Transient receptor potential(TRP)channels are strongly associated with colon cancer development and progression.This study leveraged a multivariate Cox regression model on publicly available datasets to construct a TR...Transient receptor potential(TRP)channels are strongly associated with colon cancer development and progression.This study leveraged a multivariate Cox regression model on publicly available datasets to construct a TRP channels-associated gene signature,with further validation of signature in real world samples from our hospital treated patient samples.Kaplan-Meier(K-M)survival analysis and receiver operating characteristic(ROC)curves were employed to evaluate this gene signature’s predictive accuracy and robustness in both training and testing cohorts,respectively.Additionally,the study utilized the CIBERSORT algorithm and single-sample gene set enrichment analysis to explore the signature’s immune infiltration landscape and underlying functional implications.The support vector machine algorithm was applied to evaluate the signature’s potential in predicting chemotherapy outcomes.The findings unveiled a novel three TRP channels-related gene signature(MCOLN1,TRPM5,and TRPV4)in colon adenocarcinoma(COAD).The ROC and K-M survival curves in the training dataset(AUC=0.761;p=1.58e-05)and testing dataset(AUC=0.699;p=0.004)showed the signature’s robust predictive capability for the overall survival of COAD patients.Analysis of the immune infiltration landscape associated with the signature revealed higher immune infiltration,especially an increased presence of M2 macrophages,in high-risk group patients compared to their low-risk counterparts.High-risk score patients also exhibited potential responsiveness to immune checkpoint inhibitor therapy,evident through increased CD86 and PD-1 expression profiles.Moreover,the TRPM5 gene within the signature was highly expressed in the chemoresistance group(p=0.00095)and associated with poor prognosis(p=0.036)in COAD patients,highlighting its role as a hub gene of chemoresistance.Ultimately,this signature emerged as an independent prognosis factor for COAD patients(p=6.48e-06)and expression of model gene are validated by public data and real-world patients.Overall,this bioinformatics study provides valuable insights into the prognostic implications and potential chemotherapy resistance mechanisms associated with TRPs-related genes in colon cancer.展开更多
The study titled“Transient receptor potential-related risk model predicts prognosis of hepatocellular carcinoma patients”is a significant contribution to hepatocellular carcinoma(HCC)research,highlighting the role o...The study titled“Transient receptor potential-related risk model predicts prognosis of hepatocellular carcinoma patients”is a significant contribution to hepatocellular carcinoma(HCC)research,highlighting the role of transient receptor potential(TRP)family genes in the disease’s progression and prognosis.Utilizing data from The Cancer Genome Atlas database,it establishes a new risk assessment model,emphasizing the interaction of TRP genes with tumor proliferation pathways,key metabolic reactions like retinol metabolism,and the tumor immune microenvironment.Notably,the overexpression of the TRPC1 gene in HCC correlates with poorer patient survival outcomes,suggesting its potential as a prognostic biomarker and a target for personalized therapy,particularly in strategies combining immunotherapy and anti-TRP agents.展开更多
Spodoptera frugiperda is a highly destructive pest that has become a global problem due to its robust reproductive and migratory capabilities.Transient receptor potential(TRP)channels,which constitute a vast ion chann...Spodoptera frugiperda is a highly destructive pest that has become a global problem due to its robust reproductive and migratory capabilities.Transient receptor potential(TRP)channels,which constitute a vast ion channel family,play pivotal roles in sensing the external environment and maintaining internal homeostasis in insects.TRP channels have been widely investigated for their critical roles in regulating various insect behaviors in recent years.In this study,we identified 15 TRP gene loci encoding 26 transcripts in the genome of S.frugiperda and analyzed their expression profiles at different developmental stages.The results revealed that S.frugiperda possesses four TRPC genes,six TRPA genes,one TRPM gene,two TRPV genes,one TRPN gene,and one TRPML gene,while a canonical TRPP is absent.Moreover,the SfruTRPA1 was functionally characterized using the Xenopus oocyte expression system.The results showed that SfruTRPA1 is activated by temperature increases from 20 to 45℃,and there is no significant desensitization after repeated stimuli within the same temperature range.Additionally,SfruTRPA1 is activated by certain natural chemicals,including allyl isothiocyanate(AITC)and cinnamaldehyde(CA).These findings provide valuable insights to the TRP genes in S.frugiperda.展开更多
Aim： To investigate the expression and distribution of the members of the transient receptor potential （TRP） channel members of TRP melastatin （TRPM） and TRP vanilloid （TRPV） subfamilies in rat prostatic tissue...Aim： To investigate the expression and distribution of the members of the transient receptor potential （TRP） channel members of TRP melastatin （TRPM） and TRP vanilloid （TRPV） subfamilies in rat prostatic tissue. Methods： Prostate tissue was obtained from male Sprague-Dawley rats. Reverse transcription polymerase chain reaction （RT-PCR） and quantitative real-time polymerase chain reaction （PCR） were used to check the expression of all TRPM and TRPV channel members with specific primers. Immunohistochemistry staining for TRPM8 and TRPV1 were also performed in rat tissues. Results： TRPM2, TRPM3, TRPM4, TRPM6, TRPM7, TRPMS, TRPV2 and TRPV4 mRNA were detected in all rat prostatic tissues. Very weak signals for TRPM1, TRPVI and TRPV3 were also detected. The mRNA of TRPM5, TRPV5 and TRPV6 were not detected in all RT-PCR experiments. Quantitative real-time RT-PCR showed that TRPM2, TRPM3, TRPM4, TRPMS, TRPV2 and TRPV4 were the most abundantly expressed TRPM and TRPV subtypes, respectively. Fluorescence immunohistochemistry indicated that TRPM8 and TRPV 1 are highly expressed in both epithelial and smooth muscle cells. Conclusion： Our results demonstrate that mRNA or protein for TRPM1, TRPM2, TRPM3, TRPM4, TRPM6, TRPM7, TRPMS, TRPV1, TRPV2, TRPV3 and TRPV4 exist in rat prostatic tissue. The data presented here assists in elucidating the physiological function of TRPM and TRPV channels.展开更多
BACKGROUND Transient receptor potential vanilloid-1(TRPV1),a nonselective cation channel,is activated by capsaicin,a pungent ingredient of hot pepper.Previous studies have suggested a link between obesity and capsaici...BACKGROUND Transient receptor potential vanilloid-1(TRPV1),a nonselective cation channel,is activated by capsaicin,a pungent ingredient of hot pepper.Previous studies have suggested a link between obesity and capsaicin-associated pathways,and activation of TRPV1 may provide an alternative approach for obesity treatment.However,data on the TRPV1 distribution in human gastric mucosa are limited,and the degree of TRPV1 distribution in the gastric and duodenal mucosal cells of obese people in comparison with normal-weight individuals is unknown.AIM To clarify gastric and duodenal mucosal expression of TRPV1 in humans and compare TRPV1 expression in obese and healthy individuals.METHODS Forty-six patients with a body mass index(BMI)of>40 kg/m^(2) and 20 patients with a BMI between 18-25 kg/m^(2) were included.Simultaneous biopsies from the fundus,antrum,and duodenum tissues were obtained from subjects between the ages of 18 and 65 who underwent esophagogastroduodenoscopy.Age,sex,history of alcohol and cigarette consumption,and past medical history regarding chronic diseases and medications were accessed from patient charts and were analyzed accordingly.Evaluation with anti-TRPV1 antibody was performed separately according to cell types in the fundus,antrum,and duodenum tissues using an immunoreactivity score.Data were analyzed using SPSS 17.0.RESULTS TRPV1 expression was higher in the stomach than in the duodenum and was predominantly found in parietal and chief cells of the fundus and mucous and foveolar cells of the antrum.Unlike foveolar cells in the antrum,TRPV1 was relatively low in foveolar cells in the fundus(4.92±0.49 vs 0.48±0.16,P<0.01,Mann-Whitney U test).Additionally,the mucous cells in the duodenum also had low levels of TRPV1 compared to mucous cells in the antrum(1.33±0.31 vs 2.95±0.46,P<0.01,Mann-Whitney U test).TRPV1 expression levels of different cell types in the fundus,antrum,and duodenum tissues of the morbidly obese group were similar to those of the control group.Staining with TRPV1 in fundus chief cells and antrum and duodenum mucous cells was higher in patients aged≥45 years than in patients<45 years(3.03±0.42,4.37±0.76,2.28±0.55 vs 1.9±0.46,1.58±0.44,0.37±0.18,P=0.03,P<0.01,P<0.01,respectively,Mann-Whitney U test).The mean staining levels of TRPV1 in duodenal mucous cells in patients with diabetes and hypertension were higher than those in patients without diabetes and hypertension(diabetes:2.11±0.67 vs 1.02±0.34,P=0.04;hypertension:2.42±0.75 vs 1.02±0.33,P<0.01 Mann-Whitney U test).CONCLUSION The expression of TRPV1 is unchanged in the gastroduodenal mucosa of morbidly obese patients demonstrating that drugs targeting TRPV1 may be effective in these patients.展开更多
