Transient Receptor Potential Vanilloid 1 Expression Research Articles

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.

Construction of a mouse model for sensitive skin research.

Current animal models of sensitive skin do not adequately reflect the objective symptoms or physiological manifestations observed in human sensitive skin. To construct and validate a sensitive skin model in mice. Tape stripping (TS) was used to induce partial mechanical disruption of the lipid film and stratum corneum. Subsequently, propylene glycol (PG) was applied to disrupt the lipid structure in the skin barrier, and capsaicin (CS) activate transient receptor potential vanilloid 1 (TRPV1) receptors of keratinocytes to simulate the formation of sensitive skin. Evident itching and tingling sensations, scaly skin, vasodilation, local congestion, increased transepidermal water loss (TEWL), elevated TRPV1 expression, and inflammatory symptoms were subsequently evaluated. TS combined with PG and CS application resulted in skin flakes; skin barrier disruption; vascular dilation; increased itching, stinging, and inflammation; TRPV1 upregulation in the epidermis; and a significant increase in lactic acid-induced itching and stinging. Using a combination of TS and PG, and CS application, a mouse model of sensitive skin was successfully established involving various skin phenotypes and physiological manifestations, including skin flakes, vasodilation, increased blood flow and TEWL, itching and stinging sensations, inflammation, and elevated TRPV1 expression.

Exploring the high-quality ingredients and mechanisms of Da Chuanxiong Formula in the treatment of neuropathic pain based on network pharmacology, molecular docking, and molecular dynamics simulation

Da Chuanxiong Formula (DCXF) is a traditional herbal prescription used for pain management. It consists of Chuanxiong Rhizoma (CR) and Gastrodiae Rhizoma (GR). Despite its long history of use, the underlying therapeutic mechanism of DCXF remains insufficiently understood. Therefore, in this study, key target genes were obtained through network pharmacology research methods and molecular docking techniques, including transient receptor potential vanilloid 1 (TRPV1), adenosine A2a receptor (ADORA2A), nuclear receptor subfamily 3 group C member 1 (NR3C1), and protein kinase C beta (PRKCB). Molecular dynamics simulations demonstrated the favorable binding between all four key genes and their corresponding compounds. Notably, chronic constriction injury (CCI) treatment resulted in a significant decrease in mechanical threshold and thermal latency period for rat foot contraction, which was ameliorated upon administration of DCXF. Furthermore, real-time quantitative reverse transcription PCR (RT-qPCR) and western blot (WB) analyses indicated an upregulation of TRPV1, ADORA2A, NR3C1, and PRKCB expression in the rat dorsal root ganglion following CCI, which was attenuated by treatment with DCXF. The expressions of inflammatory factors, including tumor necrosis factor-α (TNF-α), interleukin 1 beta (IL-1β), and interleukin 6 (IL-6), in the rat dorsal root ganglion were assessed using ELISA, confirming consistent trends with the aforementioned findings. The results of this study offer a promising theoretical foundation for the utilization of DCXF in the treatment of neuropathic pain (NP).

Piezoelectric Analgesia Blocks Cancer-Induced Bone Pain.

The manipulation of cell surface receptors' activity will open a new frontier for drug development and disease treatment. However, limited by the desensitization of drugs, effective physical intervention strategy remains challenging. Here, the controllable internalization of transient receptor potential vanilloid 1 (TRPV1) on neural cells by local piezoelectric field is reported. Single-cell-level local electric field is construct by synthesizing piezoelectric BiOIO3 nanosheets (BIONSs). Upon a mild ultrasound of 0.08Wcm-2, an electric field of 15.29µV is generated on the surface of BIONSs, further inducing TRPV1 internalization in 5min. The as-downregulated TRPV1 expression results in the reduction of Ca2+ signal in a spinal neuron and the inhibition of the activity of wide range dynamic neurons, therefore effectively preventing the transmission of cancer-induced bone pain (CIBP). This strategy not only charts a new course for CIBP alleviation, but also introduces a promising nanotechnology for regulating cell surface receptors, showing significant potential in neuropathological and receptor-related diseases.

