breakthrough disease in high-risk populations.
Background: Autonomic side effects are a major determinant of tolerability for many psychotherapeutic drugs. While often attributed to receptor-mediated mechanisms, the potential contribution of direct modulation of smooth muscle excitability remains poorly characterized at a comparative pharmacological level. Methods: A systematic comparative pharmacological profiling of a broad panel of psychotherapeutic drugs (antidepressants, antipsychotics, and anxiolytics) was conducted using a standardized ex vivo model. Potassium chloride (KCl, 105 mM) was used to induce depolarization-dependent contraction in three isolated smooth muscle preparations (rat uterus, rat vas deferens, and guinea-pig ileum). Inhibitory potency (IC50), dose-dependency, and tissue consistency were integrated to define functional inhibitory profiles. Results: Psychotherapeutic drugs exhibited marked heterogeneity in their ability to inhibit K+-induced smooth muscle contraction. Integrative analysis stratified compounds into four distinct functional profiles: (i) High Inhibitory Liability (e.g., nortriptyline, paroxetine), characterized by low micromolar IC50 values and dose-dependent inhibition across multiple tissues; (ii) Non-Selective Inhibition (e.g., flunarizine, cinnarizine), showing consistent but dose-independent inhibition; (iii) Tissue-Dependent Inhibition (e.g., risperidone, reboxetine); and (iv) Minimal Inhibition (e.g., moclobemide). Agents classified within the High Inhibitory Liability profile correspond to drugs known to carry a higher clinical burden of autonomic adverse effects. Conclusions: This study reveals a previously underrecognized pharmacodynamic dimension of psychotherapeutic drugs and establishes a comparative functional taxonomy based on their direct, non-receptor-mediated inhibition of smooth muscle excitability. The identified profiles provide a mechanism-informed framework for contextualizing autonomic side-effect liability and may support improved safety evaluation in psychotherapeutic drug development.
HLA-E's function as an immune checkpoint in cancer depends on its display of the canonical peptide (VL9), yet direct profiling of these complexes has been stymied by lack of specific reagents. We now introduce ABX002, a fully human TCR-mimic antibody capable of recognizing all tested VL9/HLA-E complexes with high affinity and specificity in situ. Using ABX002, we reveal that canonical VL9/HLA-E surface expression is tightly controlled by inflammatory cues, remarkably infrequent on tumors without stimulation, and almost absent from immune cells except myeloid-lineage cells. ABX002 unlocks cell-type and context-specific quantification of HLA-E antigen presentation, providing unprecedented insight into immune evasion and regulation. It additionally disrupts the NKG2A checkpoint, restoring cytotoxic lymphocyte function and enabling mechanistic and therapeutic mapping of HLA-E restricted peptide presentation. Together, these findings position ABX002 as a transformative tool for dissecting the landscape and biology of canonical peptide restriction in cancer immunity.
Metamorphosis is a key event in the life history of many organisms, including amphibians, because it can involve abrupt changes in morphology and habitat. However, metamorphosis can also be bypassed by paedomorphic processes that allow reproduction at the larval stage. The evolution of these alternative developmental processes depends on the payoffs of life in larval and adult environments, as well as the cost of transition. Previous studies on the cost of metamorphosis have focused on the larval stage, which is still subject to the achievement of a minimal size threshold as well as growth to adulthood. Therefore, facultatively paedomorphic species could be valuable models for testing the direct costs of metamorphosis. This is because facultative paedomorphs are sexually dimorphic adults that are capable of metamorphosis. By modelling weight loss using an experimental, longitudinal design that manipulated the ecological drivers of metamorphosis in a facultatively paedomorphic amphibian, the palmate newt (Lissotriton helveticus), we found that metamorphosis imposes costs in terms of body weight, whereas temperature has a smaller effect. In contrast, newts that do not metamorphose did not lose weight. The costs were sex-related with females at a disadvantage during metamorphosis. Furthermore, the decrease in food consumption associated with metamorphosis resulted in a loss of body weight. Overall, these results emphasise the importance of considering direct costs when studying the evolutionary ecology of metamorphosis. They also show that polymorphic species are suitable models for investigating the drivers of metamorphosis and its loss in micro- and macroevolution.
