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Beta cells AND statins

Christian Henninger, Gerhard Fritz
Cancer patients receiving anthracycline-based chemotherapy are at risk to develop life-threatening chronic cardiotoxicity with the pathophysiological mechanism of action not fully understood. Besides the most common hypothesis that anthracycline-induced congestive heart failure (CHF) is mainly caused by generation of reactive oxygen species, recent data point to a critical role of topoisomerase II beta (TOP2B), which is a primary target of anthracycline poisoning, in the pathophysiology of CHF. As the use of the only clinically approved cardioprotectant dexrazoxane has been limited by the FDA in 2011, there is an urgent need for alternative cardioprotective measures...
January 19, 2017: Cell Death & Disease
Fabiana K Ludka, Maurício P Cunha, Tharine Dal-Cim, Luisa Bandeira Binder, Leandra C Constantino, Caio M Massari, Wagner C Martins, Ana Lúcia S Rodrigues, Carla I Tasca
Intracerebroventricular (icv) amyloid-beta (Aβ)1-40 infusion to mice has been demonstrated to cause neurotoxicty and depressive-like behavior and it can be used to evaluate antidepressant and neuroprotective effect of drugs. Atorvastatin is a widely used statin that has demonstrated antidepressant-like effect in predictable animal behavioral models and neuroprotective effect against Aβ1-40 infusion. The purpose of this study was to determine the effect of in vivo atorvastatin treatment against Aβ1-40-induced changes in mood-related behaviors and biochemical parameters in ex vivo hippocampal slices from mice...
October 5, 2016: Molecular Neurobiology
Pablo Carbonell, Oriol Lopez, Alexander Amberg, Manuel Pastor, Ferran Sanz
The present study applies a systems biology approach for the in silico predictive modeling of drug toxicity on the basis of high-quality preclinical drug toxicity data with the aim of increasing the mechanistic understanding of toxic effects of compounds at different levels (pathway, cell, tissue, organ). The model development has been carried out using 77 compounds for which gene expression data are available in the LINCS database for primary human hepatocytes treated with the compounds, as well as rodent in vivo hepatotoxicity information is available in the eTOX database...
September 30, 2016: ALTEX
Hongxi Sun, Yu Li, Bei Sun, Ningning Hou, Juhong Yang, Miaoyan Zheng, Jie Xu, Jingyu Wang, Yi Zhang, Xianwei Zeng, Chunyan Shan, Bai Chang, Liming Chen, Baocheng Chang
BACKROUND: Type 2 diabetes has become a global epidemic disease. Atorvastatin has become a cornerstone in the prevention and treatment of atherosclerosis. However, increasing evidence showed that statins can dose-dependently increase the risk of diabetes mellitus. The mechanism is not clear. OBJECTIVE: The Ras complex pathway (Ras/Raf/extracellular signal-regulated kinase [ERK]/cAMP response element-binding protein [CREB]) is the major pathway that regulates the gene transcription...
September 2016: Medicine (Baltimore)
Mark F McCarty, James DiNicolantonio
Lysophosphatidic acid (LPA), generated in the microenvironment of cancer cells, can drive the proliferation, invasion, and migration of cancer cells by activating G protein-coupled LPA receptors. Moreover, in cancer cells that have metastasized to bone, LPA signaling can promote osteolysis by inducing cancer cell production of cytokines, such as IL-6 and IL-8, which can stimulate osteoblasts to secrete RANKL, a key promoter of osteoclastogenesis. Indeed, in cancers prone to metastasize to bone, LPA appears to be a major driver of the expansion of osteolytic bone metastases...
August 25, 2016: Healthcare (Basel, Switzerland)
Vishal A Salunkhe, Inês G Mollet, Jones K Ofori, Helena A Malm, Jonathan L S Esguerra, Thomas M Reinbothe, Karin G Stenkula, Anna Wendt, Lena Eliasson, Jenny Vikman
Statins are beneficial in the treatment of cardiovascular disease (CVD), but these lipid-lowering drugs are associated with increased incidence of new on-set diabetes. The cellular mechanisms behind the development of diabetes by statins are elusive. Here we have treated mice on normal diet (ND) and high fat diet (HFD) with rosuvastatin. Under ND rosuvastatin lowered blood glucose through improved insulin sensitivity and increased glucose uptake in adipose tissue. In vitro rosuvastatin reduced insulin secretion and insulin content in islets...
August 2016: EBioMedicine
İlhan Elmaci, Meric A Altinoz
Pancreatic cancer (PC) and glioblastoma multiforme (GBM) are among the human cancers with worst prognosis which require an urgent need for efficient therapies. Here, we propose to apply to treat both malignancies with a triple combination of drugs, which are already in use for different indications. Recent studies demonstrated a considerable link between risk of PC and diabetes. In experimental models, anti-diabetogenic agents suppress growth of PC, including metformin (M), pioglitazone (P) and lithium (L)...
