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https://www.readbyqxmd.com/read/28731589/effects-of-nitric-oxide-on-large-conductance-ca-2-activated-k-currents-in-human-cardiac-fibroblasts-through-pka-and-pkg-related-pathways
#1
Hyemi Bae, Inja Lim
The human cardiac fibroblast (HCF) is the most abundant cell type in the myocardium, and HCFs play critical roles in maintaining normal cardiac function. However, unlike cardiomyocytes, the electrophysiology of HCFs is not well established. In the cardiovascular system, Ca(2+) -activated K(+) (KCa) channels have distinct physiological and pathological functions, and nitric oxide (NO) play key roles. In this study, we investigated the potential effects of NO on KCa channels in HCFs. We recorded strong oscillating, well-maintained outward K(+) currents without marked inactivation throughout the test pulse period and detected outward rectification in the I-V curve; these are all characteristics that are typical of KCa currents...
July 21, 2017: Clinical and Experimental Pharmacology & Physiology
https://www.readbyqxmd.com/read/28729555/inhibition-of-phosphodiesterase-5-suppresses-calcineurin-nfat-mediated-trpc6-expression-in-pulmonary-artery-smooth-muscle-cells
#2
Shaojun Li, Yilin Pan, Rui Ke, Xinming Xie, Cui Zhai, Wenhua Shi, Jian Wang, Xin Yan, Limin Chai, Qingting Wang, Qianqian Zhang, Xiaofan Su, Lan Yang, Li Gao, Manxiang Li
The up-regulation of transient receptor potential channel 6 (TRPC6) has been found to contribute to the proliferation of pulmonary artery smooth muscle cells (PASMCs), and inhibition of phosphodiesterase-5 (PDE5) has been shown to suppress TRPC6 expression in PASMCs. However, the molecular mechanisms underlying the up-regulation of TRPC6 expression and PDE5 modulation of TRPC6 expression in PASMCs remain largely unclear. The aim of this study is to address these issues. Endothelin-1 (ET-1) dose and time-dependently up-regulated TRPC6 expression in primary cultured rat PASMCs, and this was accompanied with the activation of calcineurin and subsequent translocation of NFATc4 to the nucleus...
July 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28717180/a-three-mirnas-signature-predicts-survival-in-cervical-cancer-using-bioinformatics-analysis
#3
Bin Liang, Yunhui Li, Tianjiao Wang
Growing evidences showed that a large number of miRNAs were abnormally expressed in cervical cancer tissues and played irreplaceable roles in tumorigenesis, progression and metastasis. The aim of the present study was to identify the differential miRNAs expression between cervical cancer and normal cervical tissues by analyzing the high-throughput miRNA data downloaded from TCGA database. Additionally, we evaluated the prognostic values of the differentially expressed miRNAs and constructed a three-miRNA signature that could effectively predict patient survival...
July 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28716990/proof-of-principle-for-a-novel-class-of-antihypertensives-that-target-the-oxidative-activation-of-protein-kinase-g-i%C3%AE
#4
Joseph R Burgoyne, Oleksandra Prysyazhna, Daniel A Richards, Philip Eaton
Arterial hypertension continues to be a major health burden. Development of new antihypertensive drugs that engage vasodilatory mechanisms not harnessed by available therapies offer therapeutic potential. Oxidants induce an interprotein disulfide in protein kinase G Iα (PKG Iα) at C42, which is associated with its targeting and activation, resulting in vasodilation and blood pressure lowering. Consequently, we developed an assay and screened for electrophilic drugs that activate PKG Iα by selectively targeting C42, as such compounds have potential as novel antihypertensives with a mechanism of action that differs from current therapies...