Maintenance of intracellular Ca^(2+)levels at orders of magnitude below those in the extracellular environment is a requisite for preserving cell viability.Membrane channels contribute to such control through modulati...Maintenance of intracellular Ca^(2+)levels at orders of magnitude below those in the extracellular environment is a requisite for preserving cell viability.Membrane channels contribute to such control through modulating their time-dependent opening and closing behaviour.Such regulation requires Ca^(2+)to serve as a second messenger mediating receptor control of numerous life-sustaining responses.Transient receptor potential(TRP)channels signal transduce a wide variety of different sensory stimuli to induce responses modulating cellular function.These channels are non-selective cation channels with variable Ca^(2+)selectivity having extensive sequence homology.They constitute a superfamily made up of 28 different members that are subdivided into 7 different subfamilies based on differences in sequence homology.Some of these TRP channel isotypes are expressed in the eye and localized to both neuronal and non-neuronal cell membranes.Their activation generates intracellular Ca^(2+)transients and other downstream-linked signalling events that affect numerous responses required for visual function.As there is an association between changes in functional TRP expression in various ocular diseases,there are efforts underway to determine if these channels can be used as drug targets to reverse declines in ocular function.We review here our current knowledge about the expression,function and regulation of TRPs in different eye tissues in health and disease.Furthermore,some of the remaining hurdles are described to developing safe and efficacious TRP channel modulators for use in a clinical setting.展开更多
Background: It is important to maintain skin homeostasis for cosmetic and medical reasons. Many ceramide-related ingredients and cosmetics have been developed to improve the skin barrier function and skin hydration. S...Background: It is important to maintain skin homeostasis for cosmetic and medical reasons. Many ceramide-related ingredients and cosmetics have been developed to improve the skin barrier function and skin hydration. Similar to extracellular lipids, the cornified envelope, which is a structure formed beneath the plasma membrane, contributes to the skin barrier function as a scaffold for extracellular lipids. Therefore, in this study, we focused on transglutaminase 1 (TGM1) which is the key enzyme for formation of the cornified envelope Objective: The objectives of this study were to identify compounds that could upregulate the expression of TGM1 and evaluate their underlying action mechanisms. Methods: Expression of the transient receptor potential channel vanilloid subfamily member 4 (TRPV4) at the mRNA and protein levels was estimated by PCR and western blotting. Effects of baicalein and Salvia officinalis (SO) extract on TGM1 mRNA expression were measured by PCR. The involvement of TRPV4 in TGM1 mRNA expression was evaluated by the inhibition and silencing of TRPV4. Results: TRPV4 was expressed in both basal cell-like HaCaT cells and suprabasal cell-like HaCaT cells. Baicalein and SO extract upregulated TGM1 mRNA expression in basal cell-like HaCaT cells. However, inhibition and silencing of TRPV4 abrogated the effects of baicalein and SO extract. Conclusion: Baicalein and SO extract upregulated the expression of TGM1 mRNA via the activation of TRPV4, suggesting that it may improve the skin barrier function by enhancing cornified envelope formation.展开更多
Transient receptor potential channel A1 is one of the important transducers of noxious stimuli in the primary afferents, which may contribute to generation of neurogenic inflammation and hyperalgesia. The present stud...Transient receptor potential channel A1 is one of the important transducers of noxious stimuli in the primary afferents, which may contribute to generation of neurogenic inflammation and hyperalgesia. The present study was designed to investigate if activation of transient receptor potential channel A1 may induce calcitonin gene-related peptide release from the primary afferent neurons. We found that application of allyl isothiocyanate, a transient receptor potential channel A1 activator, caused calcitonin gene-related peptide release from the cultured rat dorsal root ganglion neurons. Knock- down of transient receptor potential channel A1 with an antisense oligodeoxynucleotide prevented calcitonin gene-related peptide release by allyl isothiocyanate application in cultured dorsal root ganglion neurons. Thus, we concluded that transient receptor potential channel A1 activation caused calcitonin gene-related peptide release in sensory neurons.展开更多
BACKGROUND Diabetic cardiomyopathy(DCM) is a serious complication of end-stage diabetes that presents symptoms such as cardiac hypertrophy and heart failure. The transient receptor potential channel 6(TRPC6) protein i...BACKGROUND Diabetic cardiomyopathy(DCM) is a serious complication of end-stage diabetes that presents symptoms such as cardiac hypertrophy and heart failure. The transient receptor potential channel 6(TRPC6) protein is a very important selective calcium channel that is closely related to the development of various cardiomyopathies.AIM To explore whether TRPC6 affects cardiomyocyte apoptosis and proliferation inhibition in DCM.METHODS We compared cardiac function and myocardial pathological changes in wild-type mice and mice injected with streptozotocin(STZ), in addition to comparing the expression of TRPC6 and P-calmodulin-dependent protein kinase Ⅱ(P-CaMKⅡ) in them. At the same time, we treated H9C2 cardiomyocytes with high glucose and then evaluated the effects of addition of SAR, a TRPC6 inhibitor, and KN-93, a CaMKⅡ inhibitor, to such H9C2 cells in a high-glucose environment.RESULTS We found that STZ-treated mice had DCM, decreased cardiac function, necrotic cardiomyocytes, and limited proliferation. Western blot and immunofluorescence were used to detect the expression levels of various appropriate proteins in the myocardial tissue of mice and H9C2 cells. Compared to those in the control group, the expression levels of the apoptosis-related proteins cleaved caspase 3 and Bax were significantly higher in the experimental group, while the expression of the proliferation-related proteins proliferating cell nuclear antigen(PCNA) and CyclinD1 was significantly lower. In vivo and in vitro, the expression of TRPC6 and P-CaMKⅡ increased in a high-glucose environment. However, addition of inhibitors to H9C2 cells in a high-glucose environment resulted in alleviation of both apoptosis and proliferation inhibition.CONCLUSION The inhibition of apoptosis and proliferation of cardiomyocytes in a high-glucose environment may be closely related to activation of the TRPC6/P-CaMKⅡ pathway.展开更多
The transient receptor potential cation channel subfamily V member 1（TRPV1） provides the sensation of pain（nociception）. However, it remains unknown whether TRPV1 is activated after peripheral nerve injury, or whe...The transient receptor potential cation channel subfamily V member 1（TRPV1） provides the sensation of pain（nociception）. However, it remains unknown whether TRPV1 is activated after peripheral nerve injury, or whether activation of TRPV1 affects neural regeneration. In the present study, we established rat models of unilateral sciatic nerve crush injury, with or without pretreatment with AMG517（300 mg/kg）, a TRPV1 antagonist, injected subcutaneously into the ipsilateral paw 60 minutes before injury. At 1 and 2 weeks after injury, we performed immunofluorescence staining of the sciatic nerve at the center of injury, at 0.3 cm proximal and distal to the injury site, and in the dorsal root ganglia. Our results showed that Wallerian degeneration occurred distal to the injury site, and neurite outgrowth and Schwann cell regeneration occurred proximal to the injury. The number of regenerating myelinated and unmyelinated nerve clusters was greater in the AMG517-pretreated rats than in the vehicle-treated group, most notably 2 weeks after injury. TRPV1 expression in the injured sciatic nerve and ipsilateral dorsal root ganglia was markedly greater than on the contralateral side. Pretreatment with AMG517 blocked this effect. These data indicate that TRPV1 is activated or overexpressed after sciatic nerve crush injury, and that blockade of TRPV1 may accelerate regeneration of the injured sciatic nerve.展开更多
