Search Results (855)

Inflammatory pain arises from the interaction between nociceptive activation and immune signalling within injured or inflamed tissues. While the production of inflammatory mediators has been extensively investigated, less attention has been directed toward mechanisms governing their clearance and spatial redistribution. In this review, we examine how lymphatic vessels actively regulate inflammatory signal persistence in the interstitial space by integrating endothelial barrier behaviour, structural remodelling and intrinsic contractility. The lymphatic system, traditionally regarded as a passive conduit for fluid return and immune cell trafficking, is increasingly recognised as a dynamic regulator of tissue homeostasis. Neuropeptides released from nociceptive afferents, including calcitonin gene-related peptide (CGRP) and substance P (SP), influence lymphatic permeability, lymphangiogenesis and lymph propulsion, thereby shaping the kinetics of inflammatory mediator clearance. Endogenous opioid signalling and pain-related anaesthetic agents may further modulate lymphatic function through effects on lymphatic muscle excitability and endothelial dynamics. Collectively, we propose a systems-level framework in which lymphatic physiology operates as a regulatory interface linking neural activation to immune resolution. Recognising this integrative role may refine current concepts of inflammatory pain and provide a physiologically grounded basis for future translational investigation. Full article

Despite its established role as a cornerstone of chemotherapy for solid tumors, 5-Fluorouracil (5-FU) clinical efficacy remains limited by chemoresistance and heterogeneous drug response. Traditional explanations have focused on intracellular metabolism and genetic determinants; however, increasing evidence identifies the plasma membrane as a critical regulatory interface controlling drug availability, signaling integration, and cell fate. Here, we propose a membrane-centered framework in which compartmentalized cAMP/PKA signaling, modulated by repurposed vasoregulatory agents—levosimendan, milrinone, and terbutaline—enhances 5-FU response by functionally remodeling the cancer cell membrane. This remodeling may influence lipid raft organization, ENT1/SLC29A1 transporter trafficking, and the balance between drug influx and efflux, increasing intracellular 5-FU bioavailability and overcoming membrane-mediated pseudo-resistance. In parallel, cAMP-dependent signaling may modulate redox homeostasis, mitochondria-associated membranes, and apoptotic threshold regulation, shifting the cellular response toward irreversible cell death. Importantly, this framework is reconciled with canonical resistance mechanisms—including TYMS upregulation, DPD overexpression, and MMR deficiency—positioning membrane phenotype as a functionally upstream regulatory layer. Differential sensitivity observed experimentally in bladder versus prostate cancer models supports the concept of integrated membrane phenotype biomarkers. Clinical translation requires rigorous pharmacokinetic–pharmacodynamic validation and cardiovascular safety assessment. Redefining the plasma membrane as a dynamic therapeutic interface may provide a rationale for drug repurposing, patient stratification, and personalized combination strategies. Full article

Organophosphate flame retardants (OPFRs) are widely used as flame-retardant additives in plastics, electronics, and building materials. However, growing evidence suggests these compounds may pose significant neurotoxic risks. This study evaluated phenotypic alterations, such as cell viability, reactive oxygen species generation, and acetylcholinesterase activity, induced by seven widely detected OPFRs in SH-SY5Y human neuroblastoma cells. Aromatic OPFRs such as triphenyl phosphate (TPhP), 2-ethylhexyldiphenyl phosphate (EHDPhP) and tricresyl phosphate (TCP) exhibited the strongest effects, including decreased cell viability, increased oxidative stress and AChE inhibition. Therefore, 3D brain organoid models were used to further explore the potential lipidomic alterations induced by aromatic OPFRs. Lipidomic analysis of brain organoids exposed to aromatic OPFRs (TPhP, EHDPhP and TCP) showed significant alterations across major lipid classes, especially glycerophospholipids, sphingolipids, and glycerolipids. The depletion of bis(monoacylglycerol)phosphate (BMP) species suggests perturbations in endolysosomal lipid homeostasis and membrane trafficking pathways. Increased levels of ether-linked lysophosphatidylcholine (LPC-O) species, together with altered phosphatidylethanolamine (PE) and phosphatidylserine (PS) species, indicate extensive membrane lipid remodeling and changes in cellular signaling. Furthermore, the accumulation of diacylglycerol (DG) and triacylglycerol (TG) species points to disturbances in lipid storage and metabolism. Overall, these findings indicate that aromatic OPFRs induce cytotoxicity, oxidative stress, and alteration of cholinergic function, and are associated with lipid dysregulation linked to neurotoxicity in brain organoids. Future research should explore chronic low-dose exposure and long-term neurological effects. Full article

