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Many ion channels are known to behave as an allosteric protein, coupling environmental stimuli captured by specialized sensing domains to the opening of a central pore. The classic Monod-Wyman-Changeux (MWC) model, originally proposed to describe binding of gas molecules to hemoglobin, has been widely used as a framework for analyzing ion channel gating. Here, we address the issue of how accurately the MWC model predicts activation of the capsaicin receptor TRPV1 by vanilloids. Taking advantage of a concatemeric design that makes it possible to lock TRPV1 in states with zero to four bound vanilloid molecules, we showed quantitatively that the overall gating behavior is satisfactorily predicted by the MWC model. There is, however, a small yet detectable subunit position effect: ligand binding to two kitty-corner subunits is 0.3-0.4 kcal/mol more effective in inducing opening than binding to two neighbor subunits. This difference-less than 10% of the overall energetic contribution from ligand binding-might be due to the restriction on subunit arrangement imposed by the planar membrane; if this is the case, then the position effect is not expected in hemoglobin, in which each subunit is related equivalently to all the other subunits.

Transient Receptor Potential (TRP) ion channels are important for sensing environmental temperature. In rodents, TRPV4 senses warmth (25-34 °C), TRPV1 senses heat (>42 °C), TRPA1 putatively senses cold (

Background and Purpose Experimental Approach Key Results Conclusion and Implications The dorsal hippocampus (dHIP) is pivotal for learning, memory, and defensive responses. Transient receptor potential vanilloid type 1 (TRPV1) receptors in the dHIP modulate contextual fear conditioning by triggering a cascade involving glutamate release, nitric oxide (NO) formation and cyclic guanosine monophosphate (cGMP) production. The present study investigated the involvement of dHIP TRPV1 receptors and their interaction with the glutamate/NO/cGMP signalling pathway in modulating the expression of contextual fear conditioning (CFC).Male Wistar rats were submitted to an aversive contextual conditioning session and, 48 h later, were re‐introduced to the same aversive environment where the freezing response and autonomic activity (evidenced by increased arterial pressure and heart rate and a decrease in tail temperature) were measured.The results demonstrated that the TRPV1 antagonist 6‐I‐CPS in dHIP reduced the expression of CFC, whereas the agonist capsaicin had the opposite effect. Furthermore, dHIP pre‐treatment with an NMDA receptor antagonist (AP7), neuronal NO synthase inhibitor (N‐propyl‐L‐arginine), NO scavenger (c‐PTIO) or guanylate cyclase inhibitor (ODQ) attenuated capsaicin‐induced increases in CFC. Finally, we observed that re‐exposure to the aversive chamber increased dHIP NO levels in conditioned animals compared with a non‐conditioned group, which was prevented by the administration of the TRPV1 antagonist, 6‐I‐CPS.Our study revealed that TRPV1 receptors in the dHIP play a crucial role in modulating contextual fear expression by acting through the NMDA receptor/NO/cGMP signalling pathway, providing important insights into the underlying mechanisms and potential therapeutic avenues associated with these pathways. [ABSTRACT FROM AUTHOR]

TRPV4 antagonists that could be potential drugs for treatment and management of neuropathic pain. This study was conducted to systematically design several amino derivatives of 2,4′‐dimethyl‐[4,5′‐bithiazol]‐2‐yl as antagonists. In silico computational methods, such as 3D quantitative structure‐activity relationship modeling (3D‐QSAR), molecular docking, and pharmacokinetic property assessment (ADMET), were used to discover new compounds with strong antagonistic activity. The best‐performing 3D‐QSAR model was developed using a partial least squares approach and comparative molecular similarity analysis (CoMSIA). The developed model demonstrated an excellent ability to correlate and predict properties (R2 = 0.932, Q2 = 0.620, and SEE = 0.109). It was observed that variations in biological activity were significantly influenced by interactions with steric, electrostatic, and hydrophobic fields. Molecular docking was used to validate the 3D‐QSAR methods and to explain the binding site and interactions between the most active ligands and the receptor. Based on these results, a new series of compounds was predicted. The best‐anchored molecules underwent MD simulation to confirm their dynamic behavior and stability, and they also underwent retrosynthetic analysis to assist in their synthesis. [ABSTRACT FROM AUTHOR]

Pain, detected by nociceptors, is an integral part of injury, yet whether and how it can impact tissue physiology and recovery remain understudied. Here, we applied chemogenetics in mice to locally activate dermal TRPV1 innervations in naive skin and found that it triggered new regenerative cycling by dormant hair follicles (HFs). This was preceded by rapid apoptosis of dermal macrophages, mediated by the neuropeptide calcitonin gene-related peptide (CGRP). TRPV1 activation also triggered a macrophage-dependent induction of osteopontin (Spp1)-expressing dermal fibroblasts. The neuropeptide CGRP and the extracellular matrix protein Spp1 were required for the nociceptor-triggered hair growth. Finally, we showed that epidermal abrasion injury induced Spp1-expressing dermal fibroblasts and hair growth via a TRPV1 neuron and CGRP-dependent mechanism. Collectively, these data demonstrated a role for TRPV1 nociceptors in orchestrating a macrophage and fibroblast-supported mechanism to promote hair growth and enabling the efficient restoration of this mechano- and thermo-protective barrier after wounding. [Display omitted] • Activation of cutaneous TRPV1 innervations accelerated hair growth in naive skin • TRPV1 activation induced a rapid apoptosis of dermal macrophages via CGRP • TRPV1 activation triggered the expansion of Spp1-expressing dermal fibroblasts • TRPV1, CGRP, and Spp1 expression control hair regrowth after skin abrasion Ben-Shaanan et al. demonstrate a cellular pathway causally connecting pain-mediating cutaneous TRPV1 innervations with accelerated hair growth in naive skin, as well as hair regrowth after epidermal abrasion. This cellular pathway involves dermal macrophage apoptosis triggered by the neuropeptide CGRP, followed by a macrophage-dependent increase in the frequency of fibroblasts expressing the hair growth-promoting factor Spp1. [ABSTRACT FROM AUTHOR]

Transient receptor potential vanilloid (TRPV) channel proteins belong to the superfamily of TRP proteins that form cationic channels in the animal cell membranes. These proteins have various subtype-specific functions, serving, for example, as sensors for pain, pressure, pH, and mechanical extracellular stimuli. The sensing of extracellular cues by TRPV4 triggers Ca2+-influx through the channel, subsequently coordinating numerous intracellular signaling cascades in a spatio-temporal manner. As TRPV channels play such a wide role in various cellular and physiological functions, loss or impaired TRPV protein activity naturally contributes to many pathophysiological processes. This review concentrates on the known functions of TRPV4 sensor proteins and their potential as a therapeutic target. [ABSTRACT FROM AUTHOR]

The salivary microbiota of Italian and sub-Saharan African individuals was investigated using Nanopore sequencing technology (ONT: Oxford Nanopore Technologies). We detected variations in community composition in relation to endogenous (ethnicity, sex, and diplotypic variants of the TRPV1 gene) and exogenous (sensitivity to capsaicin) factors. The results showed that Prevotella, Haemophilus, Neisseria, Streptococcus, Veillonella, and Rothia are the most abundant genera, in accordance with the literature. However, alpha diversity and frequency spectra differed significantly between DNA pools. The microbiota in African, male TRPV1 bb/ab diplotype and capsaicin low-sensitive DNA pools was more diverse than Italian, female TRPV1 aa diplotype and capsaicin high-sensitive DNA pools. Relative abundance differed at the phylum, genus, and species level. [ABSTRACT FROM AUTHOR]

Aging is associated with a decline in oral immune function, marked by reduced levels of antimicrobial peptides such as defensins. Capsaicin, a bioactive component found in chili peppers, has been theorized to modulate immune responses through specific receptor pathways. This study examined the effects of aging on oral defensin levels and the potential mitigating role of capsaicin, mediated by the immune response in oral tissues. We conducted a comparative analysis between young and aged mice, with or without capsaicin supplementation, for 3 months. The effect of capsaicin was also studied in vitro in senescence‐induced human oral keratinocytes. We found that aging did not reduce defensin levels uniformly but did so in some instances. Capsaicin treatment increased defensin levels in these cases, potentially through transient receptor potential cation channel subfamily V member 1 (TRPV1)‐mediated pathways in the oral cavity. Capsaicin supplementation may counteract age‐related declines in oral defensin levels, enabling the maintenance of oral immune function during aging. [ABSTRACT FROM AUTHOR]

