scholarly journals Novel Potentials of the DPP-4 Inhibitor Sitagliptin against Ischemia-Reperfusion (I/R) Injury in Rat Ex-Vivo Heart Model

2018 ◽  
Vol 19 (10) ◽  
pp. 3226 ◽  
Author(s):  
Amin Al-awar ◽  
Nikoletta Almási ◽  
Renáta Szabó ◽  
Istvan Takacs ◽  
Zsolt Murlasits ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Trp Channels ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Oral Treatment ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Dipeptidyl Peptidase 4 ◽  
Regional Ischemia ◽  
Transient Receptor

Dipeptidyl peptidase-4 (DPP-4) inhibitors are a class of oral anti-diabetic drugs, implicated in pleiotropic secondary cardioprotective effects. The aim of the study was to unveil the unknown and possible cardioprotective targets that can be exerted by sitagliptin (Sitg) against ischemia-reperfusion (I/R) injury. Male wistar rats received 2 weeks’ Sitg oral treatment of different doses (25, 50, 100, and 150 mg/kg/day), or saline as a Control. Hearts were then isolated and subjected to two different I/R injury protocols: 10 min perfusion, 45 min regional ischemia, and 120 min reperfusion for infarct size (IS) measurement, or: 10 min perfusion, 45 min regional ischemia and 10 min reperfusion for biochemical analysis: nitric oxide synthases (NOSs) and DPP-4 activity, glucagon-like peptide-1 (GLP-1), Calcium, transient receptor potential vanilloid (TRPV)-1 and calcitonin gene-related peptide (CGRP) levels, transient receptor potential canonical (TRPC)-1 and e-NOS protein expression. NOS inhibitor (l-NAME) and TRPV-1 inhibitor (Capsazepine) were utilized to confirm the implication of both signaling mechanisms in DPP-4 inhibition-induced at the level of IS. Findings show that Sitg (50 mg) resulted in significant decrease in IS and DPP-4 activity, and significant increase in GLP-1, NOS activity, e-NOS expression, TRPV-1 level and TRPC-1 expression, compared to controls. Results of CGRP are in line with TRPV-1, as a downstream regulatory effect. NOS system and transient receptor potential (TRP) channels can contribute to DPP-4 inhibition-mediated cardioprotection against I/R injury using Sitagliptin.

scholarly journals Analgesic Effects of Lipid Raft Disruption by Sphingomyelinase and Myriocin via Transient Receptor Potential Vanilloid 1 and Transient Receptor Potential Ankyrin 1 Ion Channel Modulation

2021 ◽  
Vol 11 ◽  
Author(s):  
Ádám Horváth ◽  
Maja Payrits ◽  
Anita Steib ◽  
Boglárka Kántás ◽  
Tünde Biró-Süt ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Lipid Raft ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Receptor Potential ◽  
Membrane Microdomains ◽  
Neuronal Cultures ◽  
Transient Receptor Potential Vanilloid ◽  
Peripheral Sensitization ◽  
Transient Receptor

Transient Receptor Potential (TRP) Vanilloid 1 and Ankyrin 1 (TRPV1, TRPA1) cation channels are expressed in nociceptive primary sensory neurons, and integratively regulate nociceptor and inflammatory functions. Lipid rafts are liquid-ordered plasma membrane microdomains rich in cholesterol, sphingomyelin and gangliosides. We earlier showed that lipid raft disruption inhibits TRPV1 and TRPA1 functions in primary sensory neuronal cultures. Here we investigated the effects of sphingomyelinase (SMase) cleaving membrane sphingomyelin and myriocin (Myr) prohibiting sphingolipid synthesis in mouse pain models of different mechanisms. SMase (50 mU) or Myr (1 mM) pretreatment significantly decreased TRPV1 activation (capsaicin)-induced nocifensive eye-wiping movements by 37 and 41%, respectively. Intraplantar pretreatment by both compounds significantly diminished TRPV1 stimulation (resiniferatoxin)-evoked thermal allodynia developing mainly by peripheral sensitization. SMase (50 mU) also decreased mechanical hyperalgesia related to both peripheral and central sensitizations. SMase (50 mU) significantly reduced TRPA1 activation (formalin)-induced acute nocifensive behaviors by 64% in the second, neurogenic inflammatory phase. Myr, but not SMase altered the plasma membrane polarity related to the cholesterol composition as shown by fluorescence spectroscopy. These are the first in vivo results showing that sphingolipids play a key role in lipid raft integrity around nociceptive TRP channels, their activation and pain sensation. It is concluded that local SMase administration might open novel perspective for analgesic therapy.

