TRPV1 Research Articles

From pain to meningitis: bacteria hijack nociceptors to promote meningitis

Bacterial meningitis is a severe and life-threatening infection of the central nervous system (CNS), primarily caused by Streptococcus pneumoniae and Neisseria meningitidis. This condition carries a high risk of mortality and severe neurological sequelae, such as cognitive impairment and epilepsy. Pain, a central feature of meningitis, results from the activation of nociceptor sensory neurons by inflammatory mediators or bacterial toxins. These nociceptors, abundantly present in the meninges, trigger neuroimmune signaling pathways that influence the host immune response. However, the mechanisms by which bacteria hijack these nociceptors to promote CNS invasion and exacerbate the disease remain poorly understood. This review examines the interactions between bacteria and meningeal nociceptors, focusing on their direct and indirect activation via ion channels, such as transient receptor potential vanilloid-1 (TRPV1) and transient receptor potential ankyrin 1 (TRPA1), or through the release of neuropeptides like calcitonin gene-related peptide (CGRP). These interactions suppress immune defenses by inhibiting macrophage activity and neutrophil recruitment, thus facilitating bacterial survival and invasion of the CNS. Understanding this neuroimmune axis may open potential therapeutic targets for treating bacterial meningitis by enhancing host defenses and mitigating pain. Further research using advanced methodologies is essential to clarify the role of nociceptor-mediated immune modulation in this disease.

The Role of TRPV1/CGRP Pathway Activated by Prevotella melaninogenica in Pathogenesis of Oral Lichen Planus

The distinctive clinicopathologic characteristics of OLP indicated that both microbial dysbiosis and neurogenic inflammation may be jointly involved in its progression, and transient receptor potential vanilloid receptor-1 (TRPV1) may be a crucial element. The purpose of this study was to explore how TRPV1 mediated P. melaninogenica-induced inflammation. Meanwhile, we aimed to unravel how IL-36γ dysregulated the barrier function in oral keratinocytes. Here, the expression of TRPV1, calcitonin gene-related peptide (CGRP), and its receptor receptor activity-modifying protein 1 (RAMP1) in OLP patients were detected. Prevotella melaninogenica (P. melaninogenica) was used to build a mouse model of oral chronic inflammation. Normal human oral keratinocytes (NHOKs) stimulated by P. melaninogenica were used to examine TRPV1 activation and CGRP release. To investigate the effect of exogenous CGRP on Interleukin-36 gamma (IL-36γ) expression in NHOKs and bacterial viability, P. melaninogenica and NHOKs were treated with it, respectively. Recombinant IL-36γ protein was used to probe its regulation of oral epithelial barrier function. TRPV1, CGRP, and RAMP1 were substantially expressed in OLP. P. melaninogenica increased TRPV1 expression in mice and caused the release of CGRP and an increase in pro-inflammatory cytokines via activating TRPV1 in NHOKs. Blockade of TRPV1 suppressed P. melaninogenica-induced inflammation. CGRP boosted the production of IL-36γ released by NHOKs, resulting in lower expression of zonula occludens-1 (ZO-1). Also, CGRP can decrease the viability of P. melaninogenica. Together, these findings provide fresh insight into the vital role performed by P. melaninogenica-induced functional changes in oral epithelial cells and neurons in an intricate OLP inflammatory process.

Involvement of Inwardly Rectifying Potassium (Kir) Channels in the Toxicity of Flonicamid to Drosophila melanogaster

Inwardly rectifying potassium (Kir) channels regulate essential physiological processes in insects and have been identified as potential targets for developing new insecticides. Flonicamid has been reported to inhibit Kir channels, disrupting the functions of salivary glands and renal tubules. However, the precise molecular target of flonicamid remains debated. It is unclear whether flonicamid directly targets Kir channels or acts on other sites involved in the activation of transient receptor potential vanilloid (TRPV) channels. In this study, we observed that flonicamid is more toxic to flies than its metabolite, flumetnicam. This higher toxicity is difficult to reconcile if nicotinamidase is the active target, as flonicamid does not inhibit nicotinamidase. An alternative explanation is that flonicamid and flumetnicam may have distinct targets or act on multiple targets. Furthermore, reducing the expression of three individual Kir genes in the salivary glands of D. melanogaster significantly decreased the flies’ susceptibility to both flonicamid and flumetnicam. The double knockdown of Kir1 with Kir3 or Kir2 with Kir3 further reduced the flies’ sensitivity to both compounds. These findings confirm the involvement of Kir channels in mediating the toxic effects of flonicamid on flies. Overall, this study offers new insights into the physiological roles of insect Kir channels and flonicamid toxicity.

