29 research outputs found
Central GPR109A Mediates Neuronal Oxidative Stress and Pressor Response in Conscious Rats
No full textThe primary goal of this study was to characterize the role of GPR109A in the rostral ventrolateral medulla (RVLM) in blood pressure (BP) regulation and to elucidate the mechanisms involved in the hypertensive response elicited by central GPR109A activation. The central hypothesis of this study was "central GPR109A activation causes neuronal oxidative stress and pressor response via local glutamate/prostaglandins release". The data provide the first evidence for GPR109A expression in the RVLM, the major cardiovascular regulatory nucleus of the brainstem, and in pheochromocytoma cell line (PC12 cells), used as surrogates of the RVLM neurons. GPR109A co-localization was evident in tyrosine hydroxylase (TH)-expressing neurons and in PC12 cells. The anti-hyperlipidemic drug, nicotinic acid (NA) a known GPR109A agonist that activate the receptor and Ca2+-dependently release prostaglandins (PGs), was used in the study. Our findings demonstrated that intra-RVLM activation of GPR109A receptors with NA produced a robust dose-dependent glutamate-like elevation in sympathetic tone and BP in normotensive conscious male Sprague Dawley (SD) rats. The pressor response was abolished by prior blockade of the NMDA glutamate receptor (NMDAR) using 2-amino-5-phosphonopentanoic acid (AP5) or the prostanoid EP3 receptor (EP3R) using N-[(5-Bromo-2-methoxyphenyl) sulfonyl]-3-[2-(2-naphthalenylmethyl)phenyl]-2-propenamide (L-798106). Further, the NA pressor response was exacerbated by a prior application of the glutamate uptake inhibitor, L-trans-Pyrrolidine-2,4-dicarboxylic acid (PDC). Ex vivo studies revealed that intra-RVLM GPR109A activation (NA; 20[mu]g) increased local prostaglandin E2 (PGE2) levels, enhanced RVLM ERK1/2 and nNOS phosphorylation and increased c-Fos immunoreactivity. Further, NA induced oxidative stress in the RVLM of NA-treated rats (increased ROS levels and NADPH oxidase activity and decreased catalase activity). Prior EP3R blockade (L-798106) abrogated the biochemical and the pressor response caused by intra-RVLM NA. NMDAR (AP5) or EP3R blockade similarly abolished NA-mediated pressor response, indicating the involvement of both glutamate and PGE2 in this effect. Selective inhibition of RVLM nNOS (N[omega]-propyl-L-arginine; NPLA) abolished the intra-RVLM NA-evoked pressor response. Further, NPLA abrogated the GPR109A-mediated increases in RVLM nNOS phosphorylation and c-Fos and ROS levels. Our in vitro (PC12) studies supported and extended the in-vivo findings as NA increased Ca2+, PGE2, L-glutamate and NO levels as well as ROS levels in cultured PC12 cells. The increase in L-glutamate level is likely mediated by PGE2/EP3R because L-798106 attenuated NA or PGE2-evoked L-glutamate release. The above-mentioned effects are mediated via GPR109A because the use of the inactive isomer, IsoNA failed to produce any hemodynamic or biochemical changes. Further, NA failed to increase Ca2+ or L-glutamate levels in PC12 cells following siRNA-evoked GPR109A knockdown. Collectively, these studies provide insight into identifying the role of central GPR109A activation in cardiovascular regulation in conscious animals and the potential mechanisms involved in this effect
Syzygium aqueum: A Polyphenol- Rich Leaf Extract Exhibits Antioxidant, Hepatoprotective, Pain-Killing and Anti-inflammatory Activities in Animal Models
Get PDFSyzygium aqueum is widely used in folk medicine. A polyphenol-rich extract from its leaves demonstrated a plethora of substantial pharmacological properties. The extract showed solid antioxidant properties in vitro and protected human keratinocytes (HaCaT cells) against UVA damage. The extract also reduced the elevated levels of ALT, AST, total bilirubin (TB), total cholesterol (TC) and triglycerides (TG) in rats with acute CCl4 intoxication. In addition to reducing the high MDA level, the extract noticeably restored GSH and SOD to the normal control levels in liver tissue homogenates and counteracted the deleterious histopathologic changes in liver after CCl4 injection. Additionally, the extract exhibited promising anti-inflammatory activities in vitro where it inhibited LOX, COX-1, and COX-2 with a higher COX-2 selectivity than that of indomethacin and diclofenac and reduced the extent of lysis of erythrocytes upon incubation with hypotonic buffer solution. S. aqueum extract also markedly reduced leukocyte numbers