Distribution of transient receptor potential vanilloid-1 channels in gastrointestinal tract of patients with morbid obesity

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.

New perspectives in prognostication of hepatocellular carcinoma:The role and clinical implications of transient receptor potential family genes

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.

Role of transient receptor potential vanilloid-1 in behavioral thermoregulation of the Mongolian gerbil Meriones unguiculatus

Ambient temperature considerably affects the physiology and behavior of mammals.Thermosensory and thermoregulatory abilities play an important role in the response to changing ambient temperature in endotherms.However,the molecular mechanisms of behavioral thermoregulation remain poorly understood.Transient receptor potential vanilloid-1(TRPV1)is activated by changes in ambient temperature and is involved in acute thermoregulation.Here,we aimed to determine whether TRPV1 is involved in behavioral thermoregulation in wild rodents by conducting 2 experiments.In the first,42 adult Mongolian gerbils(Meriones unguiculatus;14 per treatment)were randomly assigned to 3 housing temperatures(4,23,and 36℃for 4 weeks.In the second,20 gerbils(10 per treatment)were randomly injected with capsaicin(TRPV1 agonist)or AMG517(TRPV1 antagonist).The results showed a significant decrease in food intake and non-shivering thermogenesis in the gerbils housed at 36℃.Additionally,there was a significant increase in the preference of gerbils housed at 4℃ to low temperatures.The expression of TRPV1 protein in the brown adipose tissue(BAT)and liver was significantly positively correlated with that of protein kinase A(PKA).The expression of TRPV1 and PKA proteins in the BAT was positively correlated with the temperature preference of the gerbils.The gerbils injected with capsaicin preferred significantly lower temperatures than the control group gerbils.These findings suggest that TRPV1 and PKA are involved in behavioral thermoregulation in Mongolian gerbils.

The transient receptor potential melastatin 2:a new therapeutical target for Parkinson's disease?

The transient receptor potential melastatin 2 is a calcium-permeable cation channel member of the TRP family. Also known as an oxidative stress-activated channel, the transient receptor potential melastatin 2 gating mechanism is dependent on reactive oxygen species. In pathological conditions, transient receptor potential melastatin 2 is overactivated, leading to a Ca~(2+) influx that alters cell homeostasis and promotes cell death. The role of transient receptor potential melastatin 2 in neurodegenerative diseases, including Alzheimer's disease and ischemia, has already been described and reviewed. However, data on transient receptor potential melastatin 2 involvement in Parkinson's disease pathology has emerged only in recent years and the issue lacks review studies that focus specifically on this topic. The present review aims to elucidate the role of the transient receptor potential melastatin 2 channel in Parkinson's disease by reviewing, summarizing, and discussing the in vitro, in vivo, and human studies published until August 2022. Here we describe fourteen studies that evaluated the transient receptor potential melastatin 2 channel in Parkinson's disease. The Parkinson's disease model used, transient receptor potential melastatin 2 antagonist and genetic approaches, and the main outcomes reported were discussed. The studies described transient receptor potential melastatin 2 activation and enhanced expression in different Parkinson's disease models. They also evidenced protective and restorative effects when using transient receptor potential melastatin 2 antagonists, knockout, or silencing. This review provides a literature overview and suggests where there is a need for more research. As a perspective point, this review shows evidence that supports transient receptor potential melastatin 2 as a pharmacological target for Parkinson's disease in the future.

Transient receptor potential-related risk model predicts prognosis of hepatocellular carcinoma patients

BACKGROUND Members of the transient receptor potential(TRP)protein family shape oncogenic development,but the specific relevance of TRP-related genes in hepatocellular carcinoma(HCC)has yet to be defined.AIM To investigate the role of TRP genes in HCC,their association with HCC development and treatment was examined.METHODS HCC patient gene expression and clinical data were downloaded from The Cancer Genome Atlas database,and univariate and least absolute shrinkage and selection operator Cox regression models were employed to explore the TRP-related risk spectrum.Based on these analyses,clinically relevant TRP family genes were selected,and the association between the key TRP canonical type 1(TRPC1)gene and HCC patient prognosis was evaluated.RESULTS In total,28 TRP family genes were screened for clinical relevance,with multivariate analyses ultimately revealing three of these genes(TRPC1,TRP cation channel subfamily M member 2,and TRP cation channel subfamily M member 6)to be significantly associated with HCC patient prognosis(P<0.05).These genes were utilized to establish a TRP-related risk model.Patients were separated into low-and high-risk groups based on the expression of these genes,and high-risk patients exhibited a significantly poorer prognosis(P=0.001).Functional analyses highlighted pronounced differences in the immune status of patients in these two groups and associated enriched immune pathways.TRPC1 was identified as a candidate gene in this family worthy of further study,with HCC patients expressing higher TRPC1 levels exhibiting poorer survival outcomes.Consistently,quantitative,immunohistochemistry,and western blot analyses revealed increased TRPC1 expression in HCC.CONCLUSION These three TRP genes help determine HCC patient prognosis,providing insight into tumor immune status and immunological composition.These findings will help design combination therapies including immunotherapeutic and anti-TRP agents.