Targeting TRPV1 signaling: Galangin improves ethanol-induced gastric mucosal injury

Galangin, a bioactive compound extracted from Alpinia officinarum Hance (Zingiberaceae), a plant with significant ethnopharmacological importance, has been used for thousands of years as a spice, condiment, and medicinal agent for various conditions, including gastrointestinal disorders. Although there is evidence suggesting its potential to improve gastric ulcers, the molecular mechanisms underlying its anti-ulcer properties are not fully understood. of the Study: This study aimed to investigate the effects of galangin on ethanol-induced acute gastric mucosal injury (AGMI) in mice and elucidate its molecular mechanisms. Sixty BALB/c mice were randomly assigned into two main groups: a normal control group (n=10) and an ethanol-induced group (n=50). After establishing the AGMI model in mice using a combination of 40% ethanol and anhydrous ethanol, the ethanol-induced group was further subdivided into five subgroups (n=10): an omeprazole control group (20mg/kg), an untreated ethanol group, and three treatment groups receiving high-dose (50mg/kg) or low-dose (25mg/kg) galangin or capsazepine (CPZ, 2mg/kg). The protective effects of galangin were evaluated through mucosal injury indices, hematoxylin and eosin staining, and quantification of inflammatory markers (IL-1β, IL-6, IL-8, and TNF-α). Oxidative stress levels and matrix metalloproteinase activity were measured using specific assay kits. Molecular docking was conducted to assess the binding affinity of galangin to key proteins within the transient receptor potential vanilloid 1 (TRPV1) pathway. Real-time fluorescence quantitative PCR (qPCR) was used to determine mRNA expression levels of TRPV1, calmodulin (CaM), substance P (SP), and CGRP in gastric tissues. Protein expression levels of TRPV1, nerve growth factor (NGF), tropomyosin receptor kinase A (TRKA), transforming growth factor beta (TGF-β), cyclooxygenase-2 (COX-2), and nuclear factor kappa B (NF-κB) were assessed through Western blot analysis. In cellular experiments, Culture of Human Gastric Epithelial Cells (GES-1) were treated with various concentrations of galangin after 7% ethanol induction. Cell proliferation, apoptosis, and migration were evaluated using Hoechst 33258 staining and transwell migration assays. TRPV1 protein expression was detected using immunofluorescence, and the expression levels of Bcl-2, BCL2-Associated X (BAX), and Caspase-3 were quantified by qPCR. Additionally, specific probe kits were used to measure intracellular calcium ions (Ca2+) and mitochondrial membrane potential. The findings indicate that galangin significantly improved mucosal pathology by reducing ulcer indices and inflammatory levels, while enhancing superoxide dismutase (SOD) activity and decreasing malondialdehyde (MDA) concentration. Galangin also reduced matrix metalloproteinase-2 (MMP-2), m metalloproteinase-9 (MMP-9) levels, promoting mucosal repair. At the cellular level, galangin decreased intracellular calcium ion concentration and mitigated the decline in mitochondrial membrane potential, enhance the restoration of mucosal cells, increased migration and proliferation, and reduced apoptosis. Molecularly, galangin demonstrated favorable binding to TRPV1, NGF, TRKA, TGF-β, COX-2, and NF-κB, and reversed the elevated expression of these proteins. Additionally, galangin downregulated the mRNA expression of TRPV1, CaM, SP, CGRP, BAX, and Caspase-3 in gastric tissues/cells, while upregulating Bcl-2 mRNA expression. Galangin mitigates AGMI by inhibiting the overactivation of the TRPV1 pathway, thereby blocking aberrant signal transduction. This study suggests that galangin has therapeutic potential against ethanol-induced AGMI and may be a viable alternative for the treatment of alcohol-induced gastric mucosal injuries.

