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L Atkinson, M Z Yusuf, A Aburima, Y Ahmed, S G Thomas, K M Naseem, S D J Calaminus
Evidence has emerged to suggest that thrombi are dynamic structures with distinct areas of differing platelet activation and inhibition. We hypothesised that Nitric oxide (NO), a platelet inhibitor, can modulate the actin cytoskeleton reversing platelet spreading, and therefore reduce the capability of thrombi to withstand a high shear environment. Our data demonstrates that GSNO, DEANONOate, and a PKG-activating cGMP analogue reversed stress fibre formation and increased actin nodule formation in adherent platelets...
February 14, 2018: Scientific Reports
Aurelie Nguyen Dinh Cat, Glaucia E Callera, Malou Friederich-Persson, Ana Sanchez, Maria Gabriela Dulak-Lis, Sofia Tsiropoulou, Augusto C Montezano, Ying He, Ana M Briones, Frederic Jaisser, Rhian M Touyz
Activation of aldosterone/mineralocorticoid receptors (MR) has been implicated in vascular dysfunction of diabetes. Underlying mechanisms are elusive. Therefore, we investigated the role of Rho kinase (ROCK) in aldosterone/MR signaling and vascular dysfunction in a model of diabetes. Diabetic obese mice (db/db) and control counterparts (db/+) were treated with MR antagonist (MRA, potassium canrenoate, 30 mg/kg/day, 4 weeks) or ROCK inhibitor, fasudil (30 mg/kg/day, 3 weeks). Plasma aldosterone was increased in db/db versus db/+...
February 13, 2018: Scientific Reports
Eleonora Vighi, Andreas Rentsch, Philipp Henning, Antonella Comitato, Dorit Hoffmann, Daniela Bertinetti, Evelina Bertolotti, Frank Schwede, Friedrich W Herberg, Hans-Gottfried Genieser, Valeria Marigo
Melanoma is one of the most aggressive cancers and displays high resistance to conventional chemotherapy underlining the need for new therapeutic strategies. The cGMP/PKG signaling pathway was detected in melanoma cells and shown to reduce migration, proliferation and to increase apoptosis in different cancer types. In this study, we evaluated the effects on cell viability, cell death, proliferation and migration of novel dimeric cGMP analogues in two melanoma cell lines (MNT1 and SkMel28). These new dimeric cGMP analogues, by activating PKG with limited effects on PKA, significantly reduced proliferation, migration and increased cell death...
January 12, 2018: Oncotarget
Yan Wu, Miaomiao Yuan, Wenbin Su, Miaolin Zhu, Xiaoyuan Yao, Ying Wang, Hai Qian, Lu Jiang, Yan Tao, Min Wu, Ji Pang, Yongchang Chen
Type II cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG II) is a membrane-anchored enzyme expressed mainly in the intestinal mucosa and the brain, and is associated with various physiological or pathological processes. Upregulation of PKG II is known to induce apoptosis and inhibit proliferation and metastasis of cancer cells. The inhibitory effect of PKG II has been shown to be dependent on the inhibition of the activation of epidermal growth factor receptor (EGFR) and blockade of EGFR downstream signal transduction in vitro...
2018: Therapeutic Advances in Medical Oncology
Anees A Banday, Mustafa F Lokhandwala
Reactive oxygen species induce vascular dysfunction and hypertension by directly interacting with nitric oxide (NO) which leads to NO inactivation. In addition to a decrease in NO bioavailability, there is evidence that oxidative stress can also modulate NO signaling during hypertension. Here, we investigated the effect of oxidative stress on NO signaling molecules cGMP-dependent protein kinase (PKG) and vasodilator-stimulated phosphoprotein (VASP) which are known to mediate vasodilatory actions of NO. Male Sprague Dawley (SD) rats were provided with tap water (control), 30 mM L-buthionine sulfoximine (BSO, a pro-oxidant), 1 mM tempol (T, an antioxidant) and BSO + T for 3 wks...