Alzheimer’s disease （AD） is an age-related eurodegenerative disease that represents the most common cause of dementia among the elderly people. With the increasingly aging population, AD has presented an overwhelmi...Alzheimer’s disease （AD） is an age-related eurodegenerative disease that represents the most common cause of dementia among the elderly people. With the increasingly aging population, AD has presented an overwhelming healthcare challenge to modern society; the World Alzheimer Report 2015 has estimated that 46.8 million people worldwide lived with dementia in 2015 and this number will rise to 74.7 million in 2030 and that the total cost of dementia was 818 billion in US$ in 2015 and will reach two trillion in 2030. Post-mortem studies have identified two histopathological hallmarks in the brains of AD patients; extracellular senile plaque with elevated deposition of amyloid β （Aβ） peptides, and intracellular neurofibrillary tangle composed of hyper-phosphorylated microtubule-associated protein tau.Etiologically, progressive neuronal loss within the cerebral cortex and hippocampus regions of the brain leads to irreversible decline in, and eventually complete loss of, memory and other cognitive functions that afflict AD patients. The widely-accepted amyloid cascade hypothesis for AD pathogenesis holds that accumulation and aggregation of neurotoxic Aβ peptides, due to imbalance of their generation and clearance as a result of changes in genetic makeup, aging and/or exposure to environmental risk factors, is a major and early trigger of AD. This hypothesis has continuously gained support by preclinical and clinical studies （Selkoe and Hardy, 2016）. However, the intensive and costly drug discovery efforts over the past decades based on such a hypothesis have proved extremely frustrating in developing effective therapeutics to treat or slow down the progress of AD, highlighting the need for more research to improve our understanding towards the cellular and molecular mechanisms by which Aβ peptides bring about neurotoxicity and cognitive dysfunction.展开更多
Moxibustion is an important component part of Traditional Chinese Medicine(TCM).Among different kinds of moxibustion methods,thermal stimulation seems to be a pivotal impact factor to the theraputic efficacy.Based on ...Moxibustion is an important component part of Traditional Chinese Medicine(TCM).Among different kinds of moxibustion methods,thermal stimulation seems to be a pivotal impact factor to the theraputic efficacy.Based on its thermal characteristic and treated area-skin,we hypothesize that the thermosensitive TRPV channels may involve in the mechanism of moxibustion.This study,by referring to various experimental and clinical data,analyzes the properties and features of transient receptor potential vanilloid(TRPV)subfamily 1-4 and the impact of moxibustion on these channels.The factors impacting the efficacy of moxibustion treatment were analyzed on three levels:the independent ba-sic factors of moxibustion(temperature,space and time);moxibustion intensity(a compound factor achieved through comprehensive control of the three individual basic factors mentioned above);and moxibustion quantity(the amount of temperature stimulation applied within a certain unit of time,including the total amount of moxibustion treatment).The results from present study show that the effect of moxibustion therapy appears to be determined by the activation of TRPV1-4,mainly TRPV1 and TRPV2.Temperature(the degree of heat stimulation),time and area(how long the treatment lasts and how many TRPV1-4 channels are activated)affect the intensity of moxibustion treatment to form effective moxibustion quantity;this should be considered in clinical moxibustion application.展开更多
Objective Renal fibrosis is the ultimate pathway of various forms of acute and chronic kidney damage.Notably,the knockout of transient receptor potential channel 6(TRPC6)has shown promise in alleviating renal fibrosis...Objective Renal fibrosis is the ultimate pathway of various forms of acute and chronic kidney damage.Notably,the knockout of transient receptor potential channel 6(TRPC6)has shown promise in alleviating renal fibrosis.However,the regulatory impact of TRPC6 on renal fibrosis remains unclear.Methods In vivo,TRPC6 knockout(TRPC6−/−)mice and age-matched 129 SvEv(WT)mice underwent unilateral renal ischemia-reperfusion(uIR)injury surgery on the left renal pedicle or sham operation.Kidneys and serum were collected on days 7,14,21,and 28 after euthanasia.In vitro,primary tubular epithelial cells(PTECs)were isolated from TRPC6−/−and WT mice,followed by treatment with transforming growth factorβ1(TGFβ1)for 72 h.The anti-fibrotic effect of TRPC6−/−and the underlying mechanisms were assessed through hematoxylin-eosin staining,Masson staining,immunostaining,qRT-PCR,and Western blotting.Results Increased TRPC6 expression was observed in uIR mice and PTECs treated with TGFβ1.TRPC6−/−alleviated renal fibrosis by reducing the expression of fibrotic markers(Col-1,α-SMA,and vimentin),as well as decreasing the apoptosis and inflammation of PTECs during fibrotic progression both in vivo and in vitro.Additionally,we found that the phosphatidylinositol 3-kinase(PI3K)/protein kinase B(AKT)/glycogen synthase kinase 3 beta(GSK3β)signaling pathway,a pivotal player in renal fibrosis,was down-regulated following TRPC6 deletion.Conclusion These results suggest that the ablation of TRPC6 may mitigate renal fibrosis by inhibiting the apoptosis and inflammation of PTECs through down-regulation of the PI3K/AKT/GSK3βpathway.Targeting TRPC6 could be a novel therapeutic strategy for preventing chronic kidney disease.展开更多
During the last decade, transient receptor potential （TRP） channels emerge as key proteins in central mechanisms of the carcinogenesis such as cell proliferation, apoptosis and migration. Initial studies showed that...During the last decade, transient receptor potential （TRP） channels emerge as key proteins in central mechanisms of the carcinogenesis such as cell proliferation, apoptosis and migration. Initial studies showed that expression profile of some TRP channels, notably TRP melastatin 8 （TRPM8）, TRP vanilloid 6 （TRPV6）,TRP canonical （TRPC6） and TRPV2, is changing during the development and the progression of prostate cancer towards the hormone-refractory stages. The link between the change in expression levels and the functional role of these channels in prostate cancer is step by step being elucidated. These recent advances are here described and discussed.展开更多
Stem cells hold indefinite self-renewable capability that can be differentiated into all desired cell types.Based on their plasticity potential,they are divided into totipotent(morula stage cells),pluripotent(embryoni...Stem cells hold indefinite self-renewable capability that can be differentiated into all desired cell types.Based on their plasticity potential,they are divided into totipotent(morula stage cells),pluripotent(embryonic stem cells),multipotent(hematopoietic stem cells,multipotent adult progenitor stem cells,and mesenchymal stem cells[MSCs]),and unipotent(progenitor cells that differentiate into a single lineage)cells.Though bone marrow is the primary source of multipotent stem cells in adults,other tissues such as adipose tissues,placenta,amniotic fluid,umbilical cord blood,periodontal ligament,and dental pulp also harbor stem cells that can be used for regenerative therapy.In addition,induced pluripotent stem cells also exhibit fundamental properties of self-renewal and differentiation into specialized cells,and thus could be another source for regenerative medicine.Several diseases including neurodegenerative diseases,cardiovascular diseases,autoimmune diseases,virus infection(also coronavirus disease 2019)have limited success with conventional medicine,and stem cell transplantation is assumed to be the best therapy to treat these disorders.Importantly,MSCs,are by far the best for regenerative medicine due to their limited immune modulation and adequate tissue repair.Moreover,MSCs have the potential to migrate towards the damaged area,which is regulated by various factors and signaling processes.Recent studies have shown that extracellular calcium(Ca^(2+))promotes the proliferation of MSCs,and thus can assist in transplantation therapy.Ca^(2+)signaling is a highly adaptable intracellular signal that contains several components such as cell-surface receptors,Ca^(2+)channels/pumps/exchangers,Ca^(2+)buffers,and Ca^(2+)sensors,which together are essential for the appropriate functioning of stem cells and thus modulate their proliferative and regenerative capacity,which will be discussed in this review.展开更多