with similar activities to diclofenac in rats challenged with carrageenan. Additionally, administration of the extract abolished writhes induced by acetic acid in mice and prolonged the response latency in hot plate test. Meanwhile, the identified polyphenolics from the extract showed a certain affinity for the active pockets of 5-lipoxygenase (5-LOX), cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) explaining the observed anti-inflammatory activities. Finally, 87 secondary metabolites (mostly phenolics) were tentatively identified in the extract based on LC-MS/MS analyses. Syzygium aqueum displays good protection against oxidative stress, free radicals, and could be a good candidate for treating oxidative stress related diseases
Renin‐angiotensin system blockade modulates both the peripheral and central components of neuropathic pain in rats: Role of calcitonin gene–related peptide, substance P and nitric oxide
No full textRETRACTED ARTICLE: Mechanisms Involved in Superiority of Angiotensin Receptor Blockade over ACE Inhibition in Attenuating Neuropathic Pain Induced in Rats
No full textDoxazosin down‐regulates sodium‐glucose cotransporter‐2 and exerts a renoprotective effect in rat models of acute renal injury
No full textCentral GPR109A Mediates Neuronal Oxidative Stress and Pressor Response in Conscious Rats
No full textThe primary goal of this study was to characterize the role of GPR109A in the rostral ventrolateral medulla (RVLM) in blood pressure (BP) regulation and to elucidate the mechanisms involved in the hypertensive response elicited by central GPR109A activation. The central hypothesis of this study was "central GPR109A activation causes neuronal oxidative stress and pressor response via local glutamate/prostaglandins release". The data provide the first evidence for GPR109A expression in the RVLM, the major cardiovascular regulatory nucleus of the brainstem, and in pheochromocytoma cell line (PC12 cells), used as surrogates of the RVLM neurons. GPR109A co-localization was evident in tyrosine hydroxylase (TH)-expressing neurons and in PC12 cells. The anti-hyperlipidemic drug, nicotinic acid (NA) a known GPR109A agonist that activate the receptor and Ca2+-dependently release prostaglandins (PGs), was used in the study. Our findings demonstrated that intra-RVLM activation of GPR109A receptors with NA produced a robust dose-dependent glutamate-like elevation in sympathetic tone and BP in normotensive conscious male Sprague Dawley (SD) rats. The pressor response was abolished by prior blockade of the NMDA glutamate receptor (NMDAR) using 2-amino-5-phosphonopentanoic acid (AP5) or the prostanoid EP3 receptor (EP3R) using N-[(5-Bromo-2-methoxyphenyl) sulfonyl]-3-[2-(2-naphthalenylmethyl)phenyl]-2-propenamide (L-798106). Further, the NA pressor response was exacerbated by a prior application of the glutamate uptake inhibitor, L-trans-Pyrrolidine-2,4-dicarboxylic acid (PDC). Ex vivo studies revealed that intra-RVLM GPR109A activation (NA\; 20[mu]g) increased local prostaglandin E2 (PGE2) levels, enhanced RVLM ERK1/2 and nNOS phosphorylation and increased c-Fos immunoreactivity. Further, NA induced oxidative stress in the RVLM of NA-treated rats (increased ROS levels and NADPH oxidase activity and decreased catalase activity). Prior EP3R blockade (L-798106) abrogated the biochemical and the pressor response caused by intra-RVLM NA. NMDAR (AP5) or EP3R blockade similarly abolished NA-mediated pressor response, indicating the involvement of both glutamate and PGE2 in this effect. Selective inhibition of RVLM nNOS (N[omega]-propyl-L-arginine\; NPLA) abolished the intra-RVLM NA-evoked pressor response. Further, NPLA abrogated the GPR109A-mediated increases in RVLM nNOS phosphorylation and c-Fos and ROS levels. Our in vitro (PC12) studies supported and extended the in-vivo findings as NA increased Ca2+, PGE2, L-glutamate and NO levels as well as ROS levels in cultured PC12 cells. The increase in L-glutamate level is likely mediated by PGE2/EP3R because L-798106 attenuated NA or PGE2-evoked L-glutamate release. The above-mentioned effects are mediated via GPR109A because the use of the inactive isomer, IsoNA failed to produce any hemodynamic or biochemical changes. Further, NA failed to increase Ca2+ or L-glutamate levels in PC12 cells following siRNA-evoked GPR109A knockdown. Collectively, these studies provide insight into identifying the role of central GPR109A activation in cardiovascular regulation in conscious animals and the potential mechanisms involved in this effect