Daikenchuto (Da-Jian-Zhong-Tang) ameliorates intestinal fibrosis by activating myofibroblast transient receptor potential ankyrin 1 channel

AIM To investigate the anti-fibrotic effects of the traditional oriental herbal medicine Daikenchuto(DKT) associated with transient receptor potential ankyrin 1(TRPA1) channels in intestinal myofibroblasts. METHODS Inflammatory and fibrotic changes were detected in a2,4,6-trinitrobenzenesulfonic acid(TNBS) chronic colitis model of wild-type and TRPA1-knockout(TRPA1-KO) mice via pathological staining and immunoblotting analysis.Ca^(2+) imaging experiments examined the effects of DKT and its components/ingredients on intestinal myofibroblast(In Myo Fib) cell TRPA1 channel function.Profibrotic factors and transforming growth factor (TGF) -β1-associated signaling were tested in an In Myo Fib cell line by q PCR and immunoblotting experiments.Samples from non-stenotic and stenotic regions of the intestines of patients with Crohn’s disease (CD) were used for pathological analysis. RESULTS Chronic treatment with TNBS caused more severe inflammation and fibrotic changes in TRPA1-KO than in wild-type mice.A one-week enema administration of DKT reduced fibrotic lesions in wild-type but not in TRPA1-KO mice.The active ingredients of DKT,i.e.,hydroxyα-sanshool and 6-shogaol,induced Ca^(2+) influxes in In Myo Fib,and this was antagonized by co-treatment with a selective TRPA1 channel blocker,HC-030031.DKT counteracted TGF-β1-induced expression of TypeⅠcollagen andα-smooth muscle actin (α-SMA) ,which were accompanied by a reduction in the phosphorylation of Smad-2 and p38-mitogen-activated protein kinase (p38-MAPK) and the expression of myocardin.Importantly,24-h incubation with a DKT active component Japanese Pepper increased the m RNA and protein expression levels of TRPA1 in In Myo Fibs,which in turn negatively regulated collagen synthesis.In the stenotic regions of the intestines of CD patients,TRPA1 expression was significantly enhanced.CONCLUSION The effects of DKT on the expression and activation of the TRPA1 channel could be advantageous for suppressing intestinal fibrosis,and benefit inflammatory bowel disease treatment.

Transient receptor potential channel A1 involved in calcitonin gene-related peptide release in neurons

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.

Blockade of transient receptor potential cation channel subfamily V member 1 promotes regeneration after sciatic nerve injury

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.

Transient Receptor Potential Ankyrin 1 Ion Channel Facilitates Acute Inflammation Induced by Surgical Incision in Mice

Background: Transient receptor potential ankyrin (TRPA) 1 is known as a peripheral initiator of acute inflammation and hyperalgesia. However, its role in the facilitation of innate immune responses followed by resolution of the inflammation triggered by a surgical incision has not been fully investigated. Therefore, we evaluated the mechanism by which TRPA1 regulates the inflammatory responses mainly facilitated by neutrophils and macrophages in the early course of wound repair after an incision. Methods: Plantar incision was performed in wild-type and TRPA1-/- mice. The infiltration of polymorphonuclear neutrophils, macrophage phenotype, and induction of inflammatory mediators were assessed for 7 days postoperatively. Results: TRPA1-/-?mice exhibited decreased infiltration of polymorphonuclear neutrophilscompared with wild-type mice on day 1. Consistently, the influx of F4/80+ iNOS+ proinflammatory M1 macrophages to incised sites was markedly decreased on day 2. Similarly, F4/80+ CD206+M2 macrophages, which regulate the resolution of inflammation and promote wound healing in the later phase of acute inflammation, were significantly decreased in TRPA1-/- compared with those in wild-type mice on day 7. In addition, the induction of heme oxygenase-1, which promotes wound healing by switching phenotype of macrophages, was decreased in the early phase of acute inflammation, whereas the expression of proinflammatory mediators such as tumor necrosis factor and cyclooxygenase-2, and 15-lipoxygenase, which are involved in the resolution of inflammation was increased in the late phase in TRPA1-/- mice. Conclusions: Early innate immune responses including neutrophil infiltration and macrophage polarization at incised sites were inhibited in TRPA1-/- mice, associated with increased pro-inflammatory mediators in later phase. Peripheral TRPA1 may facilitate the acute inflammatory process, leading to the promotion of macrophage-mediated resolution of inflammation and wound repair after a surgical incision.

