The cGMP/PKG pathway as a common mediator of cardioprotection: translatability and mechanism

British Journal of Pharmacology, Journal Year: 2014, Volume and Issue: 172(8), P. 1996 - 2009

Published: Oct. 9, 2014

Cardiomyocyte cell death occurring during myocardial reperfusion (reperfusion injury) contributes to final infarct size after transient coronary occlusion. Different interrelated mechanisms of injury have been identified, including alterations in cytosolic Ca 2+ handling, sarcoplasmic reticulum‐mediated oscillations and hypercontracture, proteolysis secondary calpain activation mitochondrial permeability transition. All these occur the initial minutes are inhibited by intracellular acidosis. The cGMP/PKG pathway modulates rate recovery pH, but has also direct effect on is depressed cardiomyocytes ischaemia/reperfusion preserved ischaemic postconditioning, which importantly postconditioning protection. present article reviews consequences pathway, different pharmacological strategies aimed stimulate it evidence, limitations promise translation clinical practice. Overall, preclinical evidence suggests that modulation may be a therapeutic target context infarction. Linked Articles This part themed section Conditioning Heart – Pathways Translation. To view other articles this visit http://dx.doi.org/10.1111/bph.2015.172.issue‐8

Language: Английский

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Pharmacological profile of novel psychoactive benzofurans

British Journal of Pharmacology, Journal Year: 2015, Volume and Issue: 172(13), P. 3412 - 3425

Published: March 13, 2015

Benzofurans are newly used psychoactive substances, but their pharmacology is unknown. The aim of the present study was to pharmacologically characterize benzofurans in vitro.

Language: Английский

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Signalling pathways and mechanisms of protection in pre‐ and postconditioning: historical perspective and lessons for the future

British Journal of Pharmacology, Journal Year: 2014, Volume and Issue: 172(8), P. 1913 - 1932

Published: Sept. 10, 2014

Ischaemic pre- and postconditioning are potent cardioprotective interventions that spare ischaemic myocardium decrease infarct size after periods of myocardial ischaemia/reperfusion. They dependent on complex signalling pathways involving ligands released from myocardium, G-protein-linked receptors, membrane growth factor phospholipids, kinases, NO, PKC PKG, mitochondrial ATP-sensitive potassium channels, reactive oxygen species, TNF-α sphingosine-1-phosphate. The final effector is probably the permeability transition pore produces protection by preventing formation. Many investigators have worked to produce a roadmap this with hope it would reveal where one could intervene therapeutically protect patients acute infarction whose hearts being reperfused. However, attempts date show efficacy such an intervention in large clinical trials been unsuccessful. Reasons for inability translate successes experimental laboratory arena evaluated review. It suggested all coronary syndromes currently presenting hospital treated platelet P2Y12 receptor antagonists, current standard care, indeed already benefiting conditioning outlined earlier. If proves be case, then future further will rely which different mechanism.

Language: Английский

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The histone acetylranseferase hMOF acetylates Nrf2 and regulates anti‐drug responses in human non‐small cell lung cancer

British Journal of Pharmacology, Journal Year: 2014, Volume and Issue: 171(13), P. 3196 - 3211

Published: Feb. 26, 2014

The histone acetyltransferase MOF is a member of the MYST family. In mammals, plays critical roles by acetylating H4 at K16 and non-histone substrates such as p53. Here we have investigated role in human lung cancer possible new hMOF.Samples non-small cell (NSCLC) were used to correlate with clinicopathological parameters NF-E2-related factor 2 (Nrf2) downstream genes. 293T-cells study interactions between Nrf2, acetylation Nrf2 MOF. Mouse embryonic fibroblast A549 cells utilized assess involvement antioxidative anti-drug responses. analysis response vitro vivo.hMOF was overexpressed NSCLC tissues associated large tumour size, advanced disease stage metastasis, poor prognosis. hMOF levels positively correlated Nrf2-downstream MOF/hMOF physically interacted acetylated Lys(588) . MOF-mediated increased nuclear retention transcription its Importantly, essential for anti-oxidative responses regulated growth drug resistance vivo an Nrf2-dependent manner.hMOF predictor survival. hMOF-mediated are may provide therapeutic target treatment NSCLC.

