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PDE AND mitochondria

Hao Ding, Feng Bai, Hongdi Cao, Jing Xu, Li Fang, Jining Wu, Qi Yuan, Yang Zhou, Qi Sun, Weichun He, Chunsun Dai, Ke Zen, Lei Jiang, Junwei Yang
AIMS: Cyclic adenosine 3'5'-monophosphate (cAMP) is a universal second messenger that plays an important role in intracellular signal transduction. cAMP is synthesized by adenylate cyclases from adenosine triphosphate and terminated by the phosphodiesterases (PDEs). In the present study, we investigated the role of the cAMP pathway in tubular epithelial cell mitochondrial biogenesis in the pathogenesis of renal fibrosis. RESULTS: We found that the cAMP levels were decreased in fibrotic kidney tissues, and replenishing cAMP could ameliorate tubular atrophy and extracellular matrix deposition...
February 22, 2018: Antioxidants & Redox Signaling
Liliane Tetsi, Anne-Laure Charles, Stéphanie Paradis, Anne Lejay, Samy Talha, Bernard Geny, Claire Lugnier
Mitochondria play a critical role in skeletal muscle metabolism and function, notably at the level of tissue respiration, which conduct muscle strength as well as muscle survival. Pathological conditions induce mitochondria dysfunctions notably characterized by free oxygen radical production disturbing intracellular signaling. In that way, the second messengers, cyclic AMP and cyclic GMP, control intracellular signaling at the physiological and transcription levels by governing phosphorylation cascades. Both nucleotides are specifically and selectively hydrolyzed in their respective 5'-nucleotide by cyclic nucleotide phosphodiesterases (PDEs), which constitute a multi-genic family differently tissue distributed and subcellularly compartmentalized...
May 2017: Cellular and Molecular Life Sciences: CMLS
Ryan M Whitaker, Lauren P Wills, L Jay Stallons, Rick G Schnellmann
Recent studies demonstrate that mitochondrial dysfunction is a mediator of acute kidney injury (AKI). Consequently, restoration of mitochondrial function after AKI may be key to the recovery of renal function. Mitochondrial function can be restored through the generation of new, functional mitochondria in a process called mitochondrial biogenesis (MB). Despite its potential therapeutic significance, very few pharmacological agents have been identified to induce MB. To examine the efficacy of phosphodiesterase (PDE) inhibitors (PDE3: cAMP and cGMP activity; and PDE4: cAMP activity) in stimulating MB, primary cultures of renal proximal tubular cells (RPTCs) were treated with a panel of inhibitors for 24 hours...
December 2013: Journal of Pharmacology and Experimental Therapeutics
Katalin Módis, Panagiotis Panopoulos, Ciro Coletta, Andreas Papapetropoulos, Csaba Szabo
Although hydrogen sulfide (H₂S) is generally known as a mitochondrial poison, recent studies show that lower concentrations of H₂S play a physiological role in the stimulation of mitochondrial electron transport and cellular bioenergetics. This effect involves electron donation at Complex II. Other lines of recent studies demonstrated that one of the biological actions of H₂S involves inhibition of cAMP and cGMP phosphodiesterases (PDEs). Given the emerging functional role of the mitochondrial isoform of cAMP PDE (PDE2A) in the regulation of mitochondrial function the current study investigated whether cAMP-dependent mechanisms participate in the stimulatory effect of NaHS on mitochondrial function...
November 1, 2013: Biochemical Pharmacology
Dan Wang, Zhuo Wang, Yan Li, Xin Chen, Gui Yuan Sun
PURPOSE: The purpose of the present study was to investigate the effect of nimodipine (NMD), a calcium channel blocker, on N-methyl-N-nitrosourea (MNU)-induced retinal degeneration. MATERIALS AND METHODS: 60 mg/kg MNU was given intraperitoneally to 6-week-old female Sprague-Dawley rats, and NMD was injected intraperitoneally for up to 5 days after MNU. The effect of NMD was evaluated by electron microscopy and electroretinography (ERG). Proteins of Bax, Bcl-2, Caspase-3, and mitochondrial membrane potential (MMP) were analyzed with flow cytometry...