Baicalein and Salvia officinalis Extract Upregulate Transglutaminase 1 mRNA Expression via the Activation of Transient Receptor Potential Channel V4

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.

Identification of transient receptor potential channel genes and functional characterization of TRPA1 in Spodoptera frugiperda

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.

低频脉冲磁场诱导TRPC1改善COVID-19患者康复期下肢的肌肉无力症状

背景:肌肉无力是新型冠状病毒(COVID-19)感染后的常见症状,影响康复期人体日常活动能力。在强度1.5 mT,频率3300 Hz的低频脉冲磁场刺激下可通过诱导和激活经典瞬时感受器电位通1(classical transient receptor potential channel 1,TRPC1),提升人体骨骼肌的最大自主收缩力与力量耐力,对肌肉组织产生一系列生理支持效应,该手段是否会改善新型冠状病毒肺炎患者康复期的肌无力症状尚无研究。目的:选用低频脉冲磁场对新型冠状病毒肺炎患者下肢肌群进行磁刺激,以观察该刺激对新型冠状病毒肺炎患者康复期下肢肌群肌无力改善的影响。方法:招募胶体金法抗原检测试剂(COVID-19)为阳性并伴有肌肉无力症状的新型冠状病毒(奥密克戎毒株)感染患者14例,将所有受试者随机分成2组,分别为接受磁场刺激的试验组和接受假治疗的对照组。试验总时长3周,试验组每隔48 h对腿部进行低频脉冲磁刺激,对照组与试验组干预流程一致但给予假刺激,两组患者均不被告知磁刺激仪器是否运行,两组患者共进行9次操作,随后观察两组患者下肢局部肌群最大自主收缩力、腿部爆发力与力量耐力的变化情况。结果与结论:①在采集的8个局部肌群中,试验组患者7个局部肌群在经过3周的低频脉冲磁场刺激,最大自主收缩力值均增长。对照组除3个肌群最大自主收缩力自行增长改善以外,其他肌群肌力无提升。②试验组的左腿前群与双腿后群提升率显著高于对照组。③两组的纵跳摸高高度与膝关节峰值角速度相比试验前测均提升,试验组摸高高度提升率高于对照组。④在疲劳状态下,试验组膝关节峰值角速度下降率显著下降,对照组膝关节峰值角速度下降率无显著性变化;试验组摸高高度下降率显著下降,而对照组摸高高度下降率无显著性变化。⑤上述数据证实,在强度1.5 mT,频率3300 Hz的低频脉冲磁场刺激方案下,新型冠状病毒肺炎患者在康复期经过3周的低频脉冲磁场刺激相比人体自愈过程可使更多的下肢局部肌群肌力获得提升,对基于腿部爆发力的全身协调发力能力及功能状态明显改善。因此,低频脉冲磁场刺激可作为一种改善新冠感染患者下肢肌肉无力症状的有效、非运动的康复手段。