Language: Английский

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Mechanisms and Characteristics of Sulfonylureas and Glinides

Current Topics in Medicinal Chemistry, Journal Year: 2019, Volume and Issue: 20(1), P. 37 - 56

Published: Dec. 30, 2019

Type 2 diabetes mellitus is a complex progressive endocrine disease characterized by hyperglycemia and life-threatening complications. It the most common disorder of pancreatic cell function that causes insulin deficiency. Sulfonylurea class oral hypoglycemic drugs. Over past half century, these drugs, together with subsequent non-sulfonylureas (glinides), have been main drugs for secretion.Through in-depth study, medical profession considers it as an important drug improving blood sugar control.The mechanism, characteristics, efficacy side effects sulfonylureas glinides were reviewed in detail.Sulfonylureas not only stimulated release from cells, but also had many extrapanular effect, such reducing clearance rate liver, secretion glucagon, enhancing sensitivity peripheral tissues to type mellitus.Sulfonylureas are effective first-line treatment mellitus. Although they risk hypoglycemia, weight gain cardiovascular disease, their clinical practicability safety can be guaranteed long reasonably used.

Language: Английский

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Developmental rodent models of fear and anxiety: from neurobiology to pharmacology

British Journal of Pharmacology, Journal Year: 2014, Volume and Issue: 171(20), P. 4556 - 4574

Published: Feb. 17, 2014

Anxiety disorders pose one of the biggest threats to mental health in world, and they predominantly emerge early life. However, research anxiety fear‐related memories during development has been largely neglected, existing treatments have developed based on adult models anxiety. The present review describes animal across what is currently known their pharmacology. To summarize, underlying mechanisms intrinsic ‘unlearned’ fear are poorly understood, especially beyond period infancy. Models using ‘learned’ reveal that through development, rats exhibit a stress hyporesponsive before postnatal day 10, where paradoxically form odour‐shock preferences, then switch more adult‐like conditioned responses. Juvenile appear forget these aversive associations easily, as observed with phenomenon infantile amnesia. also undergo robust extinction, until adolescence display increased resistance extinction. Maturation brain structures, such amygdala, prefrontal cortex hippocampus, along different temporal recruitment involvement various neurotransmitter systems (including NMDA , GABA corticosterone opioids) responsible for developmental changes. Taken together, studies described this highlight there be overcoming adverse life experience. We need understand fundamental pharmacological processes order take advantage treatment disorders. Linked Articles This article part themed section Animal Psychiatry Research. view other articles visit http://dx.doi.org/10.1111/bph.2014.171.issue-20

Language: Английский

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SGLT2 Inhibitors Play a Salutary Role in Heart Failure via Modulation of the Mitochondrial Function

Frontiers in Cardiovascular Medicine, Journal Year: 2020, Volume and Issue: 6

Published: Jan. 8, 2020

Three cardiovascular outcome trials of sodium glucose cotransporter 2 (SGLT2) inhibitors, including the EMPA-REG OUTCOME trial, CANVAS Program, and DECLARE TIMI 58 revealed that SGLT2 inhibitors were superior to a matching placebo in reducing events, mortality hospitalization for heart failure, patients with type diabetes. However, detailed mechanism underlying beneficial effects exert on diseases remains be elucidated. We herein review latest findings salutary mechanisms cardiomyocytes, especially focusing their mitochondrial function-mediated effects. The administration leads elevation plasma levels ketone bodies, which are an efficient energy source failing heart, by promoting oxidation coenzyme Q couple enhancing free cytosolic ATP hydrolysis. also promote metabolism-mediated cardioprotective These compounds could reduce intracellular overload improve energetics oxidative defense through binding NHE and/or SMIT1. Furthermore, modulate dynamics regulating fusion fission mitochondria. Together ongoing large-scale clinical evaluate efficacy intensive investigations regarding restoration cases failure would lead establishment these drugs as potent anti-heart drugs.

