Capsaicin, a novel radiosensitizer, acts via a TRPV6 mediated phenomenon.

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 23-23 ◽  
Author(s):  
L. Klotz ◽  
N. Venier ◽  
A. J. Colquhoun ◽  
H. Sasaki ◽  
D. A. Loblaw ◽  
...  
Keyword(s):  
Ionizing Radiation ◽  
Western Blot ◽  
Colony Formation ◽  
Transient Receptor Potential ◽  
Significant Inhibition ◽  
Treatment Modalities ◽  
Transient Receptor Potential Vanilloid ◽  
Protein Markers ◽  
Radiosensitizing Agents

23 Background: Radiosensitizing agents sensitize cells to the lethal effects of ionizing radiation (IR). This permits use of lower doses of radiation to achieve equivalent cancer control thereby minimizing adverse effects to normal tissues. Given their lack of toxicity compounds occurring naturally in the diet make ideal potential radiosensitizing agents. Capsaicin, a compound found in the Capsicum sp. of plants, is a widely consumed food additive in areas with low PCa incidence. Traditionally capsaicin is used to treat chronic pain syndromes; however, recently evidence using in vitro PCa models describes its anti-carcinogenic potential. The transient receptor potential vanilloid-receptor (TRPV)-1 and TRPV6 cation selective channels are thought to be partly responsible for mediating these effects. TRPV-1 and TRPV-6 expression is up-regulated in PCa tissue correlating directly with increasing tumor grade. This suggests TRPV1 and/or TRPV6 may be potential therapeutic targets for capsaicin mediated interventions in PCa patients. As IR and capsaicin both promote apoptosis and inhibit cell cycle progression in vitro we hypothesize an at least additive effect of combining these two therapies. Methods: Using clonogenic assays we assessed the effect of ionizing radiation (1-8 Gy) and/or capsaicin (1-10μ M) on colony formation rates in 4 human PCa cell lines (LNCaP, PC3, PC3AR2, DU145). Proliferative, apoptotic, TRPV-6 protein markers were assessed using Western blot analyses. Results: Exposure of cells to capsaicin (1-10μ M) or IR (1-8Gy) caused significant dose-dependent inhibition of colony formation (p<0.001). Combining capsaicin with IR resulted in further significant inhibition of colony formation rates (P<0.001). Western blot analyses showed LNCaP cells treated with capsaicin and/or IR to have increased expression of pro- apoptotic proteins BAX and Bad, tumor-suppressor proteins p21 and p27 and reduced androgen-receptor. Additionally, capsaicin monotherapy caused a dramaticalteration in TRPV1 and TRPV6 expression. Conclusions: These studies confirm the radiosensitizing capacity of capsaicin in PCa cells in vitro. Ongoing studies are further delineating the mechanism of interaction of these treatment modalities. No significant financial relationships to disclose.

scholarly journals Capsaicin, a TRPV1 Ligand, Suppresses Bone Resorption by Inhibiting the Prostaglandin E Production of Osteoblasts, and Attenuates the Inflammatory Bone Loss Induced by Lipopolysaccharide

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Megumi Kobayashi ◽  
Kenta Watanabe ◽  
Satoshi Yokoyama ◽  
Chiho Matsumoto ◽  
Michiko Hirata ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Loss ◽  
Transient Receptor Potential ◽  
Interleukin 1 ◽  
Osteoclast Differentiation ◽  
Bone Diseases ◽  
Prostaglandin E ◽  
Transient Receptor Potential Vanilloid ◽  
Cox 2

Capsaicin, a transient receptor potential vanilloid type 1 (TRPV1) ligand, regulates nerve-related pain-sensitive signals, inflammation, and cancer growth. Capsaicin suppresses interleukin-1-induced osteoclast differentiation, but its roles in bone tissues and bone diseases are not known. This study examined the effects of capsaicin on inflammatory bone resorption and prostaglandin E (PGE) production induced by lipopolysaccharide (LPS) in vitro and on bone mass in LPS-treated mice in vivo. Capsaicin suppressed osteoclast formation, bone resorption, and PGE production induced by LPS in vitro. Capsaicin suppressed the expression of cyclooxygenase-2 (COX-2) and membrane-bound PGE synthase-1 (mPGES-1) mRNAs and PGE production induced by LPS in osteoblasts. Capsaicin may suppress PGE production by inhibiting the expression of COX-2 and mPGES-1 in osteoblasts and LPS-induced bone resorption by TRPV1 signals because osteoblasts express TRPV1. LPS treatment markedly induced bone loss in the femur in mice, and capsaicin significantly restored the inflammatory bone loss induced by LPS in mice. TRPV1 ligands like capsaicin may therefore be potentially useful as clinical drugs targeting bone diseases associated with inflammatory bone resorption.

