scholarly journals Total Sesquiterpene Glycosides from Loquat Leaves Ameliorate HFD-Induced Insulin Resistance by Modulating IRS-1/GLUT4, TRPV1, and SIRT6/Nrf2 Signaling Pathways

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Ruoyun Wu ◽  
Tunyu Jian ◽  
Xiaoqin Ding ◽  
Han Lv ◽  
Xiuhua Meng ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Signaling Pathways ◽  
Transient Receptor Potential ◽  
Glucose Transporter ◽  
Receptor Potential ◽  
Causative Factor ◽  
Eriobotrya Japonica ◽  
Transient Receptor Potential Vanilloid ◽  
Related Factor

Loquat (Eriobotrya japonica Lindl.), a subtropical fruit tree native to Asia, is not only known to be nutritive but also beneficial for the treatment of diabetes in the south of China. To expand its development, this study was undertaken concerning the potential therapeutic role of total sesquiterpene glycosides (TSGs) from loquat leaves in insulin resistance (IR), the major causative factor of type 2 diabetes mellitus (T2DM). Male C57BL/6 mice were fed on high-fat diet (HFD) to induce IR and then were given TSG by oral administration at 25 and 100 mg/kg/day, respectively. TSG notably improved metabolic parameters including body weight, serum glucose, and insulin levels and prevented hepatic injury. Moreover, inflammatory response and oxidative stress were found to be remarkably alleviated in IR mice with TSG supplement. Further research in liver of IR mice demonstrated that TSG repaired the signalings of insulin receptor substrate-1 (IRS-1)/glucose transporter member 4 (GLUT4) and AMP-activated protein kinase (AMPK), which improved glucose and lipid metabolism and prevented lipid accumulation in liver. It was also observed that TSG suppressed the expression of transient receptor potential vanilloid 1 (TRPV1), whereas the signaling pathway of sirtuin-6 (SIRT6)/nuclear factor erythroid 2-related factor 2 (Nrf2) was significantly promoted. Based on the results, the current study demonstrated that TSG from loquat leaves potentially ameliorated IR in vivo by enhancing IRS-1/GLUT4 signaling and AMPK activation and modulating TRPV1 and SIRT6/Nrf2 signaling pathways.

scholarly journals Novel role of transient receptor potential vanilloid 2 in the regulation of cardiac performance

2014 ◽  
Vol 306 (4) ◽  
pp. H574-H584 ◽  
Author(s):  
Jack Rubinstein ◽  
Valerie M. Lasko ◽  
Sheryl E. Koch ◽  
Vivek P. Singh ◽  
Vinicius Carreira ◽  
...  
Keyword(s):  
Vascular Function ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Wild Type ◽  
Transient Receptor ◽  
Systolic And Diastolic Function ◽  
Myocyte Contractility

Transient receptor potential cation channels have been implicated in the regulation of cardiovascular function, but only recently has our laboratory described the vanilloid-2 subtype (TRPV2) in the cardiomyocyte, though its exact mechanism of action has not yet been established. This study tests the hypothesis that TRPV2 plays an important role in regulating myocyte contractility under physiological conditions. Therefore, we measured cardiac and vascular function in wild-type and TRPV2−/− mice in vitro and in vivo and found that TRPV2 deletion resulted in a decrease in basal systolic and diastolic function without affecting loading conditions or vascular tone. TRPV2 stimulation with probenecid, a relatively selective TRPV2 agonist, caused an increase in both inotropy and lusitropy in wild-type mice that was blunted in TRPV2−/− mice. We examined the mechanism of TRPV2 inotropy/lusitropy in isolated myocytes and found that it modulates Ca2+ transients and sarcoplasmic reticulum Ca2+ loading. We show that the activity of this channel is necessary for normal cardiac function and that there is increased contractility in response to agonism of TRPV2 with probenecid.

scholarly journals Inhibition of Microglia-Derived Oxidative Stress by Ciliary Neurotrophic Factor Protects Dopamine Neurons In Vivo from MPP+ Neurotoxicity

2018 ◽  
Vol 19 (11) ◽  
pp. 3543 ◽  
Author(s):  
Jeong Baek ◽  
Jae Jeong ◽  
Kyoung Kim ◽  
So-Yoon Won ◽  
Young Chung ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurotrophic Factor ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Ciliary Neurotrophic Factor ◽  
Dopamine Neurons ◽  
Transient Receptor Potential Vanilloid