Involvement of the TRPV1 receptor and the endocannabinoid system in schizophrenia

BackgroundSchizophrenia (SCZ) is a severe mental disorder, but its pathogenesis is still unknown, and its clinical treatment effect is very limited. Transient receptor potential vanilloid 1 (TRPV1) channel and the Endocannabinoid System (ECS)have been confirmed to be involved in the pathogenesis of SCZ, although their actions have not been fully clarified yet. The objective is to examine TRPV1 and ECS expression in the blood of schizophrenia patients and investigate their correlation with disease severity. MethodsThis is a cross-sectional investigation. Peripheral blood samples were gathered from normal controls (NC, n=37), as well as individuals with schizophrenia, including first episode (n=30) and recurrent (n=30) cases. We employed western blot and ELISA techniques to quantify TRPV1, cannabinoid receptors 1(CB1), anandamide (AEA), and 2-arachidonoylglycerol (2-AG), and assess the severity of the patient's symptoms by means of the PANSS scale. ResultsCompared to NC, TRPV1 levels showed a noticeable decrease in both first episode schizophrenia (f-SCZ group) and recurrent schizophrenia (r-SCZ group) subjects. Additionally, CB1 levels appeared increased in f-SCZ group. Furthermore, 2-AG levels were found to be elevated in both f-SCZ group and r-SCZ group compared to NC, whereas AEA levels were decreased in f-SCZ group but increased in r-SCZ group. Moreover, among schizophrenia patients, TRPV1 demonstrated a negative correlation with negative symptoms. Within r-SCZ subjects, CB1 displayed a negative correlation with relapse number, while 2-AG showed a correlation in the opposite direction. ConclusionsThis study provides initial clinical evidence of changed TRPV1 expression in schizophrenia, potentially linked to negative symptoms. These results suggest a possible dysfunction of TRPV1 and the endocannabinoid system (ECS), which might offer new avenues for medical interventions.

Transient receptor potential vanilloid 1 involved in the analgesic effects of total flavonoids extracted from Longxuejie ().

To evaluate the analgesic effects of total flavonoids of Longxuejie (Resina Dracaenae Cochinchinensis) (TFDB) and explore the possible analgesic mechanism associated with transient receptor potential vanilloid 1 (TRPV1). Whole-cell patch clamp technique was used to observe the effects of TFDB on capsaicin-induced TRPV1 currents. Rat experiments in vivo were used to observe the analgesic effects of TFDB. Western blot and immunofluorescence experiments were used to test the change of TRPV1 expression in DRG neurons induced by TFDB. Results showed that TFDB inhibited capsaicin-induced TRPV1 receptor currents in acutely isolated dorsal root ganglion (DRG) neurons of rats and the half inhibitory concentration was (16.7 ± 1.6) mg/L. TFDB (2-20 mg/kg) showed analgesic activity in the phase Ⅱ of formalin test and (0.02-2 mg per paw) reduced capsaicin-induced licking times of rats. TFDB (20 mg/kg) was fully efficacious on complete Freund's adjuvant (CFA)-induced inflammatory thermal hyperalgesia and capsaicin could weaken the analgesic effects. The level of TRPV1 expressions of DRG neurons was also decreased in TFDB-treated CFA-inflammatory pain rats. All these results indicated that the analgesic effect of TFDB may contribute to their modulations on both function and expression of TRPV1 channels in DRG neurons.

Repeated doses of captopril induce airway hyperresponsiveness by modulating the TRPV1 receptor in rats

Although TRPV1 receptors play an essential role in the adverse effects on the airways following captopril treatment, there is no available evidence of their involvement in treatment regimens involving repeated doses of captopril. Comparing the difference in these two treatment regimens is essential since captopril is a continuous-use medication. Thus, this study explored the role of the transient receptor potential vanilloid 1 (TRPV1) in the effects of captopril on rat airways using two treatment regimens. Airway resistance, bronchoalveolar lavage (BAL), and histological and immunohistochemical analyses were conducted in rats administered with single or repeated doses of captopril. This study showed that the hyperresponsiveness to bradykinin and capsaicin in captopril-treated rats was acute. Treatment with the selective B2 antagonist, HOE140 reduced bradykinin hyperresponsiveness and abolished capsaicin exacerbation in single-dose captopril-treated rats. Likewise, degeneration of TRPV1-positive neurones also reduced hyperresponsiveness to bradykinin. Single-dose captopril treatment increased leukocyte infiltration in the BAL when compared with the vehicle and this increase was reduced by TRPV1-positive neurone degeneration. However, when compared with the vehicle treatment, animals treated with repeated doses of captopril showed an increase in leukocyte influx as early as 1 h after the last captopril treatment, but this effect disappeared after 24 h. Additionally, an increase in TRPV1 expression occurred only in animals who received repeated captopril doses and the degeneration of TRPV1-positive neurones attenuated TRPV1 upregulation. In conclusion, these data strongly indicate that a treatment regimen involving multiple doses of captopril not only enhances sensitisation but also upregulates TRPV1 expression. Consequently, targeting TRPV1 could serve as a promising strategy to reduce the negative impact of captopril on the airways.