Aim: This investigation addresses Piezo1's expression and mechanistic role in dorsal root ganglion (DRG) neurons and delineates its participation in mechanical and inflammatory pain modulation. Methods: We analyzed Piezo1's expression patterns in DRG neurons and utilized Piezo1‐specific shRNA to modulate its activity. Electrophysiological assessments of mechanically activated (MA) currents in DRG neurons and behavioral analyses in mouse models of inflammatory pain were conducted to elucidate Piezo1's functional implications. Additionally, we investigated the excitability of TRPV1‐expressing DRG neurons, particularly under inflammatory conditions. Results: Piezo1 was preferentially expressed in DRG neurons co‐expressing the TRPV1 nociceptor marker. Knockdown of Piezo1 attenuated intermediately adapting MA currents and lessened tactile pain hypersensitivity in models of inflammatory pain. Additionally, silencing Piezo1 modified the excitability of TRPV1‐expressing neurons under inflammatory stress. Conclusion: Piezo1 emerges as a key mediator in the transmission of mechanical and inflammatory pain, indicating its potential as a novel target for pain management therapies. Our finding not only advances the understanding of nociceptive signaling but also emphasizes the therapeutic potential of modulating Piezo1 in the treatment of pain. [ABSTRACT FROM AUTHOR]

[Display omitted] • Pulmonary infections following severe traumatic brain injury originate from the translocation of the host's gut-resident bacteria. • TRPV1+ nociceptor in the dorsal root ganglion play a protective role against gut microbiota translocation. • The regulation of gut microbiota translocation by TRPV1+ nociceptors is contingent upon the delicate homeostasis of microfold cells. The prevalence of bacterial infections significantly increases among patients with severe traumatic brain injury (STBI), leading to a notable rise in mortality rates. While immune dysfunctions are linked to the incidence of pneumonia, our observations indicate that endogenous pathogens manifest in the lungs post-STBI due to the migration of gut commensal bacteria. This translocation involves gut-innervating nociceptor sensory neurons, which are crucial for host defense. Following STBI, the expression of transient receptor potential vanilloid 1 (TRPV1) in dorsal root ganglion (DRG) neurons significantly decreases, despite an initial brief increase. The timing of TRPV1 defects coincides with the occurrence of pulmonary infections post-STBI. This alteration in TRPV1+ neurons diminishes their ability to signal bacterial injuries, weakens defense mechanisms against intestinal bacteria, and increases susceptibility to pulmonary infections via bacterial translocation. Experimental evidence demonstrates that pulmonary infections can be successfully replicated through the chemical ablation and gene interference of TRPV1+ nociceptors, and that these infections can be mitigated by TRPV1 activation, thereby confirming the crucial role of nociceptor neurons in controlling intestinal bacterial migration. Furthermore, TRPV1+ nociceptors regulate the immune response of microfold cells by releasing calcitonin gene-related peptide (CGRP), thereby influencing the translocation of gut bacteria to the lungs. Our study elucidates how changes in nociceptive neurons post-STBI impact intestinal pathogen defense. This new understanding of endogenous risk factors within STBI pathology offers novel insights for preventing and treating pulmonary infections. [ABSTRACT FROM AUTHOR]

The article "Gut dysbiosis in patients with chronic pain: a systematic review and meta-analysis" explores the potential role of gut microbiota in chronic pain conditions. The study found that individuals with chronic pain exhibit dysbiosis in their gut microbiota, leading to changes in alpha diversity and an increase in the genus Eggerthella. This dysbiosis may impact dopamine metabolism and estrogen regulation, potentially influencing chronic pain development. Further research is needed to understand the relationship between gut microbiota, dopamine function, and estrogen stimulation in chronic pain patients, offering new avenues for pain management. [Extracted from the article]

Persistent inflammation is a major contributor in the development of various inflammatory diseases like atherosclerosis. Our study investigates how transient receptor potential vanilloid 4 (TRPV4), a mechanosensitive ion channel, interacts with microRNA-146a (miR-146a), within the context of inflammation and atherosclerosis. Micro-RNAs play a critical role in controlling gene expression, and miR-146a is notable for its anti-inflammatory actions. TRPV4 is activated by diverse soluble and mechanical stimuli, and often associated with inflammatory responses in various diseases. Here, we find that TRPV4 negatively regulates miR146a expression in macrophages, especially following stimulation by lipopolysaccharides or alterations in matrix stiffness. We show that in atherosclerosis, a condition characterized by matrix stiffening, TRPV4 decreases miR-146a expression in aortic tissue macrophages. We find that TRPV4’s impact on miR-146a is independent of activation of NFkB, Stat1, P38, and AKT, but is rather mediated through a mechanism involving histone deacetylation instead of DNA methylation at the miR-146a promoter site. Furthermore, we show that N-terminal residues 1 to 130 in TRPV4 is essential in suppression of miR-146a expression in LPS-stimulated macrophages. Altogether, this study identifies a regulatory mechanism of miR-146a expression by TRPV4 which may open new potential therapeutic strategies for managing inflammatory diseases. [ABSTRACT FROM AUTHOR]

Background: Persistent innate and adaptive immune responses in the brain contribute to the progression of Alzheimer's disease (AD). APOE4, the most important genetic risk factor for sporadic AD, encodes apolipoprotein E4, which by itself is a potent modulator of immune response. However, little is known about the immune hub that governs the crosstalk between the nervous and the adaptive immune systems. Transient receptor potential vanilloid type 1 (TRPV1) channel is a ligand-gated, nonselective cation channel with Ca2+ permeability, which has been proposed as a neuroprotective target in AD. Methods: Using Ca2+-sensitive dyes, dynamic changes of Ca2+ in microglia were measured, including exogenous Ca2+ uptake and endoplasmic reticulum Ca2+ release. The mRFP-GFP-tagged LC3 plasmid was expressed in microglia to characterize the role of TRPV1 in the autophagic flux. Transcriptomic analyses and flow cytometry were performed to investigate the effects of APOE4 on brain microglia and T cells from APOE-targeted replacement mice with microglia-specific TRPV1 gene deficiency. Results: Both APOE4 microglia derived from induced pluripotent stem cells of AD patients and APOE4-related tauopathy mouse model showed significantly increased cholesterol biosynthesis and accumulation compared to their APOE3 counterparts. Further, cholesterol dysregulation was associated with persistent activation of microglia and elevation of major histocompatibility complex II-dependent antigen presentation in microglia, subsequently accompanied by T cell infiltration. In addition, TRPV1-mediated transient Ca2+ influx mitigated cholesterol biosynthesis in microglia by suppressing the transcriptional activation of sterol regulatory element-binding protein 2, promoted autophagic activity and reduced lysosomal cholesterol accumulation, which were sufficient to resolve excessive immune response and neurodegeneration in APOE4-related tauopathy mouse model. Moreover, microglia-specific deficiency of TRPV1 gene accelerated glial inflammation, T cell response and associated neurodegeneration in an APOE4-related tauopathy mouse model. Conclusions: The findings provide new perspectives for the treatment of APOE4-dependent neurodegeneration including AD. [ABSTRACT FROM AUTHOR]

Olmsted syndrome (OS) is a rare congenital skin disorder, typically characterized by symmetrical, severe palmoplantar and periorificial keratoderma, often accompanied by alopecia, and onychodystrophy, with varying degrees of pruritus and pain. Gain-of-function variants of the transient receptor potential cation channel subfamily V member 3 (TRPV3) were described as a cause of OS. Here, we report an atypical case of OS caused by a novel mutation in the TRPV3 gene that has not been described before in OS. The patient presented with disabling, bilateral palmoplantar keratoderma, and subsequently developed squamous cell carcinoma on the right sole. Genetic analysis identified a novel heterozygous p.Val306Met missense mutation in the exon 8 of TRPV3. Our findings expand the phenotypic spectrum of TRPV3-related OS and underscore the need for vigilant long-term monitoring of these patients. [ABSTRACT FROM AUTHOR]

Introduction: The resolution of the skin's inflammatory response is only possible if its barrier function is restored. TRPV1 channel activation plays an important role during inflammation but the effect of this activation on the skin barrier under inflammatory conditions has not been clarified. We hypothesize that it could potentially aid the keratinocyte barrier by reducing inflammatory cytokine release and promoting tight junction development. Methods: To explore the role of TRPV1 activation in inflammation, we designed and optimized an in vitro model of keratinocytes with basal epidermal layer characteristics using HaCaT cells and TNFα to induce inflammation. Results: TNFα increased the gene expression of tight junction protein claudin 1 (CLDN1) by at least 2.60 ± 0.16-fold, in a concentration-dependent manner, over a 48 h period. The administration of a capsaicin pre-treatment reduced the CLDN1 expression to 1.51 ± 0.16-fold during the first 6 h after TNFα induction, whereas IL-8 cytokine release was reduced 0.64 ± 0.17-fold. After 48 h, CLDN1 protein levels increased by a factor of 6.57 ± 1.39 compared to cells only treated with TNFα. Discussion: These results suggest that activation of TRPV1 by capsaicin can potentiate the increase in CLDN1 expression and CLDN1 protein synthesis induced by TNFα in cultured keratinocytes, while reducing the release of IL-8. [ABSTRACT FROM AUTHOR]