October 2016: Biochemical Genetics
Hao Liu, Haiyan Wang, Dingcheng Xiang, Wangang Guo
INTRODUCTION: The anthracycline doxorubicin (DOX) has proved to be one of the most widely used and most effective antitumor drugs since its emergence in the 1960s. However, the utility of DOX is compromised by its potential lethal cardiotoxicity. In this review we summarize development in prevention and management of DOX-induced cardiotoxicity comprehensively. BACKGROUND: Strategies to enhance DOX efficacy in cancer cells while minimizing associated cardiotoxicity may prove clinically valuable...
2017: Mini Reviews in Medicinal Chemistry
Jarred M Griffin, Dan Kho, E Scott Graham, Louise F B Nicholson, Simon J O'Carroll
BACKGROUND: Astrocytes and cerebral endothelial cells are important components of the blood-brain barrier (BBB). Disruption to this barrier through inflammation is a major contributor to Alzheimer's disease (AD) pathology. The amyloid beta (Aβ) protein is known to exist in several forms and is a key modulator of AD that is known to cause inflammation and changes to BBB function. While one of these forms, fibrillary Aβ (fAβ), is known to cause endothelial cell death at the BBB, no studies have looked specifically at its role on inflammation in a model of the human BBB...
2016: PloS One
Fabrizio Sallustio, Valeria Studer
Alzheimer's disease (AD) is the most common cause of dementia among the elderly. It is pathologically characterized by diffused extracellular deposits, senile plaques, and intracellular neurofibrillary tangles in the brain, responsible for neuronal dysfunction and cell death. Memory, language and other cognitive functions can be affected to a limited extent in the initial stage called mild cognitive impairment (MCI) or in a more severe and daily life interfering manner in the later stage called dementia. Currently no effective disease-modifying treatment exists for the majority of neurodegenerative diseases...
2016: CNS & Neurological Disorders Drug Targets
Ashley M Driver, Lisa E Kratz, Richard I Kelley, Rolf W Stottmann
We previously reported a mutation in the cholesterol biosynthesis gene, hydroxysteroid (17-beta) dehydrogenase 7 (Hsd17b7(rudolph)), that results in striking embryonic forebrain dysgenesis. Here we describe abnormal patterns of neuroprogenitor proliferation in the mutant forebrain, namely, a decrease in mitotic cells within the ventricular zone (VZ) and an increase through the remainder of the cortex by E11.5. Further evidence suggests mutant cells undergo abnormal interkinetic nuclear migration (IKNM). Furthermore, intermediate progenitors are increased at the expense of apical progenitors by E12...
July 2016: Neurobiology of Disease
Estela Lorza-Gil, Alessandro G Salerno, Amarylis C B A Wanschel, Jean F Vettorazzi, Mônica S Ferreira, Thiago Rentz, Rodrigo R Catharino, Helena C F Oliveira
We have previously demonstrated that hypercholesterolemic LDL receptor knockout (LDLr(-/-)) mice secrete less insulin than wild-type mice. Removing cholesterol from isolated islets using methyl-beta-cyclodextrin reversed this defect. In this study, we hypothesized that in vivo treatment of LDLr(-/-) mice with the HMGCoA reductase inhibitor pravastatin would improve glucose-stimulated insulin secretion. Female LDLr(-/-) mice were treated with pravastatin (400mg/L) for 1-3 months. Isolated pancreatic islets were assayed for insulin secretion rates, intracellular calcium oscillations, cholesterol levels, NAD(P)H and SNARE protein levels, apoptosis indicators and lipidomic profile...
February 17, 2016: Toxicology
Alexandros Briasoulis, Emmanuel Androulakis, Theodoros Christophides, Dimitris Tousoulis
Chronic inflammation underlies a variety of seemingly unrelated conditions including coronary artery disease. The interest in exploring the role of inflammation in heart failure (CHF) arises from earlier observations that circulating pro-inflammatory biomarker levels are elevated in patients with both ischaemic and non-ischaemic cardiomyopathies and correlate with severity of disease and prognosis (McMurray et al. in Eur Heart J 33:1787-1847, 2012; Mosterd and Hoes in Heart 93:1137-1146, 2007; Owan et al. in New Engl J Med 355:251-259, 2006)...
March 2016: Heart Failure Reviews
Jin Bo Su
The endothelium exerts multiple actions involving regulation of vascular permeability and tone, coagulation and fibrinolysis, inflammatory and immunological reactions and cell growth. Alterations of one or more such actions may cause vascular endothelial dysfunction. Different risk factors such as hypercholesterolemia, homocystinemia, hyperglycemia, hypertension, smoking, inflammation, and aging contribute to the development of endothelial dysfunction. Mechanisms underlying endothelial dysfunction are multiple, including impaired endothelium-derived vasodilators, enhanced endothelium-derived vasoconstrictors, over production of reactive oxygen species and reactive nitrogen species, activation of inflammatory and immune reactions, and imbalance of coagulation and fibrinolysis...
