scholarly journals Chemosensitization of doxorubicin against lung cancer by nature borneol, involvement of TRPM8-regulated calcium mobilization

2020 ◽  
Author(s):  
Haoqiang Lai ◽  
Chang Liu ◽  
Wenwei Lin ◽  
tf Chen ◽  
An Hong
Keyword(s):  
Lung Cancer ◽  
Therapeutic Target ◽  
Transient Receptor Potential ◽  
A549 Cells ◽  
Receptor Potential ◽  
Calcium Mobilization ◽  
Ros Generation ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor

Abstract Background Lung cancer possesses high mortality rate and tolerances to multiple chemotherapeutics. Natural Borneol (NB) is a monoterpenoid compound that found to facilitate the bioavailability of drugs. In this study, we attempted to investigate effects of NB on the chemosensitivity in A549 cells and try to elucidate its therapeutic target. Methods The effects of NB on chemosensitivity in A549 cells was examined by MTT assay. The mechanism studies were evaluated by flow cytometry and western blotting assay. Surface plasmon resonance (SPR) and LC-MS combined analysis (MS-SPRi) was performed to elucidate the candidate target of NB contributes to this synergism. The chemosensitizing capacity of NB in vivo was conducted in nude mice bearing A549 tumors. Results NB pretreatment sensitizes A549 cells to low dosage of DOX, leading to a 15.7% to 41.5% increase in apoptosis, which is corelated with ERK and AKT inactivation but activation of phosphor-p38MAPK, -JNK and p53. Furthermore, this synergism depends on reactive oxygen species (ROS) generation. The MS-SPRi analysis reveals that the transient receptor potential melastatin-8 (TRPM8) is the interaction target of NB in potentiating DOX killing potency. Genetically knock down of TRPM8 significantly suppress the chemosensitizing effects of NB with the involvement of inhibiting ROS generation through restraining calcium mobilization. Moreover, pretreatment of NB synergistically enhanced the anticancer effects of DOX to delay tumor progression in vivo. Conclusions These results suggest that TRPM8 may be a valid therapeutic target in the potential application of NB serves as a chemosensitizer for lung cancer treatment.

scholarly journals Prof. Transient receptor potential vanilloid 4 promotes the growth of non-small cell lung cancer by regulating Foxp3

2022 ◽  
Author(s):  
Jiang-tao Pu ◽  
Tao Zhang ◽  
Kai-ming He ◽  
Deng-guo Zhang ◽  
Zhang-yu Teng ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Transient Receptor Potential ◽  
A549 Cells ◽  
Receptor Potential ◽  
Small Cell ◽  
Transient Receptor Potential Vanilloid ◽  
Small Cell Lung ◽  
Transient Receptor ◽  
Nsclc Patients

Objective(s): Transient receptor potential vanilloid 4 (TRPV4) participates in malignant tumor. However, the role of TRPV4 in non-small cell lung cancer (NSCLC) remains unclear. In this study, we demonstrated TRPV4 was upregulated in NSCLC tissues and NSCLC cell lines. Materials and Methods: TRPV4 level in the NSCLC patients and cell lines were detected, and its function was studied both in vivo and vitro. Results: The level of TRPV4 showed a positive correlation with tumor size of NSCLC patients. Activation TRPV4 by agonist GSK1016790A promoted cell proliferation and decreased apoptosis in A549 cells, and these effects were enhanced when the cells have overexpressed TRPV4. Moreover, GSK1016790A induced inhibitory effects on apoptosis of A549 cells was impaired when GSK1016790A used together with TRPV4 selective antagonist HC-067047, or impaired when the cells have already downregulated TRPV4 expression by TRPV4 siRNA. In vivo study, pharmacological inhibition of TRPV4 prevented A549 cells transplanted tumor growth. It was showed Foxp3 level was significantly increased in the NSCLC tissues, and showed a positive correlation with the level of TRPV4. Deactivation of TRPV4 using TRPV4 siRNA or HC-067047 significantly reduced expression of Foxp3 in GSK1016790A treated NSCLC cells. Moreover, downregulation Foxp3 by transfection of Foxp3 siRNA significantly impaired TRPV4 induced NSCLC cells proliferations in vitro. Conclusions: Antitumor effects caused by TRPV4 inhibition in NSCLC might be attributed to the suppression of Foxp3 which induced subsequent cell apoptosis. Thus, pharmacological inhibition of TRPV4 may be a promising option for NSCLC treatment.  