Endothelial dysfunction is an early event in the development of cardiovascular diseases and is characterized by impaired barrier function, inflammatory activation of endothelial cells (ECs), and alterations in lipid metabolism. In addition to typical (mononuclear) endothelial cells (TECs), multinucleated variant endothelial cells (MVECs) are present within the vascular wall; however, their functional role remains poorly understood. The aim of the present study was to investigate the molecular and functional characteristics of MVECs and their potential contribution to the development of endothelial dysfunction. Primary human umbilical vein endothelial cells (HUVECs) were used, and multinucleated cells were generated by polyethylene glycol-induced fusion. Cells were incubated under control conditions or exposed to low-density lipoproteins (LDL; 100 µg/mL, 24 h). A comprehensive analysis was performed, including transcriptomic and proteomic (secretome) profiling using gene set enrichment analysis (GSEA), as well as functional assays assessing transendothelial LDL transport, intracellular cholesterol accumulation, macrophage migration, and the expression and secretion of pro-inflammatory cytokines (IL-6, IL-8). MVECs exhibited pronounced differences compared to TECs. GSEA revealed reduced enrichment of pathways related to canonical nuclear factor kappa B (NF-κB) signaling and negative regulation of NF-κB transcription factor activity, actin cytoskeleton organization, focal adhesion assembly, basement membrane organization, and vesicle-mediated transport in MVECs relative to TECs, indicating impaired cytoskeletal integrity, altered cell–matrix interactions, dysregulated inflammatory signaling, and reduced vesicular trafficking activity. Functionally, MVECs demonstrated an increased capacity for cholesterol accumulation and enhanced transendothelial migration of macrophages. Notably, transendothelial LDL transport across the MVEC monolayer was not increased, suggesting a predominance of intracellular lipid accumulation. MVECs also exhibited a pronounced pro-inflammatory phenotype, characterized by elevated expression and secretion of IL-6 and IL-8. Taken together, these findings indicate that MVECs represent a functionally altered endothelial phenotype with impaired barrier function, dysregulated lipid metabolism, and enhanced inflammatory activity. Local accumulation of MVECs within the vascular wall may contribute to the formation of pro-atherogenic regions and play a role in the initiation and progression of endothelial dysfunction. Full article

Cardiovascular disease and cancer remain the leading causes of death worldwide. Although numerous cancer therapies have improved survival rates, they also increase the risk of cardiomyopathy, heart failure, and arrhythmias. These cardiovascular complications can limit treatment options and adversely affect the long-term quality of life of cancer survivors. Ca_V1.3, an L-type calcium channel encoded by CACNA1D, emerges as a central molecular mediator linking cardiovascular disease and cancer. It regulates calcium entry into cardiomyocytes and contributes to sinoatrial pacemaking and atrioventricular conduction. It also contributes to proliferation, migration, and therapy resistance in several cancers. Chemotherapy-induced oxidative stress, inflammatory signaling, hypoxia, and transcriptional changes can modulate the expression, gating, splicing, and trafficking of Ca_V1.3 channels. All these changes destabilize diastolic depolarization and impair conduction, thereby promoting arrhythmias in cancer patients. This review focuses on Ca_V1.3 biology in cardio-oncology, along with the mechanisms of chemotherapy-induced cardiotoxicity. It outlines the role of Ca_V1.3 as a key mediator linking cancer therapies to subsequent nodal dysfunction and increased arrhythmia susceptibility. It also expands on how patient-specific induced pluripotent stem cell-derived cardiomyocytes can model Ca_V1.3 dysregulation as well as support the development of targeted therapies. We propose that Ca_V1.3 represents a mechanistic bridge linking cancer therapy, calcium signaling, and cardiac electrophysiology, and that elucidating its pathophysiology may guide the design of targeted strategies in cardio-oncology. Full article