Objective: This research is aimed at unravelling the intricate relationship between transient receptor potential vanilloid 6 (TRPV6), protein kinase A (PKA), uncoupling protein 2 (UCP2), and atherosclerosis. By shedding light on the role of the TRPV6/PKA/UCP2 pathway in inhibiting inflammatory response and cell apoptosis in coronary atherosclerotic plaques, this study provides valuable insights into potential therapeutic targets for treating coronary artery disease (CAD). Methods: We established animal and cell models of atherosclerosis. The expression of TRPV6 was measured using immunohistochemistry and immunofluorescence. Cytokine levels were detected by enzyme‐linked immunosorbent assay (ELISA). Cell viability and apoptosis ratio were measured using cell counting kit‐8 (CCK‐8) and flow cytometry. The binding relationship between TRPV6 and PKA was validated using chromatin immunoprecipitation (CHIP) and coimmunoprecipitation (CoIP). Finally, the expression of the TRPV6/PKA/UCP2 signaling pathway and apoptosis‐related factors was detected using western blot (WB) and quantitative real‐time polymerase chain reaction (qRT‐PCR). Results: TRPV6 was significantly decreased in atherosclerosis mouse and cell model. CHIP and CoIP assays indicated that TRPV6 binds to PKA and positively regulated its expression in oxidized low‐density lipoprotein (ox‐LDL)–treated human umbilical vein endothelial cells (HUVECs). Overexpression of TRPV6 significantly increased cell viability and inhibited apoptosis, whereas silencing TRPV6 had the opposite effect. Additionally, the overexpression of TRPV6 remarkably declined the expression of tumor necrosis factor‐alpha (TNF‐α), interleukin‐6 (IL‐6), and interleukin‐1 beta (IL‐1β). However, after silencing PKA, this effect was partially reversed, the cell viability and inflammatory response remarkably enhanced, and apoptosis significantly declined in oe‐TRPV6 + si‐PKA group. Conclusions: In summary, our study demonstrated that TRPV6 inhibited apoptosis and inflammatory response in the atherosclerosis cell model through the regulation of the PKA/UCP2 pathway. [ABSTRACT FROM AUTHOR]

Background: The endocannabinoid system (ECS) is highly integrated with seemingly all physiological and pathophysiological processes in the body. There is increasing interest in utilizing bioactive plant compounds, for promoting health and improving production in livestock. Given the established interaction between phytochemicals and the ECS, there are many opportunities for identification and development of therapies to address a range of diseases and disorders. However, the ECS has not been thoroughly characterized in cattle, especially in the gastrointestinal tract. The objective of this study was to characterize the distribution and transcriptional abundance of genes associated with the endocannabinoid system in bovine tissues. Methods: Tissues including brain, spleen, thyroid, lung, liver, kidney, mesenteric vein, tongue, sublingual mucosa, rumen, omasum, duodenum, jejunum, ileum and colon were collected from 10-mo old Holstein steers (n = 6). Total RNA was extracted and gene expression was measured using absolute quantification real time qPCR. Gene expression of endocannabinoid receptors CNR1 and CNR2, synthesis enzymes DAGLA, DAGLB and NAPEPLD, degradation enzymes MGLL and FAAH, and transient receptor potential vanilloids TRPV3 and TRPV6 was measured. Data were analyzed in R using a Kruskal-Wallis followed by a Wilcoxon rank-sum test. Results are reported as the median copy number/20 ng of equivalent cDNA (CN) with interquartile range (IQR). Results: The greatest expression of CNR1 and CNR2 was in the brain and spleen, respectively. Expression of either receptor was not detected in any gastrointestinal tissues, however there was a tendency (P = 0.095) for CNR2 to be expressed above background in rumen. Expression of endocannabinoid synthesis and degradation enzymes varied greatly across tissues. Brain tissue had the greatest DAGLA expression at 641 CN (IQR 52; P ≤ 0.05). DAGLB was detected in all tissues, with brain and spleen having the greatest expression (P ≤ 0.05). Expression of NAPEPLD in the gastrointestinal tract was lowest in tongue and sublingual mucosal. There was no difference in expression of NAPEPLD between hindgut tissues, however these tissues collectively had 592% greater expression than rumen and omasum (P ≤ 0.05). While MGLL was found to be expressed in all tissues, expression of FAAH was only above the limit of detection in brain, liver, kidney, jejunum and ileum. TRPV3 was expressed above background in tongue, rumen, omasum and colon. Although not different from each other, thyroid and duodenum had the greatest expression of TRPV6, with 285 (IQR 164) and 563 (IQR 467) CN compared to all other tissues (P < 0.05). Conclusions: These data demonstrate the complex distribution and variation of the ECS in bovine tissues. Expression patterns suggest that regulatory functions of this system are tissue dependent, providing initial insight into potential target tissues for manipulation of the ECS. [ABSTRACT FROM AUTHOR]

Introduction: Acupoint Catgut Embedding (ACE) is an extended and developed form of traditional acupuncture that serves as a composite stimulation therapy for various diseases. However, its local stimulation effects on acupoints remain unclear. Acupuncture can activate mechanically sensitive calcium ion channels, TRPV2 and TRPV4, located on various cell membranes, promoting Ca2+ influx in acupoint tissues to exert effects. Whether ACE can form mechanical physical stimulation to regulate these channels and the related linkage effect requires validation. Methods: This study investigates the influence of TRPV2 and TRPV4 ion channels on the local stimulation effects of ACE by embedding PGLA suture at the Zusanli (ST36) acupoint in rats and using TRPV2 and TRPV4 inhibitors. Flow cytometry, immunofluorescence, Western blot, and Real-time quantitative PCR were employed to detect intracellular Ca2+ fluorescence intensity, the expression of macrophage (Mac) CD68 and mast cell (MC) tryptase, as well as the protein and mRNA expression of TRPV2 and TRPV4 in acupoint tissues after PGLA embedding. Results: The results indicate that ACE using PGLA suture significantly increases the mRNA and protein expression of TRPV2 and TRPV4, Ca2+ fluorescence intensity, and the expression of Mac CD68 and MC tryptase in acupoint tissues, with these effects diminishing over time. The increasing trends are reduced after using inhibitors, particularly when both inhibitors are used simultaneously. Furthermore, correlation analysis shows that embedding PGLA suture at the ST36 acupoint regulates Mac and MC functions through Ca2+ signaling involving not only TRPV2 and TRPV4 but multiple pathways. Discussion: These results suggest that embedding PGLA suture at the ST36 acupoint generates mechanical physical stimulation and regulates TRPV2 and TRPV4 ion channels, which couple with Ca2+ signaling to form a linkage effect that gradually weakens over time. This provides new reference data for further studies on the stimulation effects and clinical promotion of ACE. [ABSTRACT FROM AUTHOR]

Transient receptor potential vanilloid 4 (TRPV4) channels have been associated with numerous pulmonary pathologies, including hypertension, asthma, and acute lung injury. However, their role in the alveolar epithelium remains unclear. We performed impedance-based resistance measurements in primary differentiated alveolar epithelial type I (AT1) cells from wild-type (WT) and TRPV4-deficient (TRPV4−/−) C57/BL6J mice to detect changes in AT1 barrier integrity upon TRPV4 activation. Both pharmacological (GSK1016790A) and a low pH-driven activation of TRPV4 were quantified, and the downstream effects on adherens junctions were assessed through the Western blotting of epithelial cadherin (E-cadherin) protein levels. Importantly, a drop in pH caused a rapid decrease in AT1 barrier resistance and increased the formation of a ~35 kDa E-cadherin C-terminal fragment, with both effects significantly reduced in TRPV4−/− AT1 cells. Similarly, the pharmacological activation of TRPV4 in AT1 cells triggered an immediate transient loss of barrier resistance and the formation of the same E-cadherin fragment, which was again diminished by TRPV4 deficiency. Moreover, TRPV4-mediated E-cadherin cleavage was significantly reduced by GI254023X, an antagonist of a disintegrin and metalloprotease 10 (ADAM10). Our results confirm the role of TRPV4 in regulating alveolar epithelial barrier permeability and provide insight into a novel signaling pathway by which TRPV4-induced Ca2+ influx stimulates metalloprotease-driven ectodomain shedding. [ABSTRACT FROM AUTHOR]

Purpose: In many diseases, an overabundance of macrophages contributes to adverse outcomes. While numerous studies have compared macrophage phenotype after mechanical stimulation or with varying local stiffness, it is unclear if and how macrophages directly contribute to mechanical forces in their microenvironment. Methods: Raw 264.7 murine macrophages were embedded in a confining agarose gel, and proliferated to form spheroids over days/weeks. Gels were synthesized at various concentrations to tune stiffness and were shown to support cell viability and spheroid growth. These cell-agarose constructs were treated with media supplements to promote macrophage polarization. Spheroid geometries were used to computationally model the strain generated in the agarose by macrophage spheroid growth. Agarose-embedded macrophages were analyzed for viability, spheroid size, stress generation, and gene expression. Results: Macrophages form spheroids and generate growth-induced mechanical forces (i.e., solid stress) within confining agarose gels, which can be maintained for at least 16 days in culture. Increasing agarose concentration increases gel stiffness, restricts spheroid expansion, limits gel deformation, and causes a decrease in Ki67 expression. Lipopolysaccharide (LPS) stimulation increases spheroid growth, though this effect is reversed with the addition of IFNγ. The mechanosensitive ion channels Piezo1 and TRPV4 have reduced expression with increased stiffness, externally applied compression, LPS stimulation, and M1-like polarization. Conclusions: Macrophages alone both respond to and generate solid stress. Understanding how macrophage generation of growth-induced solid stress responds to different environmental conditions will help to inform treatment strategies for the plethora of diseases that involve macrophage accumulation and inflammation. [ABSTRACT FROM AUTHOR]

