Identification and expression of transient receptor potential (TRP) genes in Urechis unicinctus and the role of TRPC5 in immune response.

Thermal boundaries of survival: A case study in a marine invertebrate.

Integrated signalling networks in the healthy lower urinary tract: A narrative review.

Impaired autophagy from TRPV4 activation drives α-synuclein pathology in a Parkinson's disease model: A toxicological insight.

The spleen plays a crucial role during inflammation through its resident macrophages, which may be influenced by modulations in neurochemical levels inside the spleen. Transient receptor potential vanilloid 1 (TRPV1) was reported to modulate the immune responses; however, its role in the spleen remains to be elucidated. We aimed to explore whether TRPV1 influences splenic-derived macrophage phenotypes through alterations in neurochemical levels (Calcitonin Gene-Related Peptide (CGRP), acetylcholine & noradrenaline), and modulation of the Nrf2/HO-1 signaling pathway. Using a glycerol- induced acute kidney injury (AKI) model, we investigated modulation of TRPV1 after splenic denervation (SDN) & capsazepine (CPZ). Furthermore, we assessed the impact of low-intensity pulsed ultrasound (LIPUS), with or without CPZ and/or SDN. The alterations in TRPV1, CGRP, acetylcholine, noradrenaline, macrophage phenotypes, Nrf2, and HO-1 were then evaluated. Our findings revealed that inhibiting TRPV1 or splenic denervation could shift macrophages toward a pro-inflammatory M1 phenotype, associated with decrease in the acetylcholine level and suppression of the Nrf2/HO-1 pathway. Notably, these effects were reversed by LIPUS treatment. TRPV1 influenced the concentrations of CGRP, acetylcholine, and noradrenaline, with significant correlations found between splenic mediators (CGRP and acetylcholine) and the pro-inflammatory M1 phenotype related biomarkers and the Nrf2/HO-1 pathway. Integrity of the splenic innervation showed significant association with CGRP, noradrenaline, and acetylcholine levels. Both splenic nerve and TRPV1 potentially influence the macrophage phenotypes-related biomarkers and the expression of Nrf2/HO-1 pathway.

Characterization and environmental stress-induced expression profiling of transient receptor potential vanilloid (TRPV) channels in the Pacific oyster (Magallana gigas) following short-heatwave and silver exposure.

Transient receptor potential canonical 6 is critical for chronic lipopolysaccharide exposure-induced pulmonary injury and fibrosis.

TG2 (transglutaminase 2) promotes PINK1/Parkin-dependent mitophagy in pulmonary hypertension by regulating the TRPC6.

The alkali cation/proton exchanger NHE6/SLC9A6 regulates luminal pH homeostasis and trafficking of recycling endosomes in most tissues, especially neurons. Loss-of-function mutations in NHE6 cause Christianson Syndrome, an X-linked neurodevelopmental and neurodegenerative disorder; however, the underlying molecular and cellular mechanisms remain unclear. Here, we describe a new role for NHE6 as a scaffolding platform for recruiting and delivering signaling molecules to the plasma membrane. The yeast two-hybrid system was used to screen a human brain cDNA library for proteins that bind to the cytoplasmic C-terminus of NHE6. Cyclin-dependent kinase 5 (CDK5) was identified as a putative interacting partner. CDK5 is widely expressed and phosphorylates diverse proteins involved in vital processes, including receptor signaling, cytoskeletal organization, endocytosis, exocytosis, and apoptosis. Formation of a NHE6/CDK5 complex was confirmed by biochemical assays and microscopy using Chinese hamster ovary AP-1 and human neuroblastoma SH-SY5Y cells. CDK5, in a complex with its activator subunit p35/CDK5R1, did not directly phosphorylate or regulate the membrane trafficking of NHE6. By contrast, NHE6 expression enhanced the localization of CDK5 and p35 to endosomal- and plasmalemmal-enriched membrane fractions and elevated cell surface accumulation of the CDK5-regulated transient receptor potential V1 (TRPV1) cation channel. These data indicate that NHE6, aside from its main pH-regulatory function, can act concomitantly as a scaffold for recruitment of CDK5/p35 to endosomes and the plasma membrane where the kinase is now primed to activate neighboring effectors important for cell function.