We demonstrated that capsaicin (CAP), an agonist of transient receptor potential vanilloid subtype 1 (TRPV1), inhibits microglia activation and microglia-derived oxidative stress in the substantia nigra (SN) of MPP+-lesioned rat. However, the detailed mechanisms how microglia-derived oxidative stress is regulated by CAP remain to be determined. Here we report that ciliary neurotrophic factor (CNTF) endogenously produced by CAP-activated astrocytes through TRPV1, but not microglia, inhibits microglial activation and microglia-derived oxidative stress, as assessed by OX-6 and OX-42 immunostaining and hydroethidine staining, respectively, resulting in neuroprotection. The significant increase in levels of CNTF receptor alpha (CNTFRα) expression was evident on microglia in the MPP+-lesioned rat SN and the observed beneficial effects of CNTF was abolished by treatment with CNTF receptor neutralizing antibody. It is therefore likely that CNTF can exert its effect via CNTFRα on microglia, which rescues dopamine neurons in the SN of MPP+-lesioned rats and ameliorates amphetamine-induced rotations. Immunohistochemical analysis revealed also a significantly increased expression of CNTFRα on microglia in the SN from human Parkinson’s disease patients compared with age-matched controls, indicating that these findings may have relevance to the disease. These data suggest that CNTF originated from TRPV1 activated astrocytes may be beneficial to treat neurodegenerative disease associated with neuro-inflammation such as Parkinson’s disease.

scholarly journals Ultrastructural and immunohistochemical localization of plasma membrane Ca2+-ATPase 4 in Ca2+-transporting epithelia

2015 ◽  
Vol 309 (7) ◽  
pp. F604-F616 ◽  
Author(s):  
R. Todd Alexander ◽  
Megan R. Beggs ◽  
Reza Zamani ◽  
Niels Marcussen ◽  
Sebastian Frische ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Plasma Membrane ◽  
Transient Receptor Potential ◽  
Basolateral Membrane ◽  
Receptor Potential ◽  
Human Kidney ◽  
Muscle Layer ◽  
Transient Receptor Potential Vanilloid ◽  
Distal Nephron

Plasma membrane Ca2+-ATPases (PMCAs) participate in epithelial Ca2+ transport and intracellular Ca2+ signaling. The Pmca4 isoform is enriched in distal nephron isolates and decreased in mice lacking the epithelial transient receptor potential vanilloid 5 Ca2+ channel. We therefore hypothesized that Pmca4 plays a significant role in transcellular Ca2+ flux and investigated the localization and regulation of Pmca4 in Ca2+-transporting epithelia. Using antibodies directed specifically against Pmca4, we found it expressed only in the smooth muscle layer of mouse and human intestines, whereas pan-specific Pmca antibodies detected Pmca1 in lateral membranes of enterocytes. In the kidney, Pmca4 showed broad localization to the distal nephron. In the mouse, expression was most abundant in segments coexpressing the epithelial ransient receptor potential vanilloid 5 Ca2+ channel. Significant, albeit lower, expression was also evident in the region encompassing the cortical thick ascending limbs, macula densa, and early distal tubules as well as smooth muscle layers surrounding renal vessels. In the human kidney, a similar pattern of distribution was observed, with the highest PMCA4 expression in Na+-Cl− cotransporter-positive tubules. Electron microscopy demonstrated Pmca4 localization in distal nephron cells at both the basolateral membrane and intracellular perinuclear compartments but not submembranous vesicles, suggesting rapid trafficking to the plasma membrane is unlikely to occur in vivo. Pmca4 expression was not altered by perturbations in Ca2+ balance, pointing to a housekeeping function of the pump in Ca2+-transporting epithelia. In conclusion, Pmca4 shows a divergent expression pattern in Ca2+-transporting epithelia, inferring diverse roles for this isoform not limited to transepithelial Ca2+ transport.

scholarly journals Oxidized lipids and signaling pathways of G2A receptor involved in nerve injury induced neuropathic pain

2021 ◽  
Author(s):  
◽  
Tabea Osthues
Keyword(s):  
Neuropathic Pain ◽  
Signaling Pathways ◽  
Nerve Injury ◽  
Inflammatory Mediators ◽  
Pain Perception ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Wild Type ◽  
Injured Nerve