Transient receptor potential vanilloid 3 channel (TRPV3) is closely associated with skin inflammation, but there is a lack of effective and specific inhibitors for clinical use. In this study, we identified antimalarial hydroxychloroquine (HCQ) as a selective TRPV3 inhibitor following the prediction by network pharmacology data analysis. In whole-cell patch-clamp recordings, HCQ inhibited the current of the TRPV3 channel, with an IC50 of 51.69 ± 4.78 mM. At the single-channel level, HCQ reduced the open probability of TRPV3 and decreased single-channel conductance. Molecular docking and sitedirected mutagenesis confirmed that residues in the pore domain were critical for the activity of HCQ. In vivo, HCQ effectively reduced carvacrol-induced epidermal thickening, erythema, and desquamation. Additionally, the serum immunoglobulin E and inflammatory factors such as tumor necrosis factor-a and interleukin-6 were markedly decreased in the dorsal skin tissues in the HCQ treatment group, as compared to the model group. Our results suggested the antimalarial HCQ may represent a potential alleviator for treating skin inflammation by inhibiting TRPV3 channels. [ABSTRACT FROM AUTHOR]

Objective: The transient receptor potential cation channel, subfamily V (vanilloid), member 1 (TRPV1) mediates pain perception to thermal and chemical stimuli in peripheral neurons. The cannabinoid receptor type 1 (CB1), on the other hand, promotes analgesia in both the periphery and the brain. TRPV1 and CB1 have also been implicated in learned fear, which involves the association of a previously neutral stimulus with an aversive event. In this review, we elaborate on the interplay between CB1 receptors and TRPV1 channels in learned fear processing. Methods: We conducted a PubMed search for a narrative review on endocannabinoid and endovanilloid mechanisms on fear conditioning. Results: TRPV1 and CB1 receptors are activated by a common endogenous agonist, arachidonoyl ethanolamide (anandamide), Moreover, they are expressed in common neuroanatomical structures and recruit converging cellular pathways, acting in concert to modulate fear learning. However, evidence suggests that TRPV1 exerts a facilitatory role, whereas CB1 restrains fear responses. Conclusion: TRPV1 and CB1 seem to mediate protective and aversive roles of anandamide, respectively. However, more research is needed to achieve a better understanding of how these receptors interact to modulate fear learning. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a devastating disorder with a multifaceted aetiology characterized by dementia, which later progresses to cognitive impairment. Significant efforts have been made to develop pharmacological interventions that slow down the pathogenesis of AD. However, conventional drugs have failed to satisfactorily treat AD and are more focussed towards symptomatic management. Thus, there is a gap in the literature regarding novel targets and modulators targeting them for the effective treatment of AD. Recent studies have demonstrated that modulation of transient receptor potential (TRP) channels has the potential to halt AD pathogenesis at an early stage and rescue hippocampal neurons from death. Amongst several members, TRP channels like TRPA1, TRPC6, TRPM2 and TRPV2 have shown promising results in the attenuation of neurobehavioural cognitive deficits as well as signalling pathways governing such cognitive decline. Furthermore, as these channels govern the ionic balance in the cell, their beneficial effects have also been known to maintain the homeostasis of Ca2+, which is the major culprit eliciting the vicious cycle of excitotoxicity, mitochondrial dysfunction, ROS generation and neurodegeneration. Despite such tremendous potential of TRP channel modulators, their clinical investigation remains elusive. Therefore, in the present review, we have discussed such agents in the light of TRP channels as molecular targets for the amelioration of AD both at the preclinical and clinical levels. [ABSTRACT FROM AUTHOR]

Cancer is a global health challenge with rising incidence and mortality rates, posing significant concerns. The World Health Organization reports cancer as a leading cause of death worldwide, contributing to nearly one in six deaths. Cancer pathogenesis involves disruptions in cellular signaling pathways, resulting in uncontrolled cell growth and metastasis. Among emerging players in cancer biology, Transient Receptor Potential (TRP) channels, notably TRPV1, have garnered attention due to their altered expression in cancer cells and roles in tumorigenesis and progression. TRPV1, also known as the capsaicin receptor, is pivotal in cancer cell death and pain mediation, offering promise as a therapeutic target. Activation of TRPV1 triggers calcium influx and affects cell signaling linked to growth and death. Additionally, TRPV1 is implicated in cancer-induced pain and chemo-sensitivity, with upregulation observed in sensory neurons innervating oral cancers. Also, when capsaicin, a compound from chili peppers, interacts with TRPV1, it elicits a "hot" sensation and influences cancer processes through calcium influx. Understanding TRPV1's multifaceted roles in cancer may lead to novel therapeutic strategies for managing cancer-related symptoms and improving patient outcomes. The current review elucidates the comprehensive role of capsaicin in cancer therapy, particularly through the TRPV1 channel, highlighting its effects in various cells via different signaling pathways and discussing its limitations. [ABSTRACT FROM AUTHOR]

The gustatory system is responsible for detecting and evaluating the palatability of the various chemicals present in food and beverages. Taste bud cells, located primarily on the tongue, communicate with the gustatory sensory neurons by means of neurochemical signals, transmitting taste information to the brain. It has also been found that the endocannabinoid system (ECS) may modulate food intake and palatability, and that taste bud cells express cannabinoid receptors. The purpose of this study was to investigate the expression of cannabinoid and cannabinoid-related receptors in the gustatory cells of the papillae vallatae and foliatae of ten piglets. Specific antibodies against the cannabinoid receptors (CB1R and CB2R), G protein-coupled receptor 55 (GPR55), transient receptor potential vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1) were applied on cryosections of lingual tissue; the lingual tissue was also processed using Western blot analysis. Cannabinoid and cannabinoid-related receptors were found to be expressed in the taste bud cells and the surrounding epithelial cells. The extra-papillary epithelium also showed strong immunolabeling for these receptors. The results showed that these receptors were present in both the taste bud cells and the extra-gustatory epithelial cells, indicating their potential role in taste perception and chemesthesis. These findings contributed to understanding the complex interactions between cannabinoids and the gustatory system, highlighting the role of the ECS within taste perception and its potential use in animal production in order to enhance food intake. [ABSTRACT FROM AUTHOR]

Cystic fibrosis (CF) is a genetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, resulting in defective chloride ion channels. This leads to thick, dehydrated mucus that severely disrupts mucociliary clearance in the respiratory system and triggers infection that eventually is the cause of death of CF patients. Current therapeutic strategies primarily focus on restoring CFTR function, blocking epithelial sodium channels to prevent mucus dehydration, or directly targeting mucus to reduce its viscosity. Among the ion channels expressed in ciliated bronchial epithelial cells, the transient receptor potential vanilloid 4 (TRPV4) channel emerges as a significant channel in CF pathogenesis. Activation of TRPV4 channels affects the regulation of airway surface liquid by modulating sodium absorption and intracellular calcium levels, which indirectly influences CFTR activity. TRPV4 is also involved in the regulatory volume decrease (RVD) process and enhances inflammatory responses in CF patients. Here, we combine current findings on TRPV4 channel modulation as a promising therapeutic approach for CF. Although limited studies have directly explored TRPV4 in CF, emerging evidence indicates that TRPV4 activation can significantly impact key pathological processes in the disease. Further investigation into TRPV4 modulators could lead to innovative treatments that alleviate severe respiratory complications and improve outcomes for CF patients. [ABSTRACT FROM AUTHOR]

Respiratory diseases (RDs) constitute a common public health problem both in industrialized and developing countries. The comprehension of the pathophysiological mechanisms underlying these conditions and the development of new therapeutic strategies are critical for improving the quality of life of affected patients. β2-adrenergic receptor (β2AR) and transient receptor potential vanilloid 1 (TRPV1) are both involved in physiological responses in the airways. β2AR is implicated in bronchodilation, mucociliary clearance, and anti-inflammatory effects, while TRPV1 is involved in the mediation of pain and cough reflexes. In RDs, such as respiratory infections, asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis, the concentration and expression of these receptors can be altered, leading to significant consequences. In this review, we provided an update on the literature about the role of β2AR and TRPV1 in these conditions. We reported how the diminished or defective expression of β2AR during viral infections or prolonged therapy with β2-agonists can increase the severity of these pathologies and impact the prognosis. Conversely, the role of TRPV1 was pivotal in neuroinflammation, and its modulation could lead to innovative treatment strategies in specific patients. We indicate future perspectives and potential personalized treatments in RDs through a comprehensive analysis of the roles of these receptors in the physiological and pathological mechanisms of these pathologies. [ABSTRACT FROM AUTHOR]