February 9, 2018: Clinical and Experimental Hypertension: CHE
Saskia Klutzny, Anna Anurin, Barbara Nicke, Joseph L Regan, Martin Lange, Luise Schulze, Karsten Parczyk, Patrick Steigemann
Cancer stem cells (CSCs) are involved in metastasis and resistance development, thus affecting anticancer therapy efficacy. The underlying pathways required for CSC maintenance and survival are not fully understood and only a limited number of treatment strategies to specifically target CSCs have been identified. To identify novel CSC targeting compounds, we here set-up an aldehyde dehydrogenase (ALDH)-based phenotypic screening system that allows for an automated and standardized identification of CSCs. By staining cancer cells for ALDH activity and applying high-content-based single-cell population analysis, the proportion of a potential CSC subpopulation with significantly higher ALDH activity (ALDHhigh) can be quantified in a heterogeneous cell population...
February 7, 2018: Cell Death & Disease
Leandro A Oliveira, Lucas Gomes-de-Souza, Ricardo Benini, Carlos C Crestani
The aims of the present study were to assess an interaction of corticotropin-releasing factor (CRF) neurotransmission within the bed nucleus of the stria terminalis (BNST) with local nitrergic signaling, as well as to investigate an involvement of activation of local NMDA glutamate receptor and nitric oxide (NO) signaling in control of cardiovascular responses to acute restraint stress by BNST CRF neurotransmission in rats. We observed that CRF microinjection into the BNST increased local NO release during restraint stress...
January 12, 2018: Psychoneuroendocrinology
Hongliang Li, Sung Eun Shin, Mi Seon Seo, Jin Ryeol An, Il-Whan Choi, Won-Kyo Jung, Amy L Firth, Dae-Sung Lee, Mi-Jin Yim, Grace Choi, Jeong Min Lee, Sung Hun Na, Won Sun Park
AIM: Considering the clinical efficacy of dapagliflozin in patients with type 2 DM and the pathophysiological relevance of Kv channels for vascular reactivity. We investigate the vasodilatory effect of dapagliflozin and related mechanisms using phenylephrine (Phe)-induced contracted aortic rings. MATERIAL AND METHODS: Arterial tone measurement was performed in aortic smooth muscle. KEY FINDINGS: Application of dapagliflozin induced vasodilation in a concentration-dependent manner...
January 31, 2018: Life Sciences
Ruiting Zhao, Ju Zhou, Xinlong Dong, Chongwen Bi, Rongcai Jiang, Jingfei Dong, Ye Tian, Hengjie Yuan, Jian-Ning Zhang
Traumatic brain injury (TBI) has high morbidity and mortality rates. The mechanisms underlying the TBI are unclear and may include the change in biological material in exosomes. Circular RNAs (circRNAs) are enriched and stable in exosomes, which can function as microRNA (miRNA) sponges to regulate gene expression levels. Therefore, we speculated that circRNAs in exosomes might play an important role in regulating gene expression after TBI and then regulate specific signaling pathways, which may protect the brain...
February 6, 2018: Journal of Neurotrauma
Lan Zhang, Luqing Pan, Lijun Xu, Lingjun Si
The effects of ammonia-N exposure (transferred from 0.07 to 2, 10 and 20 mg L-1) on the mechanism of neuroendocrine-immunoregulatory network were investigated in Litopenaeus vannamei. The results showed that biogenic amines (dopamine, noradrenaline, 5-hydroxytryptamine) concentrations in treatment groups increased significantly within 12 h. The gene expression of guanylyl cyclase increased significantly from 3 h to 24 h. And dopamine receptor D4 and α2 adrenergic receptor gene expression in treatment groups decreased significantly within 12 h, whereas the mRNA expression of 5-HT7 receptor increased significantly within 3 h and reached the peak levels at 6 h...
January 30, 2018: Fish & Shellfish Immunology
André M Leite-Moreira, João Almeida-Coelho, João S Neves, Ana L Pires, João Ferreira-Martins, Ricardo Castro-Ferreira, Ricardo Ladeiras-Lopes, Glória Conceição, Daniela Miranda-Silva, Patrícia Rodrigues, Nazha Hamdani, Melissa Herwig, Inês Falcão-Pires, Walter J Paulus, Wolfgang A Linke, André P Lourenço, Adelino F Leite-Moreira
Aims: The heart is constantly challenged with acute bouts of stretching or overload. Systolic adaptations to these challenges are known but adaptations in diastolic stiffness remain unknown. We evaluated adaptations in myocardial stiffness due to acute stretching and characterized the underlying mechanisms. Methods and Results: Left ventricles (LV) of intact rat hearts, rabbit papillary muscles and myocardial strips from cardiac surgery patients were stretched. After stretching, there was a sustained >40% decrease in end-diastolic pressure (EDP) or passive tension (PT) for 15 minutes in all species and experimental preparations...
