Search Results (864)

Retinal neurovascular unit (RNVU) dysfunction underlies major blinding and neurodegenerative conditions including glaucoma, diabetic retinopathy (DR), age-related macular degeneration (AMD), retinal ischemia–reperfusion (RIR) injury, and Alzheimer’s disease (AD)-associated retinopathy. Within the RNVU, calcium ions coordinate neurotransmission, glial activation, vascular tone, and blood–retinal barrier maintenance, and calcium dysregulation is emerging as a unifying pathogenic hub across these conditions. Although upstream triggers differ, including mechanical stress in glaucoma, hyperglycemia in DR, oxidative damage in AMD, ischemic energy failure in RIR, and amyloid-β–driven endoplasmic reticulum stress in AD, all converge on disruption of intracellular calcium homeostasis, producing shared downstream consequences including excitotoxic injury of retinal ganglion cells (RGCs), Müller cell reactive gliosis, and pericyte hypercontraction. Broad-spectrum calcium channel blockade has shown limited clinical success, underscoring the need for cell-type-specific and pathway-selective approaches. This review therefore catalogs key interventional nodes, including transient receptor potential (TRP) channel antagonists, T-type calcium channel inhibitors, calcium/calmodulin-dependent protein kinase II (CaMKII) suppressors, and mitochondrial permeability transition pore (mPTP) inhibitors, and discusses how precision targeting of these pathways may restore RNVU homeostasis and open a therapeutic window into central nervous system (CNS) degenerative disorders. Full article

Transient receptor potential ankyrin 1 (TRPA1) channels detect noxious cold and inflammatory mediators in mammals; yet their evolutionary origins and roles in neuro-immune integration remain unclear. Here, we investigated TRPA1 in Hydra vulgaris, an early metazoan with a simple nervous system, exposing polyps to noxious cold and Pseudomonas aeruginosa lysate. Using Western blotting, pharmacological modulation, and gene expression analyses, we demonstrated that TRPA1 mediates upregulation of nociceptive markers (Nrf2, NOS, SOD) and immune effectors (NF-κB, NOS, periculin, hydramacin). TRPA1 antagonism significantly reduced these responses, indicating its role as an amplifier of both nociceptive and innate immune signaling. These findings suggest that TRPA1-dependent coupling of nociceptive-like and immune responses is an ancient, conserved mechanism, providing insights into the molecular basis of integrated threat detection and offering potential avenues for targeting pain and inflammation-associated pathologies. Full article

Dental pain due to dentine hypersensitivity or pulpitis is characterized by short or lasting episodes of pain triggered by normally innocuous stimuli originating from exposed dentine. Both represent the most frequent pain of the orofacial region. Transient receptor potential (TRP) superfamily of ion channels participates in the detection of different modalities of sensibility in the mammalian sensory teeth system, i.e., trigeminal neurons and odontoblasts. In particular, some members of the melastatin family (TRPM) serve as molecular thermal sensors, and temperature is one of the most potent stimuli in triggering dentine hypersensitivity. Here we review and update the information about the distribution of TRPM channels in the trigeminal ganglion and dental pulp cells, especially odontoblasts, in humans and animal models. In addition to the well-known sensory roles of TRPM, other functions such as the development and mineralization of teeth are considered. Full article

Endometriosis is a chronic, estrogen-dependent disorder defined by ectopic endometrial-like tissue growth, persistent inflammation, and aberrant innervation. Emerging evidence indicates that disease progression and symptom severity are driven by a reciprocal interaction between hormonal dysregulation and neuroinflammatory signaling. This narrative review synthesizes human-based mechanistic and clinical evidence on the hormonal–neuroinflammatory interface in endometriosis, drawing on peer-reviewed publications retrieved from PubMed and Scopus through November 2025. The publications comprised studies using data from patient-derived tissues, primary endometriotic cells, and clinical cohorts. Several convergent molecular nodes at this interface were identified: the prostaglandin E₂–prostaglandin E receptor 2/prostaglandin E receptor 4–aromatase axis, estrogen receptor beta—nuclear factor kappa B signaling, interleukin-6/signal transducer and activator of transcription 3-mediated fibrosis, neurotrophin pathways, transient receptor potential channels (TRPV1/TRPA1), and neurokinin 1 receptor signaling. In this integrated model, endocrine dysfunction fuels neuroinflammation, which in turn impairs steroid responsiveness. This cycle explains the frequent pain–lesion mismatch and the persistence of symptoms despite standard hormonal suppression. Targeting these druggable interface pathways enables better patient stratification and more effective combination therapies for endometriosis. Full article

