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https://www.readbyqxmd.com/read/28808213/the-interaction-between-the-wnt-%C3%AE-catenin-signaling-cascade-and-pkg-activation-in-cancer
#1
Kevin Lee, Gary A Piazza
The activation of the Wnt/β-catenin signaling cascade has been well studied and documented in colorectal cancer (CRC). The long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) has been shown to reduce the incidence and risk of death from CRC in numerous epidemiological studies. The NSAID sulindac has also been reported to cause regression of precancerous adenomas in individuals with familial adenomatous polyposis who are at high risk of developing CRC. The mechanism responsible for cancer chemopreventive activity of NSAIDs is not well understood but may be unrelated to their cyclooxygenase inhibitory activity...
January 19, 2017: Journal of Biomedical Research
https://www.readbyqxmd.com/read/28807144/regulation-of-l-type-cav1-3-channel-activity-and-insulin-secretion-by-the-cgmp-pkg-signaling-pathway
#2
Alejandro Sandoval, Paz Duran, María A Gandini, Arturo Andrade, Angélica Almanza, Simon Kaja, Ricardo Felix
cGMP is a second messenger widely used in the nervous system and other tissues. One of the major effectors for cGMP is the serine/threonine protein kinase, cGMP-dependent protein kinase (PKG), which catalyzes the phosphorylation of a variety of proteins including ion channels. Previously, it has been shown that the cGMP-PKG signaling pathway inhibits Ca(2+) currents in rat vestibular hair cells and chromaffin cells. This current allegedly flow through voltage-gated CaV1.3L-type Ca(2+) channels, and is important for controlling vestibular hair cell sensory function and catecholamine secretion, respectively...
September 2017: Cell Calcium
https://www.readbyqxmd.com/read/28793191/structural-basis-of-analog-specificity-in-pkg-i-and-ii
#3
James C Campbell, Philipp Henning, Eugen Franz, Banumathi Sankaran, Friedrich W Herberg, Choel Kim
Cyclic GMP analogs, 8-Br, 8-pCPT, and PET-cGMP, have been widely used for characterizing cellular functions of cGMP dependent protein kinase (PKG) I and II isotypes. However, interpreting results obtained using these analogs has been difficult due to their low isotype specificity. Additionally each isotype has two binding sites with different cGMP affinities and analog selectivities, making understanding the molecular basis for isotype specificity of these compounds even more challenging. To determine isotype specificity of cGMP analogs and their structural basis, we generated the full-length regulatory domains of PKG I and II isotypes with each binding site disabled, determined their affinities for these analogs, and obtain co-crystal structures of both isotypes bound with cGMP analogs...
August 9, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28793049/possible-mechanisms-involved-in-the-vasorelaxant-effect-produced-by-clobenzorex-in-aortic-segments-of-rats
#4
J Lozano-Cuenca, A González-Hernández, O A López-Canales, J R Villagrana-Zesati, J D Rodríguez-Choreão, R Morín-Zaragoza, E F Castillo-Henkel, J S López-Canales
Clobenzorex is a metabolic precursor of amphetamine indicated for the treatment of obesity. Amphetamines have been involved with cardiovascular side effects such as hypertension and pulmonary arterial hypertension. The aim of the present study was to investigate whether the direct application of 10-9-10-5 M clobenzorex on isolated phenylephrine-precontracted rat aortic rings produces vascular effects, and if so, what mechanisms may be involved. Clobenzorex produced an immediate concentration-dependent vasorelaxant effect at the higher concentrations (10-7...
August 7, 2017: Brazilian Journal of Medical and Biological Research, Revista Brasileira de Pesquisas Médicas e Biológicas
https://www.readbyqxmd.com/read/28776122/mechanisms-involved-in-the-remyelinating-effect-of-sildenafil
#5
Daniela Díaz-Lucena, María Gutierrez-Mecinas, Beatriz Moreno, José Lupicinio Martínez-Sánchez, Paula Pifarré, Agustina García
Remyelination occurs in demyelinated lesions in multiple sclerosis (MS) and pharmacological treatments that enhance this process will critically impact the long term functional outcome in the disease. Sildenafil, a cyclic GMP (cGMP)-specific phosphodiesterase 5 inhibitor (PDE5-I), is an oral vasodilator drug extensively used in humans for treatment of erectile dysfunction and pulmonary arterial hypertension. PDE5 is expressed in central nervous system (CNS) neuronal and glial populations and in endothelial cells and numerous studies in rodent models of neurological disease have evidenced the neuroprotective potential of PDE5-Is...
August 3, 2017: Journal of Neuroimmune Pharmacology: the Official Journal of the Society on NeuroImmune Pharmacology
https://www.readbyqxmd.com/read/28774681/sildenafil-improves-blood-perfusion-in-steroid-induced-avascular-necrosis-of-femoral-head-in-rabbits-via-a-protein-kinase-g-dependent-mechanism
#6
Qichun Song, Jianlong Ni, Hongyuan Jiang, Zhibin Shi
OBJECTIVE: The aim of the study were to evaluate the effect of sildenafil against avascular necrosis of femoral head (ANFH) in a rabbit model, and to study the role of protein kinase G (PKG) pathway and vascular endothelial growth factor (VEGF) in ANFH. METHODS: Three weeks after inducing ANFH with methylprednisolone injection, 45 female adult New Zealand white rabbits were divided into three groups and treated as follows: group SI received daily intraperitoneal sildenafil with a dose of 10 mg/kg per day; group SD received daily sildenafil identically to group SI plus auricular vein injection DT3 (a specific PKG inhibitor); group NS received only normal saline...
