Richmond, VA, United States
Richmond, VA, United States

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Bajaj J.S.,ire Medical Center
Gut microbes | Year: 2013

A picture is now starting to emerge regarding the liver-bile acid-microbiome axis. Increasing levels of the primary bile acid cholic acid (CA) causes a dramatic shift toward the Firmicutes, particularly Clostridium cluster XIVa and increasing production of the harmful secondary bile acid deoxycholic acid (DCA). During progression of cirrhosis, the microbiome, both through their metabolism, cell wall components (LPS) and translocation lead to inflammation. Inflammation suppresses synthesis of bile acids in the liver leading to a positive-feedback mechanism. Decrease in bile acids entering the intestines appears to favor overgrowth of pathogenic and pro-inflammatory members of the microbiome including Porphyromonadaceae and Enterobacteriaceae. Decreasing bile acid concentration in the colon in cirrhosis is also associated with decreases in Clostridium cluster XIVa, which includes bile acid 7α-dehydroxylating bacteria which produce DCA. Rifaximin treatment appears to act by suppressing DCA production, reducing endotoxemia and harmful metabolites without significantly altering microbiome structure. Taken together, the bile acid pool size and composition appear to be a major regulator of microbiome structure, which in turn appears to be an important regulator of bile acid pool size and composition. The balance between this equilibrium is critical for human health and disease.


Simons F.E.R.,University of Sfax | Edwards E.S.,Virginia Commonwealth University | Read Jr. E.J.,Virginia Commonwealth University | Read Jr. E.J.,ire Medical Center | And 2 more authors.
Journal of Allergy and Clinical Immunology | Year: 2010

Background: Epinephrine auto-injectors provide life-saving prehospital treatment for individuals experiencing anaphylaxis in community settings. Objective: To determine the number, demographics, and associated circumstances and outcomes of unintentional injections from epinephrine auto-injectors. Methods: We searched the databases of the American Association of Poison Control Centers and the Food and Drug Administration's Safety Information and Adverse Event Report System for these incidents as reported by members of the public and by health care professionals. Results: From 1994 to 2007, a total of 15,190 unintentional injections from epinephrine auto-injectors were reported to US Poison Control Centers, 60% of them from 2003 to 2007. Those unintentionally injected had a median age of 14 years (interquartile range, 8-35), 55% were female, and 85% were injected in a home or other residence. Management was documented in only 4101 cases (27%), of whom 53% were observed without intervention, 29% were treated, 13% were neither held for observation nor treated, and 4% refused treatment. In contrast, from 1969 to 2007, only 105 unintentional injections from epinephrine auto-injectors were reported to MedWatch. Forty percent of these occurred during attempts to treat allergic reactions. Injuries resulting in permanent sequelae were rarely reported to either US Poison Control Centers or to MedWatch. Conclusion: The number of reported unintentional injections from epinephrine auto-injectors increased annually from 1994 to 2007. To prevent these unintentional injections, improved epinephrine auto-injector design is needed, along with increased vigilance in training the trainers and in training and coaching the users, as well as efforts to increase public awareness of the role of epinephrine auto-injectors in the first-aid treatment of anaphylaxis in the community. © 2010 American Academy of Allergy, Asthma & Immunology.


Danyi P.,Johns Hopkins University | Elefteriades J.A.,Yale University | Jovin I.S.,Yale University | Jovin I.S.,ire Medical Center | Jovin I.S.,Virginia Commonwealth University
Trends in Cardiovascular Medicine | Year: 2012

Thoracic aortic aneurysm is a major health problem with multiple etiologies and potentially devastating consequences. Currently, no large randomized trial has shown that medical therapy can significantly slow or halt the progressive dilatation that eventually leads to dissection and rupture. A recent study that suggested that angiotensin receptor blocking agents slow the development of aneurysm dilatation in Marfan syndrome has revived interest in medical interventions to improve outcomes for patients with aortic aneurysm. In this article, we review the available data on established medical therapies and investigational medical therapies for thoracic aortic aneurysms. © 2012.