February 1, 2018: Cardiovascular Research
Yan Wu, Ying Liu, Zhensheng Cai, Huijuan Qin, Hongfan Li, Wenbin Su, Ying Wang, Hai Qian, Lu Jiang, Min Wu, Ji Pang, Yongchang Chen
BACKGROUND The mammalian cyclic guanosine monophosphate (cGMP)-dependent protein kinases type II (PKG II) plays critical physiological or pathological functions in different tissues. However, the biological effects of PKG II are dependent on cGMP. Published data indicated that L-arginine (L-Arg) promoted NO production, NO can activate soluble guanylate cyclase (sGC), and catalyzes guanosine triphosphate (GTP) into cGMP, which suggested L-Arg could activate PKG II. Therefore, the present work was performed to address: (i) whether L-Arg could be a potential alternative in PKG II activation, and (ii) whether L-Arg also contributes to PKG II against cancer...
February 5, 2018: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
Dianxin Liu, Ryan P Ceddia, Sheila Collins
OBJECTIVE: Activation of thermogenesis in brown adipose tissue (BAT) and the ability to increase uncoupling protein 1 (UCP1) levels and mitochondrial biogenesis in white fat (termed 'browning'), has great therapeutic potential to treat obesity and its comorbidities because of the net increase in energy expenditure. β-adrenergic-cAMP-PKA signaling has long been known to regulate these processes. Recently PKA-dependent activation of mammalian target of rapamycin complex 1 (mTORC1) was shown to be necessary for adipose 'browning' as well as proper development of the interscapular BAT...
January 17, 2018: Molecular Metabolism
Kristofer J Haushalter, Darren E Casteel, Andrea Raffeiner, Eduard Stefan, Hemal H Patel, Susan S Taylor
cAMP-dependent protein kinase (PKAc) is a pivotal signaling protein in eukaryotic cells. PKAc has two well-characterized regulatory subunit proteins, RI and RII (each having α and β isoforms), which keep the PKAc catalytic subunit in a catalytically inactive state until activation by cAMP. Previous reports showed that the RIα regulatory subunit is phosphorylated by cGMP-dependent protein kinase (PKG) in vitro, whereupon phosphorylated RIα no longer inhibits PKAc at normal (1:1) stoichiometric ratios. However, the significance of this phosphorylation as a mechanism for activating Type I PKA holoenzymes has not been fully explored, especially in cellular systems...
January 29, 2018: Journal of Biological Chemistry
Muniesh Muthaiyan Shanmugam, Prerana Bhan, Hsin-Yi Huang, Jung Hsieh, Tzu-En Hua, Gong-Her Wu, Helly Punjabi, Víctor Daniel Lee Aplícano, Chih-Wei Chen, Oliver Ingvar Wagner
To understand how ciliopathies such as polycystic kidney disease or Bardet-Biedl syndrome develop, we need to understand the basic molecular mechanisms underlying cilia development. Cilia growth depends on a functional intraflagellar transport (IFT) machinery, and we hypothesized that various kinases and phosphatases might be involved in this regulatory process. A candidate screen revealed two kinases PKG-1 (a cGMP-dependent protein kinase) and GCK-2 (a MAP4K3 kinase involved in mTOR signaling) significantly affecting dye filling, chemotaxis, cilia morphology, and IFT component distribution...
