TRPV1 activation in human Langerhans cells and T cells inhibits mucosal HIV-1 infection via CGRP-dependent and independent mechanisms.

Upon its mucosal transmission, HIV type 1 (HIV-1) rapidly targets genital antigen-presenting Langerhans cells (LCs), which subsequently transfer infectious virus to CD4+ T cells. We previously described an inhibitory neuroimmune cross talk, whereby calcitonin gene-related peptide (CGRP), a neuropeptide secreted by peripheral pain-sensing nociceptor neurons innervating all mucosal epithelia and associating with LCs, strongly inhibits HIV-1 transfer. As nociceptors secret CGRP following the activation of their Ca2+ ion channel transient receptor potential vanilloid 1 (TRPV1), and as we reported that LCs secret low levels of CGRP, we investigated whether LCs express functional TRPV1. We found that human LCs expressed mRNA and protein of TRPV1, which was functional and induced Ca2+ influx following activation with TRPV1 agonists, including capsaicin (CP). The treatment of LCs with TRPV1 agonists also increased CGRP secretion, reaching its anti-HIV-1 inhibitory concentrations. Accordingly, CP pretreatment significantly inhibited LCs-mediated HIV-1 transfer to CD4+ T cells, which was abrogated by both TRPV1 and CGRP receptor antagonists. Like CGRP, CP-induced inhibition of HIV-1 transfer was mediated via increased CCL3 secretion and HIV-1 degradation. CP also inhibited direct CD4+ T cells HIV-1 infection, but in CGRP-independent manners. Finally, pretreatment of inner foreskin tissue explants with CP markedly increased CGRP and CCL3 secretion, and upon subsequent polarized exposure to HIV-1, inhibited an increase in LC-T cell conjugate formation and consequently T cell infection. Our results reveal that TRPV1 activation in human LCs and CD4+ T cells inhibits mucosal HIV-1 infection, via CGRP-dependent/independent mechanisms. Formulations containing TRPV1 agonists, already approved for pain relief, could hence be useful against HIV-1.

Inhibition of transient receptor potential vanilloid 1 reduces shedding and transmission during Streptococcus pneumoniae co-infection with influenza.

Transmission is the first step for a microorganism to establish colonization in the respiratory tract and subsequent development of infectious disease. Streptococcus pneumoniae is a leading pathogen that colonizes the mucosal surfaces of the human upper respiratory tract and causes subsequent transmission and invasive infections especially in co-infection with influenza A virus. Host factors contributing to respiratory contagion are poorly understood. Transient receptor potential vanilloid (TRPV) channels have various roles in response to microoorganism. Inhibition of TRPV exacerbates invasive infection by Streptococcus pneumoniae, but it is unclear how TRPV channels influence pneumococcal transmission. Here, we describe the effect of inhibition of TRPV1 on pneumococcal transmission. We adopted a TRPV1-deficient infant mouse model of pneumococcal transmission during co-infection with influenza A virus. We also analyzed the expression of nasal mucin or pro-inflammatory cytokines. TRPV1 deficiency attenuated pneumococcal transmission and shedding during co-infection with influenza A virus. TRPV1 deficiency suppressed the expression of nasal mucin. In addition, there were increases in the expression of tumor necrosis factor-α and type I interferon, followed by the suppressed replication of influenza A virus in TRPV1-deficient mice. Inhibition of TRPV1 was shown to attenuate pneumococcal transmission by reducing shedding through the suppression of nasal mucin during co-infection with influenza A virus. Inhibition of TRPV1 suppressed nasal mucin by modulation of pro-inflammatory responses and regulation of replication of influenza A virus. TRPV1 could be a new target in preventive strategy against pneumococcal transmission.

Reduced capsaicin-induced mechanical allodynia and neuronal responses in the dorsal root ganglion in the presence of protein tyrosine phosphatase non-receptor type 6 overexpression.