The aim of this research was to assess the antinociceptive activity of the transient receptor potential （TRP） channel TRPV1, TRPM8, and TRPA1 antagonists in neurogenic, tonic, and neuropathic pain models in mice. Fo...The aim of this research was to assess the antinociceptive activity of the transient receptor potential （TRP） channel TRPV1, TRPM8, and TRPA1 antagonists in neurogenic, tonic, and neuropathic pain models in mice. For this purpose, TRP channel antagonists were administered into the dorsal surface of a hind paw 15 min before capsaicin, allyl isothiocyanate （AITC）, or formalin. Their antiallodynic and antihyperalgesic efficacies after intraperitoneal ad- ministration were also assessed in a paclitaxel-induced neuropathic pain model. Motor coordination of paclitaxel- treated mice that received these TRP channel antagonists was investigated using the rotarod test. TRPV1 antagonists, capsazepine and SB-366791, attenuated capsaicin-induced nociceptive reaction in a concentration-dependent manner. At 8 pg/20 pl, this effect was 51% （P〈0.001） for capsazepine and 37% （P〈0.05） for SB-366791. A TRPA1 antagonist, A-967079, reduced pain reaction by 48% （P〈0.05） in the AITC test and by 54% （P〈0.001） in the early phase of the formalin test. The test compounds had no influence on the late phase of the formalin test. In paclitaxel-treated mice, they did not attenuate heat hyperalgesia but N-（3-aminopropyl）-2-{[（3-methylphenyl）methyl]oxy}-N-（2-thienylmethyl） benzamide hydrochloride salt （AMTB）, a TRPM8 antagonist, reduced cold hyperalgesia and tactile allodynia by 31% （P〈0.05） and 51% （P〈0.01）, respectively. HC-030031, a TRPA1 channel antagonist, attenuated tactile allodynia in the von Frey test （62%; P〈0.001）. In conclusion, distinct members of TRP channel family are involved in different pain models in mice. Antagonists of TRP channels attenuate nocifensive responses of neurogenic, tonic, and neuropathic pain, but their efficacies strongly depend on the pain model used.展开更多
Objective::This study was performed to investigate the effects of honokiol on the activation of transient receptor potential channel V1(TRPV1)and the secretion of thymic stromal lymphopoietin(TSLP)in a human benign ep...Objective::This study was performed to investigate the effects of honokiol on the activation of transient receptor potential channel V1(TRPV1)and the secretion of thymic stromal lymphopoietin(TSLP)in a human benign epidermal keratinocyte line(HaCaT).Methods::HaCaT keratinocytes were cultivated and divided into six groups:capsaicin-induced model control group,capsazepine control group,solvent control group,and three honokiol treatment groups(7.81,15.63,and 31.25 mg/L of honokiol).The effect of honokiol on calcium(Ca^(2+))influx was measured by a Ca^(2+)fluorescence imaging system.The fluorescence intensity(F)of cells was measured.The rate of change in F(ΔF/F0)was calculated,and theΔF/F0-time curve was constructed.HaCaT keratinocytes were stimulated with polyinosinic:polycytidylic acid,recombinant human tumor necrosis factorα,and recombinant human interleukin 4.Different concentrations of honokiol(15.63,7.81,and 3.91 mg/L)were added to the cells in the respective honokiol groups;20 mg/L of dexamethasone or 0.5%dimethyl sulfoxide was added to the cells in the positive control group or solvent control group.The TSLP concentration in the HaCaT keratinocytes of each group was detected by enzyme-linked immunosorbent assay.Statistical analysis was performed by one-way analysis of variance and Dunnett t test.Results::The capsaicin-induced Ca^(2+)fluorescence intensity in HaCaT keratinocytes was significantly inhibited in the 31.25 mg/L honokiol group;ΔF/F0 at 45 second was 0.76 in the model control group and 0 in the 31.25 mg/L honokiol group.The TSLP level in the 15.63 and 7.81 mg/L honokiol groups was lower than that in the solvent control group(t=7.382,P=0.003,and t=2.766,P=0.023,respectively),while the TSLP level in the 3.91 mg/L honokiol group was not significantly different from that in the solvent control group(t=1.872,P=0.124).Conclusions::Honokiol inhibited the Ca^(2+)influx induced by capsaicin(TRPV1 agonist)in HaCaT keratinocytes.Honokiol has an inhibitory effect on TSLP secretion in HaCaT keratinocytes.展开更多
We investigated the effects of transient receptor potential M8(TRPM8)channel on the proliferation and motility of androgen-independent prostate cancer PC-3 cells.After being permanently transfected with an empty vecto...We investigated the effects of transient receptor potential M8(TRPM8)channel on the proliferation and motility of androgen-independent prostate cancer PC-3 cells.After being permanently transfected with an empty vector and cDNA encoding the TRPM8 protein,cells were analysed for cell cycle distribution and motility using flow cytometry and scratch assay.Immunocytochemistry and Ca^(2+)imaging analysis revealed the overexpression of functional TRPM8 channel on both endoplasmic reticulum and plasma membrane of PC-3-TRPM8 cells.Cell cycle distribution and scratch assay analysis revealed that TRPM8 induced cell cycle arrest at the G_(0)/G_(1)stage(P<0.05)and facilitated the cell apoptosis induced by starvation(P<0.05).Furthermore,TRPM8 inhibited the migration of PC-3-TRPM8 cells(P<0.01)through the inactivation of focal-adhesion kinase.It appears that TRPM8 was not essential for the survival of PC-3 cells;however,the overexpression of TRPM8 had negative effects on the proliferation and migration of PC-3 cells.Thus,TRPM8 and its agonists may serve as important targets for the treatment of prostate cancer.展开更多
AIM To evaluate whether non-steroidal anti-inflammatory drugs(NSAIDs)-induced gastropathy is a clinically predictive model of referred visceral hypersensitivity.METHODS Gastric ulcer pain was induced by the oral admin...AIM To evaluate whether non-steroidal anti-inflammatory drugs(NSAIDs)-induced gastropathy is a clinically predictive model of referred visceral hypersensitivity.METHODS Gastric ulcer pain was induced by the oral administration of indomethacin to male,CD1 mice(n = 10/group) and then assessed by measuring referred abdominal hypersensitivity to tactile application. A diverse range of pharmacological mechanisms contributing to the pain were subsequently investigated. These mechanisms included: transient receptor potential(TRP),sodium and acid-sensing ion channels(ASICs) as well as opioid receptors and guanylate cyclase C(GC-C). RESULTS Results showed that two opioids and a GC-C agonist,morphine,asimadoline and linaclotide,respectively,the TRP antagonists,AMG9810 and HC-030031 and the sodium channel blocker,carbamazepine,elicited a dose-and/or time-dependent attenuation of referred visceral hypersensitivity,while the ASIC blocker,amiloride,was ineffective at all doses tested. CONCLUSION Together,these findings implicate opioid receptors,GC-C,and sodium and TRP channel activation as possible mechanisms associated with visceral hypersensitivity. More importantly,these findings also validate NSAID-induced gastropathy as a sensitive and clinically predictive mouse model suitable for assessing novel molecules with potential pain-attenuating properties.展开更多
OBJECTIVE We want to investigate the mechanism of organophosphate-induced delayed neuropathy(OPIDN) and find appropriate therapeutic medicine.OPIDN,often leads to paresthesias,ataxia and paralysis,occurs in the late-s...OBJECTIVE We want to investigate the mechanism of organophosphate-induced delayed neuropathy(OPIDN) and find appropriate therapeutic medicine.OPIDN,often leads to paresthesias,ataxia and paralysis,occurs in the late-stage of acute poisoning or after repeated exposures to organophosphate(OP) insecticides or nerve agents,and may contribute to the Gulf War Syndrome.METHODS FDSS Ca2^(+)-influx assays,single-cell calcium imaging and patch-clamp electrophysiology were the major testing techniques.Transfected HEK293 cells and dorsal root ganglion(DRG) neurons were used to evaluate the effects of compounds.Wild type and trpa1 knockout mice and adult hyline brown hens were used to evaluate the neuropathological damages caused by the OPs.Transmission electron microscopy imaging was used to observe the nerve injuries ultrastructurally.High-throughput screen for TRPA1 inhibitors was accomplished by Ion Works Barracuda(IWB) automated electrophysiology assay.RESULTS TRPA1(Transient receptor potential cation channel,member A1) channel mediates OPIDN.A variety of OPs,exemplified by malathion,activates TRPA1 but not other neuronal TRP channels.Malathion increases the intracellular calcium levels and upregulates the excitability of mouse DRG neurons in vitro.Mice with repeated exposures to malathion also develop local tissue nerve injuries and pain-related behaviors,which resembles the early symptoms of OPIDN.Both the neuropathological changes and the nocifensive behaviors can be attenuated by treatment of TRPA1 antagonist HC030031 or abolished by knockout of Trpa1 gene.In the classic hens OPIDN model,malathion causes nerve injuries and ataxia to a similar level as the positive inducer tri-ortho-cresyl phosphate(TOCP),which also activates TRPA1 channel.Treatment with HC030031 reduces the damages caused by malathion or TOCP.Duloxetine and Ketotifen,two commercially available drugs exhibiting TRPA1 inhibitory activity,show neuroprotective effects against OPIDN and might be used in emergency situations.CONCLUSION TRPA1 is the major mediator of OPIDN and targeting TRPA1 is an effective way for the treatment of OPIDN.展开更多
基金the Ethics Committee of University Magdeburg(Ethical code:33/0119.03.2001).