Background information: The purinergic ligand‐gated ion channel 7 receptor (P2X7R) is an ATP‐gated ion channel that transmits extracellular signals and induces corresponding biological effects, transient receptor potential vanilloid type 1 (TRPV1) is a non‐selective cation channel that maintains normal physiological functions; numerous studies showed that P2X7R and TRPV1 are associated with inflammatory reactions. Results: The effect of P2X7R knockdown in satellite glial cells (SGCs) on neuronal TRPV1 expression under high glucose and high free fat (HGHF) environment was investigated. P2X7 short hairpin RNA (shRNA) was utilized to downregulate P2X7R in SGCs, and treated and untreated SGCs were co‐cultured with neuronal cell lines. The expression levels of inflammatory factors and signaling pathways in SGCs and neurons were measured using Western blot analysis, RT‐qPCR, immunofluorescence, and enzyme‐linked immunosorbent assays. Results suggested that P2X7 shRNA reduced the expression levels of P2X7R protein and mRNA in SGCs surrounding DRG neurons and downregulated the release of tumor necrosis factor‐alpha and interleukin‐1 beta via the Ca2+/p38 MAPK/NF‐κB pathway. Additionally, the downregulation of P2X7R might decrease TRPV1 expression in neurons via the Ca2+/PKC‐ɛ/p38 MAPK pathway.Conclusions: Reducing P2X7R expression in SCGs in an HGHF environment could decrease neuronal TRPV1 expression via the Ca2+/PKC‐ɛ/p38 MAPK pathway. [ABSTRACT FROM AUTHOR]

Background: Transient receptor potential vanilloid type 4 (TRPV4) is a versatile ion channel with diverse roles in immune cells, including macrophages. While its function in inflammation remains debated, we investigated its role in regulating IL-10 production and its impact on macrophage reprogramming during inflammation. Methods: We investigated the connection between TRPV4 activation and CREB-mediated IL-10 production during inflammation. Notably, this signaling pathway was found to reprogram macrophages and enhance their ability to resist inflammatory damage. The experiments were conducted on primary macrophages and were further corroborated by animal studies. Results: In response to TRPV4 activation during inflammation, we observed a significant increase in intracellular Ca2+ levels, which triggered the activation of the transcription factor CREB, subsequently upregulating IL-10 production. This IL-10 played a pivotal role in reprogramming macrophages to withstand inflammatory damage. Using a mouse model of acute lung injury (ALI), we confirmed that TRPV4 activation during ALI led to IL-10 secretion, but this increase did not significantly contribute to inflammation resolution. Moreover, we found that TRPV4 prevented the accumulation of dysfunctional mitochondria in macrophages through the CREB-IL-10 axis during inflammation. Suppression of CREB or TRPV4 inhibition exacerbated mitochondrial dysfunction, while treatment with recombinant IL-10 mitigated these effects. Additionally, IL-10 induced mitophagy and cleared dysfunctional mitochondria in LPS-exposed cells. Conclusion: Our study highlights the essential role of TRPV4 in regulating IL-10 production and mitochondrial health in macrophages during inflammation. These findings contribute to understand the role of TRPV4 in immune responses and suggest potential therapeutic targets for modulating inflammation-induced cellular dysfunction. [ABSTRACT FROM AUTHOR]

Background and Purpose Experimental Approach Key Results Conclusion and Implications Transient receptor potential vanilloid 2 (TRPV2) is a Ca2+‐permeable non‐selective cation channel. Despite the significant roles of TRPV2 in immunological response, cancer progression and cardiac development, pharmacological probes of TRPV2 remain to be identified. We aimed to discover TRPV2 inhibitors and to elucidate their molecular mechanism of action.Fluorescence‐based Ca2+ assay in HEK‐293 cells expressing murine TRPV2 was used to identify plumbagin as a novel TRPV2 inhibitor. Patch‐clamp, in silico docking and site‐directed mutagenesis were applied to investigate the molecular mechanisms critical for plumbagin interaction. ELISA and qPCR were used to assess nitric oxide release and mRNA levels of inflammatory mediators, respectively. si‐RNA interference was used to knock down TRPV2 expression, which was validated by western blotting. Neurological and histological analyses were used to examine brain injury of mice following middle cerebral artery occlusion/reperfusion (MCAO/R).Plumbagin is a potent TRPV2 negative allosteric modulator with an IC50 value of 0.85 μM, exhibiting >14‐fold selectivity over TRPV1, TRPV3 and TRPV4. Plumbagin suppresses TRPV2 activity by decreasing the channel open probability without affecting the unitary conductance. Moreover, plumbagin binds to an extracellular pocket formed by the pore helix and flexible loop between transmembrane helices S5 and S6 of TRPV2. Plumbagin effectively suppresses LPS‐induced inflammation of BV‐2 microglia and ameliorates brain injury of MCAO/R mice.Plumbagin is a novel pharmacological probe to study TRPV2 pathophysiology. TRPV2 is a novel molecular target for the treatment of neuroinflammation and ischemic stroke. [ABSTRACT FROM AUTHOR]

The TRPV1 channel is actively involved in various neuronal processes and is found in various structures of the nervous system, including peripheral and central neurons, sensory ganglia, spinal cord, and various parts of the brain. Due to its ability to respond to various stimuli, TRPV1 can have a significant impact on the body's responses to stress. Studies indicate the involvement of TRPV1 in the regulation of anxiety behavior. Suppression of TRPV1 activity leads to a decrease in the level of anxiety in animals, which indicates the importance of this channel in psychoemotional regulation. A promising compound for inhibiting this channel is the APHC3 peptide, which is a selective receptor antagonist. The results obtained this study show that this peptide has a pronounced anxiolytic effect, reducing the level of anxiety in the studied animals. [ABSTRACT FROM AUTHOR]

Chronic prostatitis is a prevalent male urinary system disorder characterized by pelvic discomfort or pain, bladder dysfunction, sexual dysfunction, and infertility. Pain and lower urinary tract symptoms (LUTS) are the most common symptoms, significantly impacting patients' quality of life and driving them to seek medical attention. Transient receptor potential vanilloid subtype 1 (TRPV1) is a nonselective calcium ion-dependent cation channel in the TRPV channel family that is widely distributed in neural tissue and plays a role in signal transmission. In this review, we provide a comprehensive overview of the current understanding of the role of TRPV1 in chronic prostatitis. The discussion focuses on the connection between TRPV1 and prostatitis pain and LUTS, and highlights the potential for targeting this channel in the development of novel treatment strategies. [ABSTRACT FROM AUTHOR]

Transient receptor potential vanilloid‐1 (TRPV1) is a capsaicin receptor that employs use‐dependent desensitization to protect highly evolved mammals from noxious heat damage in response to repeated or constant heat stimuli. However, the underlying structural factor or motif has not been precisely resolved. In this computational study, the graph theory‐based grid thermodynamic model was used to reveal how temperature‐dependent noncovalent interactions, as identified in the 3D structures of rat TRPV1, could develop a well‐organized fluidic grid‐like mesh network. This network features various topological grids constrained as thermosensitive rings that range in size from the biggest to the smallest, governing distinct structural and functional traits of the channel in response to different temperature degrees. After discovering that heat unfolding of three specific biggest grids, one in the closed state and two in the open state, respectively, causes the reversible activation at 43°C and thermal inactivation between 56°C and 61°C, a smaller random grid was also found to be responsible for irreversible inactivation and use‐dependent desensitization from the pre‐open closed state within the temperature range of 43°C–61°C. Thus, these two distinct inactivation pathways of TRPV1 may be involved in protecting those mammals against noxious heat damage. Key Points: A perturbation at the protein–water interface was accompanied by partial heat or cold unfolding of the membrane protein.A reversible or irreversible gating transition of an ion channel may result from a specific or random interaction between two active sites, respectively.Kinetically driven protein aggregation was not the cause of thermodynamically trapped irreversible inactivation, but rather a later stage of partial heat‐induced unfolding. [ABSTRACT FROM AUTHOR]