The Popeye domain-containing protein 1 (Popdc1), also known as Bves, plays a crucial role in maintaining skeletal muscle homeostasis, with its variants leading to limb–girdle muscular dystrophy type R25. Skeletal muscles of patients with the homozygous missense variant of Bves exhibit impaired membrane trafficking, while skeletal muscle fibers in bves^S191F homozygous mutant zebrafish are significantly reduced and disorganized. However, the mechanism by which the absence of bves induces skeletal muscle atrophy remains unclear. In this study, we discovered a novel mechanism whereby bves deficiency drives skeletal muscle atrophy by disrupting mitochondrial structure and function. Our findings indicate that bves knockout leads to a significant decrease in zebrafish’s ability to swim, atrophy of skeletal muscle tissue, loss of cell membrane localization signals, and abnormalities in mitochondrial structure and function. After an 8-week intervention of regular aerobic exercise, the symptoms of skeletal muscle atrophy in bves knockout zebrafish were significantly alleviated, and the expression levels of genes and proteins related to mitochondrial were effectively rescued. These findings establish a connection between bves deficiency-induced disruption of mitochondrial structure and function and the onset and progression of skeletal muscle tissue atrophy symptoms, thereby laying a molecular foundation for exercise rehabilitation strategies in atrophic myopathy. Full article

Atherosclerosis (AS) is the primary underlying cause of cardiovascular and cerebrovascular diseases. The occurrence and development of AS are closely related to lipid deposition, chronic inflammation, phenotypic modulation of vascular smooth muscle cells (VSMCs), and extracellular matrix (ECM) remodeling. Numerous studies indicate that low-density lipoprotein receptor-associated protein 1 (LRP1), as a multifunctional receptor, contributes to vascular homeostasis in AS and vascular remodeling by regulating lipid handling, inflammatory responses, transforming growth factor beta (TGFβ) signaling, and platelet-derived growth factor receptor beta (PDGFRβ) trafficking. Rather than treating the LRP1-TGFβ-PDGFRβ relationship as a fully established linear pathway, this review distinguishes demonstrated mechanisms from inferred cross-talk and proposes an integrated, cell- and stage-dependent regulatory model. This article systematically elaborates on the structure and function of LRP1; LRP1-mediated regulation of TGFβ and PDGFRβ in AS and vascular remodeling; the possible relationship among LRP1, TGFβ, and PDGFRβ; and cell-specific effects in VSMCs, macrophages, endothelial cells, and pericytes. Meanwhile, this article summarizes potential translational strategies such as lipid-lowering, anti-inflammatory therapy, PDGFRβ inhibitor repositioning, TGFβ pathway modulation, biomarker-based stratification, and LRP1-targeted delivery. A deeper understanding of the cell-specificity and stage-dependence of the LRP1-TGFβ-PDGFRβ signaling network may help elucidate the progression mechanism of AS and provide new ideas for risk stratification and precise intervention. Full article