文摘Transient receptor potential(TRP)channels are strongly associated with colon cancer development and progression.This study leveraged a multivariate Cox regression model on publicly available datasets to construct a TRP channels-associated gene signature,with further validation of signature in real world samples from our hospital treated patient samples.Kaplan-Meier(K-M)survival analysis and receiver operating characteristic(ROC)curves were employed to evaluate this gene signature’s predictive accuracy and robustness in both training and testing cohorts,respectively.Additionally,the study utilized the CIBERSORT algorithm and single-sample gene set enrichment analysis to explore the signature’s immune infiltration landscape and underlying functional implications.The support vector machine algorithm was applied to evaluate the signature’s potential in predicting chemotherapy outcomes.The findings unveiled a novel three TRP channels-related gene signature(MCOLN1,TRPM5,and TRPV4)in colon adenocarcinoma(COAD).The ROC and K-M survival curves in the training dataset(AUC=0.761;p=1.58e-05)and testing dataset(AUC=0.699;p=0.004)showed the signature’s robust predictive capability for the overall survival of COAD patients.Analysis of the immune infiltration landscape associated with the signature revealed higher immune infiltration,especially an increased presence of M2 macrophages,in high-risk group patients compared to their low-risk counterparts.High-risk score patients also exhibited potential responsiveness to immune checkpoint inhibitor therapy,evident through increased CD86 and PD-1 expression profiles.Moreover,the TRPM5 gene within the signature was highly expressed in the chemoresistance group(p=0.00095)and associated with poor prognosis(p=0.036)in COAD patients,highlighting its role as a hub gene of chemoresistance.Ultimately,this signature emerged as an independent prognosis factor for COAD patients(p=6.48e-06)and expression of model gene are validated by public data and real-world patients.Overall,this bioinformatics study provides valuable insights into the prognostic implications and potential chemotherapy resistance mechanisms associated with TRPs-related genes in colon cancer.
文摘The study titled“Transient receptor potential-related risk model predicts prognosis of hepatocellular carcinoma patients”is a significant contribution to hepatocellular carcinoma(HCC)research,highlighting the role of transient receptor potential(TRP)family genes in the disease’s progression and prognosis.Utilizing data from The Cancer Genome Atlas database,it establishes a new risk assessment model,emphasizing the interaction of TRP genes with tumor proliferation pathways,key metabolic reactions like retinol metabolism,and the tumor immune microenvironment.Notably,the overexpression of the TRPC1 gene in HCC correlates with poorer patient survival outcomes,suggesting its potential as a prognostic biomarker and a target for personalized therapy,particularly in strategies combining immunotherapy and anti-TRP agents.
基金funded by the Shenzhen Science and Technology Program,China(KQTD20180411143628272)the Special Funds for Science Technology Innovation and Industrial Development of Shenzhen Dapeng New District,China(pt202101-02)the National Key R&D Program of China(2022YFE0116500).
文摘Spodoptera frugiperda is a highly destructive pest that has become a global problem due to its robust reproductive and migratory capabilities.Transient receptor potential(TRP)channels,which constitute a vast ion channel family,play pivotal roles in sensing the external environment and maintaining internal homeostasis in insects.TRP channels have been widely investigated for their critical roles in regulating various insect behaviors in recent years.In this study,we identified 15 TRP gene loci encoding 26 transcripts in the genome of S.frugiperda and analyzed their expression profiles at different developmental stages.The results revealed that S.frugiperda possesses four TRPC genes,six TRPA genes,one TRPM gene,two TRPV genes,one TRPN gene,and one TRPML gene,while a canonical TRPP is absent.Moreover,the SfruTRPA1 was functionally characterized using the Xenopus oocyte expression system.The results showed that SfruTRPA1 is activated by temperature increases from 20 to 45℃,and there is no significant desensitization after repeated stimuli within the same temperature range.Additionally,SfruTRPA1 is activated by certain natural chemicals,including allyl isothiocyanate(AITC)and cinnamaldehyde(CA).These findings provide valuable insights to the TRP genes in S.frugiperda.
文摘Aim： To investigate the expression and distribution of the members of the transient receptor potential （TRP） channel members of TRP melastatin （TRPM） and TRP vanilloid （TRPV） subfamilies in rat prostatic tissue. Methods： Prostate tissue was obtained from male Sprague-Dawley rats. Reverse transcription polymerase chain reaction （RT-PCR） and quantitative real-time polymerase chain reaction （PCR） were used to check the expression of all TRPM and TRPV channel members with specific primers. Immunohistochemistry staining for TRPM8 and TRPV1 were also performed in rat tissues. Results： TRPM2, TRPM3, TRPM4, TRPM6, TRPM7, TRPMS, TRPV2 and TRPV4 mRNA were detected in all rat prostatic tissues. Very weak signals for TRPM1, TRPVI and TRPV3 were also detected. The mRNA of TRPM5, TRPV5 and TRPV6 were not detected in all RT-PCR experiments. Quantitative real-time RT-PCR showed that TRPM2, TRPM3, TRPM4, TRPMS, TRPV2 and TRPV4 were the most abundantly expressed TRPM and TRPV subtypes, respectively. Fluorescence immunohistochemistry indicated that TRPM8 and TRPV 1 are highly expressed in both epithelial and smooth muscle cells. Conclusion： Our results demonstrate that mRNA or protein for TRPM1, TRPM2, TRPM3, TRPM4, TRPM6, TRPM7, TRPMS, TRPV1, TRPV2, TRPV3 and TRPV4 exist in rat prostatic tissue. The data presented here assists in elucidating the physiological function of TRPM and TRPV channels.
文摘BACKGROUND Transient receptor potential vanilloid-1(TRPV1),a nonselective cation channel,is activated by capsaicin,a pungent ingredient of hot pepper.Previous studies have suggested a link between obesity and capsaicin-associated pathways,and activation of TRPV1 may provide an alternative approach for obesity treatment.However,data on the TRPV1 distribution in human gastric mucosa are limited,and the degree of TRPV1 distribution in the gastric and duodenal mucosal cells of obese people in comparison with normal-weight individuals is unknown.AIM To clarify gastric and duodenal mucosal expression of TRPV1 in humans and compare TRPV1 expression in obese and healthy individuals.METHODS Forty-six patients with a body mass index(BMI)of>40 kg/m^(2) and 20 patients with a BMI between 18-25 kg/m^(2) were included.Simultaneous biopsies from the fundus,antrum,and duodenum tissues were obtained from subjects between the ages of 18 and 65 who underwent esophagogastroduodenoscopy.Age,sex,history of alcohol and cigarette consumption,and past medical history regarding chronic diseases and medications were accessed from patient charts and were analyzed accordingly.Evaluation with anti-TRPV1 antibody was performed separately according to cell types in the fundus,antrum,and duodenum tissues using an immunoreactivity score.Data were analyzed using SPSS 17.0.RESULTS TRPV1 expression was higher in the stomach than in the duodenum and was predominantly found in parietal and chief cells of the fundus and mucous and foveolar cells of the antrum.Unlike foveolar cells in the antrum,TRPV1 was relatively low in foveolar cells in the fundus(4.92±0.49 vs 0.48±0.16,P<0.01,Mann-Whitney U test).Additionally,the mucous cells in the duodenum also had low levels of TRPV1 compared to mucous cells in the antrum(1.33±0.31 vs 2.95±0.46,P<0.01,Mann-Whitney U test).TRPV1 expression levels of different cell types in the fundus,antrum,and duodenum tissues of the morbidly obese group were similar to those of the control group.Staining with TRPV1 in fundus chief cells and antrum and duodenum mucous cells was higher in patients aged≥45 years than in patients<45 years(3.03±0.42,4.37±0.76,2.28±0.55 vs 1.9±0.46,1.58±0.44,0.37±0.18,P=0.03,P<0.01,P<0.01,respectively,Mann-Whitney U test).The mean staining levels of TRPV1 in duodenal mucous cells in patients with diabetes and hypertension were higher than those in patients without diabetes and hypertension(diabetes:2.11±0.67 vs 1.02±0.34,P=0.04;hypertension:2.42±0.75 vs 1.02±0.33,P<0.01 Mann-Whitney U test).CONCLUSION The expression of TRPV1 is unchanged in the gastroduodenal mucosa of morbidly obese patients demonstrating that drugs targeting TRPV1 may be effective in these patients.
