Alcohol and its metabolites dysregulate cellular bioenergetics and induce oxidative and endoplasmic reticulum stress in primary human bronchial epithelial cells.

Background: Chronic alcohol consumption/misuse is a significant risk factor for pneumonia and lung infection leading to the development of chronic pulmonary disorders such as chronic obstructive pulmonary disease (COPD) and lung fibrosis. In this study, we sought to delineate the mechanism of alcohol-associated lung disease. We did so by measuring in vitro mitochondrial, endoplasmic reticulum (ER) oxidative stress in human bronchial epithelial cells (hBECs) treated with ethanol and its oxidative (acetaldehyde) and nonoxidative (fatty acid ethyl esters or FAEEs) metabolites.

Dysregulated pancreatic lipid phenotype, inflammation and cellular injury in a chronic ethanol feeding model of hepatic alcohol dehydrogenase-deficient deer mice.

Aims: Dysregulation of pancreatic fat and lipotoxic inflammation are common clinical findings in alcoholic chronic pancreatitis (ACP). In this study, we investigated a relationship between dysregulated pancreatic lipid metabolism and the development of injury in a chronic ethanol (EtOH) feeding model of hepatic alcohol dehydrogenase 1- deficient (ADH) deer mice.

Methods: ADH and hepatic ADH normal (ADH) deer mice were fed a liquid diet containing 3 % EtOH for three months and received a single gavage of binge EtOH with/without fatty acid ethyl esters (FAEEs) one week before the euthanasia.

Exposure to binge ethanol and fatty acid ethyl esters exacerbates chronic ethanol-induced pancreatic injury in hepatic alcohol dehydrogenase-deficient deer mice.

Alcoholic chronic pancreatitis (ACP) is a fibroinflammatory disease of the pancreas. However, metabolic basis of ACP is not clearly understood. In this study, we evaluated differential pancreatic injury in hepatic alcohol dehydrogenase-deficient (ADH) deer mice fed chronic ethanol (EtOH), chronic plus binge EtOH, and chronic plus binge EtOH and fatty acid ethyl esters (FAEEs, nonoxidative metabolites of EtOH) to understand the metabolic basis of ACP.

Differential cytotoxicity, ER/oxidative stress, dysregulated AMPKα signaling, and mitochondrial stress by ethanol and its metabolites in human pancreatic acinar cells.

Background: Alcoholic chronic pancreatitis (ACP) is a serious inflammatory disorder of the exocrine pancreatic gland. A previous study from this laboratory showed that ethanol (EtOH) causes cytotoxicity, dysregulates AMPKα and ER/oxidative stress signaling, and induces inflammatory responses in primary human pancreatic acinar cells (hPACs). Here we examined the differential cytotoxicity of EtOH and its oxidative (acetaldehyde) and nonoxidative (fatty acid ethyl esters; FAEEs) metabolites in hPACs was examined to understand the metabolic basis and mechanism of ACP.

Activation of AMP-activated protein kinase attenuates ethanol-induced ER/oxidative stress and lipid phenotype in human pancreatic acinar cells.

Primary toxicity targets of alcohol and its metabolites in the pancreas are cellular energetics and endoplasmic reticulum (ER). Therefore, the role of AMP-Activated Protein Kinase (AMPKα) in amelioration of ethanol (EtOH)-induced pancreatic acinar cell injury including ER/oxidative stress, inflammatory responses, the formation of fatty acid ethyl esters (FAEEs) and mitochondrial bioenergetics were determined in human pancreatic acinar cells (hPACs) and AR42J cells incubated with/without AMPKα activator [5-aminoimidazole-4-carboxamide ribonucleotide (AICAR)]. EtOH treated hPACs showed concentration and time-dependent increases for FAEEs and inactivation of AMPKα, along with the upregulation of ACC1 and FAS (key lipogenic proteins) and downregulation of CPT1A (involved β-oxidation of fatty acids).

Recent Advances in Understanding the Complexity of Alcohol-Induced Pancreatic Dysfunction and Pancreatitis Development.