瞬时受体电位香草酸亚型1在急性呼吸窘迫综合征中的作用及研究进展

急性呼吸窘迫综合征(acute respiratory distress syndrome,ARDS)是由肺内和肺外病因引发的一种严重的、以顽固性低氧血症为显著特征的呼吸系统危重症,起病较急,发病率和死亡率较高。随着全球范围内的呼吸道病毒的流行和变异,ARDS的诊疗也变得更加复杂,因此临床上亟待探索有关ARDS发生发展的分子机制和有效的治疗方法。研究发现,ARDS的发病机制涉及炎症反应及氧化还原反应失衡、内皮细胞功能失调、肺泡毛细血管屏障的破坏、凝血功能异常等多个因素的相互作用。虽然基因组学、蛋白质组学等分子生物学技术的发展已为ARDS的发病机制提供了全新视角,但仍缺乏早期诊断ARDS的生物标志物和针对性治疗ARDS的有效药物。目前,越来越多的研究表明,瞬时受体电位香草酸亚型1(transient receptor potential vanilloid-1,TRPV1;即辣椒素受体)广泛分布于上呼吸道、气道平滑肌、肺泡和肺血管等部位,参与调解气道舒张和收缩、咳嗽反射、炎症和疼痛相关的炎症介质释放,以及呼吸系统对温度、化学物质和机械牵拉等刺激的感知并传递各种生物信号,在呼吸系统疾病中扮演着重要角色,且已成为肺炎、肺水肿、咳嗽、哮喘、急性肺损伤等呼吸系统疾病的研究热点。基于此,该文以脓毒症、创伤性脑损伤和呼吸道病毒引发的ARDS与TRPV1的相关性和分子机制为切入点进行综述,总结了调控TRPV1的表达对ARDS发病进程所发挥的积极作用,旨在为加强ARDS的早期诊断和有效干预措施提供参考。

靶向瞬时受体电位香草酸亚型1离子通道的Nplus-RhTx多肽抑制剂理性设计及功能验证

目的:获得靶向瞬时受体电位香草酸亚型1(TRPV1)通道的多肽抑制剂。方法:基于已有的靶向TRPV1通道的多肽激动剂红头蜈蚣毒素(RhTx)进行理性设计,在其氨基末端增加带正电荷的氨基酸,并在细胞上使用膜片钳电生理验证设计的多肽对TRPV1通道的抑制作用。结果:理性设计了8条Nplus-RhTx多肽,在膜片钳电生理记录中发现其中4条可以抑制TRPV1的辣椒素激活,4条Nplus-RhTx多肽的半数有效抑制浓度分别为(188.3±4.7)、(193.6±18.0)、(282.8±11.9)和(299.5±6.4)µmol/L。结论:通过对RhTx多肽的氨基端进行理性设计改变其性质,可获得靶向TRPV1的多肽抑制剂。

TRPV1通道在感染性疾病中的研究进展

瞬时感受器电位香草酸受体1(TRPV1)是瞬时感受电位家族成员中的一种非选择性阳离子通道,主要表达在感觉神经元上。TRPV1在体内分布广泛,生物作用复杂。近年来,研究发现通过激活或抑制TRPV1可以调控炎性因子、疼痛信号传导、体温和神经元敏感性等,参与感染性疾病的产生,但目前还未用于临床。本文参阅国内外相关文献,以TRPV1为靶点,对TRPV1在感染性疾病中的生理作用及其调控机制的研究进展作一综述,为感染性疾病的防治提供新思路。

Overexpression of TRPV1 activates autophagy in human lens epithelial cells under hyperosmotic stress through Ca^(2+)-dependent AMPK/mTOR pathway

●AIM:To explore whether autophagy functions as a cellular adaptation mechanism in lens epithelial cells(LECs)under hyperosmotic stress.●METHODS:LECs were treated with hyperosmotic stress at the concentration of 270,300,400,500,or 600 mOsm for 6,12,18,24h in vitro.Polymerase chain reaction(PCR)was employed for the mRNA expression of autophagyrelated genes,while Western blotting detected the targeted protein expression.The transfection of stub-RFP-sens-GFPLC3 autophagy-related double fluorescence lentivirus was conducted to detect the level of autophagy flux.Scanning electron microscopy was used to detect the existence of autolysosome.Short interfering RNA of autophagy-related gene(ATG)7,transient receptor potential vanilloid(TRPV)1 overexpression plasmid,related agonists and inhibitors were employed to their influence on autophagy related pathway.Flow cytometry was employed to test the apoptosis and intracellular Ca^(2+)level.Mitochondrial membrane potential was measured by JC-1 staining.The cell counting kit-8 assay was used to calculate the cellular viability.The wound healing assay was used to evaluate the wound closure rate.GraphPad 6.0 software was utilized to evaluate the data.●RESULTS:The hyperosmotic stress activated autophagy in a pressure-and time-dependent manner in LECs.Beclin 1 protein expression and conversion of LC3B II to LC3B I increased,whereas sequestosome-1(SQSTM1)protein expression decreased.Transient Ca^(2+)influx was stimulated caused by hyperosmotic stress,levels of mammalian target of rapamycin(mTOR)phosphorylation decreased,and the level of AMP-activated protein kinase(AMPK)phosphorylation increased in the early stage.Based on this evidence,autophagy activation through the Ca^(2+)-dependent AMPK/mTOR pathway might represent an adaptation process in LECs under hyperosmotic stress.Hyperosmotic stress decreased cellular viability and accelerated apoptosis in LECs and cellular migration decreased.Inhibition of autophagy by ATG7 knockdown had similar results.TRPV1 overexpression increased autophagy and might be crucial in the occurrence of autophagy promoted by hyperosmotic stress.●CONCLUSION:A combination of hyperosmotic stress and autophagy inhibition may be a promising approach to decrease the number of LECs in the capsular bag and pave the way for improving prevention of posterior capsular opacification and capsular fibrosis.