Canine mammary carcinoma (CMC) is characterised by a chronic inflammatory microenvironment resembling human breast cancer; however, the upstream regulatory mechanisms driving this phenotype remain unclear. The endocannabinoid system (ECS) has emerged as a potential modulator of inflammation and tumour biology. This study investigated the role of the ECS in CMC and evaluated the anti-inflammatory effects of cannabidiol (CBD). Primary cell cultures were established from surgically excised CMC tissues, with matched normal mammary epithelium used as controls. Basal mRNA expression of ECS-related receptors (CB1, CB2, transient receptor potential vanilloid 1 [TRPV1], G-protein-coupled receptor 55 [GPR55] and peroxisome proliferator-activated receptor alpha [PPAR-α]) and inflammatory mediators (COX-1, COX-2, interleukin [IL]-4, IL-6, IL-33, IL-17A, tumour necrosis factor-alpha [TNF-α] and LCN2) was assessed by reverse transcription quantitative polymerase chain reaction. Cytokine secretion (IL-6, IL-8, TNF-α and IL-17A) was quantified by enzyme-linked immunosorbent assay. Cell viability assays were performed to determine the 24-h IC50 of CBD (32µM), and sub-cytotoxic concentrations (3, 10 and 20µM) were subsequently applied for 24 h. Canine mammary carcinoma-derived cells exhibited significant overexpression of ECS receptors (CB1, CB2, TRPV1, GPR55 and PPAR-α) compared to normal controls. These cells also showed increased secretion of pro-inflammatory cytokines, including IL-6, IL-8, TNF-α and IL-17A. Treatment with CBD at 10-20µM significantly downregulated key inflammatory genes, particularly COX-2, IL-6 and TNF-α, and reduced corresponding cytokine release without compromising cell viability. The ECS is upregulated in CMC and appears to contribute to the inflammatory tumour microenvironment. Cannabidiol effectively attenuates this inflammatory phenotype at sub-cytotoxic concentrations, supporting its potential as a therapeutic agent in CMC.

Oncostatin M (OSM), a member of the interleukin 6 (IL-6) pro-inflammatory cytokine family, is upregulated in the dorsal root ganglia of patients with neuropathic pain and thus may be an important contributor to this condition. Although suggested to contribute to itch in mice, the effects of OSM on nociceptive behavior and nociceptors in rats remain undefined. Here we show that a singular intrathecal dose of OSM (10 ng) induces significant mechanical hypersensitivity in both sexes of rats, yet does not alter thermal withdrawal latencies. When applied to cultured rat dorsal root ganglion (DRG) neurons, OSM (10 ng/mL) elicited robust action potential discharges and exaggerated fluctuations in membrane potential that was not mitigated by an IL-6 receptor antagonist. Neurons reactive to OSM typically did not respond to capsaicin, aligning with the behavioral observations. Immunohistochemical analysis revealed frequent co-localization of OSM and its receptor (OSMR) with isolectin B4-positive and calcitonin gene-related peptide-positive DRG neurons, but only scarce co-localization in transient receptor potential vanilloid 1-positive DRG neurons. In a model of paclitaxel chemotherapy-induced peripheral neuropathy, there is a notable increase in DRG neurons expressing OSM or its receptor (OSMR), alongside an upsurge in several OSM/OSMR downstream signaling molecules. These findings suggest that OSM acts as a signal for mechanical nociception and that heightened OSM expression and OSMR signaling in the DRG may be a key factor in the sensitization of specific nociceptor subsets. Consequently, targeting the OSM/OSMR pathway may offer a promising avenue for treatment in particular neuropathic pain phenotypes.