Physical integration between endosymbiotic algae and host mitochondria is a recurring feature across photosynthetic symbioses, yet the structural nature of this association has remained unresolved. In the ciliate Paramecium bursaria, each endosymbiotic Chlorella cell is enclosed by a perialgal vacuole (PV) membrane consistently surrounded by host mitochondria, suggesting a conserved architecture for metabolic interaction. Although transmission electron microscopy has shown close membrane apposition, it has remained unclear whether this reflects incidental proximity or a reinforced adhesion. Here, we provide direct evidence that the PV membrane and host mitochondrial membrane form a stable physical association. Using discontinuous Percoll centrifugation, we isolated intact units in which Chlorella and mitochondria co-sedimented, indicating that their association withstands mechanical disruption. By fluorescently labeling the PV and mitochondrial membranes with BODIPY FL C5-ceramide (BC5C), together with a mitochondria-specific monoclonal antibody and DAPI, we visualized the PV membrane under light microscopy and demonstrated that the mitochondrial-PV membrane complex persists after homogenization and centrifugation. As expected from the membrane-insertion behavior of BC5C, this fluorescent labeling revealed that the PV-mitochondrial membrane association is structurally reinforced rather than incidental, providing a mechanistic framework for understanding how Chlorella cells are stably positioned beneath the host cortex.
Background: Venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism, is increasingly recognized as a thromboinflammatory disorder involving coagulation, innate immunity, endothelial dysfunction, and vascular homeostasis. Emerging evidence suggests that gut microbiome-related inflammatory and metabolic signals may influence pathways potentially relevant to VTE through intestinal barrier dysfunction, microbial translocation, and microbiome-derived metabolites. This review critically examines the direct and indirect evidence relating gut dysbiosis to mechanisms potentially relevant to venous thrombogenesis. Methods: A structured literature search of PubMed, Scopus, and Web of Science was conducted from database inception to February 2026. Observational, translational, experimental, preclinical, and selected genetic studies were narratively synthesized across heterogeneous evidence types. Results: Available evidence suggests that intestinal barrier dysfunction and microbial translocation may increase systemic exposure to lipopolysaccharide and other microbial products, potentially contributing to inflammatory signaling and procoagulant responses. Proposed downstream effects include tissue factor (TF) activation, platelet reactivity, neutrophil extracellular traps (NETs) formation, complement signaling, endothelial perturbation, and impaired balance of anticoagulant and fibrinolytic pathways. Microbiome-derived metabolites, including trimethylamine N-oxide (TMAO), phenylacetylglutamine (PAGln), bile acids, and short-chain fatty acids (SCFAs), have been linked, mainly in experimental or non-VTE settings, to thrombosis-related biology. However, most evidence remains indirect, associative, or experimental, whereas direct human VTE-specific evidence is limited and heterogeneous. Conclusions: The gut microbiome-VTE axis is biologically plausible and supported mainly by mechanistic and indirect evidence, but current data are insufficient to support strong causal conclusions. Further longitudinal, well-phenotyped, mechanistically informed studies are needed to determine whether microbiome-related pathways have measurable clinical relevance in human VTE.
Gene expression begins with transcription initiation. However, the control of gene activation encompasses events that precede transcription and extend beyond it, and that are prominently regulated by the noncoding genome. Here we discuss the pivotal roles of long noncoding RNAs (lncRNAs) and the related enhancer RNAs (eRNAs) as genomic rheostats of the magnitude and duration of activation of transcription by RNA polymerase II, acting in trans by influencing general transcription factors and co-transcriptional and post-transcriptional processes, and in cis through their interactions with enhancers, promoters and other noncoding RNA genes. We further discuss how these lncRNAs are often produced at active enhancers or boundaries of topologically associating domains and can accumulate in biomolecular condensates. We propose models of lncRNA action that account for pre-existing chromatin states, and for the interactions between DNA, RNA and proteins. Understanding how lncRNAs fit within the dynamic process of transcription activation is essential for obtaining a comprehensive view of the regulation of gene expression.
Fibroblast growth factor 23 (FGF23) is an endocrine regulator of phosphate homeostasis produced by bone. This review aims to examine the role of FGF23 in bone biology, with a focus on its contributions to skeletal abnormalities in hereditary hypophosphatemia and chronic kidney disease (CKD). In hereditary hypophosphatemic disorders, FGF23 excess leads to renal phosphate wasting and impaired bone mineralization. Therapies targeting FGF23 demonstrated clear clinical benefits in restoring phosphate levels and improving skeletal defects. Recent evidence indicates that FGF23 may also exert direct effects on osteoblast differentiation independent of phosphate levels. In CKD, preclinical studies suggest that reducing FGF23 improves bone outcomes, but the contribution of FGF23 to altered osteoblast differentiation and bone loss in CKD remains to be tested directly. FGF23 contributes to bone disease both indirectly by regulating phosphate homeostasis and directly by inhibiting osteoblast differentiation. Targeting FGF23 represents a promising therapeutic approach, but in CKD, strategies blocking FGF23 must be carefully balanced against the risk of further disrupting phosphate balance. A better understanding of the mechanisms underlying the direct effects of FGF23 on bone is essential for the development of safe and effective treatments.