基金Stefan Mergler is supported by DFG(Me 1706/14-1)about a TRP channel related research project and received a grant from the DFG priority program 1629 ThyroidTransAct(Me 1706/13-1).
文摘Maintenance of intracellular Ca^(2+)levels at orders of magnitude below those in the extracellular environment is a requisite for preserving cell viability.Membrane channels contribute to such control through modulating their time-dependent opening and closing behaviour.Such regulation requires Ca^(2+)to serve as a second messenger mediating receptor control of numerous life-sustaining responses.Transient receptor potential(TRP)channels signal transduce a wide variety of different sensory stimuli to induce responses modulating cellular function.These channels are non-selective cation channels with variable Ca^(2+)selectivity having extensive sequence homology.They constitute a superfamily made up of 28 different members that are subdivided into 7 different subfamilies based on differences in sequence homology.Some of these TRP channel isotypes are expressed in the eye and localized to both neuronal and non-neuronal cell membranes.Their activation generates intracellular Ca^(2+)transients and other downstream-linked signalling events that affect numerous responses required for visual function.As there is an association between changes in functional TRP expression in various ocular diseases,there are efforts underway to determine if these channels can be used as drug targets to reverse declines in ocular function.We review here our current knowledge about the expression,function and regulation of TRPs in different eye tissues in health and disease.Furthermore,some of the remaining hurdles are described to developing safe and efficacious TRP channel modulators for use in a clinical setting.
文摘Background: It is important to maintain skin homeostasis for cosmetic and medical reasons. Many ceramide-related ingredients and cosmetics have been developed to improve the skin barrier function and skin hydration. Similar to extracellular lipids, the cornified envelope, which is a structure formed beneath the plasma membrane, contributes to the skin barrier function as a scaffold for extracellular lipids. Therefore, in this study, we focused on transglutaminase 1 (TGM1) which is the key enzyme for formation of the cornified envelope Objective: The objectives of this study were to identify compounds that could upregulate the expression of TGM1 and evaluate their underlying action mechanisms. Methods: Expression of the transient receptor potential channel vanilloid subfamily member 4 (TRPV4) at the mRNA and protein levels was estimated by PCR and western blotting. Effects of baicalein and Salvia officinalis (SO) extract on TGM1 mRNA expression were measured by PCR. The involvement of TRPV4 in TGM1 mRNA expression was evaluated by the inhibition and silencing of TRPV4. Results: TRPV4 was expressed in both basal cell-like HaCaT cells and suprabasal cell-like HaCaT cells. Baicalein and SO extract upregulated TGM1 mRNA expression in basal cell-like HaCaT cells. However, inhibition and silencing of TRPV4 abrogated the effects of baicalein and SO extract. Conclusion: Baicalein and SO extract upregulated the expression of TGM1 mRNA via the activation of TRPV4, suggesting that it may improve the skin barrier function by enhancing cornified envelope formation.
基金supported by the Research Basis Formation Supporting Project for Private University
文摘Transient receptor potential channel A1 is one of the important transducers of noxious stimuli in the primary afferents, which may contribute to generation of neurogenic inflammation and hyperalgesia. The present study was designed to investigate if activation of transient receptor potential channel A1 may induce calcitonin gene-related peptide release from the primary afferent neurons. We found that application of allyl isothiocyanate, a transient receptor potential channel A1 activator, caused calcitonin gene-related peptide release from the cultured rat dorsal root ganglion neurons. Knock- down of transient receptor potential channel A1 with an antisense oligodeoxynucleotide prevented calcitonin gene-related peptide release by allyl isothiocyanate application in cultured dorsal root ganglion neurons. Thus, we concluded that transient receptor potential channel A1 activation caused calcitonin gene-related peptide release in sensory neurons.
文摘BACKGROUND Diabetic cardiomyopathy(DCM) is a serious complication of end-stage diabetes that presents symptoms such as cardiac hypertrophy and heart failure. The transient receptor potential channel 6(TRPC6) protein is a very important selective calcium channel that is closely related to the development of various cardiomyopathies.AIM To explore whether TRPC6 affects cardiomyocyte apoptosis and proliferation inhibition in DCM.METHODS We compared cardiac function and myocardial pathological changes in wild-type mice and mice injected with streptozotocin(STZ), in addition to comparing the expression of TRPC6 and P-calmodulin-dependent protein kinase Ⅱ(P-CaMKⅡ) in them. At the same time, we treated H9C2 cardiomyocytes with high glucose and then evaluated the effects of addition of SAR, a TRPC6 inhibitor, and KN-93, a CaMKⅡ inhibitor, to such H9C2 cells in a high-glucose environment.RESULTS We found that STZ-treated mice had DCM, decreased cardiac function, necrotic cardiomyocytes, and limited proliferation. Western blot and immunofluorescence were used to detect the expression levels of various appropriate proteins in the myocardial tissue of mice and H9C2 cells. Compared to those in the control group, the expression levels of the apoptosis-related proteins cleaved caspase 3 and Bax were significantly higher in the experimental group, while the expression of the proliferation-related proteins proliferating cell nuclear antigen(PCNA) and CyclinD1 was significantly lower. In vivo and in vitro, the expression of TRPC6 and P-CaMKⅡ increased in a high-glucose environment. However, addition of inhibitors to H9C2 cells in a high-glucose environment resulted in alleviation of both apoptosis and proliferation inhibition.CONCLUSION The inhibition of apoptosis and proliferation of cardiomyocytes in a high-glucose environment may be closely related to activation of the TRPC6/P-CaMKⅡ pathway.
基金supported by the National Natural Science Foundation of China,No.81171178the Natural Science Foundation of Shanxi Province in China,No.2012011036-3Scientific Research Foundation of Shanxi Province of China for the Returned Overseas Chinese Scholars,No.2013011054-2
文摘The transient receptor potential cation channel subfamily V member 1（TRPV1） provides the sensation of pain（nociception）. However, it remains unknown whether TRPV1 is activated after peripheral nerve injury, or whether activation of TRPV1 affects neural regeneration. In the present study, we established rat models of unilateral sciatic nerve crush injury, with or without pretreatment with AMG517（300 mg/kg）, a TRPV1 antagonist, injected subcutaneously into the ipsilateral paw 60 minutes before injury. At 1 and 2 weeks after injury, we performed immunofluorescence staining of the sciatic nerve at the center of injury, at 0.3 cm proximal and distal to the injury site, and in the dorsal root ganglia. Our results showed that Wallerian degeneration occurred distal to the injury site, and neurite outgrowth and Schwann cell regeneration occurred proximal to the injury. The number of regenerating myelinated and unmyelinated nerve clusters was greater in the AMG517-pretreated rats than in the vehicle-treated group, most notably 2 weeks after injury. TRPV1 expression in the injured sciatic nerve and ipsilateral dorsal root ganglia was markedly greater than on the contralateral side. Pretreatment with AMG517 blocked this effect. These data indicate that TRPV1 is activated or overexpressed after sciatic nerve crush injury, and that blockade of TRPV1 may accelerate regeneration of the injured sciatic nerve.