The gut microbiota is a key regulator of host metabolism and skeletal muscle physiology, yet its role in muscle fiber-type transformation in pigs remains unclear. Here, we used germ-free (GF) and specific pathogen-free (SPF) Rongcheng piglets to explore how microbial absence influences muscle development. GF piglets showed significantly reduced body weight and an increased proportion of fast-twitch fibers compared with SPF controls. Transcriptome sequencing identified 1332 differentially expressed genes (DEGs), notably those involved in cGMP-PKG, Thyroid hormone, HIF-1, VEGF, and Butanoate metabolism signaling pathways, which are essential for myofiber specification. Non-targeted metabolomic profiling revealed 320 differentially expressed metabolites (DEMs), with major alterations in Bile secretion. Integrated transcriptomic and metabolomic uncovered 10 KEGG pathways co-enriched with DEGs and metabolites, including Bile secretion, Ferroptosis, Inflammatory mediator regulation of TRP channels, and HIF-1 signaling pathway. Correlation analysis revealed that strong positive correlations were observed between fast-twitch fiber genes (e.g., PRKCA, MYOZ3, NFATC1) and fatty acid-related metabolites (e.g., Dodecanoic acid, Valproic Acid, and Decanoic acid), whereas negative correlations were detected between these genes and bile acid-related metabolites (e.g., Cholic acid and 7-Ketolithocholic acid), suggesting microbial metabolites is associated with muscle fiber phenotype via metabolic and signaling crosstalk. Collectively, our findings demonstrate that gut microbial absence in pigs disrupts bile acid metabolism and fatty acid metabolism, which in turn drives the shift of skeletal muscle fiber composition toward fast-twitch glycolytic fibers. These metabolites are identified as key microbial mediators linking the gut microbiota to the transcriptional regulatory function of porcine muscle fiber type specialization, providing new insights into the gut-muscle axis and highlighting the important role of microbiota-derived metabolites in maintaining porcine muscle fiber composition and metabolic balance.

Peripheral cannabinoid receptor activation attenuates frostbite-induced chronic pain via modulation of TRP channels, neuroinflammation, and autophagy.

The transient receptor potential vanilloid 1 (TRPV1) channel is a critical mediator in pruritus signaling, and its antagonists represent a promising therapeutic strategy to disrupt the "itch-scratch" cycle in atopic dermatitis (AD). This meta-analysis was conducted to evaluate the efficacy and safety of TRPV1 antagonists for AD, with available evidence focusing on the topical agent asivatrep. A systematic search was performed across seven databases (e.g., CENTRAL, Embase, and MEDLINE) from inception to December 27, 2025, without language restrictions. With study selection, data extraction, and risk-of-bias assessment completed independently by two investigators, a random-effects model was applied for meta-analysis. Although our search strategy was designed to capture all TRPV1 antagonists, only two randomized controlled trials (RCTs, n = 431) met the inclusion criteria, both evaluating the topical, highly selective TRPV1 antagonist asivatrep (PAC-14028) 1.0% cream. Compared with the vehicle control, asivatrep significantly improved physician-assessed skin lesions (e.g., Investigator's Global Assessment 0/1 response: risk ratio [RR] 3.23, 95% confidence interval [CI] 2.02 to 5.17; Eczema Area and Severity Index (EASI)-75 response: RR 1.84, 95% CI 1.18 to 2.87) and significantly alleviated patient-reported pruritus and sleep disturbance. The incidence of all adverse events (RR 1.41, 95% CI 0.53 to 3.76) and drug-related adverse events (RR 0.64, 95% CI 0.08 to 4.97) in the Asivatrep 1.0% group did not differ significantly from the vehicle group. In conclusion, topical asivatrep (1.0% cream) effectively and safely improves lesion severity and pruritus in patients with mild-to-moderate AD. However, as current evidence is confined to asivatrep in mild-to-moderate AD, a class effect for TRPV1 antagonists cannot be established.

The development of foam cells is crucial in the advancement of atherosclerosis (AS). Tanshinone IIA (Tan IIA), the primary lipophilic component of Salvia miltiorrhiza, has various pharmacological effects. Despite this, the precise role of Tan IIA in AS has not been fully elucidated. In this research, we employed ApoE-/- mice to establish an AS model. Oil Red O and HE staining indicated that Tan IIA obviously reduced plaque areas in both the aorta and aortic arch. Additionally, serum analysis revealed that Tan IIA notably decreased lipid and inflammatory factor levels in AS mice. In vitro studies showed that Tan IIA primarily prevented foam cell formation by enhancing cholesterol efflux rather than increasing lipid uptake. Mechanistic investigations reveal that Tan IIA suppresses the Hedgehog (Hh) signaling pathway by downregulating the expression of transient receptor potential melastatin 2 (TRPM2) and subsequently inhibiting Ca²⁺ influx. This cascade ultimately attenuates foam cell formation and impedes the progression of AS. Overall, this research provides a solid theoretical foundation for the potential application of Tan IIA in the treatment of AS.