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 Down-regulation of MAPK pathway alleviates TRPV4-mediated trigeminal neuralgia by inhibiting the activation of histone acetylation

2021 ◽  
Author(s):  
Weidong Liu ◽  
Benfang Pu ◽  
Mindi Liu ◽  
Xuejun Zhang ◽  
Ran Zeng
Keyword(s):  
Trigeminal Neuralgia ◽  
Western Blot ◽  
Histone Acetylation ◽  
Transient Receptor Potential ◽  
Mapk Pathway ◽  
Quantitative Polymerase Chain Reaction ◽  
Infraorbital Nerve ◽  
Enzyme Linked Immunosorbent Assay ◽  
Transient Receptor Potential Vanilloid ◽  
Down Regulation

AbstractOur objective of this study is to determine the molecular mechanism of MAPKs (mitogen activated protein kinase systems) on TRPV4 (transient receptor potential vanilloid 4)-mediated trigeminal neuralgia (TN). Partial chronic constriction injury of the infraorbital nerve (CCI-ION) ligation model was used in this research. When treated with antagonists of p38, JNK or ERK, the mechanical hyperalgesia threshold, nerve fiber disorder, myelinoclasis, and Schwann cells proliferation could be reversed. RT-PCR (real-time quantitative polymerase chain reaction), Western blot and IHC (immunohistochemistry) showed that TRPV4 mRNA and protein levels, TRPV4-positive cells and small positive neurons decreased remarkably in TN group treated with antagonists of p38, JNK or ERK. ELISA (enzyme-linked immunosorbent assay) was performed to discover inhibition of MAPK pathway can down-regulate the expression of HATs (histone acetyltransferases), and up-regulate the expression of HDACs (histone deacetylases) in TN, thus inhibiting histone acetylation. Finally, Western blot was performed to identify the phosphorylation status of p38, JNK and ERK, finding decreased phosphorylation forms in antagonists treated TN groups compared with TN groups. Based on the above investigation method, on a whole, our study showed that down-regulation of MAPK pathway could alleviate TRPV4-mediated trigeminal neuralgia, via inhibiting the activation of histone acetylation.

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 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 In vitro and in vivo evidence for an inflammatory role of the calcium channel TRPV4 in lung epithelium: Potential involvement in cystic fibrosis

2016 ◽  
Vol 311 (3) ◽  
pp. L664-L675 ◽  
Author(s):  
Clémence O. Henry ◽  
Emilie Dalloneau ◽  
Maria-Teresa Pérez-Berezo ◽  
Cristina Plata ◽  
Yongzheng Wu ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Calcium Channel ◽  
Lung Inflammation ◽  
Transient Receptor Potential ◽  
Biologically Active ◽  
Transient Receptor Potential Vanilloid ◽  
Anti Inflammatory

Cystic fibrosis (CF) is an inherited disease associated with chronic severe lung inflammation, leading to premature death. To develop innovative anti-inflammatory treatments, we need to characterize new cellular and molecular components contributing to the mechanisms of lung inflammation. Here, we focused on the potential role of “transient receptor potential vanilloid-4” (TRPV4), a nonselective calcium channel. We used both in vitro and in vivo approaches to demonstrate that TRPV4 expressed in airway epithelial cells triggers the secretion of major proinflammatory mediators such as chemokines and biologically active lipids, as well as a neutrophil recruitment in lung tissues. We characterized the contribution of cytosolic phospholipase A2, MAPKs, and NF-κB in TRPV4-dependent signaling. We also showed that 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids, i.e., four natural lipid-based TRPV4 agonists, are present in expectorations of CF patients. Also, TRPV4-induced calcium mobilization and inflammatory responses were enhanced in cystic fibrosis transmembrane conductance regulator-deficient cellular and animal models, suggesting that TRPV4 is a promising target for the development of new anti-inflammatory treatments for diseases such as CF.

Mediation of multiple pathways regulating cell proliferation, migration, and apoptosis in the human malignant glioma cell line U87MG via unphosphorylated STAT1

2013 ◽  
Vol 118 (6) ◽  
pp. 1239-1247 ◽  
Author(s):  
Haitao Ju ◽  
Xin Li ◽  
Hong Li ◽  
Xiaojuan Wang ◽  
Hongwei Wang ◽  
...  
Keyword(s):  
Cell Growth ◽  
Western Blot ◽  
Caspase 3 ◽  
Apoptotic Cell ◽  
Glioma Cell Line ◽  
Significant Inhibition ◽  
Cell Counting ◽  
Nuclear Antigen ◽  
Normal Brain