Lung cancer, particularly non-small cell lung cancer (NSCLC), remains the leading cause of cancer mortality worldwide. While immune checkpoint inhibitors (ICIs) have revolutionized treatment, primary and acquired resistance, and immune-related adverse events (irAEs) limit their therapeutic efficacy. Recent evidence highlights the gut and local microbial communities as a modifiable determinant of NSCLC outcomes, especially in the context of ICI use. Emerging data support the concept of a gut–lung-immune axis, a tridirectional communication pathway, in which gut and lung microbial communities influence local and systemic antitumor immunity through immune cell trafficking, cytokine signaling, and microbial-derived metabolites. In this review, we synthesize current clinical and mechanistic studies examining the role of gut, tumor-resident, and circulating microbiota in shaping ICI efficacy and toxicity in NSCLC. Distinct gut and tumor microbial signatures, such as the abundance of Akkermansia muciniphila and Bifidobacterium, correlate with improved ICI response, whereas dysbiosis promotes immune suppression, resistance, and irAEs. Additionally, we highlight emerging microbial-based biomarkers, including fecal microbial profiles, circulating microbial DNA, and composite tools such as TOPOSCORE, which show promise for predicting response, toxicity, and optimal treatment duration. Overall, these findings underscore the gut–lung-immune axis as a key regulator of immunotherapy outcomes in NSCLC and suggest that microbiome-informed strategies may enable more precise, effective, and safer personalization of ICI therapy. Full article

Plant immune genes are traditionally classified as resistance genes, susceptibility genes, or positive/negative regulators of defense. However, this framework does not fully explain a subset of immune-associated genes that display paradoxical disease phenotypes, in which genetic disruption enhances resistance despite the normal involvement of these genes in defense-related processes. GSL5/PMR4 is a representative example. As a pathogen-induced callose synthase, GSL5 contributes to papillary callose deposition and structural defense. Paradoxically, loss of GSL5 confers resistance to powdery mildew through salicylic acid- and N-hydroxypipecolic acid-associated pathways, as well as broad-spectrum resistance to Plasmodiophora brassicae through jasmonic acid-dependent immunity. Here, we refer to such genes as dual-state immune regulators, whose functional presence and genetic disruption promote resistance through distinct immune states. Similar regulatory patterns have been reported in several immune-related processes, including MAPK signaling, calcium influx, membrane trafficking, and receptor-proximal immune signaling. Representative examples include the MEKK1–MKK1/MKK2–MPK4 module, CNGC2/CNGC4, EXO70B1 and BIK1. This review uses GSL5 as a central example to discuss paradoxical immune phenotypes and dual-state immune regulators in plants, focusing on their biological features, potential mechanisms, and implications for resistance breeding. Full article

Acute myeloid leukemia (AML) presents significant challenges for CAR T-cell therapy due to its pronounced heterogeneity and the lack of leukemia-specific surface antigens. Frequently targeted antigens, such as CD33, CD123, and CLL-1, are also present on normal hematopoietic progenitors, resulting in on-target, off-tumor toxicity and restricting clinical translation. To address these challenges, logic-gated CAR T-cell strategies have been developed to enable combinatorial antigen recognition. These approaches incorporate engineered circuits, including AND, OR, and NOT gates, as well as synNotch receptors, split-CAR configurations, and inhibitory platforms (iCARs and Tmod), to improve discrimination between leukemic and normal cells. In AML, CAR T-cell efficacy and persistence are further affected by the immunosuppressive bone marrow and lymphoid microenvironment, which involves immune cell trafficking, cytokine signaling, and lymphatic immune regulation. Preclinical studies employing dual-target strategies, such as CD33/CD123 and CLL-1/CD123, have shown improved antileukemic efficacy with reduced hematopoietic toxicity. This review summarizes the molecular principles underlying logic-gated CAR-T systems and examines their translational application in AML. Additionally, it highlights emerging evidence connecting the regulation of lymphatic and immune microenvironments to CAR T-cell persistence, trafficking, and toxicity and discusses future strategies, such as single-cell antigen mapping, computational circuit engineering, and synthetic immune programming, to enhance the precision and clinical feasibility of next-generation AML immunotherapies. Full article