Transient receptor potential vanilloid-1 (TRPV1) plays a critical role in noxious heat sensation in physiological conditions and pain hypersensitivity in pathological pain. Capsaicin, a classic TRPV1 agonist, is used to relieve pain partially through induction of TRPV1 desensitization. Multiple mechanisms have been proposed to contribute to TRPV1 desensitization. However, the limiting factors or antagonistic mechanisms of TRPV1 desensitization remain poorly understood. Stimulation of TRPV1 by capsaicin (1 µM) activates calpain without causing obvious cellular injury. Calpain cleaves rTRPV1 at the G819/S820 site located in the distal carboxyl terminus. The truncated mutant, TRPV1 Δ820, shows reduced plasma membrane localization partially due to impaired subunit assembly. Notably, TRPV1 Δ820 shows increased resistance to tachyphylaxis as induced by repetitive capsaicin stimulation, whereas calpain-1 knockdown slightly enhances TRPV1 tachyphylaxis. In vivo delivery of TRPV1 Δ820 rescued the pain behavioral deficits in nociceptive pain models of Tprv1-/- mice, but not in inflammatory pain models. Calpain is activated following the activation of TRPV1 and cleaves its distal carboxyl terminus. This reduces the plasma membrane localization of TRPV1 while enhancing its resistance to receptor tachyphylaxis. This study revealed a constraining mechanism for TRPV1 desensitization, which maintains the receptor function in an appropriate range.

Activation of TRPV4 ion channel during acute lung injury (ALI) exacerbates lung dysfunction by promoting edema and inflammation. Pharmacological inhibition of TRPV4 signaling in the lungs offers protective benefits, reducing vascular leakage, enhancing blood oxygenation, and alleviating edema. We designed, synthesized, and preclinically evaluated cannabidiol-derived TRPV4 channel inhibitors for potential therapeutic application in ALI and future clinical translation. We identified a lead cannabidiol-derived TRPV4 inhibitor through specific in vitro screening assays. The lead compound was then tested in a series of animal models of ALI. Initial evaluation employed the lipopolysaccharide (LPS) induced lung injury model, followed by models involving TRPV4 overexpression in alveolar macrophages, as well as models featuring TRPV4 hyperactivation. These models were strategically chosen to replicate key pathological features of clinical ALI. Our investigation revealed that administration of the lead derivative CS-85(4j) demonstrated significant protective effects in a mouse model of ALI. CS-85 effectively prevented lung edema and maintained the integrity of pulmonary vascular barrier. Notably, it inhibited neutrophil influx into the lung, reduced proinflammatory cytokine production, and mitigated associated pathological changes. In additional relevant preclinical in vivo models, we further investigated how TRPV4 hyperactivation via pharmacological stimulation and overexpression in alveolar macrophages through liposome-mediated gene delivery exacerbated key features of ALI. CS-85 effectively reduced this exaggerated lung inflammation and alleviated the ALI features. In exploring the downstream mechanisms of CS-85, we found that its pharmacological efficacy is mediated through modulation of the NLRP3-caspase-1, NFAT, and NF-ĸB signaling pathways, all of which are crucial inflammatory cascades. We identified CS-85 as a potent and promising TRPV4 inhibitor that demonstrates strong preclinical efficacy in mitigating ALI by preserving vascular integrity and modulating key inflammatory signaling pathways. Its dual mechanism of action highlights its therapeutic potential for ALI and supports further clinical evaluation.

Metabolomics analysis reveals potential response mechanisms to cold stress in Altay sheep.