scholarly journals Deletion of Trpm4 alters the function and expression of NaV1.5 channel in murine cardiac myocytes

2020 ◽  
Author(s):  
Ozhathil Lijo Cherian ◽  
Jean-Sébastien Rougier ◽  
Prakash Arullampalam ◽  
Maria C. Essers ◽  
Hugues Abriel
Keyword(s):  
Cardiac Myocytes ◽  
Transient Receptor Potential ◽  
Conduction Block ◽  
Receptor Potential ◽  
Intraventricular Conduction ◽  
Cardiac Electrical Activity ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor ◽  
And Function

AbstractTransient receptor potential melastatin member 4 (TRPM4) encodes a Ca+ -activated non-selective cation channel that is functionally expressed in several tissues including the heart. Pathogenic mutants in TRPM4 have been reported in patients with inherited cardiac diseases including conduction block and Brugada syndrome. Heterologous expression of mutant channels in cell lines indicates that these mutations can lead to an increase or decrease in TRPM4 expression and function at the cell surface. While the expression and clinical variant studies further stress the importance of TRPM4 in cardiac function, the cardiac electrophysiological phenotypes in Trpm4 knockdown mouse models remain incompletely characterized. To study the functional consequences of Trpm4 deletion on cardiac electrical activity in mice, we performed perforated-patch clamp and immunohistochemistry studies on isolated atrial and ventricular cardiac myocytes and surface, pseudo and intracardiac ECGs either in vivo or on Langendorff-perfused explanted mouse hearts. We observed that Trpm4 is expressed in atrial and ventricular cardiac myocytes and that deletion of Trpm4 unexpectedly reduces the peak Na+ currents in the myocytes. Hearts from Trpm4-/- mice presented increased sensitivity towards mexiletine, a Na+ channel blocker, and slower intraventricular conduction, consistent with the reduction of peak Na+ current observed in the isolated cardiac myocytes. This reduction in Na+ current is explained by the observed decrease in protein expression of NaV1.5 in Trpm4-/- mice. This study suggests that Trpm4 expression impacts Na+ current in murine cardiac myocytes and points towards a novel function of Trpm4 regulating the NaV1.5 expression in murine cardiac myocytes.

scholarly journals A key role for Mg2+ in TRPM7's control of ROS levels during cell stress

2012 ◽  
Vol 445 (3) ◽  
pp. 441-448 ◽  
Author(s):  
Hsiang-Chin Chen ◽  
Li-Ting Su ◽  
Omayra González-Pagán ◽  
Jeffrey D. Overton ◽  
Loren W. Runnels
Keyword(s):  
Cell Survival ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Cell Types ◽  
Cell Stress ◽  
Mitogen Activated Protein Kinase ◽  
Ros Generation ◽  
Dependent Manner ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor

The TRPM7 (transient receptor potential melastatin 7) channel has been shown to play a pivotal role in cell survival during brain ischaemia as well as in the survival of other cell types challenged with apoptotic stimuli. Ca2+ is thought to be central to the channel's ability to regulate ROS (reactive oxygen species) production. However, channel-mediated entry of Mg2+ and Zn2+ have also been implicated in cell death. In the present study, we show that depletion of TRPM7 by RNA interference in fibroblasts increases cell resistance to apoptotic stimuli by decreasing ROS levels in an Mg2+-dependent manner. Depletion of TRPM7 lowered cellular Mg2+, decreased the concentration of ROS and lessened p38 MAPK (mitogen-activated protein kinase) and JNK (c-Jun N-terminal kinase) activation as well as decreased caspase 3 activation and PARP [poly(ADP-ribose) polymerase] cleavage in response to apoptotic stimuli. Re-expression of TRPM7 or of a kinase-inactive mutant of TRPM7 in TRPM7-knockdown cells increased cellular Mg2+ and ROS levels, as did expression of the Mg2+ transporter SLC41A2 (solute carrier family 41 member 2). In addition, expression of SLC41A2 increased the sensitivity of TRPM7-knockdown cells to apoptotic stimuli and boosted ROS generation in response to cell stress. Taken together, these data uncover an essential role for Mg2+ in TRPM7's control of cell survival and in the regulation of cellular ROS levels.