Transient Receptor Potential Vanilloid 1 (TRPV1) is a nonselective cation channel expressed by pain-sensing neurons and has been an attractive target for the development of drugs to treat pain. Recently, Src homology region two domain-containing phosphatase-1 (SHP-1, encoded by Ptpn6) was shown to dephosphorylate TRPV1 in dorsal root ganglia (DRG) neurons, which was linked with alleviating different pain phenotypes. These previous studies were performed in male rodents only and did not directly investigate the role of SHP-1 in TRPV-1 mediated sensitization. Therefore, our goal was to determine the impact of Ptpn6 overexpression on TRPV1-mediated neuronal responses and capsaicin-induced pain behavior in mice of both sexes. Twelve-week-old male and female mice overexpressing Ptpn6 (Shp1-Tg) and their wild type (WT) littermates were used. Ptpn6 overexpression was confirmed in the DRG of Shp1-Tg mice by RNA in situ hybridization and RT-qPCR. Trpv1 and Ptpn6 were found to be co-expressed in DRG sensory neurons in both genotypes. Functionally, this overexpression resulted in lower magnitude intracellular calcium responses to 200 nM capsaicin stimulation in DRG cultures from Shp1-Tg mice compared to WTs. In vivo, we tested the effects of Ptpn6 overexpression on capsaicin-induced pain through a model of capsaicin footpad injection. While capsaicin injection evoked nocifensive behavior (paw licking) and paw swelling in both genotypes and sexes, only WT mice developed mechanical allodynia after capsaicin injection. We observed similar level of TRPV1 protein expression in the DRG of both genotypes, however, a higher amount of tyrosine phosphorylated TRPV1 was detected in WT DRG. These experiments suggest that, while SHP-1 does not mediate the acute swelling and nocifensive behavior induced by capsaicin, it does mediate a protective effect against capsaicin-induced mechanical allodynia in both sexes. The protective effect of SHP-1 might be mediated by TRPV1 dephosphorylation in capsaicin-sensitive sensory neurons of the DRG.

Methylglyoxal activates transient receptor potential A1/V1 via reactive oxygen species in the spinal dorsal horn.

Methylglyoxal (MGO), a highly reactive dicarbonyl metabolite of glucose primarily formed during the glycolytic pathway, is a precursor of advanced glycation end-products (AGEs). Recently, numerous studies have shown that MGO accumulation can cause pain and hyperalgesia. However, the mechanism through which MGO induces pain in the spinal dorsal horn remains unclear. The present study investigated the effect of MGO on spontaneous excitatory postsynaptic currents (sEPSC) in rat spinal dorsal horn neurons using blind whole-cell patch-clamp recording. Perfusion of MGO increased the frequency and amplitude of sEPSC in spinal horn neurons in a concentration-dependent manner. Additionally, MGO administration increased the number of miniature EPSC (mEPSC) in the presence of tetrodotoxin, a sodium channel blocker. However, 6-cyano-7-nitroqiunocaline-2,3-dione (CNQX), an AMPA/kainate receptor antagonist, blocked the enhancement of sEPSC by MGO. HC-030031, a TRP ankyrin-1 (TRPA1) antagonist, and capsazepine, a TRP vanilloid-1 (TRPV1) antagonist, inhibited the action of MGO. Notably, the effects of MGO were completely inhibited by HC-030031 and capsazepine. MGO generates reactive oxygen species (ROS) via AGEs. ROS also potentially induce pain via TRPA1 and TRPV1 in the spinal dorsal horn. Furthermore, we examined the effect of MGO in the presence of N-tert-butyl-α-phenylnitrone (PBN), a non-selective ROS scavenger, and found that the effect of MGO was completely inhibited. These results suggest that MGO increases spontaneous glutamate release from the presynaptic terminal to spinal dorsal horn neurons through TRPA1, TRPV1, and ROS and could enhance excitatory synaptic transmission.

Kilohertz high-frequency electrical stimulation ameliorate hyperalgesia by modulating transient receptor potential vanilloid-1 and N-methyl-D-aspartate receptor-2B signaling pathways in chronic constriction injury of sciatic nerve mice.

