scholarly journals Cinnamaldehyde Induces Release of Cholecystokinin and Glucagon-Like Peptide 1 by Interacting with Transient Receptor Potential Ankyrin 1 in a Porcine Ex-Vivo Intestinal Segment Model

Animals ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 2262
Author(s):  
Elout Van Liefferinge ◽  
Maximiliano Müller ◽  
Noémie Van Noten ◽  
Jeroen Degroote ◽  
Shahram Niknafs ◽  
...  
Keyword(s):  
Small Intestine ◽  
Transient Receptor Potential ◽  
Ex Vivo ◽  
Receptor Potential ◽  
Intestinal Segment ◽  
Gastric Function ◽  
Segment Model ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Transient Receptor

Cinnamaldehyde and capsaicin have been reported to exert effects on the gastric function, mediated by the interaction with transient receptor potential ankyrin channel 1 (TRPA1) and transient receptor potential vanilloid channel 1 (TRPV1), respectively. This study examined whether these compounds could trigger the release of cholecystokinin (CCK) and/or glucagon-like peptide 1 (GLP-1) in the pig’s gut in a porcine ex-vivo intestinal segment model. Furthermore, it was verified whether this response was mediated by TRPA1 or TRPV1 by using the channel’s antagonist. These gut peptides play a key role in the “intestinal brake", a feedback mechanism that influences the function of proximal parts of the gut. Structural analogues of cinnamaldehyde were screened as well, to explore structure-dependent activation. Results showed a significant effect of capsaicin on GLP-1 release in the proximal small intestine, TRPV1 independent. TRPA1 showed to be strongly activated by cinnamaldehyde, both in proximal and distal small intestine, evidenced by the release of CCK and GLP-1, respectively. Out of all structural derivates, cinnamaldehyde showed the highest affinity for TRPA1, which elucidates the importance of the α,β-unsaturated aldehyde moiety. In conclusion, cinnamaldehyde as a TRPA1 agonist, is a promising candidate to modulate gastric function, by activating intestinal brake mechanisms.

scholarly journals Capsazepine decreases corneal pain syndrome in severe dry eye disease

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Darine Fakih ◽  
Adrian Guerrero-Moreno ◽  
Christophe Baudouin ◽  
Annabelle Réaux-Le Goazigo ◽  
Stéphane Mélik Parsadaniantz
Keyword(s):  
In Situ Hybridization ◽  
Inflammatory Pain ◽  
Transient Receptor Potential ◽  
Ex Vivo ◽  
Receptor Potential ◽  
Eye Disease ◽  
Ocular Pain ◽  
Trpv1 Antagonist ◽  
Transient Receptor

Abstract Background Dry eye disease (DED) is a multifactorial disease of the ocular surface accompanied by neurosensory abnormalities. Here, we evaluated the effectiveness of transient receptor potential vanilloid-1 (TRPV1) blockade to alleviate ocular pain, neuroinflammation, and anxiety-like behavior associated with severe DED. Methods Chronic DED was induced by unilateral excision of the Harderian and extraorbital lacrimal glands of adult male mice. Investigations were conducted at 21 days after surgery. The mRNA levels of TRPV1, transient receptor potential ankyrin-1 (TRPA1), and acid-sensing ion channels 1 and 3 (ASIC1 and ASIC3) in the trigeminal ganglion (TG) were evaluated by RNAscope in situ hybridization. Multi-unit extracellular recording of ciliary nerve fiber activity was used to monitor spontaneous and stimulated (cold, heat, and acid) corneal nerve responsiveness in ex vivo eye preparations. DED mice received topical instillations of the TRPV1 antagonist (capsazepine) twice a day for 2 weeks from d7 to d21 after surgery. The expression of genes involved in neuropathic and inflammatory pain was evaluated in the TG using a global genomic approach. Chemical and mechanical corneal nociception and spontaneous ocular pain were monitored. Finally, anxiety-like behaviors were assessed by elevated plus maze and black and white box tests. Results First, in situ hybridization showed DED to trigger upregulation of TRPV1, TRPA1, ASIC1, and ASIC3 mRNA in the ophthalmic branch of the TG. DED also induced overexpression of genes involved in neuropathic and inflammatory pain in the TG. Repeated instillations of capsazepine reduced corneal polymodal responsiveness to heat, cold, and acidic stimulation in ex vivo eye preparations. Consistent with these findings, chronic capsazepine instillation inhibited the upregulation of genes involved in neuropathic and inflammatory pain in the TG of DED animals and reduced the sensation of ocular pain, as well as anxiety-like behaviors associated with severe DED. Conclusion These data provide novel insights on the effectiveness of TRPV1 antagonist instillation in alleviating abnormal corneal neurosensory symptoms induced by severe DED, opening an avenue for the repositioning of this molecule as a potential analgesic treatment for patients suffering from chronic DED.