Investigation on Transient Receptor Potential Vanilloid 1 (TRPv1) Activation in Skeletal Muscle: Pilot Studies

Transient Receptor Potential Vanilloid 1 (TRPv1) is a Ca2+ ion channel predominately studied in neuronal cells and has been found to have sex-differential expression in mouse arterial smooth muscle. More recently, TRPv1 expression has also been observed in skeletal muscle. Among other stimuli, osmotic stress has shown to activate TRPv1 in different tissues (e.g., retinal ganglion and supraoptic nuclear cells). However, the effect of hyperglycemia- and dehydration-induced osmotic stress and the sex-differential expression on TRPv1 in skeletal muscle is not known. PURPOSES: To examine the effect of sex ( Pilot 1), hyperglycemia ( Pilot 2), and dehydration ( Pilot 3) on TRPv1 in skeletal muscle. HYPOTHESES: We hypothesized that TRPv1 would be different between sexes ( Pilot 1), would be higher in hyperglycemic rats compared to healthy controls ( Pilot 2), and would be greater in dehydrated than hydrated state in men ( Pilot 3). METHODS: To accomplish these purposes, we analyzed a subset of samples from three previously completed projects. Pilot 1: Vastus lateralis (VL) muscles were collected from untrained men ( n=3) and women ( n=3) at baseline. Pilot 2: Rats fed a high fat diet and injected with streptozotocin (35 mg/kg) (HFD; n=3; non-fasting blood glucose (NFBG) ≥300mg/dL) were compared to rats fed a normal diet (CON; n=3; NFBG <300mg/dL). Soleus (Sol) muscle was collected after 7 weeks of feeding. Pilot 3: Lastly, VL muscles were collected from trained men (n=5) either dehydrated (DEHY; 296 ± 6 plasma mmol/kg) or hydrated (EUHY; 283 ± 5 plasma mmol/kg) for 24 hours. Rat Sol and human VL samples were analyzed for TRPv1 and p-TRPv1ser502 protein content. TRPv1 activation was calculated as p-TRPv1ser502/ TRPv1/ total protein. Student’s T-tests and effect sizes (ES; small [≤0.49], medium [0.5-0.79], or large [≥0.8] effect) were used to detect differences. Results: Pilot 1: A significant ( p<0.05) difference was observed for TRPv1 with greater expression in men than women (43%, p=0.03, d=2.757). A medium ES was observed for TRPv1 activation (31%, p=0.42, d=0.728) being greater in men compared to women. Pilot 2: No significant difference was observed for TRPv1 and TRPv1 activation between CON and HFD rats. A medium ES was observed for TRPv1 expression (-9%, p=0.31, d=0.441) being lower in HFD compared to CON. A large effect size was observed for TRPv1 activation (30%, p=0.18, d=1.689) being greater in HFD compared to CON. Pilot 3: No significant difference was observed for TRPv1 and TRPv1 activation between EUHY and DEHY. A large ES was observed for TRPv1 (34%, p=0.15, d=0.995) and small ES was observed for TRPv1 activation (2%, p=0.80, d=0.164) being greater in DEHY compared to EUHY. CONCLUSION: These data are the first to illustrate the potential difference in TRPv1 in skeletal muscle. Future research is needed to explore the impact of differential TPRv1 activation on downstream Ca2+ signaling between sexes, dehydration, and hyperglycemic models. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Transient receptor potential vanilloid-1 (TRPV1) channels act as suppressors of the growth of glioma

The aim of this study was to investigate the expression and function of the transient receptor potential vanilloid 1 (TRPV1) in glioma. We found that the expression of TRPV1 mRNA and protein were upregulated in glioma compared with normal brain by qPCR and western blot analysis. In order to investigate the function of TRPV1 in glioma, short hairpin RNA (shRNA) and the inhibitor of TRPV1 were used. In vitro, the activation of TRPV1 induced cell apoptosis with decreased migration capability and inhibited proliferation, which was abolished upon TRPV1 pharmacological inhibition and silencing. Mechanistically, TRPV1 modulated glioma proliferation through the protein kinase B (Akt) signaling pathway. More importantly, in immunodeficient (NOD-SCID) mouse xenograft models, tumor size was significantly increased when TRPV1 expression was disrupted by a shRNA knockdown approach in vivo. Altogether, our findings indicate that TRPV1 negatively controls glioma cell proliferation in an Akt-dependent manner, which suggests that targeting TRPV1 may be a potential therapeutic strategy for glioma.