The number of patients with neuropathic pain is increasing in recent years, but drug treatments for neuropathic pain have a low success rate and often come with significant side effects. Consequently, the development of innovative therapeutic strategies has become an urgent necessity. Kilohertz High Frequency Electrical Stimulation (KHES) offers pain relief without inducing paresthesia. However, the specific therapeutic effects of KHES on neuropathic pain and its underlying mechanisms remain ambiguous, warranting further investigation. In our previous study, we utilized the Gene Expression Omnibus (GEO) database to identify datasets related to neuropathic pain mice. The majority of the identified pathways were found to be associated with inflammatory responses. From these pathways, we selected the transient receptor potential vanilloid-1 (TRPV1) and N-methyl-D-aspartate receptor-2B (NMDAR2B) pathway for further exploration. Mice were randomly divided into four groups: a Sham group, a Sham/KHES group, a chronic constriction injury of the sciatic nerve (CCI) group, and a CCI/KHES stimulation group. KHES administered 30 min every day for 1 week. We evaluated the paw withdrawal threshold (PWT) and thermal withdrawal latency (TWL). The expression of TRPV1 and NMDAR2B in the spinal cord were analyzed using quantitative reverse-transcriptase polymerase chain reaction, Western blot, and immunofluorescence assay. KHES significantly alleviated the mechanical and thermal allodynia in neuropathic pain mice. KHES effectively suppressed the expression of TRPV1 and NMDAR2B, consequently inhibiting the activation of glial fibrillary acidic protein (GFAP) and ionized calcium binding adapter molecule 1 (IBA1) in the spinal cord. The administration of the TRPV1 pathway activator partially reversed the antinociceptive effects of KHES, while the TRPV1 pathway inhibitor achieved analgesic effects similar to KHES. KHES inhibited the activation of spinal dorsal horn glial cells, especially astrocytes and microglia, by inhibiting the activation of the TRPV1/NMDAR2B signaling pathway, ultimately alleviating neuropathic pain.

Lysophosphatidic acid contributes to myocardial ischemia/reperfusion injury by activating TRPV1 in spinal cord.

Lysophosphatidic acid (LPA) is a bioactive phospholipid that plays a crucial role in cardiovascular diseases. Here, we question whether LPA contributes to myocardial ischemia/reperfusion (I/R) injury by acting on transient receptor potential vanilloid 1 (TRPV1) in spinal cord. By ligating the left coronary artery to establish an in vivo I/R mouse model, we observed a 1.57-fold increase in LPA level in the cerebrospinal fluid (CSF). The I/R-elevated CSF LPA levels were reduced by HA130, an LPA synthesis inhibitor, compared to vehicle treatment (4.74 ± 0.34 vs. 6.46 ± 0.94 µg/mL, p = 0.0014). Myocardial infarct size was reduced by HA130 treatment compared to the vehicle group (26 ± 8% vs. 46 ± 8%, p = 0.0001). To block the interaction of LPA with TRPV1 at the K710 site, we generated a K710N knock-in mouse model. The TRPV1K710N mice were resistant to LPA-induced myocardial injury, showing a smaller infarct size relative to TRPV1WT mice (28 ± 4% vs. 60 ± 7%, p < 0.0001). Additionally, a sequence-specific TRPV1 peptide targeting the K710 region produced similar protective effects against LPA-induced myocardial injury. Blocking the K710 region through K710N mutation or TRPV1 peptide resulted in reduced neuropeptides release and decreased activity of cardiac sensory neurons, leading to a decrease in cardiac norepinephrine concentration and the restoration of intramyocardial pro-survival signaling, namely protein kinase B/extracellular regulated kinase/glycogen synthase kinase-3ß pathway. These findings suggest that the elevation of CSF LPA is strongly associated with myocardial I/R injury. Moreover, inhibiting the interaction of LPA with TRPV1 by blocking the K710 region uncovers a novel strategy for preventing myocardial ischemic injury.

Comparative effectiveness of nitro dihydrocapsaicin, new synthetic derivative capsaicinoid, and capsaicin in alleviating oxidative stress and inflammation on lipopolysaccharide-stimulated corneal epithelial cells.