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a serious therapy-limiting side effect of commonly used anticancer drugs. Previous studies suggest that lipids may play a role in CIPN. Therefore, the present study aimed to identify the particular types of lipids that are regulated as a consequence of paclitaxel administration and may be associated with the occurrence of post-therapeutic neuropathy. Methods: High-resolution mass spectrometry lipidomics was applied to quantify d=255 different lipid mediators in the blood of n=31 patients drawn before and after paclitaxel therapy for breast cancer treatment. A variety of supervised statistical and machine-learning methods was applied to identify lipids that were regulated during paclitaxel therapy or differed among patients with and without post-therapeutic neuropathy. Results: Twenty-seven lipids were identified that carried relevant information to train machine learning algorithms to identify, in new cases, whether a blood sample was drawn before or after paclitaxel therapy with a median balanced accuracy of up to 90%. One of the top hits, sphinganine1-phosphate (SA1P), was found to induce calcium transients in sensory neurons via the transient receptor potential vanilloid 1 (TRPV1) channel and sphingosine-1-phosphate receptors.SA1P also showed different blood concentrations between patients with and without neuropathy. Conclusions: Present findings suggest a role for sphinganine-1-phosphate in paclitaxel-induced biological changes associated with neuropathic side effects. The identified SA1P, through its receptors, may provide a potential drug target for co-therapy with paclitaxel to reduce one of its major and therapy-limiting side effects. Funding: This work was supported by the Deutsche Forschungsgemeinschaft (German Research Foundation, DFG, Grants SFB1039 A09 and Z01) and by the Fraunhofer Foundation Project: Neuropathic Pain as well as the Fraunhofer Cluster of Excellence for Immune-Mediated Diseases (CIMD). This work was also supported by the Leistungszentrum Innovative Therapeutics (TheraNova) funded by the Fraunhofer Society and the Hessian Ministry of Science and Arts. Jörn Lötsch was supported by the Deutsche Forschungsgemeinschaft (DFG LO 612/16-1). [ABSTRACT FROM AUTHOR]

Gastric cancer (GC) remains a significant health challenge due to its high mortality rate and the limited efficacy of current targeted therapies. A critical barrier in developing more effective treatments is the lack of understanding of specific mechanisms driving GC progression. This study investigates the role of Transient Receptor Potential Vanilloid 1 (TRPV1), a non-selective cation channel known for its high Ca2+ permeability and tumor-suppressive properties in gastrointestinal cancers. Specifically, we explore the impact of SUMOylation—a dynamic and reversible post-translational modification—on TRPV1's function in GC. We demonstrate that SUMOylation of TRPV1 inhibits cell proliferation and migration in MGC-803 and AGS GC cells. By mutating amino acids near TRPV1's existing SUMO motif (slKpE), we created a bidirectional SUMO motif (EψKψE) that enhances TRPV1 SUMOylation, resulting in further suppression of GC cell proliferation and migration. In vivo studies support these findings, showing that TRPV1 SUMOylation prevents spontaneous tumorigenesis in a mouse GC model. Further investigation reveals that TRPV1 SUMOylation increases the protein's membrane expression by inhibiting its interaction with the adaptor-related protein complex 2 mu 1 subunit (AP2M1). This elevated membrane expression leads to increased intracellular Ca2+ influx, activating the AMP-activated protein kinase (AMPK) pathway, which in turn inhibits the proliferation and migration of GC cells. [ABSTRACT FROM AUTHOR]

Breast cancer, the most prevalent and aggressive tumor affecting women, requires identification of disease determinants to facilitate the development of effective therapeutic strategies. Transient receptor potential vanilloid 2 (TRPV2), an ion channel highly permeable for calcium (Ca2+), is implicated in physiological and pathological processes. Nevertheless, the role of TRPV2 in breast cancer remains poorly elucidated. In this study, we found high levels of TRPV2 expression associated with advanced malignancy, thereby suggesting its potential as a biomarker for breast cancer staging. We demonstrated that TRPV2 activation promotes breast cancer cell proliferation, migration, and invasion, while silencing of TRPV2 suppresses breast cancer progression, highlighting the oncogenic role of TRPV2. Moreover, we reveal that TRPV2 facilitates cancer progression by modulating the CaMKKβ/AMPK/ULK1-autophagic axis through mediating calcium influx, providing new insights into TRPV2 as a novel therapeutic target for breast cancer treatment. [ABSTRACT FROM AUTHOR]

Introduction: Monoiodoacetate (MIA)-induced osteoarthritis (OA) is the most commonly used rodent model for testing anti-OA drug candidates. Herein, we investigated the effects of our patented multitarget drug candidate SZV-1287 (3- (4,5-diphenyl-1,3-oxazol-2-yl) propanal oxime) that is currently under clinical development for neuropathic pain and characterized the mouse model through complex functional, in vivo imaging, and morphological techniques. Methods: Knee OA was induced by intraarticular MIA injection (0.5 and 0.8 mg). Spontaneous pain was assessed based on weight distribution, referred pain by paw mechanonociception (esthesiometry), edema by caliper, neutrophil myeloperoxidase activity by luminescence, matrix metalloproteinase activity, vascular leakage and bone remodeling by fluorescence imaging, bone morphology by micro-CT, histopathological alterations by semiquantitative scoring, and glia activation by immunohistochemistry. Then, SZV-1287 (20 mg/kg/day) or its vehicle was injected intraperitoneally over a 21-day period. Results: MIA induced remarkably decreased thresholds of weight bearing and paw withdrawal, alterations in the tibial and femoral structures (reactive sclerosis, increased trabeculation, and cortical erosions), histopathological damage (disorganized cartilage structure, hypocellularity, decreased matrix staining and tidemark integrity, and increased synovial hyperplasia and osteophyte formation), and changes in the astrocyte and microglia density in the lumbar spinal cord. There were no major differences between the two MIA doses in most outcome measures. SZV-1287 inhibited MIA-induced weight bearing reduction, hyperalgesia, edema, myeloperoxidase activity, histopathological damage, and astrocyte and microglia density. Conclusion: SZV-1287 may have disease-modifying potential through analgesic, anti-inflammatory, and chondroprotective effects. The MIA mouse model is valuable for investigating OA-related mechanisms and testing compounds in mice at an optimal dose of 0.5 mg. [ABSTRACT FROM AUTHOR]

Nerve injury can induce aberrant changes in the spine; these changes are due to, or at least partly governed by, transcription factors that contribute to the genesis of neuropathic allodynia. Here, we showed that spinal nerve ligation (SNL, a clinical neuropathic allodynia model) increased the expression of the transcription factor Tbx5 in the injured dorsal horn in male Sprague Dawley rats. In contrast, blocking this upregulation alleviated SNL-induced mechanical allodynia, and there was no apparent effect on locomotor function. Moreover, SNL-induced Tbx5 upregulation promoted the recruitment and interaction of GATA4 and Brd4 by enhancing its binding activity to H3K9Ac, which was enriched at the Trpv1 promotor, leading to an increase in TRPV1 transcription and the development of neuropathic allodynia. In addition, nerve injury-induced expression of Fbxo3, which abates Fbxl2-dependent Tbx5 ubiquitination, promoted the subsequent Tbx5-dependent epigenetic modification of TRPV1 expression during SNL-induced neuropathic allodynia. Collectively, our findings indicated that spinal Tbx5-dependent TRPV1 transcription signaling contributes to the development of neuropathic allodynia via Fbxo3-dependent Fbxl2 ubiquitination and degradation. Thus, we propose a potential medical treatment strategy for neuropathic allodynia by targeting Tbx5. [ABSTRACT FROM AUTHOR]

The Streptomyces sp. is considered the vast reservoir of bioactive natural products belonging to different classes like polyketides, terpenoids, lanthipeptides, and non-ribosomal peptides to name a few. The ubiquitous distribution of the genus makes them capable of producing distinct compounds. Many of those compounds contain a unique γ-pyrone with various chemical structures and exhibit different bioactivities. One such class, nitrophenyl-γ-pyrone, constitutes different bioactive compounds isolated from Streptomyces sp. from different sources ranging from soil to marine environments. In addition, such compounds have antinematodal, cytotoxicity activities, and inhibition of adipogenesis. These compounds include aureothin (3), spectinabilin (7), and their derivatives. Moreover, there are other compounds like actinopyrones (11–16), benwamycins (22–23), and peucemycin and its derivatives (24–26) that also have antibacterial and anticancer activities. The other group classified as anthra-γ-pyrone has various bioactive natural products. For instance, tetrahydroanthra-γ-pyrone, shellmycin A-D (27–30) possess antibacterial as well as anticancer activities. In addition, the pluramycin family compounds belonging to anthra-γ-pyrone group also possess cytotoxic activity, for instance, kidamycin (31), rubiflavin, and their derivatives (33–37). Xanthones are another important group of natural products that also contain γ-pyrone ring producing different bioactivities. Albofungin (42) and its derivatives (43–46) belong to subgroup polycyclic tetrahydro xanthones that possess antibacterial, anticancer, and antibiofilm, antimacrofouling activities. Similarly, other compounds, belonging to this subgroup, exhibit different bioactivities like antifungal, antimalarial, and antibacterial activities and block transient receptor potential vanilloid 1 (TRPV1). These compounds include cervinomycins (48–55), citreamycins (56–57), sattahipmycin (59), and chrexanthomycins (60–63). This review gives succinct information on the γ-pyrone containing natural products isolated from Streptomyces sp. focusing on their structure and bioactivities. Key points: • The Streptomyces sp. is the producer of various bioactive natural products including the one with γ-pyrone ring. • These γ-pyrone compounds are structurally different and possess different bioactivities. • The Streptomyces has the potential to produce such compounds and the reservoir of these compounds is expected to increase in the future. [ABSTRACT FROM AUTHOR]

