Medicine and Health Sciences Commons^™

Abaloparatide Maintains Normal Rat Blood Calcium Level In Part Via 1,25-Dihydroxyvitamin D/Osteocalcin Signaling Pathway, Yanmei Yang, Wei-Ju Louis Tseng, Bin Wang

Center for Translational Medicine Faculty Papers

The PTH-related peptide(1-34) analog, abaloparatide (ABL), is the second anabolic drug available for the treatment of osteoporosis. Previous research demonstrated that ABL had a potent anabolic effect but caused hypercalcemia at a significantly lower rate. However, the mechanism by which ABL maintains the stability of blood calcium levels remains poorly understood. Our in vivo data showed that ABL treatment (40 µg/kg/day for 7 days) significantly increased rat blood level of 1,25-dihydroxyvitamin D [1,25-(OH)2D] without raising the blood calcium value. ABL also significantly augmented the carboxylated osteocalcin (Gla-Ocn) in the blood and bone that is synthesized by osteoblasts, and increased noncarboxylated …

Ap-1 And Nf-Κb Synergize To Transcriptionally Activate Latent Hiv Upon T-Cell Receptor Activation., Joseph Hokello, Adhikarimayum Lakhikumar Sharma, Mudit Tyagi

Center for Translational Medicine Faculty Papers

Latent HIV-1 proviruses are capable of reactivating productive lytic infection, but the precise molecular mechanisms underlying emergence from latency are poorly understood. In this study, we determined the contribution of the transcription factors NF-κB, NFAT, and AP-1 in the reactivation of latent HIV following T-cell receptor (TCR) activation using Jurkat T-cell clones harboring single latent HIV proviruses. Our findings demonstrate that during reactivation from latency, NF-κB enhances HIV transcription while NFAT inhibits it by competing with NF-κB for overlapping binding sites on the HIV long terminal repeat (LTR). We have also demonstrated for the first time the molecular contribution of …

Pepducins As A Potential Treatment Strategy For Asthma And Copd., Reynold A. Panettieri, Tonio Pera, Stephen B B. Liggett, Jeffrey L. Benovic, Raymond B. Penn

Center for Translational Medicine Faculty Papers

Current therapies to treat asthma and other airway diseases primarily include anti-inflammatory agents and bronchodilators. Anti-inflammatory agents target trafficking and resident immunocytes and structural cells, while bronchodilators act to prevent or reverse shortening of airway smooth muscle (ASM), the pivotal tissue regulating bronchomotor tone. Advances in our understanding of the biology of G protein-coupled receptors (GPCRs) and biased agonism offers unique opportunities to modulate GPCR function that include the use of pepducins and allosteric modulators. Recent evidence suggests that small molecule inhibitors of Gα _q as well as pepducins targeting G _q -coupled receptors can broadly inhibit contractile agonist-induced ASM …

Mir-181a Increases Foxo1 Acetylation And Promotes Granulosa Cell Apoptosis Via Sirt1 Downregulation., Mei Zhang, Qun Zhang, Yali Hu, Lu Xu, Yue Jiang, Chunxue Zhang, Lijun Ding, Ruiwei Jiang, Jianxin Sun, Haixiang Sun, Guijun Yan

Center for Translational Medicine Faculty Papers

Oxidative stress impairs follicular development by inducing granulosa cell (GC) apoptosis, which involves enhancement of the transcriptional activity of the pro-apoptotic factor Forkhead box O1 (FoxO1). However, the mechanism by which oxidative stress promotes FoxO1 activity is still unclear. Here, we found that miR-181a was upregulated in hydrogen peroxide (H

Akt Kinase C-Terminal Modifications Control Activation Loop Dephosphorylation And Enhance Insulin Response., Tung O. Chan, Jin Zhang, Brian C. Tiegs, Brian Blumhof, Linda Yan, Nikhil Keny, Morgan Penny, Xue Li, John M. Pascal, Roger S. Armen, Ulrich Rodeck, Raymond B. Penn

Center for Translational Medicine Faculty Papers

The Akt protein kinase, also known as protein kinase B, plays key roles in insulin receptor signalling and regulates cell growth, survival and metabolism. Recently, we described a mechanism to enhance Akt phosphorylation that restricts access of cellular phosphatases to the Akt activation loop (Thr(308) in Akt1 or protein kinase B isoform alpha) in an ATP-dependent manner. In the present paper, we describe a distinct mechanism to control Thr(308) dephosphorylation and thus Akt deactivation that depends on intramolecular interactions of Akt C-terminal sequences with its kinase domain. Modifications of amino acids surrounding the Akt1 C-terminal mTORC2 (mammalian target of rapamycin …

Isoform-Specific Dynamic Translocation Of Pkc By Α1-Adrenoceptor Stimulation In Live Cells., Jin O-Uchi, Jaime Sorenson, Bong Sook Jhun, Jyotsna Mishra, Stephen Hurst, Kaleef Williams, Shey-Shing Sheu, Coeli M.B. Lopes