Loss of tear homeostasis, characterized by hyperosmolarity of the ocular surface, induces cell damage through inflammation and oxidation. Transient receptor potential vanilloid 1 (TRPV1), a sensor for osmotic changes, plays a crucial role as a calcium ion channel in the pathogenesis of hypertonic-related eye diseases. Capsaicin (CAP), a potent phytochemical, alleviates inflammation during oxidative stress events by activating TRPV1. However, the pharmacological use of CAP for eye treatment is limited by its pungency. Nitro dihydrocapsaicin (NDHC) was synthesized with aromatic ring modification of CAP structure to overcome the pungent effect. We compared the molecular features of NDHC and CAP, along with their biological activities in human corneal epithelial (HCE) cells, focusing on antioxidant and anti-inflammatory activities. The results demonstrated that NDHC maintained cell viability, cell shape, and exhibited lower cytotoxicity compared to CAP-treated cells. Moreover, NDHC prevented oxidative stress and inflammation in HCE cells following lipopolysaccharide (LPS) administration. These findings underscore the beneficial effect of NDHC in alleviating ocular surface inflammation, suggesting that NDHC may serve as an alternative anti-inflammatory agent targeting TRPV1 for improving hyperosmotic stress-induced ocular surface damage.

Recent advances in the knowledge of the mechanism of reflux hypersensitivity.

Reflux hypersensitivity (RH) is a subtype of gastroesophageal reflux disease. The Rome IV criteria separated RH from the original nonerosive reflux disease subgroup and classified it as a new functional oesophageal disease. Recently, the pathogenesis of RH has become the focus of research. According to the latest research reports, upregulation of acid-sensitive receptors, distribution of calcitonin gene-related peptide-positive nerve fibres, and psychiatric comorbidity have key roles in the pathogenesis of RH. This work reviews the latest findings regarding RH mechanisms.

Role of phosphorylation and vanilloid ligand structure in ligand-dependent differential activations of transient receptor potential vanilloid 1.

Vanilloid analogs, which can activate transient receptor potential vanilloid 1 (TRPV1), have been classified into two types based on susceptibility to forskolin (FSK). Treatment of cells expressing TRPV1 with FSK enhances TRPV1 responses to capsaicin-type ligands while diminishing the responses to eugenol-type ligands. In this study, we determined the effect of FSK on the activation of TRPV1 stimulated with vanilloid ligands, through the influx of Ca2+ in HEK293T cells expressing TRPV1. Our findings suggest that the effects of FSK can be attributed to the phosphorylation of TRPV1, as evidenced by using a protein kinase A (PKA) inhibitor and TRPV1 mutants at potential phosphorylation sites. Furthermore, we examined the structure-activity relationship of 13 vanilloid analogs. Our results indicated that vanilloid compounds could be classified into three types, i.e., the previously reported two types and a novel type of 10-shogaol, by which TRPV1 activation was insusceptible to the FSK treatment.

Divergent effects of olfactory receptors on transient receptor potential vanilloid 1 activation by capsaicin and eugenol.

We analyzed the effects of olfactory receptors (ORs) on transient receptor potential vanilloid 1 (TRPV1) activation using HEK293T cells co-expressing TRPV1 and OR51E1. We demonstrate here that the effect of OR51E1 on TRPV1 activation varies depending on the two TRPV1 ligands: capsaicin and eugenol. Notably, both of these ligands are vanilloid analogs. OR51E1 enhanced the response of TRPV1 to capsaicin but diminished that to eugenol. OR51E2 also showed similar effects. Based on the susceptibility to the OR's modulatory effects, various TRPV1 ligands could be classified into capsaicin and eugenol types. Activation of OR51E1 enhanced cAMP production. In addition, forskolin exhibited almost identical effects as ORs on TRPV1 responses to both types of ligands. These results suggest that OR51E1-induced cAMP elevation leads to a modification of TRPV1, presumably phosphorylation of TRPV1, which amplifies the susceptibility of TRPV1 to the two types of ligands differently.