Ferroptosis is an iron-dependent, lipid peroxidation–driven form of regulated cell death that has emerged as a therapeutic vulnerability in hepatocellular carcinoma (HCC), yet the contribution of lysosomes to this process remains incompletely understood. In this study, we investigated whether lysosomal ion channels regulate ferroptosis sensitivity in HCC cells, focusing on the two-pore channel 2 (TPC2) and the transient receptor potential mucolipin 1 (TRPML1). Using pharmacological modulation, genetic knockout models, flow cytometry-based cell death and lipid peroxidation assays, lipidomics, calcium measurements, and molecular analyses across multiple HCC cell lines, we examined how these channels influence ferroptotic signaling. We show that NAADP-dependent TPC2 activity is required for efficient ferroptosis induction, whereas TPC2 loss renders HCC cells resistant to ferroptosis triggered by system Xc⁻ inhibition or glutathione peroxidase 4 (GPX4)blockade. This resistance is associated with reduced lipid peroxidation, altered calcium signaling, and selective depletion of polyunsaturated phosphatidylethanolamine species linked to decreased Acyl-CoA Synthetase Long-Chain Family Member 4 (ACSL4) expression. In contrast, TRPML1 deficiency sensitizes cells to ferroptosis and correlates with enhanced endoplasmic reticulum stress and oxidative imbalance rather than major lipid remodeling. Collectively, these findings identify lysosomal ion channels as key modulators of ferroptosis in HCC and highlight distinct mechanisms by which TPC2 and TRPML1 regulate cellular redox balance and death susceptibility. Full article

During production, fish are exposed to multiple environmental, physiological, and physical stressors, which compromise development, productivity, and welfare and urge the implementation of effective and safe stress-mitigating strategies, particularly during early developmental stages. Larval zebrafish (Danio rerio) constitute a powerful model for studying acute stress responses due to the numerous advantages they offer, such as developmental transparency, a conserved hypothalamic–pituitary–interrenal (HPI) axis, and suitability for high-throughput screening. This review examines the potential of natural monoterpenes as stress-reducing compounds and compares their performance with conventional synthetic anesthetics. Evidence from vortex-flow stress paradigms, behavioral profiling and biochemical assays shows that acute stress in zebrafish larvae triggers metabolic disruption, behavioral hyperactivity and enzyme imbalance, with cortisol responses depending on stimulus intensity. Monoterpenes such as thymol and menthol consistently reduce stress-induced hyperactivity, support redox homeostasis and display favorable safety profiles at low doses and short exposures. Nevertheless, as research into these substances is still recent, evidence of any potential adverse effects is still limited. Although individual monoterpenes may act on different subsets of molecular targets, their multimodal mechanisms, including gamma-aminobutyric acid (GABA)ergic enhancement, voltage-gated ion channel and transient receptor potential (TRP) modulation, suggest broader and potentially safer actions compared to single-target anesthetics as tricaine methane sulfonate (MS-222). Collectively, these findings suggest that monoterpenes offer promising natural alternatives for stress mitigation in aquaculture and the refinement of research procedures involving early life stages. Full article

Background and Objectives: Sevoflurane, a widely used volatile anesthetic, can induce oxidative stress and apoptosis, but the underlying mechanisms in human cardiomyocytes remain unclear. This study investigated the role of transient receptor potential vanilloid 1 (TRPV1) channels in sevoflurane-induced cardiotoxicity and the potential mitigating effect of ascorbic acid. Materials and Methods: Human cardiomyocytes were exposed to sevoflurane (5.1%, 6 h) and/or ascorbic acid (1 mM, 30 min), with or without the TRPV1 channel antagonist capsazepine and with the TRPV1 channel agonist Capsaicin. Intracellular calcium, reactive oxygen species (ROS), apoptosis, mitochondrial membrane potential, and caspase-3/9 activities were assessed. Results: Sevoflurane significantly increased intracellular calcium levels, ROS production, mitochondrial depolarization, apoptosis, and caspase-3/9 activity compared with controls (p < 0.001). These effects were attenuated by capsazepine, suggesting a role for TRPV1 involvement. Ascorbic acid pretreatment significantly reduced sevoflurane-induced elevations in all parameters (p < 0.001). Combined ascorbic acid and capsazepine treatment yielded further reductions in calcium, ROS, apoptosis, and caspase activities compared to ascorbic acid alone (p < 0.05). Conclusions: Sevoflurane induces apoptosis in human cardiomyocytes via ROS-mediated activation of the TRPV1 channel, leading to calcium overload, mitochondrial dysfunction, and caspase-dependent cell death. Ascorbic acid exerts mitigating effects by reducing oxidative stress and modulating TRPV1 channel activity, suggesting a potential therapeutic strategy for myocardial protection during sevoflurane anesthesia. Full article