Natural phenylethanoid glycoside forsythoside A alleviates androgenetic alopecia by selectively inhibiting TRPV3 channels in mice.

Dihydrotestosterone (DHT), an androgen derivate, is known to be a key factor involved in androgenetic alopecia. DHT suppresses the growth of outer root sheath cells and induces apoptosis of hair keratinocytes, thereby causing hair follicle miniaturization and hair regrowth inhibition. Forsythoside A, a natural substance derived from Forsythia suspensa, has been shown to reduce DHT-induced apoptosis in human hair cells and suppress hair regrowth inhibition induced by DHT in mice. However, the molecular mechanism underlying the action of forsythoside A remains unclear. Here, we report that the alleviation of androgenetic alopecia by natural phenylethanoid glycoside forsythiaside A involves the selective inhibition of warmth-sensitive Ca2+-permeable transient receptor potential vanilloid-3 (TRPV3) channels. TRPV3 mRNA and protein expressions are upregulated in the skin of a mouse model of androgenetic alopecia induced by DHT. Ablation of the Trpv3 gene or subcutaneous injection of forsythoside A alleviates DHT-induced hair regrowth inhibition. In whole-cell patch clamp recordings, forsythoside A selectively inhibits macroscopic TRPV3 currents in a concentration-dependent manner with an IC50 value of 40.1 ± 4.8 μM. At the single-channel level, forsythoside A also reduces the channel open probability and open frequency without significantly altering the channel unitary conductance. Molecular docking combined with site-directed mutagenesis reveals two residues T636 and T665 critical for forsythoside A-mediated inhibition of TRPV3. Taken together, our findings demonstrate that TRPV3 inhibition is an important a mechanism by which natural forsythoside A ameliorates DHT-induced hair regrowth. Topical TRPV3 inhibitors may hold promise as a new therapeutic approach for treating androgenetic alopecia.

Capsaicin-induced Ca2+ overload and ablation of TRPV1-expressing axonal terminals for comfortable tumor immunotherapy.

As a common malignancy symptom, cancer pain significantly affects patients' quality of life. Approximately 60%-90% of patients with advanced cancer experience debilitating pain. Therefore, a comprehensive treatment system that combines cancer pain suppression and tumor treatment could provide significant benefits for these patients. Here, we designed a manganese oxide (MnO2)/Bovine serum albumin (BSA)/polydopamine (PDA) composite nanoplatform internally loaded with capsaicin for cancer pain suppression and immunotherapy. MBD&C nanoparticles (NPs) can ablate tumor-innervated sensory nerve fibers via Transient receptor potential vanilloid 1 (TRPV1) channels, thereby reducing the pain caused by various inflammatory mediators. The ablation of TRPV1+ nerve terminals can also decrease the secretion of calcitonin gene-related peptide (CGRP) and substance P (SP) in sensory nerve fibers, thus reducing the tumor pain and inhibit tumor progression. MBD&C can promote calcium influx by activating overexpressed TRPV1 channels on the tumor membrane surface, thereby achieving cancer immunotherapy induced by endogenous Ca2+ overloading. In addition, MnO2 NPs can alleviate tumor hypoxia and mitigate the immunosuppressive tumor microenvironment (TME). Ultimately, this treatment system with dual capabilities of inhibiting tumor growth and relieving cancer pain makes comfortable tumor therapy feasible and paves the way for the development of patient-centered approaches to cancer treatment in the future.