March 2013: Indian Journal of Pharmacology
Fiona Murray, Paul A Insel
INTRODUCTION: Cyclic AMP (cAMP) promotes growth arrest and/or apoptosis of various types of lymphoma, in particular chronic lymphocytic leukemia (CLL). These responses have spurred the interest in developing agents that increase cAMP to treat such malignancies and to identify mechanisms of the responses. AREAS COVERED: The murine T-lymphoma cell line S49, has provided an important, pioneering model to define mechanisms of cAMP-mediated lymphoid cell death. Studies with S49 cells demonstrated that cAMP, acting via protein kinase A (PKA), is pro-apoptotic through a mitochondria-dependent pathway and identified cAMP/PKA-regulated targets involved in apoptosis...
August 2013: Expert Opinion on Therapeutic Targets
Carmen Methner, Robert Lukowski, Karina Grube, Florian Loga, Robin A J Smith, Michael P Murphy, Franz Hofmann, Thomas Krieg
Protein kinase G type I (PKGI) plays a critical role in survival signaling of pre- and postconditioning downstream of cardiac cGMP. However, it is unclear whether PKGI exerts its protective effects in the cardiomyocyte or if other cardiac cell types are involved, and whether nitric oxide (NO) metabolism can target cardiomyocyte mitochondria independently of cGMP/PKGI. We tested whether protection against reperfusion injury by ischemic postconditioning (IPost), soluble guanylyl cyclase (sGC) activation and inhibition, adenosine A(2B) receptor (A(2B)AR) agonist, phosphodiesterase type-5 (PDE-5) inhibitor, or mitochondria-targeted S-nitrosothiol (MitoSNO) was affected by a cardiomyocyte-specific ablation of the PKGI gene in the mouse (CMG-KO)...
March 2013: Basic Research in Cardiology
Saisudha Koka, Anindita Das, Fadi N Salloum, Rakesh C Kukreja
Diabetic patients exhibit increased risk for the development of cardiovascular diseases primarily because of impaired nitric oxide (NO) bioavailability. The phosphodiesterase-5 (PDE-5) inhibitor sildenafil restores NO signaling and protects against ischemia/reperfusion (I/R) injury. In this study, we determined the effect of the long-acting PDE-5 inhibitor tadalafil on diabetes-associated complications and its role in attenuating oxidative stress after I/R injury in type 2 diabetic db/db mice. Adult male db/db mice (n=40/group) were randomized to receive dimethyl sulfoxide (10% DMSO, 0...
July 2013: Free Radical Biology & Medicine
Natasa Dragicevic, Vedad Delic, Chuanhai Cao, Neil Copes, Xiaoyang Lin, Maggie Mamcarz, Li Wang, Gary W Arendash, Patrick C Bradshaw
Caffeine and melatonin have been shown to protect the Swedish mutant amyloid precursor protein (APP(sw)) transgenic mouse model of Alzheimer's disease from cognitive dysfunction. But their mechanisms of action remain incompletely understood. These Alzheimer's mice have extensive mitochondrial dysfunction, which likely contributes to their cognitive decline. To further explore the mechanism through which caffeine and melatonin protect cognitive function in these mice, we monitored the function of isolated mitochondria from APP(sw) mice treated with caffeine, melatonin, or both in their drinking water for one month...
December 2012: Neuropharmacology
Araceli Tobío, Andrea Fernández-Araujo, Amparo Alfonso, Luis M Botana
Yessotoxin (YTX) is a marine polyether toxin previously described as a phosphodiesterase (PDE) activator in fresh human lymphocytes. This toxin induces a decrease of adenosine 3',5'-cyclic monophosphate (cAMP) levels in fresh human lymphocytes in a medium with calcium (Ca(2+) ), whereas the contrary effect has been observed in a Ca(2+) -free medium. In the present article, the effect of YTX in K-562 lymphocytes cell line has been analysed. Surprisingly, results obtained in K-562 cell line are completely opposite than in fresh human lymphocytes, since in K-562 cells YTX induces an increase of cAMP levels...