Neuropathic pain, a form of chronic pain, is a steadily rising health problem due to health costs and increasing numbers of patients. Neuropathic pain conditions arise upon metabolic disorders, infections, chemotherapeutic treatment, trauma or nerve injury. Especially nerve injury induced neuropathic pain is characterized by spontaneous or ongoing pain due to neuroimmune interactions. Thereby, inflammatory mediators, released by the injured nerve, recruit to and activate immune cells at the site of injury. Those mediators further activate transient receptor potential vanilloid 1 (TRPV1), a known channel involved in pain perception, or bind to G-protein coupled receptors (GPCR) in peripheral nerve endings. The following activated second messenger signaling pathways lead to sensitization of TRPV1. One of those GPCRs is G2A. The overall aim of this thesis was to investigate the role of G2A in nerve-injury induced neuropathic pain. For this, the common mouse model of nerve-injury induced neuropathic pain, the spared-nerve injury, was used. As measurements with dynamic plantar aesthesiometer showed, G2A-deficiency leads to reduced mechanical hypersensitivity. Upon analysis with FACS, ELISA and Luminex a reduced number of macrophages and neutrophils at the injured nerve, as well as less inflammatory mediators (TNFα, IL-6, VEGF) in G2A-deficient animals was observed. In dorsal root ganglia (DRGs) there was only a reduced number of macrophages and less IL-12 observed in G2A-deficient animals. Additionally, in wild-type mice, G2A agonist 9-HODE was elevated at the injured nerve, as a LC-MS/MS analysis showed. To investigate the underlying pathways of G2A-9-HODE signaling, a proteom screen was performed. This screen revealed upregulation of multiple proteins involved in migration in wild-type macrophages. Additionally, Ca-Imaging and transwell migration assays showed that the G2A antagonist G2A11, had desensitizing effects on DRG neurons and inhibited macrophage migration. Overall, the results suggest that loss of G2A has dual effects. On the one hand loss of G2A is antinociceptive. On the other hand, G2A-deficiency leads to reduced inflammation, suggesting G2A as promising target in treatment of neuropathic pain. Here, an antagonist had inhibitory effects on the migration and the sensitization.

scholarly journals Therapeutic inhibition of keratinocyte TRPV3 sensory channel by local anesthetic dyclonine

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Qiang Liu ◽  
Jin Wang ◽  
Xin Wei ◽  
Juan Hu ◽  
Conghui Ping ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Single Channel ◽  
Receptor Potential ◽  
Epidermal Keratinocytes ◽  
Transient Receptor Potential Vanilloid ◽  
Growth Disorders ◽  
Open Probability ◽  
Gain Of Function ◽  
Sensory Channel

The multimodal sensory channel transient receptor potential vanilloid-3 (TRPV3) is expressed in epidermal keratinocytes and implicated in chronic pruritus, allergy, and inflammation-related skin disorders. Gain-of-function mutations of TRPV3 cause hair growth disorders in mice and Olmsted Syndrome in human. We here report that mouse and human TRPV3 channel is targeted by the clinical medication dyclonine that exerts a potent inhibitory effect. Accordingly, dyclonine rescued cell death caused by gain-of-function TRPV3 mutations and suppressed pruritus symptoms in vivo in mouse model. At the single-channel level, dyclonine inhibited TRPV3 open probability but not the unitary conductance. By molecular simulations and mutagenesis, we further uncovered key residues in TRPV3 pore region that could toggle the inhibitory efficiency of dyclonine. The functional and mechanistic insights obtained on dyclonine-TRPV3 interaction will help to conceive updated therapeutics for skin inflammation.

Abstract 1287: TRPV4-Deficient Mice Exhibit Impaired Endothelium-Dependent Relaxation Induced by Acetylcholine in Vitro and in Vivo

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
David Zhang ◽  
Suelhem Mendoza ◽  
Aaron Bubolz ◽  
Makoto Suzuki ◽  
David Gutterman
Keyword(s):  
Blood Pressure ◽  
Endothelial Cells ◽  
Carotid Arteries ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Mice Model ◽  
Synthase Inhibitor

Agonist-induced Ca 2+ entry in endothelial cells is important for the synthesis and release of vasoactive factors, although mechanisms of Ca 2+ entry remain largely unknown. Emerging evidence suggests that the transient receptor potential vanilloid 4 (TRPV4) channel, a Ca 2+ -permeant TRP channel, is expressed in endothelial cells and may be involved in the regulation of vascular tone. Here we investigated the potential role of TRPV4 channels in acetylcholine-induced vasodilation in vitro and in vivo using the TRPV4 knockout (TRPV4 −/− ) mice model. Carotid arteries were isolated and preconstricted with the thromboxane A2 mimetic U46619. Concentration-dependent relaxations to acetylcholine (10 −9 –10 −5 M) were markedly reduced in carotids of TRPV4 −/− vs. wild-type (WT) mice (maximal relaxations of 31±12% vs 53±4%, respectively; n=4 mice). There was no significant change in the ED50 for Ach. In both WT and TRPV4 −/− , acetylcholine-induced relaxations were blocked and converted to constrictions by the NO synthase inhibitor L-NAME (maximal relaxations of −25±6% and −24±7%, respectively). There was no difference in papaverine-induced relaxations between WT and TRPV4 −/− mice (maximal relaxations of 93±3% vs. 90±3%, respectively). U46619 caused similar contractions in carotid arteries from those mice. We also compared in vivo vasodilator effects of acetylcholine by measuring changes in blood pressure in those animals. Intravenous administration of acetylcholine (15 ng/gm bolus) decreased blood pressure by 32±6 mmHg in WT mice (from 90±15 to 57±10 mmHg; n=6), whereas blood pressure was reduced by only 10 mmHg in TRPV4 −/− mice (from 67±6 to 56±4 mmHg; n=12). Acetylcholine caused similar reductions in heart rate in WT and TRPV4 −/− mice, with mean changes of 365±57 and 292±40 beats/min, respectively. We conclude that the endothelium-dependent vasodilator response to acetylcholine is reduced both in vitro and in vivo in TRPV4 −/− mice, and these findings may provide novel insight into the mechanisms of Ca 2+ entry evoked by chemical agonists in endothelial cells. The paradoxically lower baseline blood pressure in TRPV4 −/− mice requires further investigation.

