scholarly journals Mechanisms of Cancer Inhibition by Local Anesthetics

2021 ◽  
Vol 12 ◽  
Author(s):  
Yiguo Zhang ◽  
Yixin Jing ◽  
Rui Pan ◽  
Ke Ding ◽  
Rong Chen ◽  
...  
Keyword(s):  
Local Anesthetics ◽  
Transient Receptor Potential ◽  
Calcium Influx ◽  
Growth Factor Receptor ◽  
Cancer Recurrence ◽  
Receptor Potential ◽  
Perioperative Analgesia ◽  
Transient Receptor Potential Melastatin

The use of local anesthetics during surgical treatment of cancer patients is an important part of perioperative analgesia. In recent years, it has been showed that local anesthetics can directly or indirectly affect the progression of tumors. In vitro and in vivo studies have demonstrated that local anesthetics reduced cancer recurrence. The etiology of this effect is likely multifactorial. Numerous mechanisms were proposed based on the local anesthetic used and the type of cancer. Mechanisms center on NaV1.5 channels, Ras homolog gene family member A, cell cycle, endothelial growth factor receptor, calcium Influx, microRNA and mitochondrial, in combination with hyperthermia and transient receptor potential melastatin 7 channels. Local anesthetics significantly decrease the proliferation of cancers, including ovarian, breast, prostate, thyroid, colon, glioma, and histiocytic lymphoma cell cancers, by activating cell death signaling and decreasing survival pathways. We also summarized clinical evidence and randomized trial data to confirm that local anesthetics inhibited tumor progression.

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.

scholarly journals trpm7 Regulation of in Vivo Cation Homeostasis and Kidney Function Involves Stanniocalcin 1 and fgf23

Endocrinology ◽  
2010 ◽  
Vol 151 (12) ◽  
pp. 5700-5709 ◽  
Author(s):  
Michael R. Elizondo ◽  
Erine H. Budi ◽  
David M. Parichy
Keyword(s):  
Kidney Function ◽  
Transient Receptor Potential ◽  
Stone Formation ◽  
Fibroblast Growth Factor 23 ◽  
Receptor Potential ◽  
Larval Stages ◽  
Transient Receptor Potential Melastatin ◽  
Cation Homeostasis

The transient receptor potential melastatin 7 (trpm7) channel kinase is a primary regulator of magnesium homeostasis in vitro. Here we show that trpm7 is an important regulator of cation homeostasis as well as kidney function in vivo. Using zebrafish trpm7 mutants, we show that early larvae exhibit reduced levels of both total magnesium and total calcium. Accompanying these deficits, we show that trpm7 mutants express higher levels of stanniocalcin 1 (stc1), a potent regulator of calcium homeostasis. Using transgenic overexpression and morpholino oligonucleotide knockdown, we demonstrate that stc1 modulates both calcium and magnesium levels in trpm7 mutants and in the wild type and that levels of these cations are restored to normal in trpm7 mutants when stc1 activity is blocked. Consistent with defects in both calcium and phosphate homeostasis, we further show that trpm7 mutants develop kidney stones by early larval stages and exhibit increased levels of the anti-hyperphosphatemic factor, fibroblast growth factor 23 (fgf23). Finally, we demonstrate that elevated fgf23 expression contributes to kidney stone formation by morpholino knockdown of fgf23 in trpm7 mutants. Together, these analyses reveal roles for trpm7 in regulating cation homeostasis and kidney function in vivo and implicate both stc1 and fgf23 in these processes.

scholarly journals Emerging Roles for Ion Channels in Ovarian Cancer: Pathomechanisms and Pharmacological Treatment

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 668
Author(s):  
Concetta Altamura ◽  
Maria Raffaella Greco ◽  
Maria Rosaria Carratù ◽  
Rosa Angela Cardone ◽  
Jean-François Desaphy
Keyword(s):  
Ovarian Cancer ◽  
Ion Channels ◽  
Transient Receptor Potential ◽  
Critical Role ◽  
Gynecologic Cancer ◽  
Receptor Potential ◽  
Transient Receptor Potential Channels ◽  
Platinum Resistance

Ovarian cancer (OC) is the deadliest gynecologic cancer, due to late diagnosis, development of platinum resistance, and inadequate alternative therapy. It has been demonstrated that membrane ion channels play important roles in cancer processes, including cell proliferation, apoptosis, motility, and invasion. Here, we review the contribution of ion channels in the development and progression of OC, evaluating their potential in clinical management. Increased expression of voltage-gated and epithelial sodium channels has been detected in OC cells and tissues and shown to be involved in cancer proliferation and invasion. Potassium and calcium channels have been found to play a critical role in the control of cell cycle and in the resistance to apoptosis, promoting tumor growth and recurrence. Overexpression of chloride and transient receptor potential channels was found both in vitro and in vivo, supporting their contribution to OC. Furthermore, ion channels have been shown to influence the sensitivity of OC cells to neoplastic drugs, suggesting a critical role in chemotherapy resistance. The study of ion channels expression and function in OC can improve our understanding of pathophysiology and pave the way for identifying ion channels as potential targets for tumor diagnosis and treatment.