December 2012: Journal of Cellular Biochemistry
Daniela Mokra, Anna Drgova, Rudolf Pullmann, Andrea Calkovska
Since inflammation and oxidation play a key role in the pathophysiology of neonatal meconium aspiration syndrome, various anti-inflammatory drugs have been tested in the treatment. This study evaluated whether the phosphodiesterase (PDE) 3 inhibitor olprinone can alleviate meconium-induced inflammation and oxidative lung injury. Oxygen-ventilated rabbits intratracheally received 4 ml/kg of meconium (25 mg/ml) or saline. Thirty minutes after meconium/saline instillation, meconium-instilled animals were treated by intravenous olprinone (0...
June 2012: Pulmonary Pharmacology & Therapeutics
L De Toni, G Strapazzon, L Gianesello, N Caretta, C Pilon, A Bruttocao, C Foresta
OBJECTIVE: An excess of adipose tissue (AT) in obese individuals is linked to increased cardiovascular risk and mitochondria have been shown to be defective in the muscle and AT of patients with metabolic disorders such as obesity and Type 2 diabetes. Nitric oxide (NO) generated by endothelial NO synthase (eNOS) plays a role in mitochondrial biogenesis through cyclic-GMP (cGMP). AT harbors the whole molecular signaling pathway of NO, together with type 5-phosphodiesterase (PDE- 5), the main cGMP catabolising enzyme...
November 2011: Journal of Endocrinological Investigation
Masami Shimizu-Albergine, Li-Chun Lisa Tsai, Enrico Patrucco, Joseph A Beavo
Phosphodiesterase (PDE) 8A and PDE8B are high-affinity, cAMP-specific phosphodiesterases that are highly expressed in Leydig cells. PDE8A is largely associated with mitochondria, whereas PDE8B is broadly distributed in the cytosol. We used a new, PDE8-selective inhibitor, PF-04957325, and genetically ablated PDE8A(-/-), PDE8B(-/-) and PDE8A(-/-)/B(-/-) mice to determine roles for these PDEs in the regulation of testosterone production. PF-04957325 treatment of WT Leydig cells or MA10 cells increased steroid production but had no effect in PDE8A (-/-)/B(-/-) double-knockout cells, confirming the selectivity of the drug...
April 2012: Molecular Pharmacology
Julia Szendroedi, Albrecht Ingo Schmid, Marek Chmelik, Martin Krssak, Peter Nowotny, Thomas Prikoszovich, Alexandra Kautzky-Willer, Michael Wolzt, Werner Waldhäusl, Michael Roden
BACKGROUND: Aging and insulin resistance have been related to reduced mitochondrial function and oxidative stress. Muscular phosphodiesters (PDE) are comprised of metabolites of phospholipid breakdown and may reflect membrane damage. We aimed to test the hypothesis that myocellular PDE are increased in patients with type 2 diabetes (T2D) and correlate inversely with mitochondrial ATP turnover. METHODS: A Cross-sectional study in the Clinical Research Facility of an University hospital was performed...
2011: PloS One
Rebeca Acin-Perez, Michael Russwurm, Kathrin Günnewig, Melanie Gertz, Georg Zoidl, Lavoisier Ramos, Jochen Buck, Lonny R Levin, Joachim Rassow, Giovanni Manfredi, Clemens Steegborn
Mitochondria are central organelles in cellular energy metabolism, apoptosis, and aging processes. A signaling network regulating these functions was recently shown to include soluble adenylyl cyclase as a local source of the second messenger cAMP in the mitochondrial matrix. However, a mitochondrial cAMP-degrading phosphodiesterase (PDE) necessary for switching off this cAMP signal has not yet been identified. Here, we describe the identification and characterization of a PDE2A isoform in mitochondria from rodent liver and brain...