N-acetyl-L-tryptophan provides radioprotection to mouse and primate models by antagonizing the TRPV1 receptor and substance P inhibition

Purpose The present study was carried out to evaluate the radioprotective activities of N-acetyl-L-tryptophan (L-NAT) using rodent and non-human primate (NHP) models. Materials and methods The antagonistic effect of L-NAT on the Transient receptor potential vanilloid-1 (TRPV1) receptor and substance P inhibition was determined using molecular docking and Elisa assays. The in vivo radioprotective activity of L-NAT was evaluated using whole-body survival assays in mice and NHPs. Radioprotective activity of L-NAT was also determined at the systemic level using quantitative histological analysis of bone marrow, jejunum, and seminiferous tubules of irradiated mice. Results Molecular docking studies revealed a strong binding of L-NAT with TRPV1 receptor at similar binding pockets to which capsaicin, an agonist of the TRPV1 receptor, binds. Further, capsaicin and gamma radiation were found to induce substance P levels in the intestines and serum of the mice, while L-NAT pretreatment was found to inhibit it. Significant whole-body survival (>80%) was observed in irradiated (9.0 Gy) mice that pretreated with L-NAT (150 mg/kg, b.wt. im) compared to 0% survival in irradiated mice that not pretreated with L-NAT. The quantitative histology of the hematopoietic, gastrointestinal, and male reproductive systems demonstrated significant protection against radiation-induced cellular degeneration. Interestingly, 100% survival was observed with irradiated NHPs (6.5 Gy) that pretreated with L-NAT (37.5 mg/kg, b.wt.im). Significant improvement in the hematology profile was observed after days 10-20 post-treatment periods in irradiated (6.5 Gy) NHPs that were pretreated with L-NAT. Conclusion L-NAT demonstrated excellent radioprotective activity in the mice and NHP models, probably by antagonizing TRPV1 receptor and subsequently inhibiting substance P expression.

Capsaicin: pharmacological applications and prospects for drug designing.

A primary objective of this review is to summarize the evidence-based pharmacological applications of capsaicin, particularly its use to manage pain and treat various health conditions. A second goal of the review is to research how recent technological advances are improving the bioavailability and therapeutic index of capsaicin, as well as the development of novel capsaicin-mimetics that are able to enhance therapeutic responses in various human diseases. In the review, numerous human clinical trials and preclinical studies are examined to determine how effective, safe, and optimal dosages of capsaicin can be used in pain management and therapeutic applications. Furthermore, it discusses capsaicin's mechanisms of action, specifically its interactions with the transient receptor potential vanilloid 1 (TRPV1) channel. As a result of this review, the potential of nanotechnology systems for bypassing the limits of capsaicin's pungency is discussed. The review takes into account individual factors such as pain tolerance and skin sensitivity. For topical applications, capsaicin is typically used in concentrations ranging from 0.025% to 0.1%, with higher concentrations being used under medical supervision for neuropathic pain. The formulation can come in the form of creams, gels, or patches, which provide sustained release over the course of time. A condition such as arthritis or neuropathy can be relieved with capsaicin as it depletes substance P from nerves. Neuropathy and osteoarthritis as well as musculoskeletal disorders have been treated successfully with this herbal medicine. A major mechanism through which capsaicin relieves pain is through activating TRPV1 channels, which induce calcium influx and neurotransmitter release. Additionally, it affects the transcription of genes related to pain modulation and inflammation, particularly when disease conditions or stress are present. There have been recent developments in technology to reduce capsaicin's pungency and improve its bioavailability, including nanotechnology. It is proven that capsaicin is effective in pain management as well as a variety of therapeutic conditions because of its ability to deplete substance P and desensitize nerve endings. Although capsaicin is highly pungent and associated with discomfort, advancements in delivery technologies and the development of capsaicin-mimetics promise improved therapeutic outcomes. There is a great deal of complexity in the pharmacological action of capsaicin due to its interaction with TRPV1 channels and its ability to affect gene transcription. There is a need for further research and development in order to optimize capsaicin's clinical applications and to enhance its therapeutic index in a variety of human diseases.

Solvent-mediated analgesia via the suppression of water permeation through TRPV1 ion channels.