January 29, 2018: Molecular and Cellular Biology
Roberto V Reyes, Marcela Díaz, Germán Ebensperger, Emilio A Herrera, Sebastián A Quezada, Ismael Hernandez, Emilia M Sanhueza, Julian T Parer, Dino A Giussani, Aníbal J Llanos
Llamas are born in the Alto Andino with protection against pulmonary hypertension. The physiology underlying protection against pulmonary vasoconstrictor responses to acute hypoxia in highland species is unknown. We determined the role of NO in the cardiopulmonary responses to acute hypoxia in high- and low-land newborn llamas. The cardiopulmonary function of newborn llamas, born at low (580 m) or high altitude (3600 m), was studied under acute hypoxia, with and without NO blockade. In pulmonary arteries, we measured the reactivity to potassium and SNP, and in lung we determined the content of cGMP and the expression of the NO-related proteins: BKCa, PDE5, PSer92-PDE5, PKG-1, ROCK1 and 2, MYPT1, PSer695-MYPT1, PThr696-MYPT1, MLC20 and PSer19-MLC20...
January 25, 2018: Journal of Physiology
Nathan A Holland, Jake T Francisco, Sean C Johnson, Joshua S Morgan, Troy J Dennis, Nishitha R Gadireddy, David A Tulis
Cardiovascular disease (CVD), including myocardial infarction (MI) and peripheral or coronary artery disease (PAD, CAD), remains the number one killer of individuals in the United States and worldwide, accounting for nearly 18 million (>30%) global deaths annually. Despite considerable basic science and clinical investigation aimed at identifying key etiologic components of and potential therapeutic targets for CVD, the number of individuals afflicted with these dreaded diseases continues to rise. Of the many biochemical, molecular, and cellular elements and processes characterized to date that have potential to control foundational facets of CVD, the multifaceted cyclic nucleotide pathways continue to be of primary basic science and clinical interest...
January 23, 2018: Journal of Cardiovascular Development and Disease
Kátia R L Schwarz, Fernanda C de Castro, Letícia Schefer, Ramon C Botigelli, Daniela M Paschoal, Hugo Fernandes, Cláudia L V Leal
This study aimed to determine the influence of cyclic guanosine 3'5'-monophosphate (cGMP) and cGMP-dependent kinase (PKG) during in vitro maturation (IVM) on lipolysis-related parameters in bovine cumulus-oocyte complexes (COCs), and on embryo development and cryosurvival. COCs were matured with cGMP/PKG modulators and assessed for metaphase II rates (MII), cGMP levels, lipid content in oocytes (OO), transcript abundance for genes involved in lipolysis (ATGL) and lipid droplets (PLIN2) in cumulus cells (CC) and OO, and presence of phosphorylated (active) hormone sensitive lipase (HSLser563) in OO...
2018: PloS One
Sarah McGregor, Philip Churchward, Katarzyna Soja, Denise O'Driscoll, Michelle Braybrook, Hamid Khodakarami, Andrew Evans, Parisa Farzanehfar, Garun Hamilton, Malcolm Horne
Sleep disturbances are common in Parkinson's disease (PD). We used the Parkinson's KinetiGraph (PKG), an objective movement recording system for PD to assess night time sleep in 155 people aged over 60 and without PD (controls), 72 people with PD (PwP) and 46 subjects undergoing a Polysomnogram (PSG: 36 with sleep disorder and 10 with normal sleep). The PKG system uses a wrist worn logger to capture acceleration and derive a bradykinesia score (BKS) every 2 min over 6 days. The BKS ranges from 0-160 with higher scores associated with lesser mobility...
2018: NPJ Parkinson's Disease
Andrea Mancini, Michela Tantucci, Petra Mazzocchetti, Antonio de Iure, Valentina Durante, Lara Macchioni, Carmela Giampà, Alessandra Alvino, Lorenzo Gaetani, Cinzia Costa, Alessandro Tozzi, Paolo Calabresi, Massimiliano Di Filippo
During multiple sclerosis (MS), a close link has been demonstrated to occur between inflammation and neuro-axonal degeneration, leading to the hypothesis that immune mechanisms may promote neurodegeneration, leading to irreversible disease progression. Energy deficits and inflammation-driven mitochondrial dysfunction seem to be involved in this process. In this work we investigated, by the use of striatal electrophysiological field-potential recordings, if the inflammatory process associated with experimental autoimmune encephalomyelitis (EAE) is able to influence neuronal vulnerability to the blockade of mitochondrial complex IV, a crucial component for mitochondrial activity responsible of about 90% of total cellular oxygen consumption...
January 8, 2018: Neurobiology of Disease
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