Serotonin receptor 2B induces visceral hyperalgesia in rat model and patients with diarrhea-predominant irritable bowel syndrome

BACKGROUND Serotonin receptor 2B(5-HT2B receptor)plays a critical role in many chronic pain conditions.The possible involvement of the 5-HT2B receptor in the altered gut sensation of irritable bowel syndrome with diarrhea(IBS-D)was investigated in the present study.AIM To investigate the possible involvement of 5-HT2B receptor in the altered gut sensation in rat model and patients with IBS-D.METHODS Rectosigmoid biopsies were collected from 18 patients with IBS-D and 10 patients with irritable bowel syndrome with constipation who fulfilled the Rome IV criteria and 15 healthy controls.The expression level of the 5-HT2B receptor in colon tissue was measured using an enzyme-linked immunosorbent assay and correlated with abdominal pain scores.The IBS-D rat model was induced by intracolonic instillation of acetic acid and wrap restraint.Alterations in visceral sensitivity and 5-HT2B receptor and transient receptor potential vanilloid type 1(TRPV1)expression were examined following 5-HT2B receptor antagonist adminis-tration.Changes in visceral sensitivity after administration of the TRPV1 antago-INTRODUCTION Irritable bowel syndrome(IBS)is a chronic functional bowel disorder characterized by recurrent abdominal pain with altered bowel habits that affects approximately 15%of the population worldwide[1].IBS significantly impacts the quality of life of patients.Although the pathogenesis of IBS is not completely understood,the role of abnormal visceral sensitivity in IBS has recently emerged[2,3].5-Hydroxytryptamine(5-HT)is known to play a key role in the physiological states of the gastrointestinal tract.Plasma 5-HT levels in IBS with diarrhea(IBS-D)patients were greater than those in healthy controls[4],suggesting a possible role of 5-HT in the pathogenesis of IBS-D.The serotonin receptor 2(5-HT2 receptor)family comprises three subtypes:5-HT2A,5-HT2B,and 5-HT2c.All 5-HT2 receptors exhibit 46%-50%overall sequence identity,and all of these receptors preferentially bind to Gq/11 to increase inositol phosphates and intracellular calcium mobilization[5].5-HT2B receptors are widely expressed throughout the gut,and experimental evidence suggests that the primary function of 5-HT2B receptors is to mediate contractile responses to 5-HT through its action on smooth muscle[6].The 5-HT2B receptor is localized to both neurons of the myenteric nerve plexus and smooth muscle in the human colon.The 5-HT2B receptor mediates 5-HT-evoked contraction of longitudinal smooth muscle[6].These findings suggest that the 5-HT2B receptor could play an important role in modulating colonic motility,which could affect sensory signaling in the gut.Other laboratories have shown that the 5-HT2B receptor participates in the development of mechanical and formalin-induced hyperalgesia[7,8].A 5-HT2B receptor antagonist reduced 2,4,6-trinitrobenzene sulfonic acid(TNBS)and stress-induced visceral hyperalgesia in rats[9,10].However,the role of the 5-HT2B receptor in IBS-D patients and in acetic acid-and wrap restraint-induced IBS-D rat models was not investigated.