基金supported in parts by grants from the Disciplinary Group of Psychology and Neuroscience Xinxiang Medical University,China(2016PN-KFKT-06)Department of Education of Henan Province,China(16IRTSTHN020)+1 种基金the National Natural Science Foundation of China(31471118)UK Alzheimer’s Research Trust(ART/PPG2009A/2)
文摘Alzheimer’s disease （AD） is an age-related eurodegenerative disease that represents the most common cause of dementia among the elderly people. With the increasingly aging population, AD has presented an overwhelming healthcare challenge to modern society; the World Alzheimer Report 2015 has estimated that 46.8 million people worldwide lived with dementia in 2015 and this number will rise to 74.7 million in 2030 and that the total cost of dementia was 818 billion in US$ in 2015 and will reach two trillion in 2030. Post-mortem studies have identified two histopathological hallmarks in the brains of AD patients; extracellular senile plaque with elevated deposition of amyloid β （Aβ） peptides, and intracellular neurofibrillary tangle composed of hyper-phosphorylated microtubule-associated protein tau.Etiologically, progressive neuronal loss within the cerebral cortex and hippocampus regions of the brain leads to irreversible decline in, and eventually complete loss of, memory and other cognitive functions that afflict AD patients. The widely-accepted amyloid cascade hypothesis for AD pathogenesis holds that accumulation and aggregation of neurotoxic Aβ peptides, due to imbalance of their generation and clearance as a result of changes in genetic makeup, aging and/or exposure to environmental risk factors, is a major and early trigger of AD. This hypothesis has continuously gained support by preclinical and clinical studies （Selkoe and Hardy, 2016）. However, the intensive and costly drug discovery efforts over the past decades based on such a hypothesis have proved extremely frustrating in developing effective therapeutics to treat or slow down the progress of AD, highlighting the need for more research to improve our understanding towards the cellular and molecular mechanisms by which Aβ peptides bring about neurotoxicity and cognitive dysfunction.
基金Supported by the National Key Basic Research Program 973(Dual Effects of Acupuncture on Functional Intestinal Disease and its Relationship with Autonomic Nervous Function,No.2011CB505206)the 2013 Jiangsu Province Education Department of Natural Science Research into major projects(Research into the Role of TRPV1 in the Anti-inflammatory and Analgesic Effects of Moxibustion Treatment,No.13KJA360001)+1 种基金the Academic Propagation Project on Scientific and Technical Innovation Teamthe Nanjing University of Chinese Medicine 2013 Scientific and Technical Innovation Team Project
文摘Moxibustion is an important component part of Traditional Chinese Medicine(TCM).Among different kinds of moxibustion methods,thermal stimulation seems to be a pivotal impact factor to the theraputic efficacy.Based on its thermal characteristic and treated area-skin,we hypothesize that the thermosensitive TRPV channels may involve in the mechanism of moxibustion.This study,by referring to various experimental and clinical data,analyzes the properties and features of transient receptor potential vanilloid(TRPV)subfamily 1-4 and the impact of moxibustion on these channels.The factors impacting the efficacy of moxibustion treatment were analyzed on three levels:the independent ba-sic factors of moxibustion(temperature,space and time);moxibustion intensity(a compound factor achieved through comprehensive control of the three individual basic factors mentioned above);and moxibustion quantity(the amount of temperature stimulation applied within a certain unit of time,including the total amount of moxibustion treatment).The results from present study show that the effect of moxibustion therapy appears to be determined by the activation of TRPV1-4,mainly TRPV1 and TRPV2.Temperature(the degree of heat stimulation),time and area(how long the treatment lasts and how many TRPV1-4 channels are activated)affect the intensity of moxibustion treatment to form effective moxibustion quantity;this should be considered in clinical moxibustion application.
基金supported by grants from the National Natural Science Foundation of China(Nos.31171087,30970662,and 82100715)the Henan Medical Science and Technology Research Program(Joint Construction,No.LHGJ20190246).
文摘Objective Renal fibrosis is the ultimate pathway of various forms of acute and chronic kidney damage.Notably,the knockout of transient receptor potential channel 6(TRPC6)has shown promise in alleviating renal fibrosis.However,the regulatory impact of TRPC6 on renal fibrosis remains unclear.Methods In vivo,TRPC6 knockout(TRPC6−/−)mice and age-matched 129 SvEv(WT)mice underwent unilateral renal ischemia-reperfusion(uIR)injury surgery on the left renal pedicle or sham operation.Kidneys and serum were collected on days 7,14,21,and 28 after euthanasia.In vitro,primary tubular epithelial cells(PTECs)were isolated from TRPC6−/−and WT mice,followed by treatment with transforming growth factorβ1(TGFβ1)for 72 h.The anti-fibrotic effect of TRPC6−/−and the underlying mechanisms were assessed through hematoxylin-eosin staining,Masson staining,immunostaining,qRT-PCR,and Western blotting.Results Increased TRPC6 expression was observed in uIR mice and PTECs treated with TGFβ1.TRPC6−/−alleviated renal fibrosis by reducing the expression of fibrotic markers(Col-1,α-SMA,and vimentin),as well as decreasing the apoptosis and inflammation of PTECs during fibrotic progression both in vivo and in vitro.Additionally,we found that the phosphatidylinositol 3-kinase(PI3K)/protein kinase B(AKT)/glycogen synthase kinase 3 beta(GSK3β)signaling pathway,a pivotal player in renal fibrosis,was down-regulated following TRPC6 deletion.Conclusion These results suggest that the ablation of TRPC6 may mitigate renal fibrosis by inhibiting the apoptosis and inflammation of PTECs through down-regulation of the PI3K/AKT/GSK3βpathway.Targeting TRPC6 could be a novel therapeutic strategy for preventing chronic kidney disease.
文摘During the last decade, transient receptor potential （TRP） channels emerge as key proteins in central mechanisms of the carcinogenesis such as cell proliferation, apoptosis and migration. Initial studies showed that expression profile of some TRP channels, notably TRP melastatin 8 （TRPM8）, TRP vanilloid 6 （TRPV6）,TRP canonical （TRPC6） and TRPV2, is changing during the development and the progression of prostate cancer towards the hormone-refractory stages. The link between the change in expression levels and the functional role of these channels in prostate cancer is step by step being elucidated. These recent advances are here described and discussed.
基金National Institute of Dental&Craniofacial Research,No.1R21DE028265-01A1.
文摘Stem cells hold indefinite self-renewable capability that can be differentiated into all desired cell types.Based on their plasticity potential,they are divided into totipotent(morula stage cells),pluripotent(embryonic stem cells),multipotent(hematopoietic stem cells,multipotent adult progenitor stem cells,and mesenchymal stem cells[MSCs]),and unipotent(progenitor cells that differentiate into a single lineage)cells.Though bone marrow is the primary source of multipotent stem cells in adults,other tissues such as adipose tissues,placenta,amniotic fluid,umbilical cord blood,periodontal ligament,and dental pulp also harbor stem cells that can be used for regenerative therapy.In addition,induced pluripotent stem cells also exhibit fundamental properties of self-renewal and differentiation into specialized cells,and thus could be another source for regenerative medicine.Several diseases including neurodegenerative diseases,cardiovascular diseases,autoimmune diseases,virus infection(also coronavirus disease 2019)have limited success with conventional medicine,and stem cell transplantation is assumed to be the best therapy to treat these disorders.Importantly,MSCs,are by far the best for regenerative medicine due to their limited immune modulation and adequate tissue repair.Moreover,MSCs have the potential to migrate towards the damaged area,which is regulated by various factors and signaling processes.Recent studies have shown that extracellular calcium(Ca^(2+))promotes the proliferation of MSCs,and thus can assist in transplantation therapy.Ca^(2+)signaling is a highly adaptable intracellular signal that contains several components such as cell-surface receptors,Ca^(2+)channels/pumps/exchangers,Ca^(2+)buffers,and Ca^(2+)sensors,which together are essential for the appropriate functioning of stem cells and thus modulate their proliferative and regenerative capacity,which will be discussed in this review.