scholarly journals TRPV1 channels and the progesterone receptor Sig-1R interact to regulate pain

2018 ◽  
Vol 115 (7) ◽  
pp. E1657-E1666 ◽  
Author(s):  
Miguel Ortíz-Rentería ◽  
Rebeca Juárez-Contreras ◽  
Ricardo González-Ramírez ◽  
León D. Islas ◽  
Félix Sierra-Ramírez ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Trp Channels ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Sigma 1 Receptor ◽  
Trpv1 Channels ◽  
Nociceptive Responses ◽  
Sigma 1 ◽  
Transient Receptor ◽  
Thermal Stimuli

The Transient Receptor Potential Vanilloid 1 (TRPV1) ion channel is expressed in nociceptors where, when activated by chemical or thermal stimuli, it functions as an important transducer of painful and itch-related stimuli. Although the interaction of TRPV1 with proteins that regulate its function has been previously explored, their modulation by chaperones has not been elucidated, as is the case for other mammalian TRP channels. Here we show that TRPV1 physically interacts with the Sigma 1 Receptor (Sig-1R), a chaperone that binds progesterone, an antagonist of Sig-1R and an important neurosteroid associated to the modulation of pain. Antagonism of Sig-1R by progesterone results in the down-regulation of TRPV1 expression in the plasma membrane of sensory neurons and, consequently, a decrease in capsaicin-induced nociceptive responses. This is observed both in males treated with a synthetic antagonist of Sig-1R and in pregnant females where progesterone levels are elevated. This constitutes a previously undescribed mechanism by which TRPV1-dependent nociception and pain can be regulated.

scholarly journals Investigating the Multitarget Mechanism of Traditional Chinese Medicine Prescription for Cancer-Related Pain by Using Network Pharmacology and Molecular Docking Approach

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Jinyuan Chang ◽  
Lixing Liu ◽  
Yaohan Wang ◽  
Yutong Sui ◽  
Hao Li ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Receptor Potential ◽  
Binding Activity ◽  
Mitogen Activated Protein Kinase ◽  
Network Pharmacology ◽  
Transient Receptor Potential Vanilloid ◽  
Mitogen Activated Protein ◽  
Transient Receptor

Gu-tong formula (GTF) has achieved good curative effects in the treatment of cancer-related pain. However, its potential mechanisms have not been explored. We used network pharmacology and molecular docking to investigate the molecular mechanism and the effective compounds of the prescription. Through the analysis and research in this paper, we obtained 74 effective compounds and 125 drug-disease intersection targets to construct a network, indicating that quercetin, kaempferol, and β-sitosterol were possibly the most important compounds in GTF. The key targets of GTF for cancer-related pain were Jun proto-oncogene (JUN), mitogen-activated protein kinase 1 (MAPK1), and RELA proto-oncogene (RELA). 2204 GO entries and 148 pathways were obtained by GO and KEGG enrichment, respectively, which proved that chemokine, MAPK, and transient receptor potential (TRP) channels can be regulated by GTF. The results of molecular docking showed that stigmasterol had strong binding activity with arginine vasopressin receptor 2 (AVPR2) and C-X3-C motif chemokine ligand 1 (CX3CL1) and cholesterol was more stable with p38 MAPK, prostaglandin-endoperoxide synthase 2 (PTGS2), and transient receptor potential vanilloid-1 (TRPV1). In conclusion, the therapeutic effect of GTF on cancer-related pain is based on the comprehensive pharmacological effect of multicomponent, multitarget, and multichannel pathways. This study provides a theoretical basis for further experimental research in the future.