基于TRPA1离子通道蛋白的支气管哮喘病理机制及中医药干预现代研究进展

哮喘是一种反复发作的气道阻塞和喘息为特征的气道慢性炎症性疾病,瞬时受体电位锚蛋白1(Transient Receptor Potential Al,TRPA1)离子通道存在于多种组织细胞中,参与调节气道功能和炎症。以往对于TRPA1的研究更多的是在疼痛领域,尚未对相关调控离子蛋白通道表达治疗支气管哮喘的病理机制及中医药治疗进展做系统阐述。查阅国内外相关文献资料发现,在哮喘发生发展过程中,TRPA1离子通道蛋白参与气道炎症、气道高反应等病理过程。因此调控TRPA1离子蛋白通道的表达有利于治疗支气管哮喘。目前西医的治疗手段主要以吸入糖皮质激素与支气管扩张剂联合治疗为主,但部分患者不能达到完全控制,中医药在治疗哮喘方面具有靶点多、作用广、疗效优等特点,具有祛痰平喘、宣肺下气的中药及复方可以通过抗炎等作用有效调控TRPA1在体内的表达。文章总结TRPA1离子通道蛋白及其与支气管哮喘的关系,并就近年来中医药调控TRPA1的表达治疗支气管哮喘的研究进展进行综述,以期为基于TRPA1探讨支气管哮喘新的病理机制奠定实验室基础,为支气管哮喘防治及相关中药新药研发提供新的作用靶点与研究方向。

左卡尼汀联合尼可地尔对心力衰竭患者血管内皮功能及TRPC-1、NT-proBNP水平的影响

目的探究左卡尼汀联合尼可地尔对心力衰竭患者血管内皮功能及瞬时受体电位通道1(TRPC-1)、N端前体脑钠肽(NT-proBNP)水平的影响。方法将150例心力衰竭患者随机分为2组。对照组采用尼可地尔治疗,研究组采用左卡尼汀联合尼可地尔治疗,均治疗3个月,于治疗后评估疗效,比较血管内皮功能及TRPC1、NT-proBNP水平。结果研究组总有效率高于对照组(P<0.05);治疗后,研究组患者血清内皮素-1(ET-1)、TRPC-1及N端前体脑钠肽(NT-proBNP)水平低于对照组(P<0.05);一氧化氮(NO)、肱动脉内皮依赖性血管舒张功能(FMD)高于对照组(P<0.05)。结论与单用尼可地尔相比,联合左卡尼汀治疗心力衰竭患者可提升疗效,调节患者血清TRPC-1及NT-proBNP水平,减轻患者病情严重程度,改善血管内皮功能。

Zhenxin Anshen formula(镇心安神方)ameliorates atopic der-matitis-like skin dysfunction in mice and in vitro via regulation of transient receptor potential vanilloid 1 and transient receptor potential ankyrin 1 in Neural pathways

OBJECTIVE:To investigate the efficacy of Zhenxin Anshen formula(镇心安神方,ZXAS)on atopic dermatitis(AD)by transient receptor potential vanilloid 1(TRPV1)and transient receptor potential ankyrin 1(TRPA1)signalling pathway in mice and in vitro.METHODS:AD-like lesions were induced by 1-chloro-2,4-dinitrobenzene(DNCB)to the shaved dorsal skin of BALB/c mice.BALB/c mice were divided into five groups:normal control,model control,cetirizine,low-,medium-,and high-dose of ZXAS.After ZXAS in-tervention,the skin lesions and blood samples were collected for hematoxylin and eosin-stained and measuring the concentrations of inflammatory cytokines.Immunoglobulin E(IgE),interleukin(IL)-4,IL-5,IL-13,and thymic stromal lymphopoietin(TSLP)were de-tected by Enzyme-linked immunosorbent assay(ELISA).The spinal cords were collected for measuring the expression of gastrin-releasing peptide receptor(GRPR),TRPV1,and TRPA1 by using immunohistochemistry,western blotting,and quantitative real-time polymerase chain reaction(qR T-PCR)analyses.In addition,3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide(MTT)assay,flow cytometry,ELISA,and Western blotting were conducted for analysis of primary dorsal root ganglia(DRG)neurons in vitro.RESULTS:ZXAS treatment improved DNCB-induced AD-like lesions through reducing dermatitis score,number of scratching and epidermal thickness,accompanied by the de-creased IgE and Th2 inflammatory cytokines.ZXAS also supressed the mRNA and protein expression of GRPR,TRPV1,and TRPA1 in the spinal cord.The medicated sera of ZXAS decreased capsaicin-induced Ca^(2+)influx and downregulated the expression of TRPV1,TRPA1,and phospholipase C in DRG neurons.CONCLUSIONS:The therapeutic effect of ZXAS on AD may be related to the regulation of TRPV1 and TRPA1 and inhibition of Ca^(2+)signals in neurons.