Triple targeting of mutant EGFRL858R/T790M, COX-2, and 15-LOX: design and synthesis of novel quinazolinone tethered phenyl urea derivatives for anti-inflammatory and anticancer evaluation
No full textWe designed and synthesised novel quinazolinone tethered phenyl urea derivatives (6a–p) that triple target the double mutant EGFRL858R/T790M, COX-2, and 15-LOX. Compounds (6e, 6d, 6j, 6m, and 6n) not only had low micromolar IC50 inhibitory activities against the three targets, but they also showed good selectivity for COX-2 over COX-1 and for EGFRL858R/T790M over wild-type EGFR. Except for 6e and 6n, all of the tested compounds inhibited the NO production significantly more potently than celecoxib, diclofenac, and indomethacin. Compounds 6i and 6k reduced ROS levels more effectively than celecoxib and diclofenac. In terms of inhibiting TNF-α production, 6o-treated cells showed TNF-α level, which is ∼10 times lower than celecoxib. Furthermore, 6e and 6j had the highest anticancer activity against the breast cancer cell line BT-459 with growth inhibition percentages of 67.14 and 70.07%, respectively. Docking studies confirm their favoured binding affinity. The proposed compounds could be promising multi-targeted leads
Triple targeting of mutant EGFR<sup>L858R/T790M</sup>, COX-2, and 15-LOX: design and synthesis of novel quinazolinone tethered phenyl urea derivatives for anti-inflammatory and anticancer evaluation
No full textWe designed and synthesised novel quinazolinone tethered phenyl urea derivatives (6a–p) that triple target the double mutant EGFRL858R/T790M, COX-2, and 15-LOX. Compounds (6e, 6d, 6j, 6m, and 6n) not only had low micromolar IC50 inhibitory activities against the three targets, but they also showed good selectivity for COX-2 over COX-1 and for EGFRL858R/T790M over wild-type EGFR. Except for 6e and 6n, all of the tested compounds inhibited the NO production significantly more potently than celecoxib, diclofenac, and indomethacin. Compounds 6i and 6k reduced ROS levels more effectively than celecoxib and diclofenac. In terms of inhibiting TNF-α production, 6o-treated cells showed TNF-α level, which is ∼10 times lower than celecoxib. Furthermore, 6e and 6j had the highest anticancer activity against the breast cancer cell line BT-459 with growth inhibition percentages of 67.14 and 70.07%, respectively. Docking studies confirm their favoured binding affinity. The proposed compounds could be promising multi-targeted leads.</p
Anti-Inflammatory, Antipyretic, and Analgesic Properties of <i>Potamogeton perfoliatus</i> Extract: In Vitro and In Vivo Study
No full textNatural antioxidants, especially those of plant origins, have shown a plethora of biological activities with substantial economic value, as they can be extracted from agro-wastes and/or under exploited plant species. The perennial hydrophyte, Potamogeton perfoliatus, has been used traditionally to treat several health disorders; however, little is known about its biological and its medicinal effects. Here, we used an integrated in vitro and in vivo framework to examine the potential effect of P. perfoliatus on oxidative stress, nociception, inflammatory models, and brewer’s yeast-induced pyrexia in mice. Our results suggested a consistent in vitro inhibition of three enzymes, namely 5-lipoxygenase, cyclooxygenases 1 and 2 (COX-1 and COX-2), as well as a potent antioxidant effect. These results were confirmed in vivo where the studied extract attenuated carrageenan-induced paw edema, carrageenan-induced leukocyte migration into the peritoneal cavity by 25, 44 and 64% at 200, 400 and 600 mg/kg, p.o., respectively. Moreover, the extract decreased acetic acid-induced vascular permeability by 45% at 600 mg/kg, p.o., and chemical hyperalgesia in mice by 86% by 400 mg/kg, p.o., in acetic acid-induced writhing assay. The extract (400 mg/kg) showed a longer response latency at the 3 h time point (2.5 fold of the control) similar to the nalbuphine, the standard opioid analgesic. Additionally, pronounced antipyretic effects were observed at 600 mg/kg, comparable to paracetamol. Using LC-MS/MS, we identified 15 secondary metabolites that most likely contributed to the obtained biological activities. Altogether, our findings indicate that P. perfoliatus has anti-inflammatory, antioxidant, analgesic and antipyretic effects, thus supporting its traditional use and promoting its valorization as a potential candidate in treating oxidative stress-associated diseases