Object Signal transducer and activator of transcription 1 (STAT1) is thought to be a tumor suppressor protein. The authors investigated the expression and role of STAT1 in glioblastoma. Methods Immunohistochemistry was used to detect the expression of STAT1 in glioblastoma and normal brain tissues. Reverse transcription–polymerase chain reaction and Western blot analysis were used to detect mRNA and protein expression levels of STAT1. Cell growth, proliferation, migration, apoptosis, and the expression of related genes and proteins (Bcl-2, Bax, cleaved caspase-3, caspase-9, p21, and proliferating cell nuclear antigen) were examined in vitro via cell counting kit-8, wound-healing, flow cytometry, Rhodamine B, TUNEL, and Western blot assays. Results Human glioblastoma had decreased expression of STAT1 proteins. Transfection of the U87MG cells with STAT1 plasmid in vitro demonstrated significant inhibition of cell growth and an increase in apoptotic cell death compared with cells transfected with vector or mock plasmids. These effects were associated with the upregulation of cleaved caspase-3, Bax, and p21 and the downregulation of Bcl-2 expression. Conclusions The results of this study suggest that increased expression of STAT1 by transfection with STAT1 plasmid synergistically inhibits human U87MG glioblastoma cell growth in vitro.

scholarly journals TRPV1 channel mediates NLRP3 inflammasome-dependent neuroinflammation in microglia

2021 ◽  
Vol 12 (12) ◽  
Author(s):  
Yahui Zhang ◽  
Baohua Hou ◽  
Peiyu Liang ◽  
Xin Lu ◽  
Yifan Wu ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Transient Receptor Potential ◽  
Inflammatory Diseases ◽  
Critical Role ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Inflammasome Activation ◽  
Trpv1 Channel ◽  
Nlrp3 Inflammasome Activation

AbstractMultiple sclerosis (MS) is a chronic inflammatory autoimmune disease in the central nervous system (CNS). The NLRP3 inflammasome is considered an important regulator of immunity and inflammation, both of which play a critical role in MS. However, the underlying mechanism of NLRP3 inflammasome activation is not fully understood. Here we identified that the TRPV1 (transient receptor potential vanilloid type 1) channel in microglia, as a Ca2+ influx-regulating channel, played an important role in NLRP3 inflammasome activation. Deletion or pharmacological blockade of TRPV1 inhibited NLRP3 inflammasome activation in microglia in vitro. Further research revealed that TRPV1 channel regulated ATP-induced NLRP3 inflammasome activation through mediating Ca2+ influx and phosphorylation of phosphatase PP2A in microglia. In addition, TRPV1 deletion could alleviate mice experimental autoimmune encephalomyelitis (EAE) and reduce neuroinflammation by inhibiting NLRP3 inflammasome activation. These data suggested that the TRPV1 channel in microglia can regulate NLRP3 inflammasome activation and consequently mediate neuroinflammation. Meanwhile, our study indicated that TRPV1–Ca2+–PP2A pathway may be a novel regulator of NLRP3 inflammasome activation, pointing to TRPV1 as a potential target for CNS inflammatory diseases.

scholarly journals Sendeng-4 Suppressed Melanoma Growth by Induction of Autophagy and Apoptosis

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Rina Du ◽  
Pengwei Zhao ◽  
Shikui Wu ◽  
Yaoxing Gao ◽  
Rina Wu ◽  
...  
Keyword(s):  
Cell Death ◽  
Western Blot ◽  
Colony Formation ◽  
Inflammatory Diseases ◽  
Melanoma Cancer ◽  
M Phase ◽  
Melanoma Treatment ◽  
Cell Cycle Block ◽  
Cancer Côlon

Sendeng-4 is a traditional Chinese medicine that has been successfully applied to anti-inflammatory diseases in clinical practice. Monomers within Sendeng-4 showed promising antitumor activity against lung cancer, colon cancer, and cutaneous cancer. However, potency of Sendeng-4 in melanoma has not been explored. This study aims to explore the potential application of Sendeng-4 in melanoma treatment. In the present study, we systemically investigate the possibility of Sendeng-4 for treatment of melanoma cancer in vitro by proliferation assay, colony formation, flow cell cytometry, RNA-seq, western blot, and fluorescence-based assay. Our data demonstrated that Sendeng-4 suppresses the proliferation and colony formation capacity of melanoma cells and induces cell cycle block at G2/M phase and eventually cell death. Mechanistically, transcriptome sequencing demonstrates that the PI3K-AKT pathway was significantly inactivated upon Sendeng-4 exposure, which was confirmed by western blot showing decreased phosphorylation of AKT. In addition, decreased BCL-2 expression and increased BAX expression were observed, suggesting programmed cell death via apoptosis. Moreover, LC3-II production as well as autophagosomes formation was observed as demonstrated by western blot and immunofluorescence, indicating elevated autophagy network by Sendeng-4 stimulation. Collectively, we concluded that Sendeng-4 might be used as an anticancer drug for melanoma.

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