Ononis spinosa L. (Fabaceae), commonly known as spiny restharrow, is a widely distributed medicinal plant traditionally used in European and Middle Eastern phytotherapy, particularly for the management of urological and inflammatory conditions. Despite its long-standing ethnomedicinal relevance, comprehensive syntheses of its phytochemical profile and biological activities remain limited. This review aimed to summarize current evidence regarding the chemical constituents and pharmacological effects of O. spinosa. Four electronic databases (PubMed, Scopus, Web of Science, and SpringerLink) were searched for studies published between 1997 and 2024. The search yielded 308 records; after duplicate removal and eligibility screening, 34 studies met the inclusion criteria. The phytochemical profile of O. spinosa is characterized predominantly by isoflavonoids (e.g., ononin and other formononetin derivatives), triterpenes, phenolic acids, and additional polyphenolic compounds. Although the phytochemical profile of O. spinosa includes multiple classes of secondary metabolites, this review places particular emphasis on phenolic compounds, given their prevalence and well-documented biological activities. Experimental evidence indicates a broad spectrum of biological activities, including anti-inflammatory effects (associated with cPLA2α inhibition and cytokine modulation), antibacterial and antifungal activity, antioxidant capacity, wound-healing and dermatological benefits, as well as diuretic and anti-adhesive effects in urinary models. Additional reported properties include antiproliferative, anti-adipogenic, analgesic, and neurotrophic activities. Proposed mechanisms of action involve enzyme inhibition (e.g., Hyal-1 and COX-2), modulation of transient receptor potential (TRP) channels, redox regulation, and interference with microbial adhesion and inflammatory signaling pathways. Overall, O. spinosa contains bioactive compounds exhibiting a wide range of pharmacological activities supported by in vitro and in vivo studies. Among the investigated effects, anti-inflammatory, urological, and wound-healing activities appear to be the most promising targets for future research. These findings highlight its therapeutic potential while emphasizing the need for well-designed clinical studies to further validate its medicinal applications. Full article

Arachidonic acid (AA) is an emerging regulator of fibroblast activity in pulmonary fibrosis; however, the underlying intracellular mechanisms remain unclear. This study investigated the effects of AA on the free intracellular calcium concentration ([Ca²⁺]_i), nitric oxide (NO), and reactive oxygen species (ROS) in human WI-38 lung fibroblasts. Using fluorescent imaging and pharmacological tools, we demonstrate that AA evokes a robust, concentration-dependent increase in [Ca²⁺]_i. This response is initiated by G protein-coupled receptor 40 (GPR40), which leads to endoplasmic reticulum Ca²⁺ release through inositol 1,4,5-trisphosphate receptors (IP₃Rs) and lysosomal Ca²⁺ mobilisation through two-pore channels (TPCs). Sustained Ca²⁺ elevation is primarily mediated by influx through transient receptor potential vanilloid 4 (TRPV4) channels, with a minor contribution from store-operated Ca²⁺ entry. The AA-induced Ca²⁺ signal stimulates endothelial NO synthase-dependent NO production, which in turn triggers ROS generation, revealing a tightly coupled Ca²⁺–NO–ROS signalling network. Our findings identify AA as a potent modulator of Ca²⁺ and redox signalling in lung fibroblasts, and highlight GPR40, TRPV4, IP₃Rs and lysosomal TPCs as potential therapeutic targets for intervening in pulmonary fibrosis. Full article

