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Zhao M.,Integrative Molecular and Biomedical science Graduate Program | Wang M.C.,Huffington Center on Aging | Provost C.R.,New England Biolabs | Huang J.,Sciclotron LLC | Wang J.,Baylor College of Medicine
Analyst | Year: 2016

Imaging hydrogen sulfide (H2S) at the subcellular resolution will greatly improve the understanding of functions of this signaling molecule. Taking advantage of the protein labeling technologies, we report a general strategy for the development of organelle specific H2S probes, which enables sub-cellular H2S imaging essentially in any organelles of interest. © The Royal Society of Chemistry 2016.


Mody A.,Texas A&M University | Mody A.,Baylor College of Medicine | Mody A.,Center for Translational Research on Inflammatory Diseases | Whitec D.,Center for Translational Research on Inflammatory Diseases | And 9 more authors.
Cardiovascular Endocrinology | Year: 2015

Nonalcoholic fatty liver disease (NAFLD) is a condition where there is excess accumulation of triglycerides in the liver in the absence of excess alcohol consumption. It ranges from simple steatosis to nonalcoholic steatohepatitis, which can progress to fibrosis, cirrhosis, and hepatocellular carcinoma. NAFLD, one of the most common causes of chronic liver disease in Western populations, is the hepatic component of the metabolic syndrome and is associated with increased visceral adipose tissue (VAT), insulin resistance, and dyslipidemia. Studies have also shown that testosterone deficiency is associated with increased VAT and insulin resistance in men, whereas hyperandrogenemia has been associated with increased risk of insulin resistance and VAT in women. Thus, the aims of this review are to discuss the available experimental and epidemiological data evaluating the association between testosterone and NAFLD, to discuss the potential clinical relevance of these data, and to identify gaps in the literature. Cardiovasc Endocrinol 4:83-89. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.


Lian H.,Huffington Center on Aging | Yang L.,Huffington Center on Aging | Cole A.,Huffington Center on Aging | Sun L.,Huffington Center on Aging | And 11 more authors.
Neuron | Year: 2015

Abnormal NFκB activation has been implicated in Alzheimer's disease (AD). However, the signaling pathways governing NFκB regulation and function in the brain are poorly understood. We identify complement protein C3 as an astroglial target of NFκB and show that C3 release acts through neuronal C3aR to disrupt dendritic morphology and network function. Exposure to Aβ activates astroglial NFκB and C3 release, consistent with the high levels of C3 expression in brain tissue from AD patients and APP transgenic mice, where C3aR antagonist treatment rescues cognitive impairment. Therefore, dysregulation of neuron-glia interaction through NFκB/C3/C3aR signaling may contribute to synaptic dysfunction in AD, and C3aR antagonists may be therapeutically beneficial. © 2015 Elsevier Inc.


Wollam J.,Huffington Center on Aging | Wollam J.,Baylor College of Medicine | Wollam J.,Max Planck Institute for Biology of Ageing | Antebi A.,Huffington Center on Aging | And 2 more authors.
Annual Review of Biochemistry | Year: 2011

Sterol metabolites are critical signaling molecules that regulate metabolism, development, and homeostasis. Oxysterols, bile acids (BAs), and steroids work primarily through cognate sterol-responsive nuclear hormone receptors to control these processes through feed-forward and feedback mechanisms. These signaling pathways are conserved from simple invertebrates to mammals. Indeed, results from various model organisms have yielded fundamental insights into cholesterol and BA homeostasis, lipid and glucose metabolism, protective mechanisms, tissue differentiation, development, reproduction, and even aging. Here, we review how sterols act through evolutionarily ancient mechanisms to control these processes. © 2011 by Annual Reviews. All rights reserved.


Guo Q.,Huffington Center on Aging | Guo Q.,Baylor College of Medicine | Li H.,Huffington Center on Aging | Gaddam S.S.K.,Baylor College of Medicine | And 4 more authors.
Journal of Biological Chemistry | Year: 2012