July 17, 2017: Hypertension
https://www.readbyqxmd.com/read/28705807/augmentation-of-cgmp-pkg-pathway-and-colonic-motility-by-hydrogen-sulfide
#5
Ancy D Nalli, Sayak Bhattacharya, Hongxia Wang, Derek M Kendig, John R Grider, Karnam S Murthy
Hydrogen sulfide (H2S), like nitric oxide (NO), causes smooth muscle relaxation, but unlike NO, does not stimulate soluble guanylyl cyclase (sGC) activity and generate cGMP. The aim of this study was to investigate the interplay between NO and H2S in colonic smooth muscle. In colonic smooth muscle from rabbit, mouse and human, L-cysteine, substrate of cystathionine-γ-lyase (CSE), or NaHS, an H2S donor, inhibited phosphodiesterase 5 (PDE5) activity and augmented the increase in cGMP levels, IP3 receptor phosphorylation at Ser(1756) (measured as a proxy for PKG activation), and muscle relaxation in response to NO donor, s-nitrosoglutathione (GSNO), suggesting augmentation of cGMP/PKG pathway by H2S...
July 13, 2017: American Journal of Physiology. Gastrointestinal and Liver Physiology
https://www.readbyqxmd.com/read/28690194/examining-a-role-for-pkg-i%C3%AE-oxidation-in-the-pathogenesis-of-cardiovascular-dysfunction-during-diet-induced-obesity
#6
Olena Rudyk, Philip Eaton
BACKGROUND: Protein kinase G (PKG) Iα is the end-effector kinase that mediates nitric oxide (NO)-dependent and oxidant-dependent vasorelaxation to maintain blood pressure during health. A hallmark of cardiovascular disease is attenuated NO production, which in part is caused by NO Synthase (NOS) uncoupling, which in turn increases oxidative stress because of superoxide generation. NOS uncoupling promotes PKG Iα oxidation to the interprotein disulfide state, likely mediated by superoxide-derived hydrogen peroxide, and because the NO-cyclic guanosine monophosphate (cGMP) pathway otherwise negatively regulates oxidation of the kinase to its active disulfide dimeric state...
July 6, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28688901/microrna-155-regulates-arsenite-induced-malignant-transformation-by-targeting-nrf2-mediated-oxidative-damage-in-human-bronchial-epithelial-cells
#7
Chengzhi Chen, Xuejun Jiang, Shiyan Gu, Zunzhen Zhang
Arsenite is a well-documented human lung carcinogen but the detailed mechanisms of carcinogenesis remain unclear. In this study, human bronchial epithelial (16-HBE) cells were continuously exposed to 2.5μM arsenite for about 13 weeks to induce the phenotypes of malignant transformation. Our results showed that Nrf2 expression was gradually decreased whereas no significant change was observed on NF-κB activation with increased time of arsenite exposure. To test the roles of Nrf2-meidtaed oxidative damage in the arsenite-induced malignant transformation, we compared the levels of cGMP, PKG and oxidative damage-related indicators between arsenic-transformed cells and control cells...
July 6, 2017: Toxicology Letters
https://www.readbyqxmd.com/read/28679626/the-bradykinin-bk-cgmp-pkg-pathway-augments-insulin-sensitivity-via-upregulation-of-mapk-phosphatase-5-and-inhibition-of-jun-kinase-jnk
#8
Maria E Frigolet, Garry Thomas, Kristin Beard, Huogen Lu, Lijiang Liu, I George Fantus
Bradykinin (BK) promotes insulin sensitivity and glucose uptake in adipocytes and other cell types. We demonstrated that in rat adipocytes BK enhances insulin-stimulated glucose transport via endothelial nitric oxide synthase (eNOS), nitric oxide (NO) generation, and decreased activity of the mitogen activated protein kinase (MAPK), JNK (c-Jun-N-terminal kinase). In endothelial cells, NO increases soluble guanylate cyclase (sGC) activity which in turn, activates protein kinase G (PKG) by increasing cGMP levels...