Anti-pollutant effect of oleic acid against urban particulate matter is mediated via regulation of AhR- and TRPV1-mediated signaling in vitro.

Urban Particulate Matter (UPM) induces skin aging and inflammatory responses by regulating skin cells through the transient receptor potential vanilloid 1 (TRPV1). Although oleic acid, an unsaturated free fatty acid (FFA), has some functional activities, its effect on UPM-induced skin damage has not been elucidated. Here, we investigated signaling pathways on how oleic acid is involved in attenuating UPM induced cell damage. UPM treatment increased XRE-promoter luciferase activity and increased translocation of AhR to the nucleus, resulting in the upregulation of CYP1A1 gene. However, oleic acid treatment attenuated the UPM effects on AhR signaling. Furthermore, while UPM induced activation of TRPV1 and MAPKs signaling which activated the downstream molecules NFκB and AP-1, these effects were reduced by cotreatment with oleic acid. UPM-dependent generation of reactive oxygen species (ROS) and reduction of cellular proliferation were also attenuated by the treatment of oleic acid. These data reveal that cell damage induced by UPM treatment occurs through AhR signaling and TRPV1 activation which in turn activates ERK and JNK, ultimately inducing NFκB and AP-1 activation. These effects were reduced by the cotreatment of oleic acid on HaCaT cells. These suggest that oleic acid reduces UPM-induced cell damage through inhibiting both the AhR signaling and activation of TRPV1 and its downstream molecules, leading to a reduction of pro-inflammatory cytokine and recovery of cell proliferation.

Chronic Sacral Nerve Stimulation Inhibits Visceral Hypersensitivity in Diarrhea-Predominant Irritable Bowel Syndrome Rats Model.

OBJECTIVE: Sacral nerve stimulation (SNS) is emerging as a novel treatment for irritable bowel syndrome (IBS). However, its effects are limited, and the underlying mechanisms remain largely unknown. MATERIALS AND METHODS: In this study, rats were divided into three groups (n = 12 rats per group): 1) the SNS group; 2) the sham SNS group (the sham group for short); and 3) the control group. The SNS and sham groups were exposed to chronic and acute stress to establish an IBS model. Electrode implantation surgery was performed in rats with the IBS model. The SNS group received electrical stimulation for 30 minutes every day for seven days. Abdominal withdrawal reflex (AWR) was used to evaluate the effect of SNS on visceral sensitivity in diarrhea-predominant IBS (IBS-D) rats. The frequency domain of heart rate variability (HRV) was analyzed to assess the effect of SNS on regulating the autonomic function. The expression of transient receptor potential vanilloid 1 (TRPV1) in the colon, spinal cord, and hippocampus was detected by immunohistochemistry to explore the mechanism of SNS in IBS-D rats. RESULTS: Compared with the sham group, AWR scores were significantly decreased under different gas volumes of stimulation of 0.4, 0.6, and 0.8 ml for rectal distention in the SNS group (all p < 0.05). However, there was no significant difference <1.0 ml between the two groups (p > 0.05). Compared with the sham group, the frequency domain indexes of HRV were significantly altered. Normalized low-frequency power and low frequency-to-high frequency ratio were significantly decreased, and normalized high-frequency power was significantly increased in the SNS group (all p < 0.05). Moreover, the expression of TRPV1 in the spinal cord and colon in the SNS group was significantly decreased compared with the sham group (both p < 0.05). These results suggested that chronic SNS not only improved the visceral sensitivity and autonomic dysfunction but also decreased the expression of TRPV1 in the spinal cord-gut tissue in IBS-D rats. CONCLUSION: Chronic SNS was found to have an inhibitory effect on visceral hypersensitivity in IBS-D rats, providing experimental evidence for its potential clinical application in IBS.

Gastric Carcinogenesis and Potential Role of the Transient Receptor Potential Vanilloid 1 (TRPV1) Receptor: An Observational Histopathological Study.