Activation of the ion channel transient receptor potential vanilloid 1 (TRPV1), which is integral to pain perception, leads to an expansion of channel width, facilitating the passage of cations and large organic molecules. However, the permeability of TRPV1 channels to water remains uncertain, owing to a lack of suitable tools to study water dynamics. Here, using upconversion nanophosphors to discriminate between H2O and D2O, by monitoring water permeability across activated TRPV1 at the single-cell and single-molecule levels, and by combining single-channel current measurements with molecular dynamics simulations, we show that water molecules flow through TRPV1 and reveal a direct connection between water migration, cation flow and TRPV1 functionality. We also show in mouse models of acute or chronic inflammatory pain that the administration of deuterated water suppresses TRPV1 activity, interrupts the transmission of pain signals and mitigates pain without impacting other neurological responses. Solvent-mediated analgesia may inspire alternative options for pain management.

MiR-203 modulates pregnant myometrium contractility via transient receptor potential vanilloid 4 channel expression.

Preterm labor is the leading cause of neonatal death and major morbidity but remains a poorly understood process with no effective tocolytic therapies. Recent work has identified the transient receptor potential vanilloid 4 (TRPV4) channel, a membrane calcium channel upregulated in uterine smooth muscle through gestation, as integral in the transition from quiescence to contraction in the gravid uterus. The present study builds upon these findings and investigates regulation of the TRPV4 channel during pregnancy in the murine and human uterus by micro-RNA 203 (miR-203). We find a progressive decrease in miR-203 expression during gestation, accompanied by a reciprocal increase in TRPV4 mRNA and protein expression. In human uterine smooth muscle cells (UtSMC), miR-203 overexpression reduces, and si-RNA-mediated silencing increases, TRPV4 expression. Studies using murine UtSMC demonstrate that miR-203 expression modulates TRPV4-mediated cytosolic calcium entry and contractility. Consistent with these findings, the response to pharmacologic TRVP4 agonists is increased in myometrial tissue from miRNA203 -/- mice compared to control mice. Moreover, we demonstrate that miR-203 binds specifically on the promoter region of TRPV4 to decrease expression. In murine inflammatory models of preterm labor, miR-203 overexpression prolongs pregnancy. Estradiol (E2) decreases miR-203 and increases TRPV4 expression, providing a potential physiologic link for the unique reciprocal relationship in UtSMC. Taken together, these findings provide evidence that miR-203 modulates uterine contractility during pregnancy via negative regulation of TRPV4. These findings support the hypothesis that targeting miR-203 holds the promise of an entirely novel approach to prevent prematurity and treat preterm labor.

The co-expression of the depolarizing and hyperpolarizing mechanosensitive ion channels in mammalian retinal neurons.

The elevation of the intraocular and extraocular pressures is associated with various visual conditions, including glaucoma and traumatic retinal injury. The retina expresses mechanosensitive channels (MSCs), but the role of MSCs in retinal physiology and pathologies has been unclear. Using immunocytochemistry, confocal microscopy, and patch-clamp recording techniques, we studied the co-expression of K+-permeable (K-MSCs) TRAAK and big potassium channel BK with the epithelial sodium channel ENaC and transient receptor potential channel vanilloid TPRV4 and TRPV2 favorably permeable to Ca2+ than Na+ (together named N-MSCs), and TRPV4 activity in the mouse retina. TRAAK immunoreactivity (IR) was mainly located in Müller cells. Photoreceptor outer segments (OSs) expressed BK and ENaCα intensively and TRAAK, TRPV2, and TRPV4 weakly. Somas and axons of retinal ganglion cells (RGCs) retrograde-identified clearly expressed ENaCα, TRPV4, and TRPV2 but lacked TRAAK and BK. Rod bipolar cells (RBCs) showed TRPV4-IR in somas and BK-IR in axonal globules. Horizontal cells were BK-negative, and some cone BCs lacked TRPV4-IR. TRPV4 agonist depolarized RGCs, enhanced spontaneous spikes and excitatory postsynaptic currents, reduced the visual signal reliability (VSR = 1-noise/signal) by ~50%, and resulted in ATP crisis, which could inactivate voltage-gated sodium channels in RGCs. Individual neurons co-express hyperpolarizing K-MSCs with depolarizing N-MSCs to counterbalance the pressure-induced excitation, and the level of K-MSCs relative to N-MSCs (RK/N ratio) is balanced in the outer retina but low in RGCs, bringing out novel determinants for the pressure vulnerability of retinal neurons and new targets for clinical interventions.

TRPV4 channel contributes to aortic root stiffening and atherosclerotic lesion development.