Background/Objectives: Calcium–phosphorus metabolism is critical for skeletal development in weaned piglets. This study evaluated the effects of dietary 25-hydroxyvitamin D₃ (25-OH-VD₃) in combination with phytase and probiotics on mineral metabolism, bone development, and related molecular mechanisms in weaned piglets. Methods: Sixty 28-day-old weaned piglets (7.1 ± 1.30 kg) were randomly assigned to four dietary treatments for 31 days (including 3 days of acclimation): CON (basal diet + 50 µg/kg 25-OH-VD₃), HI (CON + 50 mg/kg phytase), CY (CON +10 mg/kg probiotics), HICY (CON + 50 mg/kg phytase + 10 mg/kg probiotics). Apparent calcium digestibility, serum biochemical indices, bone mineral density (BMD), and mRNA and protein expression of calcium–phosphorus transport- and metabolism-related genes in jejunal mucosa and kidney were assessed. Results: Compared with CON, piglets in the HI, CY, and HICY groups showed higher apparent calcium digestibility (p < 0.05). Serum transforming growth factor-β was elevated in CY and HICY (p < 0.05). HI enhanced metatarsal and toe BMD (p < 0.05) and upregulated jejunal solute carrier family 34, member 2 (SLC34A2) and SLC34A3 mRNA expression (p < 0.05). In contrast, HICY reduced mRNA expression of transient receptor potential cation channel subfamily V member 6 and calcium-binding protein D28k, as well as of calcium-binding protein D9k and cytochrome P450 27B1 in the kidney (p < 0.05). Renal calcium-sensing receptor protein abundance increased in CY (p < 0.05). Conclusions: Supplementation of 25-OH-VD₃ with phytase and/or probiotics improved calcium utilization and modulated key transport pathways, contributing to enhanced bone development in weaned piglets. These findings highlight coordinated nutritional regulation of mineral metabolism during early post-weaning growth. Full article

Nasal hyperreactivity (NHR) is a core symptom of allergic rhinitis (AR) and chronic rhinosinusitis (CRS), frequently induced by cold stimuli. Accumulating evidence indicates that NHR is largely mediated by neuroimmune mechanisms rather than classical allergen-driven inflammation alone. Among the molecular sensors involved, the cold-sensitive transient receptor potential channels transient receptor potential ankyrin 1 (TRPA1) and transient receptor potential melastatin 8 (TRPM8) have emerged as key regulators linking environmental cold exposure to sensory nerve activation, neuropeptide release, and immune modulation. This review systematically summarizes the expression, functions, and neuroimmune mechanisms mediated by TRPA1 and TRPM8 in AR and CRS, with a particular focus on their roles in NHR. Furthermore, it discusses the therapeutic potential of targeting these channels to alleviate neurogenic inflammation and refractory nasal symptoms, aiming to provide new perspectives for understanding disease mechanisms and developing precise treatments. Full article

The human corneal endothelium (HCE) is critical for maintaining corneal transparency. Dysfunctions due to cell loss are linked to altered intracellular calcium ([Ca²⁺]_i) homeostasis. Transient receptor potential channels (TRPs) are key regulators of [Ca²⁺]_i, and both L-ascorbic acid (Asc) and cannabinoid receptor (CB) agonists have been implicated in modulating TRP activity. This study investigated the effects of 1 mM Asc and the CB agonist WIN 55,212-2 (WIN) (10 µM) on [Ca²⁺]_i regulation in human corneal endothelial cells (HCECs). HCEC-12 was used as the established HCE cell model. [Ca²⁺]_i dynamics were assessed by fura-2/AM fluorescence imaging, and membrane currents were analyzed using planar patch-clamp recordings. Adding 1 mM Asc increased [Ca²⁺]_i, which was partially suppressed by the TRPV1 blocker AMG-9810 (AMG) (20 µM) and the TRPV4 blocker GSK2193874 (GSK219) (10 µM). Furthermore, 1 mM Asc increased whole-cell currents. WIN also induced [Ca²⁺]_i transients that were partially attenuated by AMG, the TRPM8 blocker AMTB (20 µM), GSK219, and the CB1 inverse agonist AM251 (10 µM). In addition, combined treatment with Asc and WIN enhanced [Ca²⁺]_i elevations compared with either treatment alone. These findings provide the first evidence for a functional interaction between TRP channel activity and CB signaling in HCECs. The inhibitory effect of AM251 suggests a predominant contribution of CB1 receptors. Given the central role of Ca²⁺ homeostasis in corneal endothelial function and disease, these results may contribute to a better understanding of endothelial pathophysiology and support further investigation of TRPs and cannabinoid signaling as potential targets in corneal disorders. Full article