scholarly journals A TRPM4 Inhibitor 9-Phenanthrol Inhibits Glucose- and Glucagon-Like Peptide 1-Induced Insulin Secretion from Rat Islets of Langerhans

2017 ◽  
Vol 2017 ◽  
pp. 1-5 ◽  
Author(s):  
Zuheng Ma ◽  
Anneli Björklund ◽  
Md. Shahidul Islam
Keyword(s):  
Insulin Secretion ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Monovalent Cation ◽  
Major Effect ◽  
Hyperinsulinemic Hypoglycemia ◽  
Rat Islets ◽  
Glucagon Like Peptide 1 ◽  
Transient Receptor ◽  
Rat Islets Of Langerhans

Pancreatic β-cells express several ion channels of the transient receptor potential family, which play important roles in mediating the stimulus-secretion coupling. One of these channels, the TRPM4 is a Ca2+-activated monovalent cation channel. This channel is inhibited by 9-phenanthrol, which also inhibits the TMEM16a Cl− channel, and activates the Ca2+-activated K+ channel, Kca3.1. The net effects of ion-channel modulation by 9-phenantherol on the insulin secretion remain unclear. We tested the effects of 9-phenanthrol on glucose- and GLP-1-induced insulin secretion from isolated rat islets in static incubations. When applied to the islets in the presence of 3.3 mM glucose, 9-phenanthrol caused a small increase in insulin secretion (~7% of the insulin secretion stimulated by 10 mM glucose). 10 μM 9-phenanthrol did not inhibit glucose- or GLP-1-induced insulin secretion. 20 μM and 30 μM 9-phenanthrol inhibited glucose-induced insulin secretion by ~80% and ~85%, respectively. Inhibition of the GLP-1-induced insulin secretion by 20 μM and 30 μM 9-phenanthrol was 65% and 94%, respectively. Our study shows that the major effect of 9-phenanthrol on the islets is a strong inhibition of insulin secretion, and we speculate that compounds related to 9-phenanthrol may be potentially useful in treating the pancreatogenous hyperinsulinemic hypoglycemia syndromes.

scholarly journals Epithelial transient receptor potential ankyrin 1 (TRPA1)-dependent adrenomedullin upregulates blood flow in rat small intestine

2013 ◽  
Vol 304 (4) ◽  
pp. G428-G436 ◽  
Author(s):  
Toru Kono ◽  
Atsushi Kaneko ◽  
Yuji Omiya ◽  
Katsuya Ohbuchi ◽  
Nagisa Ohno ◽  
...  
Keyword(s):  
Blood Flow ◽  
Small Intestine ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Receptor Potential ◽  
Allyl Isothiocyanate ◽  
Antibody Treatment ◽  
Functional Roles ◽  
Transient Receptor

The functional roles of transient receptor potential (TRP) channels in the gastrointestinal tract have garnered considerable attention in recent years. We previously reported that daikenchuto (TU-100), a traditional Japanese herbal medicine, increased intestinal blood flow (IBF) via adrenomedullin (ADM) release from intestinal epithelial (IE) cells (Kono T et al. J Crohns Colitis 4: 161–170, 2010). TU-100 contains multiple TRP activators. In the present study, therefore, we examined the involvement of TRP channels in the ADM-mediated vasodilatatory effect of TU-100. Rats were treated intraduodenally with the TRP vanilloid type 1 (TRPV1) agonist capsaicin (CAP), the TRP ankyrin 1 (TRPA1) agonist allyl-isothiocyanate (AITC), or TU-100, and jejunum IBF was evaluated using laser-Doppler blood flowmetry. All three compounds resulted in vasodilatation, and the vasodilatory effect of TU-100 was abolished by a TRPA1 antagonist but not by a TRPV1 antagonist. Vasodilatation induced by AITC and TU-100 was abrogated by anti-ADM antibody treatment. RT-PCR and flow cytometry revealed that an IEC-6 cell line originated from the small intestine and purified IE cells expressed ADM and TRPA1 but not TRPV1. AITC increased ADM release in IEC cells remarkably, while CAP had no effect. TU-100 and its ingredient 6-shogaol (6SG) increased ADM release dose-dependently, and the effects were abrogated by a TRPA1 antagonist. 6SG showed similar TRPA1-dependent vasodilatation in vivo. These results indicate that TRPA1 in IE cells may play an important role in controlling bowel microcirculation via ADM release. Epithelial TRPA1 appears to be a promising target for the development of novel strategies for the treatment of various gastrointestinal disorders.