基金supported by the National Science Centre Grant(No.DEC-2012/05/B/NZ7/02705),Poland
文摘The aim of this research was to assess the antinociceptive activity of the transient receptor potential （TRP） channel TRPV1, TRPM8, and TRPA1 antagonists in neurogenic, tonic, and neuropathic pain models in mice. For this purpose, TRP channel antagonists were administered into the dorsal surface of a hind paw 15 min before capsaicin, allyl isothiocyanate （AITC）, or formalin. Their antiallodynic and antihyperalgesic efficacies after intraperitoneal ad- ministration were also assessed in a paclitaxel-induced neuropathic pain model. Motor coordination of paclitaxel- treated mice that received these TRP channel antagonists was investigated using the rotarod test. TRPV1 antagonists, capsazepine and SB-366791, attenuated capsaicin-induced nociceptive reaction in a concentration-dependent manner. At 8 pg/20 pl, this effect was 51% （P〈0.001） for capsazepine and 37% （P〈0.05） for SB-366791. A TRPA1 antagonist, A-967079, reduced pain reaction by 48% （P〈0.05） in the AITC test and by 54% （P〈0.001） in the early phase of the formalin test. The test compounds had no influence on the late phase of the formalin test. In paclitaxel-treated mice, they did not attenuate heat hyperalgesia but N-（3-aminopropyl）-2-{[（3-methylphenyl）methyl]oxy}-N-（2-thienylmethyl） benzamide hydrochloride salt （AMTB）, a TRPM8 antagonist, reduced cold hyperalgesia and tactile allodynia by 31% （P〈0.05） and 51% （P〈0.01）, respectively. HC-030031, a TRPA1 channel antagonist, attenuated tactile allodynia in the von Frey test （62%; P〈0.001）. In conclusion, distinct members of TRP channel family are involved in different pain models in mice. Antagonists of TRP channels attenuate nocifensive responses of neurogenic, tonic, and neuropathic pain, but their efficacies strongly depend on the pain model used.
基金This work was supported by Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences(No.CAMS-2017-I2M-1-011).
文摘Objective::This study was performed to investigate the effects of honokiol on the activation of transient receptor potential channel V1(TRPV1)and the secretion of thymic stromal lymphopoietin(TSLP)in a human benign epidermal keratinocyte line(HaCaT).Methods::HaCaT keratinocytes were cultivated and divided into six groups:capsaicin-induced model control group,capsazepine control group,solvent control group,and three honokiol treatment groups(7.81,15.63,and 31.25 mg/L of honokiol).The effect of honokiol on calcium(Ca^(2+))influx was measured by a Ca^(2+)fluorescence imaging system.The fluorescence intensity(F)of cells was measured.The rate of change in F(ΔF/F0)was calculated,and theΔF/F0-time curve was constructed.HaCaT keratinocytes were stimulated with polyinosinic:polycytidylic acid,recombinant human tumor necrosis factorα,and recombinant human interleukin 4.Different concentrations of honokiol(15.63,7.81,and 3.91 mg/L)were added to the cells in the respective honokiol groups;20 mg/L of dexamethasone or 0.5%dimethyl sulfoxide was added to the cells in the positive control group or solvent control group.The TSLP concentration in the HaCaT keratinocytes of each group was detected by enzyme-linked immunosorbent assay.Statistical analysis was performed by one-way analysis of variance and Dunnett t test.Results::The capsaicin-induced Ca^(2+)fluorescence intensity in HaCaT keratinocytes was significantly inhibited in the 31.25 mg/L honokiol group;ΔF/F0 at 45 second was 0.76 in the model control group and 0 in the 31.25 mg/L honokiol group.The TSLP level in the 15.63 and 7.81 mg/L honokiol groups was lower than that in the solvent control group(t=7.382,P=0.003,and t=2.766,P=0.023,respectively),while the TSLP level in the 3.91 mg/L honokiol group was not significantly different from that in the solvent control group(t=1.872,P=0.124).Conclusions::Honokiol inhibited the Ca^(2+)influx induced by capsaicin(TRPV1 agonist)in HaCaT keratinocytes.Honokiol has an inhibitory effect on TSLP secretion in HaCaT keratinocytes.
基金the Natural Science Foundation of Guangdong Province,China(No.7001197)National Natural Science Foundation of China(No.30872572)We thank Dr David Julius,Department of Cellular and Molecular Pharmacology,University of California,San Francisco,USA,for the gift of the rat TRPM8 cDNA construct,which was critical for the completion of this study.
文摘We investigated the effects of transient receptor potential M8(TRPM8)channel on the proliferation and motility of androgen-independent prostate cancer PC-3 cells.After being permanently transfected with an empty vector and cDNA encoding the TRPM8 protein,cells were analysed for cell cycle distribution and motility using flow cytometry and scratch assay.Immunocytochemistry and Ca^(2+)imaging analysis revealed the overexpression of functional TRPM8 channel on both endoplasmic reticulum and plasma membrane of PC-3-TRPM8 cells.Cell cycle distribution and scratch assay analysis revealed that TRPM8 induced cell cycle arrest at the G_(0)/G_(1)stage(P<0.05)and facilitated the cell apoptosis induced by starvation(P<0.05).Furthermore,TRPM8 inhibited the migration of PC-3-TRPM8 cells(P<0.01)through the inactivation of focal-adhesion kinase.It appears that TRPM8 was not essential for the survival of PC-3 cells;however,the overexpression of TRPM8 had negative effects on the proliferation and migration of PC-3 cells.Thus,TRPM8 and its agonists may serve as important targets for the treatment of prostate cancer.
文摘AIM To evaluate whether non-steroidal anti-inflammatory drugs(NSAIDs)-induced gastropathy is a clinically predictive model of referred visceral hypersensitivity.METHODS Gastric ulcer pain was induced by the oral administration of indomethacin to male,CD1 mice(n = 10/group) and then assessed by measuring referred abdominal hypersensitivity to tactile application. A diverse range of pharmacological mechanisms contributing to the pain were subsequently investigated. These mechanisms included: transient receptor potential(TRP),sodium and acid-sensing ion channels(ASICs) as well as opioid receptors and guanylate cyclase C(GC-C). RESULTS Results showed that two opioids and a GC-C agonist,morphine,asimadoline and linaclotide,respectively,the TRP antagonists,AMG9810 and HC-030031 and the sodium channel blocker,carbamazepine,elicited a dose-and/or time-dependent attenuation of referred visceral hypersensitivity,while the ASIC blocker,amiloride,was ineffective at all doses tested. CONCLUSION Together,these findings implicate opioid receptors,GC-C,and sodium and TRP channel activation as possible mechanisms associated with visceral hypersensitivity. More importantly,these findings also validate NSAID-induced gastropathy as a sensitive and clinically predictive mouse model suitable for assessing novel molecules with potential pain-attenuating properties.
基金supported by National Key Scientific Instrument&Equipment Development Program of China(2012YQ03026010)the Joint NSFC-ISF Research Program(8146114802)+2 种基金jointly funded by the National Natural Science Foundation of China and the Israel Science Foundationthe State Key Program of Basic Research of China(2013CB910604)the National Natural Science Foundation of China(61327014 and 61175103)
文摘OBJECTIVE We want to investigate the mechanism of organophosphate-induced delayed neuropathy(OPIDN) and find appropriate therapeutic medicine.OPIDN,often leads to paresthesias,ataxia and paralysis,occurs in the late-stage of acute poisoning or after repeated exposures to organophosphate(OP) insecticides or nerve agents,and may contribute to the Gulf War Syndrome.METHODS FDSS Ca2^(+)-influx assays,single-cell calcium imaging and patch-clamp electrophysiology were the major testing techniques.Transfected HEK293 cells and dorsal root ganglion(DRG) neurons were used to evaluate the effects of compounds.Wild type and trpa1 knockout mice and adult hyline brown hens were used to evaluate the neuropathological damages caused by the OPs.Transmission electron microscopy imaging was used to observe the nerve injuries ultrastructurally.High-throughput screen for TRPA1 inhibitors was accomplished by Ion Works Barracuda(IWB) automated electrophysiology assay.RESULTS TRPA1(Transient receptor potential cation channel,member A1) channel mediates OPIDN.A variety of OPs,exemplified by malathion,activates TRPA1 but not other neuronal TRP channels.Malathion increases the intracellular calcium levels and upregulates the excitability of mouse DRG neurons in vitro.Mice with repeated exposures to malathion also develop local tissue nerve injuries and pain-related behaviors,which resembles the early symptoms of OPIDN.Both the neuropathological changes and the nocifensive behaviors can be attenuated by treatment of TRPA1 antagonist HC030031 or abolished by knockout of Trpa1 gene.In the classic hens OPIDN model,malathion causes nerve injuries and ataxia to a similar level as the positive inducer tri-ortho-cresyl phosphate(TOCP),which also activates TRPA1 channel.Treatment with HC030031 reduces the damages caused by malathion or TOCP.Duloxetine and Ketotifen,two commercially available drugs exhibiting TRPA1 inhibitory activity,show neuroprotective effects against OPIDN and might be used in emergency situations.CONCLUSION TRPA1 is the major mediator of OPIDN and targeting TRPA1 is an effective way for the treatment of OPIDN.
