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Hattangady N.G.,Georgia Regents University | Olala L.O.,Georgia Regents University | Bollag W.B.,Georgia Regents University | Bollag W.B.,Charlie Norwood Medical Center | Rainey W.E.,Georgia Regents University
Molecular and Cellular Endocrinology | Year: 2012

Aldosterone is the major mineralocorticoid synthesized by the adrenal and plays an important role in the regulation of systemic blood pressure through the absorption of sodium and water. Aldosterone production is regulated tightly by selective expression of aldosterone synthase (CYP11B2) in the adrenal outermost zone, the zona glomerulosa. Angiotensin II (Ang II), potassium (K +) and adrenocorticotropin (ACTH) are the main physiological agonists which regulate aldosterone secretion. Aldosterone production is regulated within minutes of stimulation (acutely) through increased expression and phosphorylation of the steroidogenic acute regulatory (StAR) protein and over hours to days (chronically) by increased expression of the enzymes involved in the synthesis of aldosterone, particularly CYP11B2. Imbalance in any of these processes may lead to several disorders of aldosterone excess. In this review we attempt to summarize the key molecular events involved in the acute and chronic phases of aldosterone secretion. © 2011 Elsevier Ireland Ltd.


Bollag W.B.,Charlie Norwood Medical Center | Bollag W.B.,Georgia Regents University
Comprehensive Physiology | Year: 2014

Aldosterone is a steroid hormone synthesized in and secreted from the outer layer of the adrenal cortex, the zona glomerulosa. Aldosterone is responsible for regulating sodium homeostasis, thereby helping to control blood volume and blood pressure. Insufficient aldosterone secretion can lead to hypotension and circulatory shock, particularly in infancy. On the other hand, excessive aldosterone levels, or those too high for sodium status, can cause hypertension and exacerbate the effects of high blood pressure on multiple organs, contributing to renal disease, stroke, visual loss, and congestive heart failure. Aldosterone is also thought to directly induce end-organ damage, including in the kidneys and heart. Because of the significance of aldosterone to the physiology and pathophysiology of the cardiovascular system, it is important to understand the regulation of its biosynthesis and secretion from the adrenal cortex. Herein, the mechanisms regulating aldosterone production in zona glomerulosa cells are discussed, with a particular emphasis on signaling pathways involved in the secretory response to the main controllers of aldosterone production, the renin-angiotensin II system, serum potassium levels and adrenocorticotrophic hormone. The signaling pathways involved include phospholipase C-mediated phosphoinositide hydrolysis, inositol 1,4,5-trisphosphate, cytosolic calcium levels, calcium influx pathways, calcium/calmodulin-dependent protein kinases, diacylglycerol, protein kinases C and D, 12-hydroxyeicostetraenoic acid, phospholipase D, mitogen-activated protein kinase pathways, tyrosine kinases, adenylate cyclase, and cAMP-dependent protein kinase. A complete understanding of the signaling events regulating aldosterone biosynthesis may allow the identification of novel targets for therapeutic interventions in hypertension, primary aldosteronism, congestive heart failure, renal disease, and other cardiovascular disorders. © 2014 American Physiological Society.


Reinstatler L.,Georgia Regents University | Youssef N.A.,Georgia Regents University | Youssef N.A.,Charlie Norwood Medical Center
Drugs in R and D | Year: 2015

Objective: To review the published literature on the efficacy of ketamine for the treatment of suicidal ideation (SI).Methods: The PubMed and Cochrane databases were searched up to January 2015 for clinical trials and case reports describing therapeutic ketamine administration to patients presenting with SI/suicidality. Searches were also conducted for relevant background material regarding the pharmacological function of ketamine.Results: Nine publications (six studies and three case reports) met the search criteria for assessing SI after administration of subanesthetic ketamine. There were no studies examining the effect on suicide attempts or death by suicide. Each study demonstrated a rapid and clinically significant reduction in SI, with results similar to previously described data on ketamine and treatment-resistant depression. A total of 137 patients with SI have been reported in the literature as receiving therapeutic ketamine. Seven studies delivered a dose of 0.5 mg/kg intravenously over 40 min, while one study administered a 0.2 mg/kg intravenous bolus and another study administered a liquid suspension. The earliest significant results were seen after 40 min, and the longest results were observed up to 10 days postinfusion.Conclusion: Consistent with clinical research on ketamine as a rapid and effective treatment for depression, ketamine has shown early preliminary evidence of a reduction in depressive symptoms, as well as reducing SI, with minimal short-term side effects. Additional studies are needed to further investigate its mechanism of action, long-term outcomes, and long-term adverse effects (including abuse) and benefits. In addition, ketamine could potentially be used as a prototype for further development of rapid-acting antisuicidal medication with a practical route of administration and the most favorable risk/benefit ratio. © 2015, The Author(s).