Language: Английский

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Cannabinoid–dopamine interactions in the physiology and physiopathology of the basal ganglia

British Journal of Pharmacology, Journal Year: 2015, Volume and Issue: 173(13), P. 2069 - 2079

Published: June 9, 2015

Endocannabinoids and their receptors play a modulatory role in the control of dopamine transmission basal ganglia. However, this influence is generally indirect exerted through modulation GABA glutamate inputs received by nigrostriatal dopaminergic neurons, which lack cannabinoid CB 1 although they may produce endocannabinoids. Additional evidence suggests that 2 be located certain eicosanoid‐related cannabinoids directly activate TRPV receptors, have been found thus allowing both cases direct regulation specific cannabinoids. In addition, form heteromers with provide another pathway to interactions between systems, case at postsynaptic level. Through these mechanisms or involving interact ganglia likely important effects on dopamine‐related functions structures (i.e. movement) and, particularly, different pathologies affecting processes, particular, Parkinson's disease, but also dyskinesia, dystonia other pathological conditions. The present review will address current literature supporting cannabinoid–dopamine ganglia, emphasis aspects dealing physiopathological consequences interactions. Linked Articles This article part themed section Updating Neuropathology Neuropharmacology Monoaminergic Systems. To view articles visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.13/issuetoc

Language: Английский

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Regulatory role of the cannabinoid CB₂ receptor in stress‐induced neuroinflammation in mice

British Journal of Pharmacology, Journal Year: 2014, Volume and Issue: 171(11), P. 2814 - 2826

Published: Jan. 28, 2014

Background and Purpose Stress exposure produces excitotoxicity neuroinflammation, contributing to the cellular damage observed in stress‐related neuropathologies. The endocannabinoids provide a homeostatic system, present stress‐responsive neural circuits. Here, we have assessed possible regulatory role of cannabinoid CB 2 receptors stress‐induced neuroinflammation. Experimental Approach We used wild type ( WT ), transgenic overexpressing 2x P ) receptor knockout 2‐ KO mice exposed immobilization acoustic stress (2 h·day −1 for 4 days). agonist JWH ‐133 was administered daily mg·kg , i.p.) animals. Glutamate uptake measured synaptosomes from frontal cortex; Western blots RT‐PCR were measure proinflammatory cytokines, enzymes mediators homogenates cortex. Key Results Increased plasma corticosterone induced by not modified manipulating receptors. treatment or overexpression increased control levels glutamate uptake, which reduced back levels. prevented increase cytokines TNF ‐α CCL2), NF‐κB NOS ‐2 COX consequent oxidative nitrosative (lipid peroxidation). exhibited anti‐inflammatory neuroprotective actions similar those pretreated Conversely, lack mice) exacerbated neuroinflammatory responses confirmed that effects mediated through Conclusions Implications Pharmacological manipulation is potential therapeutic strategy pathologies with component, such as depression.

Language: Английский

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Increased drug resistance is associated with reduced glucose levels and an enhanced glycolysis phenotype

British Journal of Pharmacology, Journal Year: 2014, Volume and Issue: 171(13), P. 3255 - 3267

Published: March 6, 2014

Background and Purpose The testing of anticancer compounds in vitro is usually performed hyperglycaemic cell cultures, although many tumours their vivo microenvironments are hypoglycaemic. Here, we have assessed, cultures tumour cells, the effects reduced glucose levels on resistance to drugs investigated underlying cellular mechanisms. Experimental Approach PIK3CA mutant ( AGS , HGC 27), wild‐type MKN 45, NUGC 4) gastric cancer cells were cultured high‐glucose HG 25 mM) or low‐glucose LG 5 media tested for sensitivity two cytotoxic compounds, 5‐fluorouracil (5‐ FU ) carboplatin, PI 3 K / mTOR inhibitor, 103 Ku ‐0063794. Key Results All had increased 5‐ carboplatin when compared with conditions despite having similar growth cycle characteristics. On treatment ‐0063794, only displayed conditions. selectively p‐ S 6, p‐4 EBP 1, GLUT 1 lactate production, reactive oxygen species, consistent glycolysis. Combination analysis indicated ‐0063794 synergistic only. Synergism was accompanied by signalling autophagy. Conclusions Implications Hypoglycaemia agents, especially a high dependence Dual inhibition pathway may be able attenuate such hypoglycaemia‐associated resistance.

Language: Английский

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