The potential role of the transient receptor potential Vanilloid 1 (TRPV1) non-selective cation channel in gastric carcinogenesis remains unclear. The main objective of this study was to evaluate TRPV1 expression in gastric cancer (GC) and precursor lesions compared with controls. Patient inclusion was based on a retrospective review of pathology records. Patients were subdivided into five groups: Helicobacter pylori (H. pylori)-associated gastritis with gastric intestinal metaplasia (GIM) (n = 12), chronic atrophic gastritis (CAG) with GIM (n = 13), H. pylori-associated gastritis without GIM (n = 19), GC (n = 6) and controls (n = 5). TRPV1 expression was determined with immunohistochemistry and was significantly higher in patients with H. pylori-associated gastritis compared with controls (p = 0.002). TRPV1 expression was even higher in the presence of GIM compared with patients without GIM and controls (p < 0.001). There was a complete loss of TRPV1 expression in patients with GC. TRPV1 expression seems to contribute to gastric-mucosal inflammation and precursors of GC, which significantly increases in cancer precursor lesions but is completely lost in GC. These findings suggest TRPV1 expression to be a potential marker for precancerous conditions and a target for individualized treatment. Longitudinal studies are necessary to further address the role of TRPV1 in gastric carcinogenesis.

Impact of Topical Capsaicin Cream on Thermoregulation and Perception While Walking in the Cold.

INTRODUCTION: Capsaicin, a chili pepper extract, can stimulate increased skin blood flow (SkBF) with a perceived warming sensation on application areas. Larger surface area application may exert a more systemic thermoregulatory response. Capsaicin could assist with maintaining heat transport to the distal extremities, minimizing cold weather injury risk. However, the thermoregulatory and perceptual impact of topical capsaicin cream application prior to exercise in the cold is unknown. METHODS: Following application of either a 0.1% capsaicin or control cream to the upper and lower extremities (10 g total, ∼40-50% body surface area), 11 participants in shorts and a t-shirt were exposed to 30 min of cold (0 °C, 40% relative humidity). Exposures comprised of 5 min seated rest, 20 min walking (1.6 m·s-1, 5% grade), and 5 min seated rest. Temperature (skin, core), SkBF, skin conductivity, heart rate, thermal sensation, and thermal comfort were measured throughout. RESULTS: The capsaicin treatment did not differ from the control treatment in skin temperature (treatment mean: 30.0 ± 2.5, 30.1 ± 2.4 °C, respectively, p = 0.655), core temperature (treatment mean: 37.3 ± 0.5, 37.4 ± 0.4 °C, respectively, p = 0.113), SkBF (treatment mean: -8.4 ± 10.0, -11.1 ± 10.7 A.U., respectively, p = 0.492), skin conductivity (treatment mean: -0.7 ± 5.1, 0.4 ± 6.4 µS, respectively, p = 0.651), or heart rate (treatment mean: 83 ± 29, 85 ± 28 beats·minute-1, respectively, p = 0.234). The capsaicin and control treatments also did not differ in thermal sensation (p = 0.521) and thermal comfort (p = 0.982), with perceptual outcomes corresponding with feeling "cool" and "just uncomfortable," respectively. CONCLUSIONS: 0.1% topical capsaicin application to exposed limbs prior to walking in a cold environment does not alter whole-body thermoregulation or thermal perception.

Design, synthesis and functional validation of peptide inhibitors based on TRPV1 ion channel agonist RhTx. / é¶å‘çž¬æ—¶å—ä½“ç”µä½é¦™è‰é ¸äºšåž‹1离子通道的Nplus-RhTx多肽抑制剂理性设计及功能验证.

OBJECTIVES: To design and synthesize peptide inhibitors targeting transient receptor potential vanilloid 1 (TRPV1) ion channel, and to validate their function. METHODS: Based on previous studies on the relation of molecular structure and function of red head toxin (RhTx), a series of peptides were rationally designed and synthesized, with positive charged amino acids linked to the N terminus of RhTx. These Nplus-RhTx peptides were functionally validated by patch-clamp recordings in live cells. RESULTS: Among the 8 synthesized Nplus-RhTx peptides, four inhibited TRPV1 ion channel activated by capsaicin with IC50 of (188.3±4.7), (193.6±18.0), (282.8±11.9) and (299.5±6.4) µmol/L, respectively. CONCLUSIONS: It is feasible to develop TRPV1 peptide inhibitors by using rational design based on N terminal residues of RhTx.