Jiang M.,Georgia Regents University | Liu K.,Georgia Regents University | Luo J.,Charlie Norwood Medical Center | Luo J.,University of Kentucky | Dong Z.,Georgia Regents University
American Journal of Pathology | Year: 2010

Autophagy mediates bulk degradation and recycling of cytoplasmic constituents to maintain cellular homeostasis. In response to stress, autophagy is induced and may either contribute to cell death or serve as a cell survival mechanism. Very little is known about autophagy in renal pathophysiology. This study examined autophagy and its pathological role in renal cell injury using in vitro and in vivo models of ischemia - reperfusion. We found that hypoxia (1% O 2) induced autophagy in cultured renal proximal tubular cells. Blockade of autophagy by 3-methyladenine or small-interfering RNA knockdown of Beclin-1 and ATG5 (two key autophagic genes) sensitized the tubular cells to hypoxia-induced apoptosis. In an in vitro model of ischemia - reperfusion, autophagy was not induced by anoxic (0% O 2) incubation in glucose-free buffer, but was induced during subsequent recovery/reperfusion period. In this model, suppression of autophagy also enhanced apoptosis. In vivo, autophagy was induced in kidney tissues during renal ischemia - reperfusion in mice. Autophagy was not obvious during the ischemia period, but was significantly enhanced during reperfusion. Inhibition of autophagy by chloroquine and 3-methyladenine worsened renal ischemia/reperfusion injury, as indicated by renal function, histology, and tubular apoptosis. Together, the results demonstrated autophagy induction during hypoxic and ischemic renal injury. Under these pathological conditions, autophagy may provide a protective mechanism for cell survival. Copyright © American Society for Investigative Pathology.


Eroglu B.,Georgia Regents University | Eroglu B.,Charlie Norwood Medical Center | Moskophidis D.,Georgia Regents University | Mivechi N.F.,Georgia Regents University | Mivechi N.F.,Charlie Norwood Medical Center
Molecular and Cellular Biology | Year: 2010

Accumulation of tau into neurofibrillary tangles is a pathological consequence of Alzheimer's disease and other tauopathies. Failures of the quality control mechanisms by the heat shock proteins (Hsps) positively correlate with the appearance of such neurodegenerative diseases. However, in vivo genetic evidence for the roles of Hsps in neurodegeneration remains elusive. Hsp110 is a nucleotide exchange factor for Hsp70, and direct substrate binding to Hsp110 may facilitate substrate folding. Hsp70 complexes have been implicated in tau phosphorylation state and amyloid precursor protein (APP) processing. To provide evidence for a role for Hsp110 in central nervous system homeostasis, we have generated hsp110-/- mice. Our results show that hsp110-/- mice exhibit accumulation of hyperphosphorylated-tau (p-tau) and neurodegeneration. We also demonstrate that Hsp110 is in complexes with tau, other molecular chaperones, and protein phosphatase 2A (PP2A). Surprisingly, high levels of PP2A remain bound to tau but with significantly reduced activity in brain extracts from aged hsp110-/- mice compared to brain extracts from wild-type mice. Mice deficient in the. Hsp110 partner (Hsp70) also exhibit a phenotype comparable to that of hsp110-/- mice, confirming a critical role for Hsp110-Hsp70 in maintaining tau in its unphosphorylated form during aging. In addition, crossing hsp110-/- mice with mice overexpressing mutant APP (APPβsw) leads to selective appearance of insoluble amyloid β42 (Aβ42), suggesting an essential role for Hsp110 in APP processing and Aβ generation. Thus, our findings provide in vivo evidence that Hsp110 plays a critical function in tau phosphorylation state through maintenance of efficient PP2A activity, confirming its role in pathogenesis of Alzheimer's disease and other tauopathies. Copyright © 2010, American Society for Microbiology. All Rights Reserved.