July 5, 2017: American Journal of Physiology. Endocrinology and Metabolism
https://www.readbyqxmd.com/read/28671970/cardioprotective-effects-of-pkg-activation-by-soluble-gc-activator-bay-60-2770-in-ischemia-reperfusion-injured-rat-hearts
#9
Kyung Hye Lee, So-Ra Lee, Haneul Cho, Jong Shin Woo, Jung Hee Kang, Yun-Mi Jeong, Xian Wu Cheng, Woo-Shik Kim, Weon Kim
Soluble guanylate cyclase (sGC) has been suggested as a therapeutic target for cardiac ischemia-reperfusion (IR) injury. Until now, the molecular mechanism of BAY 60-2770, a sGC activator, in cardiac IR injury has not been assessed. To identify the cardioprotective effects of BAY 60-2770 in IR-injured rat hearts, IR injury was established by occlusion of LAD for 40 min and reperfusion for 7 days, and the effects of BAY 60-2770 on myocardial protection were assessed by echocardiography and TTC staining. 5 nM and 5 μM of BAY 60-2770 were perfused into isolated rat hearts in a Langendorff system...
2017: PloS One
https://www.readbyqxmd.com/read/28668721/pde2-at-the-crossway-between-camp-and-cgmp-signalling-in-the-heart
#10
REVIEW
Silvio Weber, Miriam Zeller, Kaomei Guan, Frank Wunder, Michael Wagner, Ali El-Armouche
The cyclic nucleotides cAMP and cGMP are central second messengers in cardiac cells and critical regulators of cardiac physiology as well as pathophysiology. Consequently, subcellular compartmentalization allows for spatiotemporal control of cAMP/cGMP metabolism and subsequent regulation of their respective effector kinases PKA or PKG is most important for cardiac function in health and disease. While acute cAMP-mediated signalling is a mandatory prerequisite for the physiological fight-or-flight response, sustained activation of this pathway may lead to the progression of heart failure...
June 28, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28661475/protein-kinase-a-activation-by-the-anti-cancer-drugs-abt-737-and-thymoquinone-is-caspase-3-dependent-and-correlates-with-platelet-inhibition-and-apoptosis
#11
Natalia Rukoyatkina, Elke Butt, Hariharan Subramanian, Viacheslav O Nikolaev, Igor Mindukshev, Ulrich Walter, Stepan Gambaryan, Peter M Benz
Chemotherapy-induced thrombocytopenia is a common bleeding risk in cancer patients and limits chemotherapy dose and frequency. Recent data from mouse and human platelets revealed that activation of protein kinase A/G (PKA/PKG) not only inhibited thrombin/convulxin-induced platelet activation but also prevented the platelet pro-coagulant state. Here we investigated whether or not PKA/PKG activation could attenuate caspase-dependent apoptosis induced by the anti-cancer drugs ABT-737 (the precursor of navitoclax) and thymoquinone (TQ), thereby potentially limiting chemotherapy-induced thrombocytopenia...
June 29, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28649367/nitric-oxide-signalling-and-neuronal-nitric-oxide-synthase-in-the-heart-under-stress
#12
REVIEW
Yin Hua Zhang
Nitric oxide (NO) is an imperative regulator of the cardiovascular system and is a critical mechanism in preventing the pathogenesis and progression of the diseased heart. The scenario of bioavailable NO in the myocardium is complex: 1) NO is derived from both endogenous NO synthases (endothelial, neuronal, and/or inducible NOSs [eNOS, nNOS, and/or iNOS]) and exogenous sources (entero-salivary NO pathway) and the amount of NO from exogenous sources varies significantly; 2) NOSs are located at discrete compartments of cardiac myocytes and are regulated by distinctive mechanisms under stress; 3) NO regulates diverse target proteins through different modes of post-transcriptional modification (soluble guanylate cyclase [sGC]/cyclic guanosine monophosphate [cGMP]/protein kinase G [PKG]-dependent phosphorylation, S-nitrosylation, and transnitrosylation); 4) the downstream effectors of NO are multidimensional and vary from ion channels in the plasma membrane to signalling proteins and enzymes in the mitochondria, cytosol, nucleus, and myofilament; 5) NOS produces several radicals in addition to NO (e...