The transient receptor potential vanilloid 1 (TRPV1) channel plays a dual role in peripheral neuropathic pain (NeuP) by acting as a "pain switch" through its sensitization and desensitization. Hyperalgesia, commonly resulting from tissue injury or inflammation, involves the sensitization of TRPV1 channels, which modulates sensory transmission from primary afferent nociceptors to spinal dorsal horn neurons. In chemotherapy-induced peripheral neuropathy (CIPN), TRPV1 is implicated in neuropathic pain mechanisms due to its interaction with ion channels, neurotransmitter signaling, and oxidative stress. Sensitization of TRPV1 in dorsal root ganglion neurons contributes to CIPN development, and inhibition of TRPV1 channels can reduce chemotherapy-induced mechanical hypersensitivity. In diabetic peripheral neuropathy (DPN), TRPV1 is involved in pain modulation through pathways including reactive oxygen species and cytokine production. TRPV1's interaction with TRPA1 channels further influences chronic pain onset and progression. Therapeutically, capsaicin, a TRPV1 agonist, can induce analgesia through receptor desensitization, while TRPV1 antagonists and siRNA targeting TRPV1 show promise in preclinical studies. Cannabinoid modulation of TRPV1 provides another potential pathway for alleviating neuropathic pain. This review summarizes recent preclinical research on TRPV1 in association with peripheral NeuP. [ABSTRACT FROM AUTHOR]

Peripheral nerve regeneration depends on close interaction between neurons and Schwann cells (SCs). After nerve injury, SCs produce growth factors and cytokines that are crucial for axon re-growth. Previous studies revealed the supernatant of SCs exposed to nuclear magnetic resonance therapy (NMRT) treatment to increase survival and neurite formation of rat dorsal root ganglion (DRG) neurons in vitro. The aim of this study was to identify factors involved in transferring the observed NMRT-induced effects to SCs and consequently to DRG neurons. Conditioned media of NMRT-treated (CM NMRT) and untreated SCs (CM CTRL) were tested by beta-nerve growth factor (ßNGF) ELISA and multiplex cytokine panels to profile secreted factors. The expression of nociceptive transient receptor potential vanilloid 1 (TRPV1) channels was assessed and the intracellular calcium response in DRG neurons to high-potassium solution, capsaicin or adenosine triphosphate was measured mimicking noxious stimuli. NMRT induced the secretion of ßNGF and pro-regenerative-signaling factors. Blocking antibody experiments confirmed ßNGF as the main factor responsible for neurotrophic/neuritogenic effects of CM NMRT. The TRPV1 expression or sensitivity to specific stimuli was not altered, whereas the viability of cultured DRG neurons was increased. Positive effects of CM NMRT supernatant on DRG neurons are primarily mediated by increased ßNGF levels. [ABSTRACT FROM AUTHOR]

The rising incidence of metabolic diseases is linked to elevated blood glucose levels, contributing to conditions such as diabetes and promoting the accumulation of advanced glycation end products (AGEs). AGEs, formed by non-enzymatic reactions between sugars and proteins, build up in tissues and are implicated in various diseases. This article explores the relationship between glycemic control and AGE accumulation, focusing on fertility implications. A computational model using network theory was developed, featuring a molecular database and a network with 145 nodes and 262 links, categorized as a Barabasi–Albert scale-free network. Three main subsets of nodes emerged, centered on glycemic control, fertility, and immunity, with AGEs playing a critical role. The transient receptor potential vanilloid 1 (TRPV1), a receptor expressed in several tissues including sperm, was identified as a key hub, suggesting that the modulation of TRPV1 in sperm by AGEs may influence fertility. Additionally, a novel link between glycemic control and immunity was found, indicating that immune cells may play a role in endocytosing specific AGEs. This discovery underscores the complex interplay between glycemic control and immune function, with significant implications for metabolic, immune health, and fertility. [ABSTRACT FROM AUTHOR]

Background and Purpose: We extend the characterization of the TRPM8 antagonist VBJ103 with tests of selectivity, specificity and distribution, therapeutic efficacy of systemic administration against oxaliplatin‐induced cold hyperalgesia and the impact of systemic administration on core body temperature (CBT). Experimental Approach: Selectivity at human TRPA1 and TRPV1 as well as in vitro safety profiling was determined. Effects of systemic administration of VBJ103 were evaluated in a model of oxaliplatin‐induced cold hyperalgesia. Both peripheral and centrally mediated effects of VBJ103 on CBT were assessed with radiotelemetry. Key Results: VBJ103 had no antagonist activity at TRPV1 and TRPA1, but low potency TRPA1 activation. The only safety liability detected was partial inhibition of the dopamine transporter (DAT). VBJ103 delivered subcutaneously dose‐dependently attenuated cold hypersensitivity in oxaliplatin‐treated mice at 3, 10 and 30 mg·kg−1 (n = 7, P < 0.05). VBJ103 (30 mg·kg−1) antinociception was influenced by neither the TRPA1 antagonist HC‐030031 nor the DAT antagonist GBR12909. Subcutaneous administration of VBJ103 (3, 10 and 30 mg·kg−1, but not 100 or 300 mg·kg−1, n = 7) decreased CBT (2°C). Intraperitoneal (i.p.) administration of VBJ103 (3, 10 and 30 mg·kg−1) dose‐dependently decreased CBT to an extent larger than that detected with subcutaneous administration. Intracerebroventricular (i.c.v.) administration (306 nmol/1 μL; n = 5) did not alter CBT. Conclusions and Implications: We achieve therapeutic efficacy with subcutaneous administration of a novel TRPM8 antagonist that attenuates deleterious influences on CBT, a side effect that has largely prevented the translation of TRPM8 as a target. [ABSTRACT FROM AUTHOR]

Cannabinol (CBN) is a secondary metabolite of cannabis whose beneficial activity on inflammatory diseases of human skin has attracted increasing attention. Here, we sought to investigate the possible modulation by CBN of the major elements of the endocannabinoid system (ECS), in both normal and lipopolysaccharide‐inflamed human keratinocytes (HaCaT cells). CBN was found to increase the expression of cannabinoid receptor 1 (CB1) at gene level and that of vanilloid receptor 1 (TRPV1) at protein level, as well as their functional activity. In addition, CBN modulated the metabolism of anandamide (AEA) and 2‐arachidonoylglicerol (2‐AG), by increasing the activities of N‐acyl phosphatidylethanolamines‐specific phospholipase D (NAPE‐PLD) and fatty acid amide hydrolase (FAAH)—the biosynthetic and degradative enzyme of AEA—and that of monoacylglycerol lipase (MAGL), the hydrolytic enzyme of 2‐AG. CBN also affected keratinocyte inflammation by reducing the release of pro‐inflammatory interleukin (IL)‐8, IL‐12, and IL‐31 and increasing the release of anti‐inflammatory IL‐10. Of note, the release of IL‐31 was mediated by TRPV1. Finally, the mitogen‐activated protein kinases (MAPK) signaling pathway was investigated in inflamed keratinocytes, demonstrating a specific modulation of glycogen synthase kinase 3β (GSK3β) upon treatment with CBN, in the presence or not of distinct ECS‐directed drugs. Overall, these results demonstrate that CBN modulates distinct ECS elements and exerts anti‐inflammatory effects—remarkably via TRPV1—in human keratinocytes, thus holding potential for both therapeutic and cosmetic purposes. [ABSTRACT FROM AUTHOR]

Objective: Schizonepeta tenuifolia -Saposhnikovia divaricata (Jingjie-Fangfeng, JF) has been used for years to treat allergic inflammatory skin diseases like atopic dermatitis, but the specific effects and mechanisms of JF are still unclear. Purpose: We aim to investigate the therapeutic effect and mechanism of JF in MC903-induced atopic dermatitis-like model. Methods: JF decoction was subjected to rigorous HPLC and GC analysis. The JF decoction was then freshly prepared and administered to MC903-induced atopic dermatitis -like mice models to investigate its therapeutic effects. Our evaluation focused on several markers of inflammation including the TEWL index, ear thickness, swelling, and specific inflammation indicators such as TSLP, IL33, IgE, and immune cell presence at the lesion sites. We measured Transient Receptor Potential Vanilloid 1 (TRPV1) expression levels through immunofluorescent staining in skin tissue from both atopic dermatitis patients and the MC903-treated mice. Furthermore, TRPV1 expression and macrophage activation markers were measured in LPS/IFN-γ-stimulated Raw264.7 and THP-1 cell models in vitro. Additionally, we developed cell lines that overexpress TRPV1 and investigated how JF treatment affects NF-κB p65 phosphorylation in these cells to understand better the role of TRPV1 in atopic dermatitis. Results: The JF decoction met the standards outlined in the Chinese pharmacopeia. The JF decoction significantly alleviated inflammatory skin symptoms and helped restore skin barrier function. Additionally, it reduced the levels of IgE and pro-inflammatory cytokines TSLP, IL-33, and IL-4. There was also a noticeable decrease in mast cell infiltration and degranulation. Notably, JF decoction reduced infiltrated macrophages with limited affection on T cell infiltration. It also decreased F4/80+/TRPV1+ cells in atopic dermatitis mice and TRPV1 expression in LPS/IFNγ-stimulated microphages. Additionally, we observed that CD68+/TRPV1+ cells increased in human atopic dermatitis tissue. Further studies showed that JF water extract (JF-WE) suppressed TRPV1 expression in macrophages, potentially by affecting NF-κB p65 phosphorylation rather than the JAK-STAT6 pathway. Conclusion: This study offers initial evidence of the effectiveness of JF-WE in suppressing inflammation in atopic dermatitis. The therapeutic effect might stems from its ability to downregulate TRPV1 expression and subsequent NF-κB p65 phosphorylation in macrophages. [ABSTRACT FROM AUTHOR]