Cardiovascular disease is the number one cause of death in the developed world and atherosclerosis, a chronic arterial disease, is the most dominant underlying pathology. Epidemiologic and experimental studies suggest that arterial stiffness is a risk factor for atherosclerosis. However, there has been surprisingly limited development in mechanistic understanding of the generation of arterial stiffness and little progress in understanding the mechanisms by which matrix stiffening drives the development of atherosclerosis. Various proinflammatory and fibrotic activities of macrophages and fibroblasts, such as migration, inflammatory gene expression, and myofibroblast activation, are influenced by matrix stiffness. This influence suggests that aorta stiffening may regulate atherosclerosis via a cellular stiffness sensor. Our research indicates that mechanosensitive transient receptor potential vanilloid 4 (TRPV4) channels control inflammation and fibrosis in other organs and regulate macrophage and fibroblast activation, implicating TRPV4 as a potential stiffness sensor in atherosclerosis. This suggests a cycle where inflammation, fibrosis, and tissue stiffening reinforce each other, with macrophages playing a key role. Here, we identify a cellular stiffness sensor linking matrix stiffness and atherosclerosis using human aortic tissues, a murine atherosclerosis model, and atomic force microscopy (AFM) analysis. This novel finding suggests that targeting TRPV4 could be a selective strategy to prevent or suppress atherogenesis.

The cumulative effect of compound heterozygous variants in TRPV3 caused Olmsted syndrome

BackgroundOlmsted syndrome (OS) is a rare genodermatosis predominantly inherited in an autosomal dominant manner, typically arising from gain-of-function (GOF) variants in the transient receptor potential channel vanilloid 3 (TRPV3) gene. ObjectiveThis study aims to investigate potential mechanisms underlying OS in two cases presenting with an autosomal recessive inheritance pattern. MethodsNext-generation sequencing panel was employed to identify TRPV3 variants. TRPV3 plasmids carrying specific point variations were generated and transiently transfected into HEK293T cells. Electrophysiological patch-clamp techniques were utilized to record voltage-activated and ligand-activated currents. Celltiter-Glo luminescent assay was employed to analyze the cell viabilities. ResultsCompound heterozygous variants, c.1563 G>C (p.W521C) and c.1376 C>T (p.S459L), as well as c.1773 G>C (p.L591F) and c.2186 G>A (p.R729Q), were identified in the two OS patients respectively. Electrophysiological analysis of ligand-induced activation of TRPV3 variants demonstrated the closest correlation with clinical manifestations. All four variants displayed GOF channel activity characterized by increased sensitivity. Notably, W521C and L591F exhibited both heightened sensitivity and lower EC50 values for the TRPV3 agonist. Co-transfection with wild-type TRPV3 plasmids significantly rescued these effects. Cells co-transfected with the corresponding compound heterozygous variants exhibited intermediate electrophysiological characteristics. ConclusionsIn this study, we present two cases of OS by autosomal-recessive inheritance of TPRV3 variants. This study presents a notable observation of compound heterozygous GOF variants in TRPV3, highlighting their cumulative impact on clinical manifestations. Additionally, we advocate for the use of ligand-dependent ion channel activity assays to assess the pathogenicity of TRPV3 variants in OS.

Potential Molecular Mechanisms and Metabolic Networks in Red Ginseng-induced “Shanghuo” (上火)

Objective: To comprehensively uncover potential molecular mechanisms and metabolic networks in RG-induced “ Shanghuo”. Red ginseng (RG) could bring out the manifestations of “ Shanghuo”, which mostly presents as redness, swelling, fever, and pain. Methods: The compounds of RG were obtained from the TCMSP and SymMap databases. The putative targets of RG were determined based on the obtained compounds by STITCH. The potential targets of “ Shanghuo” were retrieved from the literature. Those interacted targets of RG and “ Shanghuo” were screened by STRING and conducted networks of RG and “ Shanghuo”. The RG-influenced “ Shanghuo” targets were further analyzed by the STRING and proved by molecular docking. Afterwards, water extract of RG was given to 6 weeks-old rats for 15 days. Observations were carried out to confirm the establishment of “ Shanghuo” model. Gas chromatography-mass spectrometry (GC-MS) were utilized to identify the differential metabolites. Results: Apolipoprotein B and Serum albumin (ALB) were the co-acting targets, while Transient Receptor Potential Channel Vanilloid 1 was a vital target of RG jointing “ Shanghuo” and RG together through the connection via ALB. Ginsenoside Rb1 was the most influential compound of RG to induce “ Shanghuo” by molecular docking. Our study indicated that fat digestion and absorption and cholesterol metabolism the potential mechanism of RG-induced “ Shanghuo”. An acceleration of energy expenditure in the “ Shanghuo” group was additionally verified by conducting the GC-MS method. Conclusion: The disorders in heat dissipation along with the accelerated fat metabolism and overactive energy expenditure might contribute to RG-induced “ Shanghuo”.