July 31, 2017: Acta Orthopaedica et Traumatologica Turcica
https://www.readbyqxmd.com/read/28771828/vegfb-vegfr1-ameliorates-ang-ii-induced-cardiomyocyte-hypertrophy-through-ca-2-mediated-pkg-i-pathway
#7
Zhijie Shen, Zhihui Zhang, Xiaoyan Wang, Kan Yang
In response to assorted stimuli, the heart will develop into cardiomyocyte hypertrophy, but sustained cardiomyocyte hypertrophy will finally lead to heart failure. This research is aimed to examine the effect of VEGFB on cardiomyocyte hypertrophy by using the cardiomyocyte-derived cell line H9C2 of cultured rates. It turns out that VEGFB can positively prevent the Ang II-induced rising in the size of cardiomyocyte as well as reduce Ang II-induced mRNA and protein levels of β-MHC (β-myosin heavy chain), BNP (brain natriuretic peptide) and ANP (atrial natriuretic peptide)...
August 3, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28769873/targeting-obesity-and-diabetes-to-treat-heart-failure-with-preserved-ejection-fraction
#8
REVIEW
Raffaele Altara, Mauro Giordano, Einar S Nordén, Alessandro Cataliotti, Mazen Kurdi, Saeed N Bajestani, George W Booz
Heart failure with preserved ejection fraction (HFpEF) is a major unmet medical need that is characterized by the presence of multiple cardiovascular and non-cardiovascular comorbidities. Foremost among these comorbidities are obesity and diabetes, which are not only risk factors for the development of HFpEF, but worsen symptoms and outcome. Coronary microvascular inflammation with endothelial dysfunction is a common denominator among HFpEF, obesity, and diabetes that likely explains at least in part the etiology of HFpEF and its synergistic relationship with obesity and diabetes...
2017: Frontiers in Endocrinology
https://www.readbyqxmd.com/read/28744974/obestatin-regulates-cardiovascular-function-and-promotes-cardioprotection-through-the-nitric-oxide-pathway
#9
Claudia Penna, Francesca Tullio, Saveria Femminò, Carmine Rocca, Tommaso Angelone, Maria C Cerra, Maria Pia Gallo, Iacopo Gesmundo, Alessandro Fanciulli, Maria Felice Brizzi, Pasquale Pagliaro, Giuseppe Alloatti, Riccarda Granata
Patients with ischaemic heart disease or chronic heart failure show altered levels of obestatin, suggesting a role for this peptide in human heart function. We have previously demonstrated that GH secretagogues and the ghrelin gene-derived peptides, including obestatin, exert cardiovascular effects by modulating cardiac inotropism and vascular tone, and reducing cell death and contractile dysfunction in hearts subjected to ischaemia/reperfusion (I/R), through the Akt/nitric oxide (NO) pathway. However, the mechanisms underlying the cardiac actions of obestatin remain largely unknown...
July 26, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/28743818/aid-ing-signaling-in-toxoplasma-gondii
#10
Kami Kim
The cyclic GMP-dependent protein kinase (PKG) of apicomplexan parasites is essential for secretion of micronemes and host cell invasion and egress. Both kinase specificity and localization can determine which substrates are phosphorylated. The functions of plasma membrane and cytosolic PKG isoforms of Toxoplasma gondii were unknown because of difficulties precisely manipulating expression of essential genes. Brown et al. (K. M. Brown, S. Long, and L. D. Sibley, mBio 8:e00375-17, https://doi.org/10.1128/mBio...
July 25, 2017: MBio
https://www.readbyqxmd.com/read/28743500/suppression-of-npr1-not-npr2-gene-function-induces-hypertrophic-growth-in-h9c2-cells-in%C3%A2-vitro
#11
Senthamizharasi Manivasagam, Elangovan Vellaichamy
Npr1 gene (coding for NPR-A) and Npr2 gene (coding for NPR-B) are identified as intrinsic anti-hypertrophic genes that opposes abnormal cardiac remodeling. However, the functional role of Npr1 and Npr2 genes during cardiac hypertrophic growth is not well understood. Hence, the present investigation was aimed to study the effect of Npr1 and Npr2 gene silencing, respectively on β-AR activation induced cardiac hypertrophic growth in H9c2 cells in vitro. The control, Npr1, and Npr2 gene suppressed H9c2 cells, respectively were treated with ISO (10(-5) M) for 48 h...
July 22, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28743391/valporic-acid-enhances-the-atrial-natriuretic-peptide-anp-mediated-anti-hypertrophic-activity-by-modulating-the-npr1-gene-transcription-in-h9c2-cells-in-vitro
#12
Senthamizharasi Manivasagam, Tamilselvi Velusamy, Boopathi Sowndharajan, Navvi Chandrasekar, Suresh Dhanusu, Elangovan Vellaichamy
The present study was aimed to determine whether stimulating Npr1 gene activity using Valporic acid (VA), a small short chain fatty acid molecule can enhance ANP mediated anti-hypertrophic activity in isoproterenol (ISO) - treated H9c2 cells in vitro. H9c2 cells were treated with ISO (10(-5) M) and co-treated with VA (10(-5) M) in the presence and absence of ANP (10(-8)M), for 48h. ATRA (10(-5) M) was used as a positive inducer of Npr1 gene transcription. The mRNA expression of Npr1 and PKG-I genes, proto-oncogenes (c-fos, c-jun and c-myc) and hypertrophic markers (ANP, BNP, α-sk and β-MyHC), genes were determined by quantitative PCR (qPCR)...
July 22, 2017: European Journal of Pharmacology
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
#13
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
#14
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
#15
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
#16
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
#17
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
#18
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...
September 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
#19
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...
August 15, 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
#20
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
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