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Madhu Kaundal, Saima Zameer, Abul Kalam Najmi, Suhel Parvez, Mohd Akhtar
Vascular dementia (VaD) is the second most common form of senile dementia, embraces memory deficits, neuroinflammation, executive function damage, mood and behavioral changes and abnormal cerebral blood flow. The purpose of the study was to explore the therapeutic potential of betulinic acid in bilateral common carotid artery occlusion (BCCAO) induced VaDin experimental rats.VaD was induced by BCCAO in rats and betulinic acid (10 and 15mg/kg/day po) was administered 1 week after surgery. The cerebral blood pressure of the animal was recorded before and after the treatment using Laser Doppler flow meter...
May 17, 2018: European Journal of Pharmacology
Ganiyu Oboh, Adeniyi A Adebayo, Ayokunle O Ademosun
BACKGROUND: Herbs have been used from ages to manage male sexual dysfunction. Hence, this study sought to investigate the effects of Eurycoma longifolia (EL) and Cylicodiscus gabunensis (CG) stem bark extracts on some enzymes implicated in erectile dysfunction in vitro. METHODS: The extracts were prepared, and their effects on phosphodiesterase-5 (PDE-5), arginase, and angiotensin-1-converting enzyme (ACE) as well as pro-oxidant-induced lipid peroxidation were assessed...
May 19, 2018: Journal of Basic and Clinical Physiology and Pharmacology
Enrico Gavagnin, Christian A Yates
Persistence of motion is the tendency of an object to maintain motion in a direction for short time scales without necessarily being biased in any direction in the long term. One of the most appropriate mathematical tools to study this behavior is an agent-based velocity-jump process. In the absence of agent-agent interaction, the mean-field continuum limit of the agent-based model (ABM) gives rise to the well known hyperbolic telegraph equation. When agent-agent interaction is included in the ABM, a strictly advective system of partial differential equations (PDEs) can be derived at the population level...
March 2018: Physical Review. E
Guohui Xiao, Liangliang Kong, Rongbo Che, Yusi Yi, Qinchao Zhang, Jie Yan, Xu'ai Lin
Leptospirosis is a widespread zoonotic disease caused by pathogenic Leptospira species. The most common species, Leptospira interrogans , can transfer from contaminated soil or water to the human body. It is able to survive these changing environments through sensing and responding to the changes of environmental cues. Cyclic di-GMP (c-di-GMP) is a special secondary messenger in bacteria, which can respond to the environment and regulate diverse bacterial behaviors. The c-di-GMP levels in bacterial cells are regulated by diguanylatecyclases (DGC) and phosphodiesterases (PDE), which are responsible for synthesizing or hydrolyzing c-di-GMP, respectively...
2018: Frontiers in Microbiology
Ze Chen, Xin Zhao, Yunzepeng Li, Rui Zhang, Zaihui Nie, Xiang Cheng, Xianrong Zhang, Hui Wang
Dexamethasone is routinely used for treating those mothers at risk for preterm delivery. However, overexposure to exogenous glucocorticoids induces bone loss in offspring, and the "critical window" and safe dose of this treatment are largely unknown. In this study, we found that femoral length, and the length of the primary ossification center were significantly reduced in fetal mice after repeated prenatal dexamethasone exposure (PDE). Compared with single-course exposure on gestational day (GD)15, newborn mice with repeated PDE (3 times, from GD15 to 17) showed a significant decrease in femoral trabecular bone mass with decreased trabecular number and thickness...
May 9, 2018: Toxicology and Applied Pharmacology
Navneet K Bhogal, Alveera Hasan, Julia Gorelik
3′-5′-cyclic adenosine monophosphate (cAMP) is a signaling messenger produced in response to the stimulation of cellular receptors, and has a myriad of functional applications depending on the cell type. In the heart, cAMP is responsible for regulating the contraction rate and force; however, cAMP is also involved in multiple other functions. Compartmentation of cAMP production may explain the specificity of signaling following a stimulus. In particular, transverse tubules (T-tubules) and caveolae have been found to be critical structural components for the spatial confinement of cAMP in cardiomyocytes, as exemplified by beta-adrenergic receptor (β-ARs) signaling...
May 3, 2018: Journal of Cardiovascular Development and Disease
Andrea Pugliese, Fabio Milner
A structured population model is described and analyzed, in which individual dynamics is stochastic. The model consists of a PDE of advection-diffusion type in the structure variable. The population may represent, for example, the density of infected individuals structured by pathogen density x, [Formula: see text]. The individuals with density [Formula: see text] are not infected, but rather susceptible or recovered. Their dynamics is described by an ODE with a source term that is the exact flux from the diffusion and advection as [Formula: see text]...