scholarly journals The nonselective cation channel TRPV4 inhibits angiotensin II receptors

2020 ◽  
Vol 295 (29) ◽  
pp. 9986-9997
Author(s):  
Nicholas W. Zaccor ◽  
Charlotte J. Sumner ◽  
Solomon H. Snyder
Keyword(s):  
Angiotensin Ii ◽  
G Protein ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Receptor Potential ◽  
Trp Channel ◽  
Luciferase Assay ◽  
Transient Receptor Potential Vanilloid ◽  
Dependent Manner ◽  
Transient Receptor

G-protein–coupled receptors (GPCRs) are a ubiquitously expressed family of receptor proteins that regulate many physiological functions and other proteins. They act through two dissociable signaling pathways: the exchange of GDP to GTP by linked G-proteins and the recruitment of β-arrestins. GPCRs modulate several members of the transient receptor potential (TRP) channel family of nonselective cation channels. How TRP channels reciprocally regulate GPCR signaling is less well-explored. Here, using an array of biochemical approaches, including immunoprecipitation and fluorescence, calcium imaging, phosphate radiolabeling, and a β-arrestin–dependent luciferase assay, we characterize a GPCR–TRP channel pair, angiotensin II receptor type 1 (AT1R), and transient receptor potential vanilloid 4 (TRPV4), in primary murine choroid plexus epithelial cells and immortalized cell lines. We found that AT1R and TRPV4 are binding partners and that activation of AT1R by angiotensin II (ANGII) elicits β-arrestin–dependent inhibition and internalization of TRPV4. Activating TRPV4 with endogenous and synthetic agonists inhibited angiotensin II–mediated G-protein–associated second messenger accumulation, AT1R receptor phosphorylation, and β-arrestin recruitment. We also noted that TRPV4 inhibits AT1R phosphorylation by activating the calcium-activated phosphatase calcineurin in a Ca2+/calmodulin–dependent manner, preventing β-arrestin recruitment and receptor internalization. These findings suggest that when TRP channels and GPCRs are co-expressed in the same tissues, many of these channels can inhibit GPCR desensitization.

scholarly journals TRP Receptors in Arthritis, Gaining Knowledge for Translation from Experimental Models

2013 ◽  
Vol 6 (1) ◽  
pp. 50-61 ◽  
Author(s):  
E.S. Fernandes ◽  
S. Awal ◽  
R. Karadaghi ◽  
S.D. Brain
Keyword(s):  
Transient Receptor Potential ◽  
Trp Channels ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Joint Movement ◽  
New Findings ◽  
Wide Range ◽  
Clinical Models ◽  
Transient Receptor ◽  
Trp Receptors

Arthritis is a condition characterised by mainly pain, reduced joint movement and signs of inflammation, such as swelling. The disorder has many different types, of which osteoarthritis (a degenerative joint disease) and rheumatoid arthritis (a chronic autoimmune disease) are the two most common forms. There are >6 million sufferers in the UK and both conditions have a huge potential to impair capabilities and contribute to social and economic burdens. Whilst there are a wide range of arthritic therapies available, many patients under treatment complain of poor pain relief. Thus there is a need for novel therapeutic approaches, and the transient receptor potential (TRP) family of receptor channels has been investigated. One particular area of recent research has been the ligand-gated transient receptor potential vanilloid 1 (TRPV1) channel. Findings from numerous pre-clinical models and scientific studies have shown that TRPV1 desensitisation, or the use of TRPV1 antagonists alleviates pain and some inflammatory aspects. New findings have started to unveil the potential of other TRP channels in mediating arthritic pain and inflammation. With the understanding that the currently available treatments for arthritis are limited, researchers have looked into the exciting prospect that TRP receptor antagonists may be developed into effective, specific drugs, which would potentially protect against the complications of arthritis. These antagonists are still under development, although only data from studies from pre-clinical models are currently available. This review acts to summarize knowledge of the potential influence of TRP receptors in arthritis to date.

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