Itokazu Y.,Georgia Regents University | Itokazu Y.,Charlie Norwood Medical Center | Yu R.K.,Georgia Regents University | Yu R.K.,Charlie Norwood Medical Center
Molecular Neurobiology | Year: 2014

Amyloid β-peptides (Aβs) aggregate to form amyloid plaques, also known as senile plaques, which are a major pathological hallmark of Alzheimer’s disease (AD). Aβs are reported to possess proliferation effects on neural stem cells (NSCs); however, this effect remains controversial. Thus, clarification of their physiological function is an important topic. We have systematically evaluated the effects of several putative bioactive Aβs (Aβ1–40, Aβ1–42, and Aβ25–35) on NSC proliferation. Treatment of NSCs with Aβ1–42 significantly increased the number of those cells (149 ± 10 %). This was not observed with Aβ1–40 which did not have any effects on the proliferative property of NSC. Aβ25–35, on the other hand, exhibited inhibitory effects on cellular proliferation. Since cell surface glycoconjugates, such as glycolipids, glycoproteins, and proteoglycans, are known to be important for maintaining cell fate determination, including cellular proliferation, in NSCs and they undergo dramatic changes during differentiation, we examined the effect of Aβs on a number of key glycoconjugate metabolizing enzymes. Significantly, we found for the first time that Aβ1–42 altered the expression of several key glycosyltransferases and glycosidases, including fucosyltransferase IX (FUT9), sialyltransferase III (ST-III), glucosylceramide ceramidase (GLCC), and mitochondrial sialidase (Neu4). FUT9 is a key enzyme for the synthesis of the Lewis X carbohydrate epitope, which is known to be expressed in stem cells. Aβ1–42 also stimulated the Notch1 intracellular domain (NICD) by upregulation of the expression of Musashi-1 and the paired box protein, Pax6. Thus, Aβ1–42 upregulates NSC proliferation by modulating the expression of several glycogenes involved in Notch signaling. © 2014, Springer Science+Business Media New York.


Wei Q.,Georgia Regents University | Dong G.,Georgia Regents University | Chen J.-K.,Georgia Regents University | Ramesh G.,Georgia Regents University | And 3 more authors.
Kidney International | Year: 2013

Bax and Bak, two pro-apoptotic Bcl-2 family proteins, have been implicated in acute kidney injury following renal ischemia/reperfusion; however, definitive evidence for a role of these genes in the disease process is lacking. Here we first examined two Bax-deficient mouse models and found that only conditional Bax deletion specifically from proximal tubules could ameliorate ischemic acute kidney injury. Global (whole mouse) knockout of Bax enhanced neutrophil infiltration without significant effect on kidney injury. In contrast, global knockout of Bak protected mice from ischemic acute kidney injury with improved renal function. Interestingly, in these models, Bax or Bak knockout attenuated renal tubular cell apoptosis without significantly affecting necrotic tubular damage. Cytochrome c release in ischemic acute kidney injury was also suppressed in conditional Bax- or global Bak-knockout mice. In addition, Bak deficiency prevented mitochondrial fragmentation in ischemic acute kidney injury. Thus, our gene-knockout studies support a critical role of Bax and Bak in tubular cell apoptosis in ischemic acute kidney. Furthermore, necrosis and apoptosis have distinguishable regulatory functions. © 2013 International Society of Nephrology.


Wei Q.,Georgia Regents University | Dong Z.,Georgia Regents University | Dong Z.,Charlie Norwood Medical Center
American Journal of Physiology - Renal Physiology | Year: 2012

Renal ischemia-reperfusion leads to acute kidney injury (AKI), a major kidney disease associated with an increasing prevalence and high mortality rates. A variety of experimental models, both in vitro and in vivo, have been used to study the pathogenic mechanisms of ischemic AKI and to test renoprotective strategies. Among them, the mouse model of renal clamping is popular, mainly due to the availability of transgenic models and the relatively small animal size for drug testing. However, the mouse model is generally less stable, resulting in notable variations in results. Here, we describe a detailed protocol of the mouse model of bilateral renal ischemia-reperfusion. We share the lessons and experiences gained from our laboratory in the past decade. We further discuss the technical issues that account for the variability of this model and offer relevant solutions, which may help other investigators to establish a wellcontrolled, reliable animal model of ischemic AKI. © 2012 the American Physiological Society.