Crosstalk between TRPV1 and immune regulation in Fuchs endothelial corneal dystrophy.

Fuchs endothelial corneal dystrophy (FECD) is the leading indication for corneal transplantation worldwide. Our aim was to investigate the role of transient receptor potential vanilloid subtype 1 (TRPV1) and the associated immune regulation contributing to this pathological condition. Significant upregulation of TRPV1 was detected in the H2O2-induced in vitro FECD model. Based on gene expression microarray dataset GSE142538 and in vitro results, a comprehensive immune landscape was studied and a negative correlation was found between TRPV1 with different immune cells, especially regulatory T cells (Tregs). Functional analyses of the 313 TRPV1-related differentially expressed genes (DEGs) revealed the involvement of TRP-regulated calcium transport, as well as inflammatory and immune pathways. Four TRPV1-related core genes (MAPK14, GNB1, GNAQ, and ARRB2) were screened, validated by microarray dataset GSE112039 and the combined validation dataset E-GEAD-399 & 564, and verified by in vitro experiments. Our study suggested a potential crosstalk between TRPV1 and immune regulation contributing to FECD pathogenesis. The identified pivotal biomarkers and immune-related pathways provide a novel framework for future mechanistic and therapeutic studies of FECD.

Neuromechanical Dimorphism of Hypoglycemic Effect of Electroacupuncture.

INTRODUCTION: Electroacupuncture (EA) has a favorable impact on blood glucose stability. Blood glucose homeostasis is linked to sexual dimorphism. The majority of research has, however, focused on male participants, and sex differences have not been adequately taken into account. METHODS: Here, we investigated how EA intervention affected pancreatic metabolic stress and explored if there were any sex-related changes in the maintenance of pancreatic function following intraperitoneal injection of a 10 g/kg glucose solution. RESULTS: The transient receptor potential vanilloid 1 (TRPV1) calcitonin gene-related peptide (CGRP)-ß cell pathway of the male pancreas is vital to maintain glucose metabolism in mice. In contrast, there is a sex bias in TRPV1, which implies that female mice have additional routes for preserving glucose homeostasis. EA is ineffective on Trpv1-/- male mice. It also revealed that TRPV1 in male mice served as a crucial mediator for the EA control of blood glucose. Meanwhile, the sympathetic marker tyrosine hydroxylase showed higher expression in the male pancreas, while the cholinergic marker choline acetyltransferase is expressed predominantly in female mice. Injecting γ-aminobutyric acid into the paraventricular nucleus of male mice caused a disruption in blood glucose and a lack of response to EA. It verified that male mice had a more pronounced sympathetic innervation of the pancreas than female mice. CONCLUSION: Our research has demonstrated that the TRPV1 sensory afferent nerve and sympathetic efferent nerve are capable of maintaining glucose homeostasis, exhibiting a distinct sexual dimorphism. Furthermore, this regulation is contingent on the EA effect.

Design, synthesis, and analgesia evaluation of novel Transient Receptor Potential Vanilloid 1 (TRPV1) agonists modified from Cannabidiol (CBD).

Pain-relief is a long-term research hotspot with huge demand in clinical treatment. The analgesics currently used have several side effects, such as being addictive and causing gastrointestinal bleeding. Therefore, new drugs and targets in analgesic field are both desirable. Transient Receptor Potential Vanilloid 1 (TRPV1) plays an essential role in pain perception and regulation, providing a new strategy for the development of antinociceptive agents. Here, a series of novel TRPV1 agonists were designed and synthesized based on Cannabidiol (CBD), a widely used pain-relieving agent with weak agonistic activity on TRPV1. According to the results of systematic in vitro and in vivo biological assays, compound 10f was finally identified as a promising TRPV1 agonist, with higher target affinity, stronger analgesic activity, and weak side effect of hyperthermia. Molecular docking simulations revealed a significant hydrogen bond interaction between 10f and Arg557, an amino acid residue key to the activity of TRPV1 protein. Taken together, compound 10f can be used as a lead compound for further optimization.