APP processing and amyloid-β production play a central role in Alzheimer disease pathogenesis. APP has been considered a ubiquitously expressed protein. In addition to amyloid-β, α- or β-secretase-dependent cleavage of APP also generates soluble secreted APP (APPsα or APPsβ, respectively). Interestingly, APPsβ has been shown to be subject to further cleavage to create an N-APP fragment that binds to the DR6 death receptor and mediates axon pruning and degeneration under trophic factor withdrawal conditions. By performing APP immunocytochemical staining, we found that, unexpectedly, many antibodies yielded nonspecific staining in APP-null samples. Screening of a series of antibodies allowed us to identify a rabbit monoclonal antibody Y188 that is highly specific forAPPand prompted us to re-examine the expression, localization, and stability of endogenous APP and APPsβ in wild-type and in APPsβ knock-in mice, respectively. In contrast to earlier studies, we found that APP is specifically expressed in neurons and that its expression cannot be detected in major types of glial cells under basal or neuroinflammatory conditions. Both APPsα and APPsβ are highly stable in the central nervous system (CNS) and do not undergo further cleavage with or without trophic factor support. Our results clarify several key questions with regard to the fundamental properties of APP and offer critical cellular insights into the pathophysiology of APP. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.


Wang B.,Huffington Center on Aging | Wang Z.,Huffington Center on Aging | Wang Z.,University of Texas Southwestern Medical Center | Sun L.,Huffington Center on Aging | And 7 more authors.
Journal of Neuroscience | Year: 2014

Impaired neurogenesis in the adult hippocampus has been implicated in AD pathogenesis. Here we reveal that the APP plays an important role in the neural progenitor proliferation and newborn neuron maturation in the mouse dentate gyrus. APP controls adult neurogenesis through a noncell-autonomous mechanism by GABAergic neurons, as selective deletion of GABAergic, but not glutamatergic, APP disrupts adult hippocampal neurogenesis. APP, highly expressed in the majority of GABAergic neurons in the dentate gyrus, enhances the inhibitory tone to granule cells. By regulating both tonic and phasic GABAergic inputs to dentate granule cells, APP maintains excitatory-inhibitory balance and preserves cognitive functions. Our studies uncover an indispensable role of APP in the GABAergic system for controlling adult hippocampal neurogenesis, and our findings indicate that APP dysfunction may contribute to impaired neurogenesis and cognitive decline associated with AD. © 2014 the authors.


PubMed | Huffington Center on Aging and Baylor College of Medicine
Type: | Journal: Rare diseases (Austin, Tex.) | Year: 2014

Myotonic dystrophy type 1 (DM1), an incurable, neuromuscular disease, is caused by the expansion of CTG repeats within the 3 UTR of DMPK on chromosome 19q. In DM1 patients, mutant DMPK transcripts deregulate RNA metabolism by altering CUG RNA-binding proteins. Several approaches have been proposed for DM1 therapy focused on specific degradation of the mutant CUG repeats or on correction of RNA-binding proteins, affected by CUG repeats. One such protein is CUG RNA-binding protein (CUGBP1). The ability of CUGBP1 to increase or inhibit translation depends on phosphorylation at Ser302, which is mediated by cyclin D3-CDK4. The mutant CUG repeats increase the levels of CUGBP1 protein and inhibit Ser302 phosphorylation, leading to the accumulation of CUGBP1 isoforms that repress translation (i.e., CUGBP1(REP)). Elevation of CUGBP1(REP) in DM1 is caused by increased GSK3 kinase, which reduces the cyclin D3-CDK4 pathway and subsequent phosphorylation of CUGBP1 at Ser302. In this review, we discuss our recent discovery showing that correction of GSK3 activity in the DM1 mouse model (i.e., HSA(LR) mice) reduces DM1 muscle pathology. These findings demonstrate that GSK3 is a novel therapeutic target for treating DM1.


PubMed | Huffington Center on Aging and Baylor College of Medicine
Type: Journal Article | Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience | Year: 2014

Impaired neurogenesis in the adult hippocampus has been implicated in AD pathogenesis. Here we reveal that the APP plays an important role in the neural progenitor proliferation and newborn neuron maturation in the mouse dentate gyrus. APP controls adult neurogenesis through a non cell-autonomous mechanism by GABAergic neurons, as selective deletion of GABAergic, but not glutamatergic, APP disrupts adult hippocampal neurogenesis. APP, highly expressed in the majority of GABAergic neurons in the dentate gyrus, enhances the inhibitory tone to granule cells. By regulating both tonic and phasic GABAergic inputs to dentate granule cells, APP maintains excitatory-inhibitory balance and preserves cognitive functions. Our studies uncover an indispensable role of APP in the GABAergic system for controlling adult hippocampal neurogenesis, and our findings indicate that APP dysfunction may contribute to impaired neurogenesis and cognitive decline associated with AD.

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