May 9, 2018: Journal of Mathematical Biology
Yufu Wang, Tianyi Fang, Lining Huang, Hao Wang, Lei Zhang, Zhidong Wang, Yunfu Cui
CD177 is considered to represent neutrophils. We analyzed mRNA expression level of CD177 and clinical follow-up survey of PDAC to estimate overall survival (OS) from Gene Expression Omnibus (GEO) dataset (GSE21501, containing samples from 102 PDAC patients) by R2 platform ( We also analyzed correlated genes of CD177 by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis to predict the potential relationship between neutrophils and prognosis of PDAC. We then performed hematoxylin and eosin (H&E) staining and immunohistochemical staining of surgical specimens to verify infiltration of neutrophils in PDAC tissues...
May 5, 2018: Biochemical and Biophysical Research Communications
Yung-Kuo Lin, Yao-Chang Chen, Yi-Ann Chen, Jen-Hung Huang, Shih-Ann Chen, Yi-Jen Chen
INTRODUCTION: Calcium overload increases the risk of atrial fibrillation (AF). Levosimedan, a calcium sensitizer, increases myofilament contractility. Clinical reports suggested that levosimendan might increase AF occurrence, but the electrophysiological effects of levosimendan on AF substrates and triggers (pulmonary veins, PVs) are not clear. METHODS AND RESULTS: Conventional microelectrodes were used to record action potentials (APs) in isolated rabbit PVs, sinoatrial nodes (SANs), the left atrium (LA), and right atrium (RA) before and after application of different concentrations of levosimendan with or without milrinone (a phosphodiesterase (PDE) III inhibitor) and glibenclamide (an ATP-sensitive potassium channel (KATP ) inhibitor)...
May 7, 2018: Journal of Cardiovascular Electrophysiology
Yong Wang, Miao Shi, Han Feng, Yalan Zhu, Songqing Liu, Ang Gao, Pu Gao
Ubiquitination constitutes one of the most important signaling mechanisms in eukaryotes. Conventional ubiquitination is catalyzed by the universally conserved E1-E2-E3 three-enzyme cascade in an ATP-dependent manner. The newly identified SidE family effectors of the pathogen Legionella pneumophila ubiquitinate several human proteins by a different mechanism without engaging any of the conventional ubiquitination machinery. We now report the crystal structures of SidE alone and in complex with ubiquitin, NAD, and ADP-ribose, thereby capturing different conformations of SidE before and after ubiquitin and ligand binding...
April 27, 2018: Cell
Tasnim Faisal, Kae Yi Tan, Si Mui Sim, Naeem Quraishi, Nget Hong Tan, Choo Hock Tan
The venom proteome of wild Pakistani Russell's viper (Daboia russelii) was investigated through nano-ESI-LCMS/MS of the reverse-phase HPLC fractions. A total of 54 venom proteins were identified and clustered into 11 protein families. Phospholipase A2 (PLA2 , 63.8%) and Kunitz-type serine protease inhibitor (KSPI, 16.0%) were most abundant, followed by snake venom serine protease (SVSP, 5.5%, mainly Factor V activating enzyme), vascular endothelial growth factor (VEGF, 4.3%), snake venom metalloprotease (SVMP, 2...
May 3, 2018: Journal of Proteomics
Mariana Ferreira Bizzi, Sergio Veloso Brant Pinheiro, Graeme B Bolger, Junia Ribeiro de Oliveira Longo Schweizer, Alexandre V Giannetti, Mary N Dang, Antonio Ribeiro-Oliveira, Márta Korbonits
Type 4 phosphodiesterases (PDE4s) of the large PDE enzyme superfamily have unique specificity for cAMP and may, therefore, be relevant for somatotroph tumorigenesis. Somatotroph adenomas typically overexpress PDEs probably as part of a compensatory mechanism to reduce cAMP levels. The rat PDE4A5 isoform (human homolog PDE4A4) interacts with the AIP protein, coded by a tumour suppressor gene mutated in a subgroup of familial isolated pituitary adenomas (FIPAs). PDE4A8 is the closest related isoform of PDE4A4...
May 3, 2018: Molecular and Cellular Endocrinology
Chia-Chi Chen, Li-Li Chen, Chung-Pin Li, Yu-Ting Hsu, Shih-Sheng Jiang, Chi-Shuan Fan, Kee Voon Chua, Sheng-Xiang Huang, Yi-Ming Shyr, Li-Tzong Chen, Tze-Sing Huang
We detected a significant elevation of serum HSP90α levels in pancreatitis patients and even more in pancreatic ductal adenocarcinoma (PDAC) patients. However, there was no significant difference in the serum HSP90α levels between patients with early-stage and late-stage PDAC. To study whether elevation of serum HSP90α levels occurred early during PDAC development, we used LSL-KrasG12D/Pdx1-Cre transgenic mice as a studying model. Elevated serum HSP90α levels were detected before PDAC formation and an extracellular HSP90α (eHSP90α) inhibitor effectively prevented PDAC development...