Chronic excessive alcohol use is a well-recognized risk factor for pancreatic dysfunction and pancreatitis development. Evidence from in vivo and in vitro studies indicates that the detrimental effects of alcohol on the pancreas are from the direct toxic effects of metabolites and byproducts of ethanol metabolism such as reactive oxygen species. Pancreatic dysfunction and pancreatitis development are now increasingly thought to be multifactorial conditions, where alcohol, genetics, lifestyle, and infectious agents may determine the initiation and course of the disease.

Linking Dysregulated AMPK Signaling and ER Stress in Ethanol-Induced Liver Injury in Hepatic Alcohol Dehydrogenase Deficient Deer Mice.

Ethanol (EtOH) metabolism itself can be a predisposing factor for initiation of alcoholic liver disease (ALD). Therefore, a dose dependent study to evaluate liver injury was conducted in hepatic alcohol dehydrogenase (ADH) deficient (ADH) and ADH normal (ADH) deer mice fed 1%, 2% or 3.5% EtOH in the liquid diet daily for 2 months.

Ethanol Exposure Impairs AMPK Signaling and Phagocytosis in Human Alveolar Macrophages: Role of Ethanol Metabolism.

Background: Chronic alcohol consumption impairs alveolar macrophage's (AM) function and increases risk for developing lung infection and pneumonia. However, the mechanism and metabolic basis of alcohol-induced AM dysfunction leading to lung infection are not well defined, but may include altered ethanol (EtOH) and reactive oxygen species metabolism and cellular energetics. Therefore, oxidative stress, endoplasmic reticulum (ER) stress, the formation of fatty acid ethyl esters [FAEEs, nonoxidative metabolites of EtOH], AMP-activated protein kinase (AMPK) signaling, and phagocytic function were examined in freshly isolated AM incubated with EtOH.

Alcohol-induced ketonemia is associated with lowering of blood glucose, downregulation of gluconeogenic genes, and depletion of hepatic glycogen in type 2 diabetic db/db mice.

Alcoholic ketoacidosis and diabetic ketoacidosis are life-threatening complications that share the characteristic features of high anion gap metabolic acidosis. Ketoacidosis is attributed in part to the massive release of ketone bodies (e.g.

Manipal diabetes coronary artery severity score.

Aims: To develop a risk score, for identifying severe and complex CAD in patients with type 2 diabetes mellitus.

Methods: In this cross sectional study, 179 patients with type 2 diabetes mellitus undergoing coronary angiogram for the evaluation of suspected coronary artery disease (CAD) were recruited at a tertiary-care hospital. Patients were divided into developmental (n=124) and validation (n=55) cohorts.

Severity of coronary artery disease in type 2 diabetes mellitus: Does the timing matter?

Aim: The aim of our study was to compare the angiographic changes in 53 nondiabetic patients, 54 type 2 diabetic patients of less than 5 years of duration, 41 patients with 5-10 years of diabetes, and 27 with more than 10 years of diabetic duration.

Methods: In this cross-sectional study, 175 patients, who underwent coronary angiogram for the evaluation of the coronary artery disease (CAD), were recruited. Based on the angiographic findings, syntax score, vessel score, and coronary collaterals grading were analyzed.

Oxidative Stress in Obese Postmenopausal Women: An Additive Burden for Atherosclerosis.

Introduction: Coronary Artery Disease are on the rise in the general population and is the leading cause of death in both men and women. The impact of CAD is underappreciated in younger women when compared to men. Women have unique risk factors for CAD and postmenopausal women are at higher risk of developing CAD when compared to normal menstruating women.

Factors associated with no apparent coronary artery disease in patients with type 2 diabetes mellitus for more than 10 years of duration: a case control study.

Background: Type 2 diabetes mellitus is an important risk factor in the development of coronary artery disease (CAD) and is often associated with severe disease. However, this risk is not uniform, some patients remain free of CAD even after many years of treatment for diabetes. The present study was aimed to identify the factors that are associated with a favorable CAD profile.

Correlation of severity of coronary artery disease with insulin resistance.

Background: Insulin resistance (IR) has known to be associated with coronary artery disease (CAD), but the assessment of severity of the CAD based on IR in type 2 diabetes mellitus has not been established in detail.

Aims: The aim of our study was to establish the correlation between IR and the severity of CAD in type 2 diabetes mellitus.

Materials And Methods: In a cross-sectional study design, 61 consecutive patients with type 2 diabetes mellitus who underwent coronary angiogram for the evaluation of CAD were recruited.