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.

Involvement of the vanilloid receptor 1 in the mechanisms of analgesic effect of amizonum

2014 ◽  
Vol 31 (1) ◽  
pp. 41-49
Author(s):  
Oleh Yadlovskyi ◽  
Tatiana Bukhtiarova ◽  
Lyudmila Bobkova ◽  
Irina Tatianshenko ◽  
Igor Monchak ◽  
...  
Keyword(s):  
Portal Vein ◽  
Active Site ◽  
Analgesic Effect ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Theoretical Background ◽  
Tail Flick ◽  
Intermolecular Complex

SUMMARY The study of features of pharmacodynamics of a new analgesic is an important and urgent task of modern pharmacology. These data allow us to clarify the nosology for application of an analgesic and to create a theoretical background to optimize its use. An effect mediated by the transient receptor potential cation channel, subfamily V, member 1 (TRPV1) activation can also be an effective mechanism of the analgesic action. We evaluated the possibility of TRPV1 participation in implementation of the analgesic effect with the antiviral action of amizonum during the experiment. It is known that amino acids Tyr511 and Ser512 are the main components of the active site of TRPV1. In this connection, dipeptide Tyr-Ser has been completely synthesized as a model of the active site of TRPV1. In the experiment model this was shown, using the spectrophotometric method, with the formation of the “capsaicin - Tyr- Ser” intermolecular complex at the level of the stability constant Kkor=0.998 and Kr=0.3•10-4 L/mol and the “amizonum - Tyr-Ser” weak intermolecular complex Kr=0.05•104 L/mol; Kkor= 0.995, respectively. The data verification was carried out in experiments in vitro (isolated ratportal vein) and in vivo (Tail-flick model), with the TRPV1 agonist. It was shown that the amplitude of smooth muscle (SM) contraction of the portal vein at a capsaicin concentration 0.1 μmol/L, 0.5 μmol/L capsazepine, and 1.0 μmol/L amizonum was +30.3±5.3%, -3.2± 2.7% and +7.1±3.2% from initial level, respectivelly. In a combined application of amizonum with capsaicin or capsazepine, the amplitude of contraction of the SM portal vein was 20.1± 1.3% and -3.0±1.4%, respectively. This indicates the absence of action of amizonum under combined use of capsaicinoids. The Tail-flick model showed atypical potentiation of the amizonum antinociception with the use of capsaicin. The obtained data suggest the low probability of the participation of TRPV1 in the implementation of the antinociceptive action of amizonum.

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.

scholarly journals Genetic background influences expression and function of the cation channel TRPM4 in the mouse heart

2020 ◽  
Vol 115 (6) ◽  
Author(s):  
Rebekka Medert ◽  
Andy Pironet ◽  
Lucas Bacmeister ◽  
Sebastian Segin ◽  
Juan E. Camacho Londoño ◽  
...  
Keyword(s):  
Genetic Background ◽  
Transient Receptor Potential ◽  
Cardiac Contractility ◽  
Receptor Potential ◽  
Disease Status ◽  
Mouse Strains ◽  
Mouse Heart ◽  
Transient Receptor Potential Melastatin ◽  
Different Genetic Background

AbstractTransient receptor potential melastatin 4 (TRPM4) cation channels act in cardiomyocytes as a negative modulator of the L-type Ca2+ current. Ubiquitous Trpm4 deletion in mice leads to an increased β-adrenergic inotropy in healthy mice as well as after myocardial infarction. In this study, we set out to investigate cardiac inotropy in mice with cardiomyocyte-specific Trpm4 deletion. The results guided us to investigate the relevance of TRPM4 for catecholamine-evoked Ca2+ signaling in cardiomyocytes and inotropy in vivo in TRPM4-deficient mouse models of different genetic background. Cardiac hemodynamics were investigated using pressure–volume analysis. Surprisingly, an increased β-adrenergic inotropy was observed in global TRPM4-deficient mice on a 129SvJ genetic background, but the inotropic response was unaltered in mice with global and cardiomyocyte-specific TRPM4 deletion on the C57Bl/6N background. We found that the expression of TRPM4 proteins is about 78 ± 10% higher in wild-type mice on the 129SvJ versus C57Bl/6N background. In accordance with contractility measurements, our analysis of the intracellular Ca2+ transients revealed an increase in ISO-evoked Ca2+ rise in Trpm4-deficient cardiomyocytes of the 129SvJ strain, but not of the C57Bl/6N strain. No significant differences were observed between the two mouse strains in the expression of other regulators of cardiomyocyte Ca2+ homeostasis. We conclude that the relevance of TRPM4 for cardiac contractility depends on homeostatic TRPM4 expression levels or the genetic endowment in different mouse strains as well as on the health/disease status. Therefore, the concept of inhibiting TRPM4 channels to improve cardiac contractility needs to be carefully explored in specific strains and species and prospectively in different genetically diverse populations of patients.