The higher incidence of cancer in patients with cardiovascular disease (CVD) has historically been explained by shared risk factors. Recent studies suggest, however, a causal relationship. Nevertheless, the mechanisms of CVD-induced cancer are incompletely understood. Here, we hypothesize that angiotensin II (ANGII) links CVD and increased cancer growth. We investigated the impact of ANGII-induced CVD on cancer growth in vivo, differentiating between a direct effect of ANGII on tumor cells or indirect effects secondary to CVD. The effect of ANGII on cancer growth was studied in C57BL/6J mice with cancer. Cancer was either induced by subcutaneous injection of Lewis lung carcinoma (LLC) cells, MC38 colon cancer cells, or by genetic susceptibility (APCmin mice). To differentiate between direct and indirect effects of ANGII on cancer growth three strategies were implemented: (i) Evaluating a protocol with and without overlap between ANGII treatment and the injection of tumor cells, (ii) comparing the effect of a high (2000 ng.kg- 1.min- 1) and low (400 ng.kg- 1.min- 1) dose of ANGII on intestinal polyp growth in APCmin mice and (iii) comparing the impact of ANGII on tumor growth in high (LLC) and low (MC38) angiotensin II receptor type I (AT1) expressing tumor cells. High dose ANGII-treatment induced left ventricle (LV) hypertrophy and cardiac fibrosis, and enhanced growth of injected tumor cells, but only when LCC tumor cells with high expression of AT1 were used, and when these cells were injected during ANGII treatment. ANGII did not increase cancer growth when LCC cells were injected after halting ANGII treatment, or when MC38 tumor cells with low AT1 levels were used. ANGII also increased the number of intestinal polyps in APCmin mice, even at a low dose that did not induce LV hypertrophy or cardiac fibrosis. Lastly, an analysis of publicly available cancer databases showed that AT1 gene copy number variation is increased in most human cancer lines and tumors. This study indicates that ANGII has direct effects on cancer growth, warranting further research into the role of an activated renin-angiotensin-aldosterone-system (RAAS) as a mechanistic link between CVD and cancer growth in AT1-positive tumors.
Fish display remarkable locomotor and social abilities, from efficient swimming to coordinated schooling, that have inspired the design of various robotic fish. While robotics has largely benefited from biology, fish-like robots are increasingly used as scientific tools to investigate fundamental questions in biomechanics, sensorimotor control, and collective behavior. This paper reviews how robotic models have been employed to study the neuromechanical basis of swimming, the role of sensory feedback in locomotion, and the mechanisms underlying social interactions in schools. We list open questions in biology and show that robotic approaches provide unique advantages to address them: they enable repeatable experiments, systematic variation of body and control parameters, and direct measurement of otherwise inaccessible quantities such as internal forces or energy use. A literature analysis reveals, however, that only a minority of robot-fish studies contribute to biological understanding, with most focusing on engineering design. Among biology-oriented studies, closed-loop robotic systems-capable of real-time adaptation-remain underrepresented but are essential for probing sensorimotor and social feedback mechanisms. We conclude by outlining future directions combining robotics, simulations, and emerging experimental technologies to unravel the multi-scale feedback loops that shape fish locomotion and schooling.
Human serum albumin (HSA) is the most abundant protein in plasma, and the redox state of circulating HSA has been used as a biomarker of systemic oxidative stress (OS) for decades. While informative, many traditional biomarkers of OS measure short-lived or downstream products of oxidative damage that offer limited perspectives on the dynamic and integrated processes that govern systemic redox biology within human populations. By moving beyond single-analyte damage markers and towards coordinated patterns of protein modifications, HSA-Cys34 adductomics offers a systems-level approach that simultaneously captures change in multiple layers of OS. Because of its high abundance in plasma and HSA's unique and highly reactive single free thiol (Cys34), HSA-Cys34 serves as an ideal sentinel target for monitoring reactions with reactive oxygen species (ROS), reactive nitrogen species (RNS), and electrophilic species produced by endogenous metabolism and responses to exogenous chemical exposures. The reaction of HSA with ROS, RNS, and reactive electrophiles yields a diverse array of protein modifications, including direct oxidation products (sulfenic, sulfinic, and sulfonic acid), low molecular weight thiol-disulfide exchange, and lipid peroxidation (LPO)-derived reactive aldehydes. With a mean residence time of about a month, these accumulated adducts serve as an integrated picture of oxidative and electrophilic stress that together function as a molecular record of systemic redox physiology. Previous studies using high-resolution mass spectrometry-based adductomics have enabled global untargeted analysis of HSA-Cys34 modifications, yielding an expansive inventory of novel redox signatures of environmental stressors and disease states. In this paper we review the chemistry and biology underlying OS-related modifications of HSA-Cys34 and highlight the important role of HSA-Cys34 adducts as integrative biomarkers of OS at the interface of molecular biology, exposure assessment, and public health research.