scholarly journals TRPM8 function and expression in vagal sensory neurons and afferent nerves innervating guinea pig esophagus

2015 ◽  
Vol 308 (6) ◽  
pp. G489-G496 ◽  
Author(s):  
Xiaoyun Yu ◽  
Youtian Hu ◽  
Fei Ru ◽  
Marian Kollarik ◽  
Bradley J. Undem ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Calcium Influx ◽  
Ex Vivo ◽  
Receptor Potential ◽  
Sensory Transduction ◽  
Dependent Manner ◽  
Preferential Expression ◽  
C Fibers ◽  
C Fiber ◽  
Transient Receptor

Sensory transduction in esophageal afferents requires specific ion channels and receptors. TRPM8 is a new member of the transient receptor potential (TRP) channel family and participates in cold- and menthol-induced sensory transduction, but its role in visceral sensory transduction is still less clear. This study aims to determine TRPM8 function and expression in esophageal vagal afferent subtypes. TRPM8 agonist WS-12-induced responses were first determined in nodose and jugular neurons by calcium imaging and then investigated by whole cell patch-clamp recordings in Dil-labeled esophageal nodose and jugular neurons. Extracellular single-unit recordings were performed in nodose and jugular C fiber neurons using ex vivo esophageal-vagal preparations with intact nerve endings in the esophagus. TRPM8 mRNA expression was determined by single neuron RT-PCR in Dil-labeled esophageal nodose and jugular neurons. The TRPM8 agonist WS-12 elicited calcium influx in a subpopulation of jugular but not nodose neurons. WS-12 activated outwardly rectifying currents in esophageal Dil-labeled jugular but not nodose neurons in a dose-dependent manner, which could be inhibited by the TRPM8 inhibitor AMTB. WS-12 selectively evoked action potential discharges in esophageal jugular but not nodose C fibers. Consistently, TRPM8 transcripts were highly expressed in esophageal Dil-labeled TRPV1-positive jugular neurons. In summary, the present study demonstrated a preferential expression and function of TRPM8 in esophageal vagal jugular but not nodose neurons and C fiber subtypes. This provides a distinctive role of TRPM8 in esophageal sensory transduction and may lead to a better understanding of the mechanisms of esophageal sensation and nociception.

scholarly journals Mechanisms of the adenosine A2Areceptor-induced sensitization of esophageal C fibers

2016 ◽  
Vol 310 (3) ◽  
pp. G215-G223 ◽  
Author(s):  
M. Brozmanova ◽  
L. Mazurova ◽  
F. Ru ◽  
M. Tatar ◽  
Y. Hu ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Mechanical Response ◽  
Kinase Inhibitor ◽  
Ex Vivo ◽  
Receptor Potential ◽  
P2x Receptor ◽  
C Fibers ◽  
C Fiber ◽  
Transient Receptor ◽  
Stimulation Of

Clinical studies indicate that adenosine contributes to esophageal mechanical hypersensitivity in some patients with pain originating in the esophagus. We have previously reported that the esophageal vagal nodose C fibers express the adenosine A2Areceptor. Here we addressed the hypothesis that stimulation of the adenosine A2Areceptor induces mechanical sensitization of esophageal C fibers by a mechanism involving transient receptor potential A1 (TRPA1). Extracellular single fiber recordings of activity originating in C-fiber terminals were made in the ex vivo vagally innervated guinea pig esophagus. The adenosine A2Areceptor-selective agonist CGS21680 induced robust, reversible sensitization of the response to esophageal distention (10–60 mmHg) in a concentration-dependent fashion (1–100 nM). At the half-maximally effective concentration (EC50: ≈3 nM), CGS21680 induced an approximately twofold increase in the mechanical response without causing an overt activation. This sensitization was abolished by the selective A2Aantagonist SCH58261. The adenylyl cyclase activator forskolin mimicked while the nonselective protein kinase inhibitor H89 inhibited mechanical sensitization by CGS21680. CGS21680 did not enhance the response to the purinergic P2X receptor agonist α,β-methylene-ATP, indicating that CGS21680 does not nonspecifically sensitize to all stimuli. Mechanical sensitization by CGS21680 was abolished by pretreatment with two structurally different TRPA1 antagonists AP18 and HC030031 . Single cell RT-PCR and whole cell patch-clamp studies in isolated esophagus-specific nodose neurons revealed the expression of TRPA1 in A2A-positive C-fiber neurons and demonstrated that CGS21682 potentiated TRPA1 currents evoked by allylisothiocyanate. We conclude that stimulation of the adenosine A2Areceptor induces mechanical sensitization of nodose C fibers by a mechanism sensitive to TRPA1 antagonists indicating the involvement of TRPA1.

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.

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