Abstract 358: Transient Receptor Potential Vanilloid 2 (TRPV2) contributes to myocardial contractility and hypertrophy via sarcoplasmic reticulum calcium handling

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Jack Rubinstein ◽  
Vivek P Singh ◽  
Valerie M Lasko ◽  
Sheryl E Koch ◽  
Evangelia Kranias ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Fold Increase ◽  
Calcium Handling ◽  
Heart Weight ◽  
Transient Receptor Potential Vanilloid ◽  
Cardiomyocyte Contractility ◽  
Transient Receptor

Background: TRPV2 is a Ca2+ channel that we have recently discovered in cardiomyocytes. The absence of this channel negatively impacts baseline contractility while stimulation results in a positive inotropic response. What remains to be established is the mechanism of this receptor and its role, if any, in the development of hypertrophy. Methods and Results: We obtained isolated cardiomyocytes from wild type (WT) and TRPV2-/- (KO) mice and found that the sarcoplasmic reticulum Ca2+ content and Ca2+ transients were reduced along with fractional shortening in the KO cardiomyocytes (figure, panels A, B, C). In vivo echocardiography confirmed a decrease in ejection fraction in KO mice in comparison to the WT counterparts (panel D). The relevance of these findings was examined in 6 WT and 5 KO mice subjected to transverse aortic constriction (TAC). These mice were followed by echocardiography weekly for a total of 8 weeks post TAC. At the conclusion, the hearts were obtained for histological and molecular analyses. We demonstrated that the KO mice developed less LV hypertrophy in comparison to WT (via echocardiography and by heart weight/body weight ratios) (figure, panels E and F). Importantly, there was a 5 fold increase in TRPV2 expression assessed by PCR in TAC WT hearts, compared to WT not subjected to TAC (0.72±0.10 vs. 0.13±0.04; p<0.01). This suggests a role for TRPV2 not only in contractility, but also in the development of hypertrophy. Conclusions: We have discovered a novel cardiac channel that alters Ca2+ cycling and is capable of modulating cardiomyocyte contractility and hypertrophy, which could lead to novel therapeutic options in heart failure and hypertrophy.

scholarly journals Calcium and TRPV4 promote metastasis by regulating cytoskeleton through the RhoA/ROCK1 pathway in endometrial cancer

2020 ◽  
Vol 11 (11) ◽  
Author(s):  
Xingchen Li ◽  
Yuan Cheng ◽  
Zhiqi Wang ◽  
Jingyi Zhou ◽  
Yuanyuan Jia ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Cancer Progression ◽  
Transient Receptor Potential ◽  
Calcium Influx ◽  
Biological Significance ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Mechanistic Investigation

AbstractTransient receptor potential vanilloid 4 (TRPV4) is a calcium-permeable cation channel that has been associated with several types of cancer. However, its biological significance, as well as its related mechanism in endometrial cancer (EC) still remains elusive. In this study, we examined the function of calcium in EC, with a specific focus on TRPV4 and its downstream pathway. We reported here on the findings that a high level of serum ionized calcium was significantly correlated with advanced EC progression, and among all the calcium channels, TRPV4 played an essential role, with high levels of TRPV4 expression associated with cancer progression both in vitro and in vivo. Proteomic and bioinformatics analysis revealed that TRPV4 was involved in cytoskeleton regulation and Rho protein pathway, which regulated EC cell migration. Mechanistic investigation demonstrated that TRPV4 and calcium influx acted on the cytoskeleton via the RhoA/ROCK1 pathway, ending with LIMK/cofilin activation, which had an impact on F-actin and paxillin (PXN) levels. Overall, our findings indicated that ionized serum calcium level was significantly associated with poor outcomes and calcium channel TRPV4 should be targeted to improve therapeutic and preventive strategies in EC.

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