Bie J.,University of Richmond | Wang J.,University of Richmond | Yuan Q.,University of Richmond | Kakiyama G.,ire Medical Center | And 2 more authors.
Journal of Lipid Research | Year: 2014

The liver plays a central role in the final elimination of cholesterol from the body either as bile acids or as free cholesterol (FC), and lipoprotein-derived cholesterol is the major source of total biliary cholesterol. HDL is the major lipoprotein responsible for removal and transport of cholesterol, mainly as cholesteryl esters (CEs), from the peripheral tissues to the liver. While HDL-FC is rapidly secreted into bile, the fate of HDL-CE remains unclear. We have earlier demonstrated the role of human CE hydrolase (CEH, CES1 ) in hepatic hydrolysis of HDL-CE and increasing bile acid synthesis, a process dependent on scavenger receptor BI expression. In the present study, we examined the hypothesis that by enhancing the elimination of HDL-CE into bile/ feces, liver-specific transgenic expression of CEH will be anti-atherogenic. Increased CEH expression in the liver significantly increased the flux of HDL-CE to bile acids. In the LDLR -/- background, this enhanced elimination of cholesterol led to attenuation of diet-induced atherosclerosis with a consistent increase in fecal sterol secretion primarily as bile acids.jlr Taken together with the observed reduction in atherosclerosis by increasing macrophage CEH-mediated cholesterol efflux, these studies establish CEH as an important regulator in enhancing cholesterol elimination and also as an anti-atherogenic target.


Chen Q.,Virginia Commonwealth University | Ross T.,Virginia Commonwealth University | Hu Y.,Virginia Commonwealth University | Lesnefsky E.J.,Virginia Commonwealth University | Lesnefsky E.J.,ire Medical Center
Journal of Aging Research | Year: 2012

Myocardial injury is increased in the aged heart following ischemia-reperfusion (ISC-REP) compared to adult hearts. Intervention at REP with ischemic postconditioning decreases injury in the adult heart by attenuating mitochondrial driven cell injury. Unfortunately, postconditioning is ineffective in aged hearts. Blockade of electron transport at the onset of REP with the reversible inhibitor amobarbital (AMO) decreases injury in adult hearts. We tested if AMO treatment at REP protects the aged heart via preservation of mitochondrial integrity. Buffer-perfused elderly Fischer 344 24 mo. rat hearts underwent 25 min global ISC and 30 min REP. AMO (2.5 mM) or vehicle was given for 3 min at the onset of REP. Subsarcolemmal (SSM) and interfibrillar (IFM) mitochondria were isolated after REP. Oxidative phosphorylation (OXPHOS) and mitochondrial inner membrane potential were measured. AMO treatment at REP decreased cardiac injury. Compared to untreated ISC-REP, AMO improved inner membrane potential in SSM and IFM during REP, indicating preserved inner membrane integrity. Thus, direct pharmacologic modulation of electron transport at REP protects mitochondria and decreases cardiac injury in the aged heart, even when signaling-induced pathways of postconditioning that are upstream of mitochondria are ineffective. © 2012 Qun Chen et al.


Bie J.,Virginia Commonwealth University | Wang J.,Virginia Commonwealth University | Osborne R.,Virginia Commonwealth University | Kakiyama G.,ire Medical Center | And 3 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2013

OBJECTIVE - : Liver is the major organ responsible for the final elimination of cholesterol from the body either as biliary cholesterol or as bile acids. Intracellular hydrolysis of lipoprotein-derived cholesteryl esters (CEs) is essential to generate the free cholesterol required for this process. Earlier, we demonstrated that overexpression of human CE hydrolase (Gene symbol CES1) increased bile acid synthesis in human hepatocytes and enhanced reverse cholesterol transport in mice. The objective of the present study was to demonstrate that liver-specific deletion of its murine ortholog, Ces3, would decrease cholesterol elimination from the body and increase atherosclerosis. APPROACH AND RESULTS - : Liver-specific Ces3 knockout mice (Ces3-LKO) were generated, and Ces3 deficiency did not affect the expression of genes involved in cholesterol homeostasis and free cholesterol or bile acid transport. The effects of Ces3 deficiency on the development of Western diet-induced atherosclerosis were examined in low density lipoprotein receptor knock out -/- mice. Despite similar plasma lipoprotein profiles, there was increased lesion development in low density lipoprotein receptor knock out -/-Ces3-LKO mice along with a significant decrease in the bile acid content of bile. Ces3 deficiency significantly reduced the flux of cholesterol from [3H]-CE-labeled high-density lipoproteins to feces (as free cholesterol and bile acids) and decreased total fecal sterol elimination. CONCLUSIONS - : Our results demonstrate that hepatic Ces3 modulates the hydrolysis of lipoprotein-delivered CEs and thereby regulates free cholesterol and bile acid secretion into the feces. Therefore, its deficiency results in reduced cholesterol elimination from the body, leading to significant increase in atherosclerosis. Collectively, these data establish the antiatherogenic role of hepatic CE hydrolysis. © 2013 American Heart Association, Inc.