September 2, 2011: Journal of Biological Chemistry
Joanna Rorbach, Thomas J J Nicholls, Michal Minczuk
Polyadenylation of mRNA in human mitochondria is crucial for gene expression and perturbation of poly(A) tail length has been linked to a human neurodegenerative disease. Here we show that 2'-phosphodiesterase (2'-PDE), (hereafter PDE12), is a mitochondrial protein that specifically removes poly(A) extensions from mitochondrial mRNAs both in vitro and in mitochondria of cultured cells. In eukaryotes, poly(A) tails generally stabilize mature mRNAs, whereas in bacteria they increase mRNA turnover. In human mitochondria, the effects of increased PDE12 expression were transcript dependent...
September 1, 2011: Nucleic Acids Research
Jesper Buchhave Poulsen, Kasper Røjkjær Andersen, Karina Hansen Kjær, Fiona Durand, Pierre Faou, Anna Lindeløv Vestergaard, Gert Hoy Talbo, Nick Hoogenraad, Ditlev Egeskov Brodersen, Just Justesen, Pia Møller Martensen
The vertebrate 2-5A system is part of the innate immune system and central to cellular antiviral defense. Upon activation by viral double-stranded RNA, 5'-triphosphorylated, 2'-5'-linked oligoadenylate polyribonucleotides (2-5As) are synthesized by one of several 2'-5'-oligoadenylate synthetases. These unusual oligonucleotides activate RNase L, an unspecific endoribonuclease that mediates viral and cellular RNA breakdown. Subsequently, the 2-5As are removed by a 2'-phosphodiesterase (2'-PDE), an enzyme that apart from breaking 2'-5' bonds also degrades regular, 3'-5'-linked oligoadenylates...
May 2011: Nucleic Acids Research
Brent P Forester, Yosef A Berlow, David G Harper, J Eric Jensen, Nicholas Lange, Michael P Froimowitz, Caitlin Ravichandran, Dan V Iosifescu, Scott E Lukas, Perry F Renshaw, Bruce M Cohen
Evidence suggests that mitochondria undergo functional and morphological changes with age. This study aimed to investigate the relationship of brain energy metabolism to healthy aging by assessing tissue specific differences in metabolites observable by phosphorus ((31)P) MRS. (31)P MRSI at 4 Tesla (T) was performed on 34 volunteers, aged 21-84, screened to exclude serious medical and psychiatric diagnoses. Linear mixed effects models were used to analyze the effects of age on phosphorus metabolite concentrations, intracellular magnesium and pH estimates in brain tissue...
April 2010: NMR in Biomedicine
Jeng-Fong Chiou, Yu-Huei Wang, Mei-Jie Jou, Tsan-Zon Liu, Chia-Yang Shiau
Photodynamic therapy (PDT) is a rapidly evolving treatment modality with diverse usages in the field of cancer therapy. Most of PDT is based on free radical-mediated photo-killing of cancer cells. This study aimed to elucidate the detailed cascade of events that lead to apoptotic cell death of HepG2 cells resulting from the photodynamic effect (PDE) of verteporfin. PDE of verteporfin could rapidly provoke hyper-oxidative stress and caspase activity. Glutathione (GSH) depletion and lipid peroxidation phenomena could simultaneously be evoked...
February 2010: Free Radical Research
Mika Fukasawa, Hirofumi Nishida, Toshiaki Sato, Masaru Miyazaki, Haruaki Nakaya
6-[4-(1-Cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2-(1H)quinolinone (cilostazol), a phosphodiesterase type 3 (PDE III) inhibitor, activates cAMP-dependent protein kinase A (PKA). The cAMP/PKA pathway potentiates the opening of mitochondrial Ca(2+)-activated K(+) (mitoK(Ca)) channels and confers cardioprotection. Although cilostazol has been reported to directly activate sarcolemmal large-conductance Ca(2+)-activated K(+) channels, it remains unclear whether cilostazol modulates the opening of mitoK(Ca) channels...
July 2008: Journal of Pharmacology and Experimental Therapeutics
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