Regulated cell death is essential for tissue homeostasis, immune defense, and disease progression, yet the lipid-based regulatory mechanisms that coordinate cell death signaling remain incompletely understood. Protein palmitoylation is a dynamic and reversible lipid post-translational modification that controls protein membrane association, trafficking, stability, and signaling complex assembly. This review summarizes the regulatory roles of palmitoylation and depalmitoylation in major forms of regulated cell death, including apoptosis, necroptosis, pyroptosis, ferroptosis, and autophagy-related cell death. Particular attention is given to representative palmitoylated substrates, including Fas cell surface death receptor (Fas), receptor-interacting protein kinase 1 (RIPK1), NLR family pyrin domain containing 3 (NLRP3), gasdermin D (GSDMD), glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), autophagy-related 16 like 1 (ATG16L1), and Beclin1. These substrates illustrate how palmitoylation links membrane organization, metabolic status, inflammatory signaling, and cell fate decisions. Disease-oriented evidence further indicates that dysregulated palmitoylation contributes to cancer, neurodegenerative diseases, and inflammatory or immune-related disorders by modulating cell death resistance, inflammatory amplification, immune evasion, or impaired proteostasis. Current challenges include limited quantitative information on palmitoylation dynamics, incomplete evidence for some enzyme–substrate relationships, and insufficient distinction between disease-driving and secondary palmitoylation events. Targeting zinc finger Asp-His-His-Cys (zDHHC) palmitoyl acyltransferases, depalmitoylating enzymes, or specific palmitoylated substrates may provide new therapeutic opportunities. Overall, this review positions protein palmitoylation as a dynamic molecular switch linking lipid metabolism, membrane signaling, regulated cell death, and disease remodeling. Full article

Pancreatic cancer remains one of the most lethal malignancies worldwide, with pancreatic ductal adenocarcinoma accounting for the vast majority of cases and characterized by extensive desmoplasia, immune exclusion, and resistance to systemic therapies. Increasing evidence implicates lysosomal cathepsins as important regulators of these defining features of pancreatic tumor biology. Cathepsin-dependent proteolysis and lysosome-associated signaling pathways contribute to extracellular matrix remodeling, regulate immune cell trafficking, and influence antigen processing and presentation. Beyond their classical degradative functions, cathepsins participate in stress-adaptive cellular programs linked to autophagy, metabolic regulation, and proteostasis, supporting tumor cell survival under hypoxic, nutrient-limited, and therapy-induced stress conditions. Within the tumor microenvironment, dysregulated cathepsin activity promotes immune evasion by reshaping cytokine networks, impairing effective antigen presentation, and reinforcing physical and functional barriers to cytotoxic T-cell infiltration. Collectively, these mechanisms position the lysosome–cathepsin system as a central regulator of proteolytic remodeling, immune exclusion, and adaptive therapy resistance in pancreatic cancer, highlighting its potential relevance for emerging combinatorial therapeutic strategies. Full article

This study examined the protective mechanisms of oleanolic acid (OA) against high-fat diet (HFD)-induced hepatic steatosis and intestinal dysbiosis in Nile tilapia. Fish were allocated to four groups: normal diet (ND), HFD, and OA-supplemented HFD (50 and 250 mg/kg). After 42 days, physiological, biochemical, and histological assessments demonstrated that OA markedly reduced hepatic lipid accumulation, mitochondrial injury, and intestinal shortening. Transcriptomic analysis revealed that OA alleviated lipid dysregulation by inhibiting de novo lipogenesis and promoting lipid trafficking and β-oxidation, effectively reversing HFD-induced changes in the PPAR, MAPK, mTOR, and autophagy-lysosome signaling pathways. 16S rRNA sequencing indicated that OA increased microbial alpha diversity, suppressing HFD-associated taxa (e.g., Nordella) while enriching beneficial genera such as Clavibacter, Bosea, and Bdellovibrio. Importantly, OA treatment restored HFD-induced depletion of intestinal butyric acid and suppressed hepatic pro-inflammatory cytokines (tnf-α, il-1β), while upregulating growth-related factors (igf1). Correlation analysis confirmed strong associations between microbial alterations (Nordella and Phreatobacter) and hepatic lipid metabolism and inflammatory gene expression. Overall, OA mitigates metabolic stress in Nile tilapia by reconfiguring the gut–liver axis, integrating microbial restoration with precise regulation of hepatic nutrient-sensing and inflammatory pathways, providing a potential therapeutic strategy for lipid metabolism disorders in aquaculture. Full article