Anti-Pollutant Activity of Porphyra yezoensis Water Extract and Its Active Compound, Porphyra 334, against Urban Particulate Matter-Induced Keratinocyte Cell Damage.

Urban particulate matter (UPM) causes skin aging and inflammatory reactions by influencing skin cells through the aryl hydrocarbon receptor (AhR) signaling pathway. Porphyra yezoensis (also known as Pyropia yezoensis), a red alga belonging to the Bangiaceae family, is an edible red seaweed. Here, we examined the anti-pollutant effect of P. yezoensis water extract. While UPM treatment induced xenobiotic response element (XRE) promoter luciferase activity, P. yezoensis water extract reduced UPM-induced XRE activity. Next, we isolated an active compound from P. yezoensis and identified it as porphyra 334. Similar to the P. yezoensis water extract, porphyra 334 attenuated UPM-induced XRE activity. Moreover, although UPM augmented AhR nuclear translocation, which led to an increase in cytochrome P450 1A1 (CYP1A1) mRNA levels, these effects were reduced by porphyra 334. Moreover, UPM induced the production of reactive oxygen species (ROS) and reduced cell proliferation. These effects were attenuated in response to porphyra 334 treatment. Furthermore, our results revealed that the increased ROS levels induced by UPM treatment induced transient receptor potential vanilloid 1 (TRPV1) activity, which is related to skin aging and inflammatory responses. However, porphyra 334 treatment reduced this reaction by inhibiting ROS production induced by CYP1A1 activation. This indicates that porphyra 334, an active compound of P. yezoensis, attenuates UP-induced cell damage by inhibiting AhR-induced ROS production, which results in a reduction in TRPV1 activation, leading to cell proliferation. This also suggests that porphyra 334 could protect the epidermis from harmful pollutants.

Functional gastrointestinal disorders are associated with capsaicin cough sensitivity in severe asthma.

BACKGROUND: Although sensory nerve dysfunction is related to the pathology of severe uncontrolled asthma and functional gastrointestinal disorders (FGIDs), the impact of comorbid FGIDs on the pathophysiology of severe uncontrolled asthma remains poorly understood. The aim was to clarify the physiological relationships between severe uncontrolled asthma and FGIDs. METHODS: Fifty-two patients with severe uncontrolled asthma who visited our hospital between September 2016 and August 2019 were retrospectively analyzed. Clinical characteristics, other comorbidities including gastroesophageal reflux disease (GERD), and biomarkers such as fractional nitric oxide (FeNO) and capsaicin cough sensitivity (C-CS) before the beginning of biologics or bronchial thermoplasty, were compared between patients with and without comorbid FGIDs. C-CS was evaluated by C5 (concentration of inhaled capsaicin that induced five or more coughs), and C5 ≤2.44 µM was defined as heightened C-CS. RESULTS: Seventeen patients had comorbid FGIDs. These patients had a lower FeNO level (21.9 ± 1.7 ppb vs. 33.9 ± 2.8 ppb, P = 0.04), a lower C5 threshold (2.24 ± 2.88 µM vs. 8.91 ± 5.5 µM, P < 0.001), a higher prevalence of comorbid GERD (64.7% vs. 31.7%, P = 0.03), and a higher prevalence of heightened C-CS (70.6% vs. 28.6%, P = 0.007) than those without FGIDs. Analysis of covariance showed a significant effect of FGIDs on C-CS in severe uncontrolled asthma without being affected by GERD. CONCLUSIONS: Comorbid FGIDs are associated with heightened C-CS in patients with severe uncontrolled asthma, and they may be an important extra-respiratory manifestation of the airway neuronal dysfunction phenotype of severe uncontrolled asthma.