2017: F1000Research
https://www.readbyqxmd.com/read/28648945/phosphodiesterase-5-inhibition-as-a-therapeutic-target-for-ischemic-stroke-a-systematic-review-of-preclinical-studies
#13
Joakim N E Ölmestig, Ida R Marlet, Atticus H Hainsworth, Christina Kruuse
Phosphodiesterase 5 inhibitors (PDE5i), such as sildenafil (Viagra®) are widely used for erectile dysfunction and pulmonary hypertension. Preclinical studies suggest that PDE5i may improve functional outcome following ischemic stroke. In this systematic review we aimed to evaluate the effects of selective PDE5i in animal models of brain ischaemia. A systematic search in Medline, Embase, and The Cochrane Library was performed including studies in English assessing the effects of selective PDE5i. 32 publications were included describing outcome in 3646 animals...
June 22, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28625489/diosmin-reduces-chronic-constriction-injury-induced-neuropathic-pain-in-mice
#14
Mariana M Bertozzi, Ana C Rossaneis, Victor Fattori, Daniela T Longhi-Balbinot, Andressa Freitas, Fernando Q Cunha, José C Alves-Filho, Thiago M Cunha, Rubia Casagrande, Waldiceu A Verri
Injury or dysfunction of somatosensory system induces a complex syndrome called neuropathic pain, which still needs adequate pharmacological control. The current pharmacological treatments were in part developed from natural compounds. Flavonoids are natural polyphenolic molecules presenting varied biological activities and low toxicity. The flavonoid diosmin is a safe compound with good tolerability and low toxicity. This study evaluated the antinociceptive effect of diosmin in the sciatic nerve chronic constriction injury (CCI)-induced neuropathic pain model...
June 15, 2017: Chemico-biological Interactions
https://www.readbyqxmd.com/read/28624955/presynaptic-inhibition-of-nociceptive-neurotransmission-by-somatosensory-neuron-secreted-suppressors
#15
REVIEW
Kaicheng Li, Bing Cai, Changlin Li, Xu Zhang
Noxious stimuli cause pain by activating cutaneous nociceptors. The Aδ- and C-fibers of dorsal root ganglion (DRG) neurons convey the nociceptive signals to the laminae I-II of spinal cord. In the dorsal horn of spinal cord, the excitatory afferent synaptic transmission is regulated by the inhibitory neurotransmitter γ-aminobutyric acid and modulators such as opioid peptides released from the spinal interneurons, and by serotonin, norepinepherine and dopamine from the descending inhibitory system. In contrast to the accumulated evidence for these central inhibitors and their neural circuits in the dorsal spinal cord, the knowledge about the endogenous suppressive mechanisms in nociceptive DRG neurons remains very limited...
June 15, 2017: Science China. Life Sciences
https://www.readbyqxmd.com/read/28614771/mantidis-ootheca-induces-vascular-relaxation-through-pi3k-akt-mediated-nitric-oxide-cyclic-gmp-protein-kinase-g-signaling-in-endothelial-cells
#16
H Y Kim, Y J Lee, B H Han, J J Yoon, Y M Ahn, M H Hong, R Tan, D G Kang, H S Lee
Mantidis ootheca (Sang Piao Xiao) is well known mantis eggs in a foamy pouch. The purpose of the present study was to investigate the underlying cellular mechanisms of the nitric oxide (NO)-releasing property of the aqueous extract of Mantidis ootheca (AMO) in rat aorta and vascular endothelial cells. AMO was examined for its vascular relaxant effect in isolated phenylephrine-precontracted rat thoracic aortic rings. The roles of the nitric oxide (NO) signaling in the AMO-induced effects were tested in human umbilical vein endothelial cells (HUVECs)...