2018: Oncoimmunology
John M Humphrey, Matthew Movsesian, Christopher W Am Ende, Stacey L Becker, Thomas A Chappie, Stephen Jenkinson, Jennifer L Liras, Spiros Liras, Christine C Orozco, Jayvardhan Pandit, Felix F Vajdos, Fabrice Vandeput, Eddie Yang, Frank S Menniti
We disclose the discovery and X-ray co-crystal data of potent, selective quinazoline inhibitors of PDE1. Inhibitor (S)-3 readily attains free plasma concentrations above PDE1 IC50 values and has restricted brain access. The racemic compound 3 inhibits >75% of PDE hydrolytic activity in soluble samples of human myocardium, consistent with heightened PDE1 activity in this tissue. These compounds represent promising new tools to probe the value of PDE1 inhibition in the treatment of cardiovascular disease.
May 2, 2018: Journal of Medicinal Chemistry
Nazanin Namazi Sarvestani, Saeedeh Saberi Firouzi, Reza Falak, Mohammad Yahya Karimi, Mohammad Davoodzadeh Gholami, Akram Rangbar, Asieh Hosseini
Diabetic neuropathy (DN) is the most common diabetic complication. It is estimated diabetic population will increase to 592 million by the year 2035. This is while at least 50-60% of all diabetic patients will suffer from neuropathy in their lifetime. Oxidative stress, mitochondrial dysfunction, apoptosis, and inflammation are crucial pathways in development and progression of DN. Since there is also no selective and effective therapeutic agent to prevent or treat high glucose (HG)-induced neuronal cell injury, it is crucial to explore tools by which one can reduce factors related to these pathways...
April 30, 2018: Metabolic Brain Disease
Li Liu, Jing Zheng, Xian-Feng Huang, Xia Zhu, Shu-Ming Ding, Heng-Ming Ke, James M O'Donnell, Han-Ting Zhang, Guo-Qiang Song, Ying Xu
AIMS: Depression is currently the most common mood disorder. Regulation of intracellular cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (cGMP) signaling by phosphodiesterase (PDE) inhibition has been paid much attention for treatment of depression. This study aimed to investigate the neuroprotective effects of Hcyb1, a novel PDE2 inhibitor, in HT-22 cells and antidepressant-like effects in mouse models of depression. METHODS: Hcyb1 was synthesized and its selectivity upon PDE2 was tested...
April 27, 2018: CNS Neuroscience & Therapeutics
Ambikaipakan Balasubramaniam, Sulaiman Sheriff, Lou Ann Friend, J Howard James
PDE4-cAMP pathway plays a predominant role in mediating skeletal muscle proteolysis in burn injury. The present investigations to determine the PDE4 isoform(s) involved in this action revealed that burn injury increased the expression of rat skeletal muscle PDE4B mRNA by 6-fold, but had little or no effect on expression of other PDE4 isoforms. These observations led us to study the effects of burn in PDE4B KO-rats. As reported by us previously, burn injury significantly increased EDL muscle total and myofibrillar proteolysis in WT-rats, but there were no significant effects on either total or myofibrillar protein breakdown in EDL muscle of PDE4B KO-rat with burn injury...
April 25, 2018: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
Si Chen, Walter E Knight, Chen Yan
Pathological cardiac hypertrophy and dysfunction is a response to various stress stimuli and can result in reduced cardiac output and heart failure. Cyclic nucleotide signaling regulates several cardiac functions including contractility, remodeling, and fibrosis. Cyclic nucleotide phosphodiesterases (PDEs), by catalyzing the hydrolysis of cyclic nucleotides, are critical in the homeostasis of intracellular cyclic nucleotide signaling and hold great therapeutic potential as drug targets. Recent studies have revealed that the inhibition of the PDE family member PDE1 plays a protective role in pathological cardiac remodeling and dysfunction by the modulation of distinct cyclic nucleotide signaling pathways...
April 23, 2018: Journal of Cardiovascular Development and Disease
Luca Romanelli, Maria Grazia Evandri
Solvents can be used in the manufacture of medicinal products provided their residual levels in the final product comply with the acceptable limits based on safety data. At worldwide level, these limits are set by the "Guideline Q3C (R6) on impurities: guideline for residual solvents" issued by the ICH. Diisopropyl ether (DIPE) is a widely used solvent but the possibility of using it in the pharmaceutical manufacture is uncertain because the ICH Q3C guideline includes it in the group of solvents for which "no adequate toxicological data on which to base a Permitted Daily Exposure (PDE) was found"...
April 2018: Toxicological Research
Atsushi Nanashima, Tetsuro Tominaga, Yorihisa Sumida, Shuichi Tobinaga, Takeshi Nagayasu
INTRODUCTION: The indocyanine green-photodynamic eye (ICG-PDE) system is useful to detect small hypervascular liver tumors, hepatocellular carcinoma (HCC), on the liver surface. This system may be also applied to improve determining the location of metastasis or tumor thrombus (TT). We herein report three case reports. ICG was administered preoperatively for functional testing and images of the tumor were observed during hepatectomy using a PDE camera. CASE SERIES: The patient in case 1 exhibited advanced HCC with TT in the portal trunk...
April 16, 2018: International Journal of Surgery Case Reports
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