The endocannabinoid system (ECS) is a complex signaling network that regulates diverse physiological processes, including pain, mood, metabolism, and immune response, through coordinated interactions among receptors, enzymes, and lipid-derived ligands. Although individual ECS components have been extensively studied, the integrated systems-level organization and structural dependencies of the ECS remain insufficiently characterized in a unified network context. Here, we present a computational, network-based systems analysis of the ECS that integrates protein-protein and protein-chemical interactions into a unified interaction framework, enabling the identification of components that occupy structurally prominent positions in the network, with potential relevance to the role of ECS in diverse physiological processes and therapeutic contexts. We constructed integrated ECS networks by combining experimentally validated protein-protein and protein-chemical interactions from multiple public databases. Network analyses were performed using centrality metrics, community detection algorithms, and targeted perturbations of highly ranked nodes to assess structural organization, modular architecture, and redistribution of topological influence. Centrality analyses systematically identified nodes with high topological prominence across the ECS network. Canonical receptors cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2) ranked consistently among the most influential nodes, while non-canonical components such as transient receptor potential vanilloid 1 (TRPV1), G-protein coupled receptor 55 (GPR55), peroxisome proliferator-activated receptor alpha (PPARα), cyclooxygenase-2 (COX-2), fatty acid amide hydrolase (FAAH), and diacylglycerol lipase alpha (DAGLα) also emerged as highly ranked nodes across multiple centrality measures. Closeness and eigenvector centrality further highlighted phytocannabinoids including cannabidiol (CBD), tetrahydrocannabivarin (THCV), and cannabidivarin (CBDV) as structurally well-connected components within the network. Community detection revealed a modular organization separating receptor-mediated signaling components from endocannabinoid metabolic processes, with clusters centered on CB1/CB2 signaling machinery and enzymes such as FAAH and diacylglycerol lipase beta (DAGLβ), which are associated with 2-arachidonoylglycerol (2-AG) turnover. Perturbation analyses demonstrated that removal of dominant hubs, particularly CB1, redistributed centrality and altered shortest-path structure, increasing the relative prominence of nodes such as CB2 and GPR55 while decreasing that of others such as DAGLβ and linoleoyl ethanolamide (LEA). These findings identify structurally influential and configuration-dependent nodes whose prominence becomes apparent through network-level analysis. By mapping the ECS as an integrated interaction network, this study provides a structural framework for understanding how receptors, enzymes, and ligands collectively shape ECS organization. Our results demonstrate that network analysis can identify structurally influential components within the ECS, highlighting nodes whose importance emerges from the overall network organization. The identification of highly ranked and perturbation-sensitive nodes offers a systematic basis for prioritizing underexplored components for hypothesis-driven experimental investigation and pharmacological study. More broadly, this work establishes a network-based foundation for expanding ECS modeling to incorporate additional molecular entities, interaction directionality, signaling dynamics, and tissue- or context-specific interactions, thereby informing future therapeutic strategies targeting the ECS and its interacting molecular pathways across diverse physiological processes and disease pathways.

Dysfunction of endothelial cells manifests early in pulmonary arterial hypertension and represents a critical therapeutic target. Nevertheless, the limited efficacy of single-target interventions underscores the need for innovative strategies that enable precise therapeutic modulation. The TRPV4 (transient receptor potential vanilloid 4)-KCa2.3 (small-conductance calcium-activated potassium channel) interaction was validated in experimental pulmonary hypertension mice using co-immunoprecipitation and fluorescence (Förster) resonance energy transfer. Based on structure-guided molecular docking, a small-molecule candidate, JNc-455, was rationally designed. Dissociation of the TRPV4-KCa2.3 complex was confirmed by both co-immunoprecipitation and fluorescence (Förster) resonance energy transfer analyses in lung tissues from patients with pulmonary arterial hypertension and experimental pulmonary hypertension mice. Endothelial cell-specific adeno-associated virus-mediated disruption of the complex promoted both the initiation and progression of pulmonary hypertension in vivo. Guided by these findings, we developed a series of compounds aimed at restoring TRPV4-KCa2.3 coupling. Among them, JNc-455 demonstrated significant therapeutic efficacy without overt toxicity. However, this effect was absent in endothelial TRPV4-deficient mice (TRPV4EC-/-), indicating that the action of JNc-455 critically depends on the structural integrity of the complex. This study investigates the critical role of the TRPV4-KCa2.3 complex in pulmonary arterial hypertension and, based on these findings, facilitates drug development and screening, thereby identifying JNc-455 as a promising novel therapeutic candidate for pulmonary arterial hypertension.