Analgesic and anti-inflammatory effects of galangin: a potential pathway to inhibit transient receptor potential vanilloid 1 receptor activation.

Galangin, commonly employed in traditional Chinese medicine for its diverse medicinal properties, exhibits potential in treating inflammatory pain. Nevertheless, its mechanism of action remains unclear. Mice were randomly divided into 4 groups for 7 days: a normal control group, a galangin-treated (25 and 50 mg/kg), and a positive control celecoxib (20 mg/kg). Analgesic and anti-inflammatory effects were evaluated using a hot plate test, acetic acid-induced writhing test, acetic acid-induced vascular permeability test, formalininduced paw licking test, and carrageenan-induced paw swelling test. The interplay between galangin, transient receptor potential vanilloid 1 (TRPV1), NF-κB, COX-2, and TNF-α proteins was evaluated via molecular docking. COX- 2, PGE2, IL-1β, IL-6, and TNF-α levels in serum were measured using ELISA after capsaicin administration (200 nmol/L). TRPV1 expression in the dorsal root ganglion was analyzed by Western blot. The quantities of substance P (SP) and calcitonin gene-related peptide (CGRP) were assessed using qPCR. Galangin reduced hot plate-induced licking latency, acetic acid-induced contortions, carrageenantriggered foot inflammation, and capillary permeability in mice. It exhibited favorable affinity towards TRPV1, NF- κB, COX-2, and TNF-α, resulting in decreased levels of COX-2, PGE2, IL-1β, IL-6, and TNF-α in serum following capsaicin stimulation. Galangin effectively suppressed the upregulation of TRPV1 protein and associated receptor neuropeptides CGRP and SP mRNA, while concurrently inhibiting the expression of NF-κB, TNF-α, COX-2, and PGE2 mRNA. Galangin exerts its anti-inflammatory pain effects by inhibiting TRPV1 activation and regulating COX-2, NF-κB/TNF-α expression, providing evidence for the use of galangin in the management of inflammatory pain.

Relation Between Reactive Oxygen Species Production and Transient Receptor Potential Vanilloid1 Expression in Human Skin During Aging.

Skin sensitivity and impaired epidermal barrier function are associated with aging and are at least partly due to increased production of reactive oxygen species (ROS). Transient receptor potential vanilloid1 (TRPV1) is expressed in keratinocytes, fibroblasts, mast cells, and endothelial cells in skin. We investigated in skin biopsies of adult and elderly donors whether TRPV1 expression is involved in the skin aging process. We found that aging skin showed a strongly reduced epidermal thickness, strongly increased oxidative stress, protease expression, and mast cell degranulation and strongly increased TRPV1 expression both in epidermis and dermis. Based on our findings, the aging-related changes observed in the epidermis of the skin level are associated with increased ROS production, and hypothesized alterations in TRPV1 expression are mechanistically linked to this process.

Downregulation of mesenteric afferent sensitivity following long-term systemic treatment of vincristine in mice