Exercise adaptation depends on overload that is resolved by recovery, yet the same biology becomes maladaptive when immune, endocrine, metabolic, and muscle-centered stress signals fail to normalize. Exercise-induced maladaptation represents a systems-level failure of biological resolution, with direct relevance to disease-like dysregulation. Functional overreaching, non-functional overreaching, and overtraining syndrome remain difficult to diagnose because no single biomarker provides adequate specificity, temporal stability, or clinical portability. This narrative review synthesizes human and mechanistic evidence across proteomics, transcriptomics, metabolomics, endocrine profiling, extracellular vesicles, and mitochondrial quality-control biology to define the molecular architecture most relevant to athlete monitoring. Across these layers, the most coherent signatures cluster in immune-acute-phase activation, redox-buffering strain, endocrine drift, altered substrate availability, excitation-contraction dysfunction, integrated stress-response signaling, and defects in autophagy-mitophagy and lysosomal remodeling. Three translational elements emerge from this synthesis: a systems-convergence model of recovery failure, a staged biomarker deployment hierarchy, and a provisional recovery failure index. The practical priority is therefore not a solitary marker, but serial phenotype-anchored multimarker panels that connect circulating signals with muscle-centered biology and support decision-making before prolonged recovery failure becomes entrenched.
Prostate cancer (PC) progression is increasingly recognized as a dynamic, inflammation-driven process in which chronic immune dysregulation contributes to disease aggressiveness and therapeutic resistance. Among inflammatory signaling pathways, nuclear factor kappa B (NF-κB) has been consistently implicated in prostate tumorigenesis, castration resistance, and apoptosis resistance. However, despite the extensive literature on NF-κB biology, the mechanisms by which its dysregulation is sustained and functionally shaped during PC progression remain incompletely understood. This review synthesizes current evidence on prostate cancer-specific NF-κB signaling, with an emphasis on stage-dependent activation, molecular regulation within the tumor microenvironment, and downstream transcriptional programs linked to survival and treatment resistance. Particular attention is given to the regulatory role of B-cell lymphoma-3 (BCL-3), an atypical nuclear IκB protein, and its potential interplay with B-cell lymphoma-2 (BCL-2), a well-established NF-κB-regulated anti-apoptotic factor in PC. Available clinical, molecular, and transcriptomic data support constitutive NF-κB activation across multiple stages of PC, particularly in advanced and castration-resistant disease. Although BCL-2 overexpression is well documented as a mediator of apoptosis resistance in PC, evidence directly linking BCL-3 to BCL-2 regulation in this disease remains limited. Data from other malignancies suggest that BCL-3 can modulate NF-κB transcriptional output and enhance BCL-2 expression; however, prostate-specific mechanistic validation is lacking. We propose a testable, hypothesis-driven model in which BCL-3 may function as a context-dependent regulator of NF-κB-mediated survival signaling in PC, potentially influencing BCL-2 expression and therapeutic resistance. However, this relationship remains speculative and is not yet supported by direct mechanistic evidence in PC. By distinguishing between established evidence and inferred mechanisms, this review highlights critical knowledge gaps and outlines experimental strategies to clarify the functional relevance of the BCL-3/BCL-2 axis. Improved understanding of NF-κB regulatory dynamics may inform the development of more precise, stage-adapted therapeutic strategies for advanced PC.
Bimolecular nucleophilic substitution (SN2) and base-induced elimination (E2) reactions play crucial roles in chemistry. Here, we report a combined study of ion-molecule crossed-beam 3D velocity map imaging experiments and dynamics simulations on an accurate 39-dimensional potential energy surface for the Cl- + (CH3)3CI reaction, allowing the most rigorous investigation of the atomistic dynamics. Good agreement between experimental and theoretical product angular and energy distributions is achieved, revealing that predominantly direct E2 reactions produce the majority of highly excited neutral products and slow ion product distributions. Moreover, we uncover a direct "flip-over" retention mechanism for the SN2 reaction, where substitution occurs via the direct flipping of the tert-butyl group, leading to retention of the tetrahedral carbon center. This mechanism manifests as a predominant forward-scattering feature in the product angular distribution and provides an important perspective on substitution dynamics in organic reactions.