scholarly journals Design, Synthesis and In Vitro Experimental Validation of Novel TRPV4 Antagonists Inspired by Labdane Diterpenes

Marine Drugs ◽  
2020 ◽  
Vol 18 (10) ◽  
pp. 519
Author(s):  
Sarah Mazzotta ◽  
Gabriele Carullo ◽  
Aniello Schiano Moriello ◽  
Pietro Amodeo ◽  
Vincenzo Di Marzo ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Calcium Influx ◽  
Biological Activities ◽  
Receptor Potential ◽  
Transient Receptor Potential Channel ◽  
Design Synthesis ◽  
Cellular Assays ◽  
Transient Receptor ◽  
Trpv4 Channel

Labdane diterpenes are widespread classes of natural compounds present in variety of marine and terrestrial organisms and plants. Many of them represents “natural libraries” of compounds with interesting biological activities due to differently functionalized drimane nucleus exploitable for potential pharmacological applications. The transient receptor potential channel subfamily V member 4 (TRPV4) channel has recently emerged as a pharmacological target for several respiratory diseases, including the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Inspired by the labdane-like bicyclic core, a series of homodrimane-derived esters and amides was designed and synthesized by modifying the flexible tail in position 1 of (+)-sclareolide, an oxidized derivative of the bioactive labdane-type diterpene sclareol. The potency and selectivity towards rTRPV4 and hTRPV1 receptors were assessed by calcium influx cellular assays. Molecular determinants critical for eliciting TRPV4 antagonism were identified by structure-activity relationships. Among the selective TRPV4 antagonists identified, compound 6 was the most active with an IC50 of 5.3 μM. This study represents the first report of semisynthetic homodrimane TRPV4 antagonists, selective over TRPV1, and potentially useful as pharmacological tools for the development of novel TRPV4 channel modulators.

Magnesium in Man: Implications for Health and Disease

2015 ◽  
Vol 95 (1) ◽  
pp. 1-46 ◽  
Author(s):  
Jeroen H. F. de Baaij ◽  
Joost G. J. Hoenderop ◽  
René J. M. Bindels
Keyword(s):  
Transient Receptor Potential ◽  
Growth Factor Receptor ◽  
Physiological Role ◽  
Calcineurin Inhibitors ◽  
Receptor Potential ◽  
Enzymatic Reactions ◽  
Comprehensive Overview ◽  
Transient Receptor Potential Melastatin ◽  
Health And Disease ◽  
Transient Receptor

Magnesium (Mg2+) is an essential ion to the human body, playing an instrumental role in supporting and sustaining health and life. As the second most abundant intracellular cation after potassium, it is involved in over 600 enzymatic reactions including energy metabolism and protein synthesis. Although Mg2+availability has been proven to be disturbed during several clinical situations, serum Mg2+values are not generally determined in patients. This review aims to provide an overview of the function of Mg2+in human health and disease. In short, Mg2+plays an important physiological role particularly in the brain, heart, and skeletal muscles. Moreover, Mg2+supplementation has been shown to be beneficial in treatment of, among others, preeclampsia, migraine, depression, coronary artery disease, and asthma. Over the last decade, several hereditary forms of hypomagnesemia have been deciphered, including mutations in transient receptor potential melastatin type 6 (TRPM6), claudin 16, and cyclin M2 (CNNM2). Recently, mutations in Mg2+transporter 1 (MagT1) were linked to T-cell deficiency underlining the important role of Mg2+in cell viability. Moreover, hypomagnesemia can be the consequence of the use of certain types of drugs, such as diuretics, epidermal growth factor receptor inhibitors, calcineurin inhibitors, and proton pump inhibitors. This review provides an extensive and comprehensive overview of Mg2+research over the last few decades, focusing on the regulation of Mg2+homeostasis in the intestine, kidney, and bone and disturbances which may result in hypomagnesemia.

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