AimsGastrointestinal paresthesia and dysmotility are common side effects of vincristine (VCR) chemotherapy, which have become one of the factors for dose reduction, therapy delay or discontinuation. However, the mechanism is not entirely clear, whether it is related to autonomic nerves injury remains unknown. Therefore, we aimed to study whether VCR-induced gastrointestinal toxicity is related to changes in mesenteric afferent activity. MethodsThe effects of a single VCR stimulation and long-term systemic VCR treatment on mesenteric afferent activity were investigated by directly recording mesenteric afferent discharge in vitro. ResultsOur results showed that a single VCR (0.001–1 μmol/L) stimulation obviously increased the spontaneous, chemically evoked and mechanically evoked discharge of jejunal and colonic mesenteric afferents. This kind of hypersensitivity of VCR could be blocked by capsazepine, a transient receptor potential vanilloid 1 (TRPV1) antagonist. For the mice treated with VCR (0.1 mg/kg/d, i.p.) for 14 days, the abdominal withdrawal reflex and writhing response scores were reduced. Meanwhile, the spontaneous discharge of colonic mesenteric afferents and the afferent response to VCR was downregulated, and the afferent sensitivity to chemical and mechanical stimulation was reduced. Moreover, the expression of TRPV1 in colon was decreased. ConclusionsThese results suggest that the direct stimulation by VCR increases the mesenteric afferent sensitivity by activating TRPV1, which may be the reason of VCR-induced abdominal pain; the long-term systemic treatment of VCR decreases mesenteric afferent sensitivity by reducing TRPV1, which may be the reason of VCR-induced constipation.

Effects of moxibustion on visceral hypersensitivity and colonic inflammatory response in mice with chronic ulcerative colitis.

To observe the effects of moxibustion at "Zusanli" (ST36) on the expression levels of tumor necrosis factor (TNF)-α, TNF receptor 1 (TNF-R1), p38 mitogen-activated protein kinase (P38 MAPK), and transient receptor potential vanilloid 1 (TRPV1) in the colon tissue of mice with chronic ulcerative colitis (UC), so as to explore the underlying mechanisms of moxibustion in improving visceral hypersensitivity in chronic UC. Male C57BL/6J mice were randomly divided into normal group, normal with moxibustion (NM) group, model group, and model with moxibustion (MM) group, with 10 mice in each group. The chronic UC model was established by drinking 2.5% dextran sodium sulfate for 3 cycles. Mice in the NM and MM groups received moxibustion at ST36 for 20 min, 5 days per week with a 2-day break, for a total of 4 weeks. The disease activity index (DAI) score of each group was evaluated before and after treatment. The minimum volume threshold of abdominal wall retraction reflex (AWR) was measured to observe the intestinal sensitivity of mice. The colon length was measured. The pathological changes of colon tissue were observed by HE staining. The expression of mucin in colon goblet cells was detected by periodate Scheff staining. The intestinal fibrosis was observed by Masson staining. The number of trypsin-positive cells (i.e., mast cell) and the expression level of TNF-α in colon tissue were detected by immunofluorescence staining. The expression levels of TNF-R1, P38 MAPK and TRPV1 in colon tissue were detected by immunohistochemistry. Compared with the normal group after treatment, the model group showed increased DAI score (P<0.001), decreased AWR minimum volume threshold (P<0.01), shortened colon length (P<0.001), significant inflammatory infiltration in the colon tissue, reduced mucin secretion (P<0.01), increased collagen fiber deposition (P<0.001), and elevated expression levels of TNF-α, TNF-R1, P38 MAPK, and TRPV1 (P<0.001, P<0.01, P<0.05). Compared with the model group, the MM group showed decreased DAI score (P<0.01), increased AWR minimum volume threshold (P<0.001), elongated colon length (P<0.001), reduced inflammatory cell infiltration, improved integrity of mucosal glandular structure, enhanced mucin secretion (P<0.01), decreased collagen fiber deposition (P<0.001), decreased number of mast cells in the colon tissue (P<0.001), and decreased expression levels of TNF-α, TNF-R1, P38 MAPK, and TRPV1 (P<0.001, P<0.01, P<0.05). There were no significant differences in the above index between the NM group and the normal group. Moxibustion can reduce visceral hypersensitivity, alleviate inflammatory infiltration and fibrotic damage in the colon tissue of mice with chronic UC. These effects may be associated with the down-regulation of TNF-α, TNF-R1, P38 MAPK, and TRPV1 expression in colon.

TRPV1 Channel in Human Eosinophils: Functional Expression and Inflammatory Modulation.

The transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel expressed on sensory neurons and immune cells. We hypothesize that TRPV1 plays a role in human eosinophil function and is modulated by inflammatory conditions. TRPV1 expression on human eosinophils was examined by qPCR, flow cytometry, and immunohistochemistry, respectively. TRPV1 functionality was analyzed by investigating calcium flux, apoptosis, modulation by cytokines and acidic pH, and CD69 externalization using flow cytometry. Activation of TRPV1 induced calcium influx and prolonged survival. Although eosinophils were not directly activated by TRPV1 agonists, activation by IL-3 or GM-CSF was mainly restricted to TRPV1-positive eosinophils. TRPV1 surface content was increased by acidic pH, IL-3, IL-31, IL-33, TSLP, TNF-α, BDNF, and NGF-β. Interestingly, TRPV1 was also expressed by eosinophils located in proximity to peripheral nerves in atopic dermatitis (AD) skin. In conclusion, eosinophils express functional TRPV1 channels which are increased by extracellular acidification and AD-related cytokines. Since eosinophils also express TRPV1 in AD skin, our results indicate an important role of TRPV1 for neuroimmune interaction mechanisms in itchy, inflammatory skin diseases, like AD.

Transient receptor potential vanilloid 1 inhibition reduces brain damage by suppressing neuronal apoptosis after intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) induces a complex sequence of apoptotic cascades and inflammatory responses, leading to neurological impairment. Transient receptor potential vanilloid 1 (TRPV1), a nonselective cation channel with high calcium permeability, has been implicated in neuronal apoptosis and inflammatory responses. This study used a mouse ICH model and neuronal cultures to examine whether TRPV1 activation exacerbates brain damage and neurological deficits by promoting neuronal apoptosis and neuroinflammation. ICH was induced by injecting collagenase in both wild-type (WT) C57BL/6 mice and TRPV1-/- mice. Capsaicin (CAP; a TRPV1 agonist) or capsazepine (a TRPV1 antagonist) was administered by intracerebroventricular injection 30 min before ICH induction in WT mice. The effects of genetic deletion or pharmacological inhibition of TRPV1 using CAP or capsazepine on motor deficits, histological damage, apoptotic responses, blood-brain barrier (BBB) permeability, and neuroinflammatory reactions were explored. The antiapoptotic mechanisms and calcium influx induced by TRPV1 inactivation were investigated in cultured hemin-stimulated neurons. TRPV1 expression was upregulated in the hemorrhagic brain, and TRPV1 was expressed in neurons, microglia, and astrocytes after ICH. Genetic deletion of TRPV1 significantly attenuated motor deficits and brain atrophy for up to 28 days. Deletion of TRPV1 also reduced brain damage, neurodegeneration, microglial activation, cytokine expression, and cell apoptosis at 1 day post-ICH. Similarly, the administration of CAP ameliorated brain damage, neurodegeneration, brain edema, BBB permeability, and cytokine expression at 1 day post-ICH. In primary neuronal cultures, pharmacological inactivation of TRPV1 by CAP attenuated neuronal vulnerability to hemin-induced injury, suppressed apoptosis, and preserved mitochondrial integrity in vitro. Mechanistically, CAP reduced hemin-stimulated calcium influx and prevented the phosphorylation of CaMKII in cultured neurons, which was associated with reduced activation of P38 and c-Jun NH2 -terminal kinase mitogen-activated protein kinase signaling. Our results suggest that TRPV1 inhibition may be a potential therapy for ICH by suppressing mitochondria-related neuronal apoptosis.

Abstract TP30: Exercise Postconditioning After Ischemic Stroke: Neuroprotection Through NGF/TRPV1-Mediated Astrocyte-Neuron Interaction