Brain arteriovenous malformations (BAVMs) are increasingly recognized as dynamic vascular diseases driven by endothelial genetic alterations and dysregulated signaling pathways, rather than as static structural anomalies. Accumulating evidence from both hereditary and sporadic forms of BAVMs has established endothelial signaling dysfunction as a central pathogenic mechanism underlying aberrant angiogenesis, progressive lesion remodeling, and vascular instability that predisposes to hemorrhage. These insights have fundamentally shifted the conceptual framework of BAVMs toward a pathway-driven disease model. Despite this progress, direct access to biologically informative molecular material from living AVM lesions remains limited, posing a major barrier to detailed mechanistic interrogation and the translation of molecular insights into clinical decision-making. Historically, molecular characterization of AVMs has relied almost exclusively on surgically resected tissue, restricting analyses to selected patient populations and frequently reflecting late-stage disease biology. Such approaches provide limited insight into disease initiation, temporal evolution, or treatment-induced molecular changes. Recent advances in minimally invasive biopsy strategies, particularly those leveraging endovascular access, have begun to overcome these limitations by enabling molecular interrogation of AVMs in vivo. In this mini review, we summarize emerging approaches for molecular profiling of AVMs, with a primary focus on BAVMs, while also drawing on relevant studies in extracranial and other arteriovenous malformations that share common endovascular access routes, technical principles, and translational implications.
Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy characterized by local invasion, lymph node metastasis, and therapeutic resistance. Chronic periodontal disease has been linked to HNSCC progression, yet the responsible pathogens and underlying molecular mechanisms remain unclear. Here, we show that the keystone periodontal pathogen Porphyromonas gingivalis promotes HNSCC metastasis and chemoresistance through two internalin proteins that are secreted via the type IX secretion system (T9SS). These internalin proteins specifically bind the EC1 domain of E-cadherin through their curved solenoid-like leucine-rich repeats (LRRs), facilitating bacterial invasion and inducing epithelial-to-mesenchymal transition (EMT). Mechanistically, internalin-E-cadherin engagement drives β-catenin nuclear translocation and activates p38 and JNK1/2 MAP kinase signaling pathways, enhancing tumor cell migration, metastatic dissemination, and resistance to cisplatin-induced apoptosis. Tissue microarrays detect internalin antigens in HNSCC specimens, supporting their in vivo relevance. Together, these findings establish a direct mechanistic link between an oral pathogen and HNSCC progression and extend the paradigm of internalin-E-cadherin interactions from microbial pathogenesis to cancer biology.
Melatonin, a well-known antioxidant, has been widely used in sperm cryopreservation of various animals, but its regulatory mechanism in fish remains unclear. This first study on teleosts suggests a potential molecular mechanism by which melatonin may improve post-thaw sperm quality of Epinephelus fuscoguttatus via targeting mitochondrial function. Compared with the melatonin group, the MT1 receptor-inhibited group showed slightly higher sperm motility (77.09 ± 3.41% vs. 76.50 ± 1.10%), significantly inhibited mitochondrial permeability transition pore (mPTP) opening (12.64 ± 1.05% vs. 18.29 ± 1.38%), and maintained higher mitochondrial membrane potential (MMP; 85.86 ± 0.18% vs. 81.81 ± 0.69%), with both groups performing better than the control. In contrast, the MT2-inhibited and MT1/2 dual-inhibited groups exhibited reduced sperm quality compared with the MT group, suggesting that MT2 may serve as the core receptor for melatonin to regulate mitochondrial homeostasis in teleosts. Mechanistically, melatonin-activated MT2 potentially inhibits mPTP opening via the PI3K/Akt/GSK-3β pathway, and this protective effect was abrogated by the PI3K and GSK-3β inhibitors. This receptor-mediated process synergized with melatonin's direct antioxidant effect, as ROS levels in all melatonin-treated groups were significantly lower than the control. This study is the first to find pharmacological evidence for the melatonin-MT2/PI3K/GSK-3β axis in maintaining teleost sperm mitochondrial function; it also reveals potential mechanistic differences between teleosts and mammals and fills a critical knowledge gap regarding this signaling cascade in teleost reproductive biology.