The skin–brain axis constitutes a complex, bidirectional network integrating cutaneous sensory, immune, and neuroendocrine systems with central neural circuits involved in emotion regulation, stress responsivity, and social cognition. Advances in psychodermatology and cosmetic science have progressively extended this framework to the emerging field of neurocosmetics, which explores how topical formulations, sensorial properties, and cutaneous neuromodulators may influence psychological well-being, affective states, and perceived stress. The aim of this narrative review is to synthesize current evidence on the biological foundations of the skin–brain axis and to critically examine the implications of these mechanisms for neurocosmetic interventions from a psychological and psychiatric perspective. It describes the biological substrates underlying skin–brain communication, including the cutaneous hypothalamic–pituitary–adrenal axis, neuropeptides, neurotrophins, transient receptor potential channels, and endocannabinoid signaling, and examines how these pathways are targeted by neurocosmetic interventions. Particular attention is devoted to neuroactive compounds, such as peptides, cannabinoids, botanicals, and aromatherapeutic molecules, as well as to sensorial strategies involving texture, temperature, and olfactory cues, which may modulate mood, anxiety, and self-perception through peripheral mechanisms. From a psychological and psychiatric perspective, the review discusses the intersection between stress-related skin conditions, body image disturbances, and emotional dysregulation, highlighting how cosmetic practices may influence subjective well-being beyond purely aesthetic outcomes. Methodological limitations of the existing literature, including the heterogeneity of study designs and outcome measures, as well as ethical considerations related to mood- and stress-related claims in cosmetic products, are critically examined. Finally, future research directions are outlined, and a translational framework is proposed to integrate dermatology, neuroscience, and mental health within next-generation cosmetic science. Full article

Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer accounting for the majority of cases and exhibiting persistent challenges related to therapy resistance and metastatic progression. Increasing evidence indicates that dysregulated G protein-coupled receptor signaling and ion channel activity function cooperatively as master regulators of tumor cell proliferation, migration, survival, and therapeutic response. Cannabinoids, including phytocannabinoids such as delta-9-tetrahydrocannabinol and cannabidiol, as well as endogenous endocannabinoids, are uniquely positioned to modulate both G protein-coupled receptors and ion channels, thereby influencing key oncogenic signaling networks. This review synthesizes current knowledge on the role of major ion channel families, including transient receptor potential channels, potassium channels, and sodium channels, and principal G protein-coupled receptor pathways involved in lung cancer progression. We further discuss how cannabinoids reprogram these interconnected signaling systems through canonical cannabinoid receptors, non-classical targets such as G protein-coupled receptor 55 and adenosine receptors, and direct modulation of ion channel activity. Special attention is given to G protein-coupled receptor–ion channel coupling within membrane microdomains and to the capacity of cannabinoids to act as biased ligands, redirecting downstream pathways, such as the phosphoinositide 3-kinase–protein kinase B–mechanistic target of rapamycin and epidermal growth factor receptor signaling, toward apoptosis and reduced metastatic potential. Emerging strategies, including cannabinoid-based combination therapies, selective receptor biasing, and targeted delivery systems, are also highlighted. Altogether, cannabinoid-driven rewiring of G protein-coupled receptor and ion channel signaling represents a promising mechanistic framework for developing innovative therapeutic approaches against lung cancer. Full article

Epilepsy is a progressive network disorder in which recurrent seizures drive maladaptive neurodevelopmental remodeling, cognitive decline, and pharmacoresistance, particularly in developmental epileptic encephalopathies. Cannabidiol (CBD) has emerged as an evidence-based adjunctive therapy for selected childhood-onset epilepsies; however, its broader clinical utility remains limited by heterogeneous responsiveness, restricted indications, and an incomplete understanding of developmental stage–specific efficacy and safety. Here, we synthesize molecular, preclinical and clinical evidence supporting the pleiotropic antiseizure and neuroprotective actions of CBD, including modulation of endocannabinoid-related G protein–coupled receptors, adenosine signaling, transient receptor potential channels, GABAergic maturation, and neuroinflammatory cascades. We highlight critical neurodevelopmental windows during which timely CBD intervention may exert disease-modifying effects by preventing pathological consolidation of hyperexcitable networks. Furthermore, we position human brain organoids as transformative translational platforms that recapitulate early human cortical development and epileptic network dynamics, enabling functional stratification of CBD-responsive phenotypes, developmental safety profiling, and precision therapeutic discovery within human-relevant neural circuits. Collectively, organoid-guided frameworks provide a mechanistic foundation for personalized, developmentally informed CBD therapy and advance precision medicine strategies aimed at modifying epileptogenic trajectories rather than solely suppressing seizures. Full article