Mild photothermal activation of TRPV1 pathway for enhanced calcium ion overload therapy of hepatocellular carcinoma

Transient receptor potential vanilloid 1 (TRPV1) pathway can result in the disruption of intracellular calcium ion (Ca2+) homeostasis, but how to effectively control the process of Ca2+ overload needs to be addressed for tumor treatment. Herein, we developed a mild photothermal activation of TRPV1 pathway strategy for enhanced Ca2+ overload therapy of hepatocellular carcinoma, in which the multifunctional nanoparticle (CNQ) loading with CaCO3, a novel polycyclic conjugated small molecule (2Br-NDIA) and quercetin (Qu) as the core for the efficient mild photothermal therapy (PTT). The photothermal property of CNQ can specifically activate the TRPV1 channel, which leads to mitochondrial Ca2+ overloading and the disruption of intracellular Ca2+ homeostasis. This CNQ-mediated activation of the TRPV1 channel by mild PTT provides an emerging paradigm for enhancing mitochondrial Ca2+ overload therapy and dismantling tumor self-defense, safely expanding cancer therapies for highly refractory tumors.

Osteopontin Regulates AQP4 Expression by TRPV4 Activation in Müller Cells: Implications for Retinal Homeostasis.

During the intense neuronal activity in the retina, Müller cells are exposed to a hypotonic environment and activate a regulatory volume decrease (RVD) response, which depends on Aquaporin-4 (AQP4) and the calcium channel Transient Receptor Potential Vanilloid 4 (TRPV4). It was reported that Osteopontin (OPN), a cytokine and component of the extracellular matrix (ECM), may modulate the RVD of Müller cells. In other cell types, OPN participates in cell survival and migration, which Müller cells undergo to maintain retinal homeostasis. Therefore, the aim of this work was to study the putative crosstalk of OPN with AQP4 and/or TRPV4 in the main functions of Müller cells: RVD, morphology maintenance and migration. We used a human Müller cell line (MIO-M1) exposed to OPN and evaluated cell volume and osmotic permeability (Pf) during an osmotic swelling, AQP4 expression, cell morphology and migration. We observed that OPN induced a reduced Pf and RVD by downregulating AQP4 expression, which was prevented by TRPV4 inhibition. OPN also induced significant changes in cell morphology with an increased number of cytoplasmic projections. Finally, OPN reduced the migration of Müller cells, being this effect dependent on TRPV4. We propose that OPN affects water permeability and cell volume regulation of Müller cells by activating TRPV4 to reduce AQP4 expression. This represents a novel mechanism of regulation of water permeability by the ECM in Müller cells. Additionally, OPN-induced changes in morphology and migration of Müller cells may have an impact on retinal physiology.

Enhancement sensitivity of TRPV1 in dorsal root ganglia via the SP-NK-1 pathway contributes to increased bladder organ sensitivity caused by prostatitis.

Chronic prostatitis/chronic pelvic pain syndrome is a prevalent condition affecting the male urinary system. The urinary dysfunction resulting from this disorder has a direct or indirect impact on the patient's quality of life. Recent studies have suggested that organ cross-sensitization between the prostate and bladder may elucidate this phenomenon; however, the specific molecular mechanisms remain unclear. In this study, we simulated the urinary symptoms of prostatitis patients using an animal model and examined the expression of relevant proteins within the prostate-bladder sensitized neural pathway. We found that transient receptor potential vanilloid 1 (TRPV1) protein is highly expressed in the dorsal root ganglia (DRG) that co-innervate both the prostate and bladder, potentially increasing the sensitivity of TRPV1 channels via the substance P-neurokinin 1 (SP-NK-1) pathway, which may exacerbate micturition symptoms. Furthermore, in the absence of bladder inflammation, elevated levels of neurogenic substances in bladder tissue were found to sensitize bladder sensory afferents. Collectively, these results underscore the significant role of TRPV1 in bladder sensitization associated with prostatitis, suggesting that the inhibition of TRPV1 along this sensitization pathway could be a promising approach to treating urinary dysfunction linked to prostatitis in the future.