Center for Translational Medicine Faculty Papers

Protein kinase C (PKC) plays key roles in the regulation of signal transduction and cellular function in various cell types. At least ten PKC isoforms have been identified and intracellular localization and trafficking of these individual isoforms are important for regulation of enzyme activity and substrate specificity. PKC can be activated downstream of Gq-protein coupled receptor (GqPCR) signaling and translocate to various cellular compartments including plasma membrane (PM). Recent reports suggested that different types of GqPCRs would activate different PKC isoforms (classic, novel and atypical PKCs) with different trafficking patterns. However, the knowledge of isoform-specific activation of PKC by each …

Wnt Signaling Exerts An Antiproliferative Effect On Adult Cardiac Progenitor Cells Through Igfbp3., Angelos Oikonomopoulos, Konstantina-Ioanna Sereti, Frank Conyers, Michael Bauer, Annette Liao, Jian Guan, Dylan Crapps, Jung-Kyu Han, Hanhua Dong, Ahmad F Bayomy, Gabriel C Fine, Karen Westerman, Travis L Biechele, Randall T Moon, Thomas Force, Ronglih Liao

Center for Translational Medicine Faculty Papers

RATIONALE: Recent work in animal models and humans has demonstrated the presence of organ-specific progenitor cells required for the regenerative capacity of the adult heart. In response to tissue injury, progenitor cells differentiate into specialized cells, while their numbers are maintained through mechanisms of self-renewal. The molecular cues that dictate the self-renewal of adult progenitor cells in the heart, however, remain unclear.

OBJECTIVE: We investigate the role of canonical Wnt signaling on adult cardiac side population (CSP) cells under physiological and disease conditions.

METHODS AND RESULTS: CSP cells isolated from C57BL/6J mice were used to study the effects of canonical …

Gsk-3alpha Directly Regulates Beta-Adrenergic Signaling And The Response Of The Heart To Hemodynamic Stress In Mice., Jibin Zhou, Hind Lal, Xiongwen Chen, Xiying Shang, Jianliang Song, Yingxin Li, Risto Kerkela, Bradley W Doble, Katrina Macaulay, Morgan Decaul, Walter J Koch, John Farber, James Woodgett, Erhe Gao, Thomas Force

Center for Translational Medicine Faculty Papers

The glycogen synthase kinase-3 (GSK-3) family of serine/threonine kinases consists of 2 highly related isoforms, alpha and beta. Although GSK-3beta has an important role in cardiac development, much remains unknown about the function of either GSK-3 isoform in the postnatal heart. Herein, we present what we believe to be the first studies defining the role of GSK-3alpha in the mouse heart using gene targeting. Gsk3a(-/-) mice over 2 months of age developed progressive cardiomyocyte and cardiac hypertrophy and contractile dysfunction. Following thoracic aortic constriction in young mice, we observed enhanced hypertrophy that rapidly transitioned to ventricular dilatation and contractile dysfunction. …

An Adrenal Beta-Arrestin 1-Mediated Signaling Pathway Underlies Angiotensin Ii-Induced Aldosterone Production In Vitro And In Vivo., Anastasios Lymperopoulos, Giuseppe Rengo, Carmela Zincarelli, Jihee Kim, Stephen Soltys, Walter J Koch

Center for Translational Medicine Faculty Papers

Aldosterone produces a multitude of effects in vivo, including promotion of postmyocardial infarction adverse cardiac remodeling and heart failure progression. It is produced and secreted by the adrenocortical zona glomerulosa (AZG) cells after angiotensin II (AngII) activation of AngII type 1 receptors (AT(1)Rs). Until now, the general consensus for AngII signaling to aldosterone production has been that it proceeds via activation of G(q/11)-proteins, to which the AT(1)R normally couples. Here, we describe a novel signaling pathway underlying this AT(1)R-dependent aldosterone production mediated by beta-arrestin-1 (betaarr1), a universal heptahelical receptor adapter/scaffolding protein. This pathway results in sustained ERK activation and subsequent …

Beta Blocker Specificity: A Building Block Toward Personalized Medicine., Brent R Degeorge, Walter J Koch

Center for Translational Medicine Faculty Papers

Drugs known as beta blockers, which antagonize the beta-adrenergic receptor (beta-AR), are an important component of the treatment regimen for chronic heart failure (HF). However, a significant body of evidence indicates that genetic heterogeneity at the level of the beta(1)-AR may be a factor in explaining the variable responses of HF patients to beta blockade. In this issue of the JCI, Rochais et al. describe how a single amino acid change in beta(1)-AR alters its structural conformation and improves its functional response to carvedilol, a beta blocker currently used in the treatment of HF (see the related article beginning on …