Ductal carcinoma in situ (DCIS) is a non-invasive precursor to invasive breast cancer. DCIS incidence continues to rise, yet its clinical management remains constrained by the absence of reliable biomarkers that can adequately distinguish indolent lesions from those with high invasive potential, to circumvent over- or under-treatment. Black women with DCIS are significantly more likely to progress to invasive breast cancer, are disproportionately diagnosed with high-grade, hormone receptor-negative lesions, and experience elevated risk of recurrence and mortality relative to White women with DCIS. These disparities persist despite comparable access to screening and treatment, suggesting underlying biological and tissue microenvironmental factors. This review synthesizes emerging evidence implicating early molecular and systemic changes that may be driving the disparity in DCIS progression. We highlight racial distinctions in interconnected pathways involving Wnt/β-catenin signaling, metabolic and nutritional dysregulation, immune microenvironment remodeling, and cellular tolerance of genomic instability. We further discuss how epigenetic alterations, obesity-associated inflammation, and immune dysregulation may arise during the pre-invasive stage that intersect with social and environmental exposures to influence racial differences in lesion fate. We spotlight candidate biomarkers disproportionately associated with aggressive disease in Black women—including KIFC1, a mediator of centrosome clustering and genomic instability tolerance, and ACKR1/DARC, a regulator of chemokine gradients and immune trafficking—as potential drivers of progression-permissive states. This review advances an integrated, equity-informed framework for DCIS progression that links early tumor evolution to coordinated alterations in genomic instability, immune regulation, metabolic signaling, and stress-adaptive pathways. Importantly, we propose that DCIS progression is governed not by isolated molecular alterations but by coordinated programs that enable survival under genomic and immunologic stress. Current clinical risk assays, which primarily capture tumor-intrinsic proliferation and hormone signaling, do not fully resolve these pathways and may therefore incompletely reflect biologically meaningful racial disparities. This synthesis underscores the need for pathway-level, microenvironment-informed, and population-representative approaches to DCIS risk stratification. Advancing such frameworks will be essential for identifying actionable biomarkers, refining early intervention strategies, and ultimately reducing racial disparities in breast cancer outcomes. Full article

The hallmarks of allergic diseases are Type 2 immunity, including IL-4 and IL-13 production, IgE antibody generation, mast cell and basophil activation, histamine release, and eosinophil activation. There are many routes by which such mediators can influence CNS biology, including cytokine entry or signaling via brain barrier receptors; leukocyte trafficking across activated barriers; cytokine signaling via circumventricular organ sites or dural immune compartments; vagus nerve afferent signaling; mast cell degranulation; and histamine neuromodulation. Neuroinflammation is a common hallmark of many neurodegenerative diseases, but whether and to what degree allergic/type 2 immune biology may be involved depends on the specific disease stage and pathology. Here, we assess studies connecting the roles of IL-4/IL-13 signaling, IgE/mast cell activation, eosinophil-attractive chemokines, and histamines in Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, amyotrophic lateral sclerosis, dementia with Lewy bodies, Huntington’s disease, prion disease, and tauopathy/atypical parkinsonism. Mechanisms appear most clear in the case of Parkinson’s disease, where epidemiology suggests an important role in dementia/Alzheimer’s disease, while for other neurodegenerative conditions the evidence is less compelling and may be either mechanistic or modulatory. Confounding issues include sex differences, drug exposures, comorbid conditions, socioeconomic factors, and coexisting inflammatory diseases. Finally, we suggest a strategy based on longitudinal immune phenotyping, CNS biomarkers, and pathway manipulation to assess the relationship between allergic immune signaling and neurodegeneration. Full article