April 2017: Journal of Physiology and Pharmacology: An Official Journal of the Polish Physiological Society
https://www.readbyqxmd.com/read/28592587/linaclotide-activates-guanylate-cyclase-c-cgmp-protein-kinase-ii-dependent-trafficking-of-cftr-in-the-intestine
#17
Md Kaimul Ahsan, Boris Tchernychev, Marco M Kessler, Robert M Solinga, David Arthur, Cristina I Linde, Inmaculada Silos-Santiago, Gerhard Hannig, Nadia A Ameen
The transmembrane receptor guanylyl cyclase-C (GC-C), expressed on enterocytes along the intestine, is the molecular target of the GC-C agonist peptide linaclotide, an FDA-approved drug for treatment of adult patients with Irritable Bowel Syndrome with Constipation and Chronic Idiopathic Constipation. Polarized human colonic intestinal cells (T84, CaCo-2BBe) rat and human intestinal tissues were employed to examine cellular signaling and cystic fibrosis transmembrane conductance regulator (CFTR)-trafficking pathways activated by linaclotide using confocal microscopy, in vivo surface biotinylation, and protein kinase-II (PKG-II) activity assays...
June 2017: Physiological Reports
https://www.readbyqxmd.com/read/28591657/agc-kinases-mechanisms-of-regulation-%C3%A2-and-innovative-drug-development
#18
REVIEW
Alejandro E Leroux, Jörg O Schulze, Ricardo M Biondi
The group of AGC kinases consists of 63 evolutionarily related serine/threonine protein kinases comprising PDK1, PKB/Akt, SGK, PKC, PRK/PKN, MSK, RSK, S6K, PKA, PKG, DMPK, MRCK, ROCK, NDR, LATS, CRIK, MAST, GRK, Sgk494, and YANK, while two other families, Aurora and PLK, are the most closely related to the group. Eight of these families are physiologically activated downstream of growth factor signalling, while other AGC kinases are downstream effectors of a wide range of signals. The different AGC kinase families share aspects of their mechanisms of inhibition and activation...
June 4, 2017: Seminars in Cancer Biology
https://www.readbyqxmd.com/read/28585197/human-protein-kinases-and-obesity
#19
Atilla Engin
The action of protein kinases and protein phosphatases is essential for multiple physiological responses. Each protein kinase displays its own unique substrate specificity, and a regulatory mechanism that may be modulated by association with other proteins. Protein kinases are classified by the target amino acid in their substrates. Some protein kinases can phosphorylate both serine/threonine, as well as tyrosine residues. This group of kinases has been known as dual specificity kinases. Unlike the dual specificity kinases, a heterogeneous group of protein phosphatases are known as dual-specificity phosphatases...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28584062/cytochrome-b5-reductase-3-modulates-soluble-guanylate-cyclase-redox-state-and-cgmp-signaling
#20
Mizanur M Rahaman, Anh T Nguyen, Megan P Miller, Scott A Hahn, Courtney Sparacino-Watkins, Soma Jobbagy, Nolan T Carew, Nadiezhda Cantu-Medellin, Katherine C Wood, Catherine J Baty, Francisco J Schopfer, Eric E Kelley, Mark T Gladwin, Emil Martin, Adam C Straub
RATIONALE: Soluble guanylate cyclase (sGC) heme iron, in its oxidized state (Fe(3+)), is desensitized to NO and limits cGMP production needed for downstream activation of protein kinase G-dependent signaling and blood vessel dilation. OBJECTIVE: Although reactive oxygen species are known to oxidize the sGC heme iron, the basic mechanism(s) governing sGC heme iron recycling to its NO-sensitive, reduced state remain poorly understood. METHODS AND RESULTS: Oxidant challenge studies show that vascular smooth muscle cells have an intrinsic ability to reduce oxidized sGC heme iron and form protein-protein complexes between cytochrome b5 reductase 3, also known as methemoglobin reductase, and oxidized sGC...
July 7, 2017: Circulation Research
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