November 26, 2015: World Journal of Cardiology
Valerie Leduc, Louise Théroux, Doris Dea, Robert Dufour, Judes Poirier
3-Hydroxy-3-methyglutaryl coenzyme A reductase (HMGCR) is a cholesterol-regulating gene with statin relevance. rs3846662 being involved in regulation of HMGCR alternative splicing, we explored its impact on HMGCR messenger RNA (mRNA) and protein levels in the brain and the associations between those levels and levels of Alzheimer's disease pathological markers. We used brain samples derived from a cohort of 33 non-demented controls and 90 Alzheimer's disease autopsied-confirmed cases. HMGCR mRNA levels were determined in the frontal cortex (n = 114) and cerebellum (n = 110) using Taqman-qPCR, and HMGCR protein levels were determined in the frontal cortex (n = 117) using a commercial enzyme immunoassay...
January 2016: Journal of Molecular Neuroscience: MN
Amanda Finan, Sylvain Richard
The healthy adult heart has a low turnover of cardiac myocytes. The renewal capacity, however, is augmented after cardiac injury. Participants in cardiac regeneration include cardiac myocytes themselves, cardiac progenitor cells, and peripheral stem cells, particularly from the bone marrow compartment. Cardiac progenitor cells and bone marrow stem cells are augmented after cardiac injury, migrate to the myocardium, and support regeneration. Depletion studies of these populations have demonstrated their necessary role in cardiac repair...
2015: Frontiers in Cell and Developmental Biology
Monica Verdoia, Patrizia Pergolini, Roberta Rolla, Matteo Nardin, Lucia Barbieri, Alon Schaffer, Giorgio Bellomo, Paolo Marino, Harry Suryapranata, Giuseppe De Luca
BACKGROUND: Low response to antiplatelet agents has been associated to an increased risk of thrombotic complications and recurrent ischemic events. Platelet size has been proposed as a potential marker of platelet reactivity. Therefore, the aim of the present study was to evaluate the impact of platelet Larger Cell Ratio (p-LCR) on platelet aggregation and the prevalence of residual high-on treatment platelet reactivity (HRPR) in patients receiving dual antiplatelet therapy (DAPT) after a recent acute coronary syndrome or coronary revascularization...
2015: Cardiovascular Drugs and Therapy
Neila Fathallah, Raoudha Slim, Sofien Larif, Houssem Hmouda, Chaker Ben Salem
Drug-induced hyperglycaemia and diabetes is a global issue. It may be a serious problem, as it increases the risk of microvascular and macrovascular complications, infections, metabolic coma and even death. Drugs may induce hyperglycaemia through a variety of mechanisms, including alterations in insulin secretion and sensitivity, direct cytotoxic effects on pancreatic cells and increases in glucose production. Antihypertensive drugs are not equally implicated in increasing serum glucose levels. Glycaemic adverse events occur more frequently with thiazide diuretics and with certain beta-blocking agents than with calcium-channel blockers and inhibitors of the renin-angiotensin system...
December 2015: Drug Safety: An International Journal of Medical Toxicology and Drug Experience
Kenji Fukui, Heather A Ferris, C Ronald Kahn
Diabetes mellitus is associated with a variety of complications, including alterations in the central nervous system (CNS). We have recently shown that diabetes results in a reduction of cholesterol synthesis in the brain due to decreased insulin stimulation of SREBP2-mediated cholesterol synthesis in neuronal and glial cells. In the present study, we explored the effects of the decrease in cholesterol on neuronal cell function using GT1-7 hypothalamic cells subjected to cholesterol depletion in vitro using three independent methods: 1) exposure to methyl-β-cyclodextrin, 2) treatment with the HMG-CoA reductase inhibitor simvastatin, and 3) shRNA-mediated knockdown of SREBP2...
October 30, 2015: Journal of Biological Chemistry
Kristina Candido, Henry Soufi, Mausumi Bandyopadhyay, Subhajit Dasgupta
Multiple sclerosis (MS) is a female predominant autoimmune demyelinating disease of central nervous system. The proper etiology is not clear. The existing therapies with interferon beta (Betaseron, Rebif), glatiramer acetate (copolymer 1, copaxone) are found to be promising for MS patients. The alpha-4 integrin antagonist monoclonal antibody Natalizumab has been found to decrease brain inflammation in relapsing-remitting MS via inhibition of alpha-4 beta- 1 integrinmediated mode of action of antigen -primed T cells to enter into central nervous system through blood brain barrier...
2016: Mini Reviews in Medicinal Chemistry
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