scholarly journals Deletion of Trpm4 Alters the Function of the Nav1.5 Channel in Murine Cardiac Myocytes

2021 ◽  
Vol 22 (7) ◽  
pp. 3401
Author(s):  
Lijo Cherian Ozhathil ◽  
Jean-Sébastien Rougier ◽  
Prakash Arullampalam ◽  
Maria C. Essers ◽  
Daniela Ross-Kaschitza ◽  
...  
Keyword(s):  
Cardiac Myocytes ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Na Channel ◽  
Na Current ◽  
Intraventricular Conduction ◽  
Cardiac Electrical Activity ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor

Transient receptor potential melastatin member 4 (TRPM4) encodes a Ca2+-activated, non-selective cation channel that is functionally expressed in several tissues, including the heart. Pathogenic mutants in TRPM4 have been reported in patients with inherited cardiac diseases, including conduction blockage and Brugada syndrome. Heterologous expression of mutant channels in cell lines indicates that these mutations can lead to an increase or decrease in TRPM4 expression and function at the cell surface. While the expression and clinical variant studies further stress the importance of TRPM4 in cardiac function, the cardiac electrophysiological phenotypes in Trpm4 knockdown mouse models remain incompletely characterized. To study the functional consequences of Trpm4 deletion on cardiac electrical activity in mice, we performed perforated-patch clamp and immunoblotting studies on isolated atrial and ventricular cardiac myocytes and surfaces, as well as on pseudo- and intracardiac ECGs, either in vivo or in Langendorff-perfused explanted mouse hearts. We observed that TRPM4 is expressed in atrial and ventricular cardiac myocytes and that deletion of Trpm4 unexpectedly reduces the peak Na+ currents in myocytes. Hearts from Trpm4−/− mice presented increased sensitivity towards mexiletine, a Na+ channel blocker, and slower intraventricular conduction, consistent with the reduction of the peak Na+ current observed in the isolated cardiac myocytes. This study suggests that TRPM4 expression impacts the Na+ current in murine cardiac myocytes and points towards a novel function of TRPM4 regulating the Nav1.5 function in murine cardiac myocytes.

The TRPM7 Channel in the Nervous and Cardiovascular Systems

2020 ◽  
Vol 21 (10) ◽  
pp. 985-992 ◽  
Author(s):  
Koichi Inoue ◽  
Zhi-Gang Xiong ◽  
Takatoshi Ueki
Keyword(s):  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Kinase Domain ◽  
Cellular Functions ◽  
Transient Receptor Potential Melastatin ◽  
Cation Permeability ◽  
Cardiovascular Systems ◽  
Transient Receptor ◽  
Excitatory Responses ◽  
Dual Operations

: Transient receptor potential melastatin 7 (TRPM7), along with the closely related TRPM6, are unique channels that have dual operations: cation permeability and kinase activity. In contrast to the limited tissue distribution of TRPM6, TRPM7 is widely expressed among tissues and is therefore implicated in a variety of cellular functions physiologically and pathophysiologically. The discovery of TRPM7’s unique structure imparting dual ion channel and kinase activities shed light onto novel and peculiar biological functions, such as Mg2+ homeostasis, cellular Ca2+ flickering, and even intranuclear transcriptional regulation by a cleaved kinase domain translocated to nuclei. Interestingly, at a higher level, TRPM7 participates in several biological processes in the nervous and cardiovascular systems, in which excitatory responses in neurons and cardiomyocytes are critical for their function. Here, we review the roles of TRPM7 in cells involved in the nervous and cardiovascular systems and discuss its potential as a future therapeutic target.