Introduction: Astrocytes activation and interaction with neurons potentially affect stroke outcomes. Transient receptor potential vanilloid 1 (TRPV1) participated in reducing brain injury and nerve growth factor (NGF) affected TRPV1 activation. The present study investigated neuroprotection induced by exercise postconditioning (PostE) and elucidated the mechanistic regulation of astrocytes-neuron crosstalk via NGF/TRPV1 pathway. Methods: Adult Sprague-Dawley rats received 2 h middle cerebral artery (MCA) occlusion, followed by 24 h of reperfusion. The treadmill exercise was then initiated 24 h after reperfusion for 3 days (PostE). Brain damage was determined by infarct volume, edema and apoptotic proteins expression (Bcl-2, BAX and Caspase-3). Neuroplasticity was determined by dendritic spine staining and protein expression of BDNF, GAP-43, PSD-95 and synaptophysin. Neuronal TRPV1 expression, astrocyte proliferation and astrocytic NGF expression was assessed with immunofluorescence. Primary astrocyte-neuron Transwell cultivation were used to determine the secretion of astrocytic NGF activating neural TRPV1. Interaction between TRPV1 and NGF or TRPV1 and A-kinase anchoring protein150 (AKAP150) were detected by immunofluorescence and Co-IP. Results: PostE significantly decreased brain damage and induced neuroplasticity in ischemic rats. PostE induced astrocyte proliferation and astrocytic NGF secretion, which, in turn, activated TRPV1 expression in neuron. Either NGF or TRPV1 inhibitor eliminated the neuroplasticity, while NGF inhibitor decreased TRPV1 expression, suggesting the potential regulating role of astrocytic NGF on TRPV1. Primary cells cultivation demonstrated a NGF/TRPV1 and TRPV1/AKAP150 interplays showing astrocyte-neuron communication. Conclusion: PostE induced neuroprotection, which was mediated by the activation of astrocytes and their interaction with neurons through the NGF/TRPV1 pathway, highlighting the significance of astrocyte-neuron crosstalk in post-stroke recovery processes.

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 1week. 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.

Capsaicin orchestrates metastasis in gastric cancer via modulating expression of TRPV1 channels and driving gut microbiota disorder

The association between capsaicin, the major natural pungent compound of chili peppers, and gastric cancer progression has engendered conflicting findings. In this work, we sought to explore the character of a high capsaicin diet in gastric cancer metastasis and its possible mechanism. The impact of high capsaicin consumption on gastric cancer metastasis was investigated in vivo (xenograft mouse and zebrafish models) and in vitro (biochemical and molecular assays). It was demonstrated that high diet of capsaicin gave rise to accelerate tumor metastasis, which was partially mediated by elevating the expression of transient receptor potential vanilloid 1 (TRPV1) in gastric cancer cells. Importantly, we found that genetic depletion of TRPV1 could reduce gastric cancer metastasis by diminishing the motility of tumor cells in vitro, but acted poorly in xenograft mouse model. Considering the distribution of capsaicin in vivo, 16S rRNA sequencing and fecal microbiota transplantation (FMT) were used to appraise whether the gut microbiota involved in the high capsaicin diet induced metastasis. It was demonstrated that the level of Firmicutes and Clostridiales was expressively boosted following the high consumption of capsaicin. This microbial shift contributed to the increased peripheral 5-hydroxytryptamine (5-HT) levels, yielding the aggravated metastatic burden. Collectively, our findings highlighted the potential risk of high capsaicin diet in promoting gastric cancer metastasis by virtue of modulating TRPV1 expression and gut microbiota composition, indicating the importance of controlled consumption of chili peppers for patients with gastric cancer.CLQ_5di4C7NjAvrz19eKZiVideo

Flow-dependent regulation of rat mesenteric lymphatic vessel contractile response requires activation of endothelial TRPV4 channels.

The objective of our study is to evaluate the involvement of the transient receptor potential vanilloid 4 (TRPV4) in the alteration of lymphatic pumping in response to flow and determine the signaling pathways involved. We used immunofluorescence imaging and western blotting to assess TRPV4 expression in rat mesenteric lymphatic vessels. We examined inhibition of TRPV4 with HC067047, nitric oxide synthase (NOS) with L-NNA and cyclooxygenases (COXs) with indomethacin on the contractile response of pressurized lymphatic vessels to flow changes induced by a stepwise increase in pressure gradients, and the functionality of endothelial TRPV4 channels by measuring the intracellular Ca2+ response of primary lymphatic endothelial cell cultures to the selective agonist GSK1016790A. TRPV4 protein was expressed in both the endothelial and the smooth muscle layer of rat mesenteric lymphatics with high endothelial expression around the valve sites. When maintained under constant transmural pressure, most lymphatic vessels displayed a decrease in contraction frequency under conditions of flow and this effect was ablated through inhibition of NOS, COX or TRPV4. Our findings demonstrate a critical role for TRPV4 in the decrease in contraction frequency induced in lymphatic vessels by increases in flow rate via the production and action of nitric oxide and dilatory prostanoids.