Sensing of noxious heat has been reported to be mediated by TRPV1, TRPA1, TRPM3, and ANO1 in mice, and this is redundant so that the loss of one receptor is at least partially compensated for by others. We have established an infusion-based human heat pain model. Heat-induced pain probed with antagonists for the four receptors did not match the redundancy found in mice. In healthy participants, only TRPV1 contributes to the detection of noxious heat; none of the other three receptors are involved. TRPV1 inhibition reduced the pain at all noxious temperatures, which can also be seen as an increase in the temperature that causes a particular level of pain. However, even if the TRPV1-dependent shift in heat detection is about 1°C, at the end of the temperature ramp to 52°C, most heat-induced pain remains unexplained. This difference between species reopens the quest for the molecular safety net for the detection of noxious heat in humans. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the leading form of dementia, characterized by the accumulation and aggregation of amyloid in brain. Transient receptor potential vanilloid 2 (TRPV2) is an ion channel involved in diverse physiopathological processes, including microglial phagocytosis. Previous studies suggested that cannabidiol (CBD), an activator of TRPV2, improves microglial amyloid-β (Aβ) phagocytosis by TRPV2 modulation. However, the molecular mechanism of TRPV2 in microglial Aβ phagocytosis remains unknown. In this study, we aimed to investigate the involvement of TRPV2 channel in microglial Aβ phagocytosis and the underlying mechanisms. Utilizing human datasets, mouse primary neuron and microglia cultures, and AD model mice, to evaluate TRPV2 expression and microglial Aβ phagocytosis in both in vivo and in vitro. TRPV2 was expressed in cortex, hippocampus, and microglia.Cannabidiol (CBD) could activate and sensitize TRPV2 channel. Short-term CBD (1 week) injection intraperitoneally (i.p.) reduced the expression of neuroinflammation and microglial phagocytic receptors, but long-term CBD (3 week) administration (i.p.) induced neuroinflammation and suppressed the expression of microglial phagocytic receptors in APP/PS1 mice. Furthermore, the hyper-sensitivity of TRPV2 channel was mediated by tyrosine phosphorylation at the molecular sites Tyr(338), Tyr(466), and Tyr(520) by protein tyrosine kinase JAK1, and these sites mutation reduced the microglial Aβ phagocytosis partially dependence on its localization. While TRPV2 was palmitoylated at Cys 277 site and blocking TRPV2 palmitoylation improved microglial Aβ phagocytosis. Moreover, it was demonstrated that TRPV2 palmitoylation was dynamically regulated by ZDHHC21. Overall, our findings elucidated the intricate interplay between TRPV2 channel regulated by tyrosine phosphorylation/dephosphorylation and cysteine palmitoylation/depalmitoylation, which had divergent effects on microglial Aβ phagocytosis. These findings provide valuable insights into the underlying mechanisms linking microglial phagocytosis and TRPV2 sensitivity, and offer potential therapeutic strategies for managing AD. [ABSTRACT FROM AUTHOR]

Transient Receptor Potential Vanilloid 1 (TRPV1) is a protein that functions as a non-selective channel receptor that is widely expressed in skin tissue, including keratinocytes, peripheral sensory nerve fibers, and immune cells. Several structural features of TRPV1 are involved in heat-induced activation, where stimulation of TRPV1 elicits a burning sensation, reflecting the receptor's important role in pain. A TRPV1-mediated signalling pathway that functions as an endogenous pain resolution mechanism by inducing nuclear translocation of β-arrestin2 to minimize desensitization of μ-opioid receptors (MOR). TRPV1 agonists can reduce pain primarily by interfering with pain nerve conduction. Several TRPV1 antagonist drug candidates have failed in clinical trials because by interfering with the detection of the above-mentioned stimuli, they triggered serious side effects such as hyperthermia and painful impaired heat detection. In the case of agonists, systemic administration causes more severe side effects such as respiratory damage. Therefore, only topical preparations with limited effectiveness have been developed. The TRPV1 agonist capsaicin is currently the only one approved for the treatment of muscle, bone, neuropathic pain and migraine, and is only available as a low-concentration cream or as a transdermal patch. [ABSTRACT FROM AUTHOR]

Polycystic kidney disease (PKD), a disease characterized by the enlargement of the kidney through cystic growth is the fourth leading cause of end-stage kidney disease world-wide. Transient receptor potential Vanilloid 4 (TRPV4), a calcium-permeable TRP, channel participates in kidney cell physiology and since TRPV4 forms complexes with another channel whose malfunction is associated to PKD, TRPP2 (or PKD2), we sought to determine whether patients with PKD, exhibit previously unknown mutations in TRPV4. Here, we report the presence of mutations in the TRPV4 gene in patients diagnosed with PKD and determine that they produce gain-of-function (GOF). Mutations in the sequence of the TRPV4 gene have been associated to a broad spectrum of neuropathies and skeletal dysplasias but not PKD, and their biophysical effects on channel function have not been elucidated. We identified and examined the functional behavior of a novel E6K mutant and of the previously known S94L and A217S mutant TRVP4 channels. The A217S mutation has been associated to mixed neuropathy and/or skeletal dysplasia phenotypes, however, the PKD carriers of these variants had not been diagnosed with these reported clinical manifestations. The presence of certain mutations in TRPV4 may influence the progression and severity of PKD through GOF mechanisms. PKD patients carrying TRVP4 mutations are putatively more likely to require dialysis or renal transplant as compared to those without these mutations. Graphical Abstract Abstract graph showing a schematic representation of a wild-type TRPV4 channel compared to the increased activity of a mutant TRPV4 channel carrying one of the two TRPV4 mutations located in the amino-terminal domain and found in a patient cohort diagnosed with polycystic kidney disease.Abstract graph showing a schematic representation of a wild-type TRPV4 channel compared to the increased activity of a mutant TRPV4 channel carrying one of the two TRPV4 mutations located in the amino-terminal domain and found in a patient cohort diagnosed with polycystic kidney disease. [ABSTRACT FROM AUTHOR]

Fibromyalgia (FM) is a widespread musculoskeletal pain associated with psychological disturbances, the etiopathogenesis of which is still not clear. One hypothesis implicates inflammatory cytokines in increasing central and peripheral sensitization along with neuroinflammation, leading to an elevation in pro-inflammatory cytokines, e.g., interleukin-17A (IL-17A), enhanced in FM patients and animal models. The intermittent cold stress (ICS)-induced FM-like model in C57BL/6 mice has been developed since 2008 and proved to have features which mimic the clinical pattern in FM patients such as mechanical allodynia, hyperalgesia, and female predominance of pain. Electroacupuncture (EA) is an effective treatment for relieving pain in FM patients, but its mechanism is not totally clear. It was reported as attenuating pain-like behaviors in the ICS mice model through the transient receptor potential vanilloid 1 (TRPV1) pathway. Limited information indicates that TRPV1-positive neurons trigger IL-17A-mediated inflammation. Therefore, we hypothesized that the IL-17A would be inactivated by EA and TRPV1 deletion in the ICS-induced FM-like model in mice. We distributed mice into a control (CON) group, ICS-induced FM model (FM) group, FM model with EA treatment (EA) group, FM model with sham EA treatment (Sham) group, and TRPV1 gene deletion (Trpv1−/−) group. In the result, ICS-induced mechanical and thermal hyperalgesia increased pro-inflammatory cytokines including IL-6, IL-17, TNFα, and IFNγ in the plasma, as well as TRPV1, IL-17RA, pPI3K, pAkt, pERK, pp38, pJNK, and NF-κB in the somatosensory cortex (SSC) and cerebellum (CB) lobes V, VI, and VII. Moreover, EA and Trpv1−/− but not sham EA countered these effects significantly. The molecular mechanism may involve the pro-inflammatory cytokines, including IL-6, IL-17, TNFα, and IFNγ. IL-17A–IL-17RA play a crucial role in peripheral and central sensitization as well as neuroinflammation and cannot be activated without TRPV1 in the ICS mice model. EA alleviated FM-pain-like behaviors, possibly by abolishing the TRPV1- and IL-17A-related pathways. It suggests that EA is an effective and potential therapeutic strategy in FM. [ABSTRACT FROM AUTHOR]