Pharmacological Inhibition of Transient Receptor Potential Melastatin 2 (TRPM2) Channels Attenuates Diabetes-induced Cognitive Deficits in Rats: A Mechanistic Study

2020 ◽  
Vol 17 (3) ◽  
pp. 249-258 ◽  
Author(s):  
Pavan Thapak ◽  
Mahendra Bishnoi ◽  
Shyam S. Sharma
Keyword(s):  
Cognitive Impairment ◽  
Cognitive Deficits ◽  
Ache Activity ◽  
Transient Receptor Potential ◽  
Mrna Level ◽  
Receptor Potential ◽  
Transient Receptor Potential Melastatin ◽  
Trpm2 Channels ◽  
Transient Receptor ◽  
Gsk 3Β

Background: Diabetes is a chronic metabolic disorder affecting the central nervous system. A growing body of evidence has depicted that high glucose level leads to the activation of the transient receptor potential melastatin 2 (TRPM2) channels. However, there are no studies targeting TRPM2 channels in diabetes-induced cognitive decline using a pharmacological approach. Objective: The present study intended to investigate the effects of 2-aminoethoxydiphenyl borate (2-APB), a TRPM2 inhibitor, in diabetes-induced cognitive impairment. Methods: Streptozotocin (STZ, 50 mg/kg, i.p.) was used to induce diabetes in rats. Animals were randomly divided into the treatment group, model group and age-matched control and pre se group. 2-APB treatment was given for three weeks to the animals. After 10 days of behavioural treatment, parameters were performed. Animals were sacrificed at 10th week of diabetic induction and the hippocampus and cortex were isolated. After that, protein and mRNA expression study was performed in the hippocampus. Acetylcholinesterase (AchE) activity was done in the cortex. Results: : Our study showed the 10th week diabetic animals developed cognitive impairment, which was evident from the behavioural parameters. Diabetic animals depicted an increase in the TRPM2 mRNA and protein expression in the hippocampus as well as increased AchE activity in the cortex. However, memory associated proteins were down-regulated, namely Ca2+/calmodulin-dependent protein kinase II (CaMKII-Thr286), glycogen synthase kinase 3 beta (GSK-3β-Ser9), cAMP response element-binding protein (CREB-Ser133), and postsynaptic density protein 95 (PSD-95). Gene expression of parvalbumin, calsequestrin and brain-derived neurotrophic factor (BDNF) were down-regulated while mRNA level of calcineurin A/ protein phosphatase 3 catalytic subunit alpha (PPP3CA) was upregulated in the hippocampus of diabetic animals. A three-week treatment with 2-APB significantly ameliorated the alteration in behavioural cognitive parameters in diabetic rats. Moreover, 2-APB also down-regulated the expression of TRPM2 mRNA and protein in the hippocampus as well as AchE activity in the cortex of diabetic animals as compared to diabetic animals. Moreover, the 2-APB treatment also upregulated the CaMKII (Thr-286), GSK-3β (Ser9), CREB (Ser133), and PSD-95 expression and mRNA levels of parvalbumin, calsequestrin, and BDNF while mRNA level of calcineurin A was down-regulated in the hippocampus of diabetic animals. Conclusion: : This study confirms the ameliorative effect of TRPM2 channel inhibitor in the diabetes- induced cognitive deficits. Inhibition of TRPM2 channels reduced the calcium associated downstream signaling and showed a neuroprotective effect of TRPM2 channels in diabetesinduced cognitive impairment.

Characterization of the function of transient receptor potential melastatin 2 in mouse pancreas

Pancreatology ◽  
2019 ◽  
Vol 19 ◽  
pp. S94
Author(s):  
Júlia Fanczal ◽  
Petra Pallagi ◽  
Marietta Görög ◽  
Csaba Péter Bíró ◽  
Tamara Madácsy ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Mouse Pancreas ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor
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