Zhou H.,Virginia Commonwealth University | Zhou H.,ire Medical Center | Hylemon P.B.,Virginia Commonwealth University | Hylemon P.B.,ire Medical Center
Steroids | Year: 2014

Bile salts play crucial roles in allowing the gastrointestinal system to digest, transport and metabolize nutrients. They function as nutrient signaling hormones by activating specific nuclear receptors (FXR, PXR, Vitamin D) and G-protein coupled receptors [TGR5, sphingosine-1 phosphate receptor 2 (S1PR2), muscarinic receptors]. Bile acids and insulin appear to collaborate in regulating the metabolism of nutrients in the liver. They both activate the AKT and ERK1/2 signaling pathways. Bile acid induction of the FXR-α target gene, small heterodimer partner (SHP), is highly dependent on the activation PKCζ, a branch of the insulin signaling pathway. SHP is an important regulator of glucose and lipid metabolism in the liver. One might hypothesize that chronic low grade inflammation which is associated with insulin resistance, may inhibit bile acid signaling and disrupt lipid metabolism. The disruption of these signaling pathways may increase the risk of fatty liver and non-alcoholic fatty liver disease (NAFLD). Finally, conjugated bile acids appear to promote cholangiocarcinoma growth via the activation of S1PR2. © 2014 Published by Elsevier Inc.


Chen Q.,Virginia Commonwealth University | Lesnefsky E.J.,Virginia Commonwealth University | Lesnefsky E.J.,ire Medical Center
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2015

Calpain 1 is an ubiquitous Ca2+-dependent cysteine protease. Although calpain 1 has been found in cardiac mitochondria, the exact location within mitochondrial compartments and its function remain unclear. The aim of the current review is to discuss the localization of calpain 1 in different mitochondrial compartments in relationship to its function, especially in pathophysiological conditions. Briefly, mitochondrial calpain 1 (mit-CPN1) is located within the intermembrane space and mitochondrial matrix. Activation of the mit-CPN1 within intermembrane space cleaves apoptosis inducing factor (AIF), whereas the activated mit-CPN1 within matrix cleaves complex I subunits and metabolic enzymes. Inhibition of the mit-CPN1 could be a potential strategy to decrease cardiac injury during ischemia-reperfusion. © 2015 Elsevier B.V.


Ridlon J.M.,Virginia Commonwealth University | Ridlon J.M.,ire Medical Center | Alves J.M.,Virginia Commonwealth University | Hylemon P.B.,Virginia Commonwealth University | And 3 more authors.
Gut Microbes | Year: 2013

A picture is now starting to emerge regarding the liver-bile acid-microbiome axis. Increasing levels of the primary bile acid cholic acid (CA) causes a dramatic shift toward the Firmicutes, particularly Clostridium cluster XIVa and increasing production of the harmful secondary bile acid deoxycholic acid (DCA). During progression of cirrhosis, the microbiome, both through their metabolism, cell wall components (LPS) and translocation lead to inflammation. Inflammation suppresses synthesis of bile acids in the liver leading to a positive- feedback mechanism. Decrease in bile acids entering the intestines appears to favor overgrowth of pathogenic and pro-inflammatory members of the microbiome including Porphyromonadaceae and Enterobacteriaceae. Decreasing bile acid concentration in the colon in cirrhosis is also associated with decreases in Clostridium cluster XIVa, which includes bile acid 7α-dehydroxylating bacteria which produce DCA. Rifaximin treatment appears to act by suppressing DCA production, reducing endotoxemia and harmful metabolites without significantly altering microbiome structure. Taken together, the bile acid pool size and composition appear to be a major regulator of microbiome structure, which in turn appears to be an important regulator of bile acid pool size and composition. The balance between this equilibrium is critical for human health and disease. © 2013 Landes Bioscience.


Chu S.,ire Medical Center | Chu S.,Virginia Commonwealth University
Gene | Year: 2012

Sp1 is a ubiquitously expressed transcription factor involved in the regulation of a large number of genes including housekeeping genes as well as actively regulated genes. Although Sp1 was discovered nearly three decades ago, its functional diversity is still not completely understood. One of the ways that make Sp1 versatile in transcriptional regulation is its post-transcriptional modification, which alters Sp1 structure in different cells and at different times. Compared to other types of modifications of the Sp1 protein, phosphorylation has been studied far more extensively. This review focuses on the inducers, pathways, enzymes, and biological effects of Sp1 phosphorylation. Recent data are beginning to reveal the biological significance and universal presence of Sp1 phosphorylation-related cell/molecular responses. Studies in this field provide a quick glance at how a simple chemical modification of a transcription factor could produce significant functional diversity of the protein. © 2012 Elsevier B.V.

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