The Benefits of Whole-Exome Sequencing in the Differential Diagnosis of Hypophosphatasia.

Hypophosphatasia (HPP) is a rare inherited disorder characterized by the decreased activity of tissue-nonspecific alkaline phosphatase (TNSALP), caused by mutations in the ALPL gene. The aim of this study was to conduct differential diagnostics in HPP patients using whole-exome sequencing (WES). The medical records of HPP patients and the genetic testing of the ALPL gene were reviewed. Seven patients were recruited and underwent WES using the Illumina or MGI sequencing platforms. All of the exome samples were matched onto a GRCh38.p13 reference genome assembly by using the Genome Analysis ToolKit (GATK) and the BWA MEM read aligner. We present the clinical and molecular findings of the seven patients referred for genetic analyses due to a clinical and biochemical suspicion of HPP. In two patients out of three (with identified heterozygous variants in the ALPL gene), we also identified c.682T>A in exon 3 of the WNT10A gene and c.3470del in exon 23 of the SMC1A gene variants for the first time. In four patients, variants in the ALPL gene were not detected, but WES allowed us to identify for the first time rare variants (c.5651A>C in exon 36 of the TRIO gene, c.880T>G in exon 6 of the TRPV4 gene, c.32078-1G>T in intron 159 of the TTN gene, c.47720_47721del in exon 235 of the TTN gene, and c.1946G>A in exon 15 of the SLC5A1 gene) and to conduct differential diagnostics with HPP. Using WES, for the first time, we demonstrate the possibility of early differential diagnostics in HPP patients with other rare genetic diseases.

TRPV4-A Multifunctional Cellular Sensor Protein with Therapeutic Potential.

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.

Human Salivary Microbiota Diversity According to Ethnicity, Sex, TRPV1 Variants and Sensitivity to Capsaicin.

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.

Increased TRPV4 Channel Expression Enhances and Impairs Blood Vessel Function in Hypertension.

Endothelial cell TRPV4 (transient receptor potential vanilloid 4) channels provide a control point that is pivotal in regulating blood vessel diameter by mediating the Ca2+-dependent release of endothelial-derived vasoactive factors. In hypertension, TRPV4-mediated control of vascular function is disrupted, but the underlying mechanisms and precise physiological consequences remain controversial. Here, using a comprehensive array of methodologies, endothelial TRPV4 channel function was examined in intact mesenteric resistance arteries from normotensive Wistar-Kyoto and spontaneously hypertensive rats. Our results show there is a notable shift in vascular reactivity in hypertension characterized by enhanced endothelium-dependent vasodilation at low levels of TRPV4 channel activation. However, at higher levels of TRPV4 activity, this vasodilatory response is reversed, contributing to the aberrant vascular tone observed in hypertension. The change in response, from dilation to constriction, was accompanied by a shift in intracellular Ca2+ signaling modalities arising from TRPV4 activity. Oscillatory TRPV4-evoked IP3 (inositol triphosphate)-mediated Ca2+ release, which underlies dilation, decreased, while the contraction inducing sustained Ca2+ rise, arising from TRPV4-mediated Ca2+ influx, increased. Our findings also reveal that while the sensitivity of endothelial cell TRPV4 to activation was unchanged, expression of the channel is upregulated and IP3 receptors are downregulated in hypertension. These data highlight the intricate interplay between endothelial TRPV4 channel expression, intracellular Ca2+ signaling dynamics, and vascular reactivity. Moreover, the data support a new unifying hypothesis for the vascular impairment that accompanies hypertension. Specifically, endothelial cell TRPV4 channels play a dual role in modulating blood vessel function in hypertension.