Abdelsaid M.A.,University of Georgia | Abdelsaid M.A.,Charlie Norwood Medical Center | El-Remessy A.B.,University of Georgia | El-Remessy A.B.,Charlie Norwood Medical Center
Journal of Cell Science | Year: 2012

Although promising, the ability to regulate angiogenesis through delivery of VEGF remains an unrealized goal. We have shown previously that physiological levels of peroxynitrite (1 μM) are required for a VEGF-mediated angiogenic response, yet the redox-regulated mechanisms that govern the VEGF signal remain unexplored. We assessed the impact of VEGF andperoxynitrite on modifying redox-state, the level of reduced-glutathione (GSH) and S-glutathionylation on regulation ofthe low molecular weight protein tyrosine phosphatase (LMW-PTP) and focal adhesion kinase (FAK), which are key mediators of VEGF-mediated cell migration. Stimulation of human microvascular endothelial (HME) cells with VEGF (20 ng/ml) or peroxynitrite (1 μM) caused an immediate and reversible negative-shift in the cellular redox-state and thiol oxidation of LMW-PTP, which culminated in cell migration. VEGF causes reversible S-glutathionylation of LMW-PTP, which inhibits its phosphorylation and activity, and causes the transient activation of FAK. Modulating the redox-state using decomposing peroxynitrite (FeTPPS, 2.5 μM) or the GSH-precursor [N-acetylcysteine (NAC), 1 mM] caused a positive-shift of the redoxstateand prevented VEGF-mediated S-glutathionylation and oxidative inhibition of LMW-PTP. NAC and FeTPPS prevented the activation of FAK, its association with LMW-PTP and cell migration. Inhibiting LMW-PTP expression markedly enhanced FAK activation and cell migration. Although mild oxidative stress achieved by combining VEGF with 0.1-0.2 mM peroxynitrite augmented cell migration, an acute shift to oxidative stress achieved by combining VEGF with 0.5 mM peroxynitrite induced and sustained FAK activation, and LMW-PTP Sglutathionylation, resulting in LMW-PTP inactivation and inhibited cell migration. In conclusion, our findings demonstrate that a balanced redox-state is required for VEGF to facilitate reversible S-glutathionylation of LMW-PTP, FAK activation and endothelial cell migration. Shifting the redox-state to reductive stress oroxidative stress inhibited the VEGF-mediated angiogenic response. © 2012.


Jin X.,University of Georgia | Jin X.,Cancer Center | Jin X.,Charlie Norwood Medical Center | Moskophidis D.,University of Georgia | And 4 more authors.
Cell Metabolism | Year: 2011

Hepatocellular carcinoma (HCC) occurrence and progression are linked tightly to progressive hepatic metabolic syndrome associated with insulin resistance, hepatic steatosis, and chronic inflammation. Heat shock transcription factor 1 (HSF1), a major transactivator of stress proteins, increases survival by protecting cells against environmental stressors. It has been implicated in the pathogenesis of cancer, but specific mechanisms by which HSF1 supports cancer development remain elusive. We propose a pathogenic mechanism whereby HSF1 activation promotes growth of premalignant cells and HCC development by stimulating lipid biosynthesis and perpetuating chronic hepatic metabolic disease induced by carcinogens. Our work shows that inactivation of HSF1 impairs cancer progression, mitigating adverse effects of carcinogens on hepatic metabolism by enhancing insulin sensitivity and sensitizing activation of AMP-activated protein kinase (AMPK), an important regulator of energy homeostasis and inhibitor of lipid synthesis. HSF1 is a potential target for the control of hepatic steatosis, hepatic insulin resistance, and HCC development. © 2011 Elsevier Inc.

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