Medical Molecular Biology Commons^™

China Suboptimal Health Cohort Study: Rationale, Design And Baseline Characteristics, Youxin Wang, Siqi Ge, Yuxiang Yan, Anxin Wang, Zhongyao Zhao, Xinwei Yu, Jing Qui, Mohamed Ali Alzain, Hao Wang, Honghong Fang, Qing Gao, Manshu Song, Jie Zhang, Yong Zhou, Wei Wang

Research outputs 2014 to 2021

Background:

Suboptimal health status (SHS) is a physical state between health and disease, characterized by the perception of health complaints, general weakness, chronic fatigue and low energy levels. SHS is proposed by the ancient concept of traditional Chinese medicine (TCM) from the perspective of preservative, predictive and personalized (precision) medicine. We previously created the suboptimal health status questionnaire 25 (SHSQ-25), a novel instrument to measure SHS, validated in various populations. SHSQ-25 thus affords a window of opportunity for early detection and intervention, contributing to the reduction of chronic disease burdens.

Methods/design:

To investigate the causative effect of SHS in non-communicable …

Human Neural Progenitor Cells Are Productively Infected By R5-Tropic Hiv-1: Opiate Interactions On Infection And Function Involve Cdk5 Signaling, Joyce Magat Balinang

Theses and Dissertations

Human immunodeficiency virus type 1 (HIV-1) is known to cause a spectrum of neurological, behavioral and motor deficits collectively termed as HIV-1 associated neurocognitive impairments (HAND). Opiates augment HIV-related CNS complications through both direct and indirect mechanisms that disrupt glial and neuronal function. All CNS macroglia and neurons derive from neural progenitor cells (NPCs) during development, and NPCs in the adult brain contribute to repair processes. Since disruptions in NPC function are known to impact CNS populations and brain function in a number of disease/injury conditions, we determined whether HIV ± opiate exposure affected the maturation and fate of human …

Expression Of Cell-Surface Marker Abcb5 Causes Characteristic Modifications Of Glucose, Amino Acid And Phospholipid Metabolism In The G3361 Melanoma-Initiating Cell Line, Norbert W. Lutz, Pallavi Banerjee, Brian J. Watson, Jie Ma, Patrick J. Cozzone, Markus H. Frank

Research outputs 2014 to 2021

We present a pilot study aimed at determining the effects of expression of ATP-binding cassette member B5 (ABCB5), a previously described marker for melanoma-initiating cells, on cellular metabolism. Metabolic profiles for two groups of human G3361 melanoma cells were compared, i.e. wildtype melanoma cells with intact ABCB5 expression (ABCB5-WT) and corresponding melanoma cell variants with inhibited ABCB5 expression, through shRNA-mediated gene knockdown (ABCB5-KD). A comprehensive metabolomic analysis was performed by using proton and phosphorus NMR spectroscopy of cell extracts to examine water-soluble metabolites and lipids. Parametric and non-parametric statistical analysis of absolute and relative metabolite levels yielded significant differences for …

How The Manipulation Of The Ras Homolog Enriched In Striatum Alters The Behavioral And Molecular Progression Of Huntington’S Disease, Franklin A. Lee

LSU New Orleans Theses and Dissertations

Huntington’s disease is an incurable, progressive neurological disorder characterized by loss of motor control, psychiatric dysfunction, and eventual dystonia leading to death. Despite the fact that this disorder is caused by a mutation in one single gene, there is no cure. The mutant Huntingtin (mHtt) protein is expressed ubiquitously throughout the brain but frank cell death is limited to the striatum. Recent work has suggested that Rhes, Ras homolog enriched in striatum, which is selectively expressed in the striatum, may play a role in Huntington’s disease neuropathology. In vitro studies have shown Rhes to be an E3 ligase for the …

Epacs: Epigenetic Regulators That Affect Cell Survival In Cancer., Catherine Murari

Theses & Dissertations

Cyclic adenosine monophosphate (cAMP) is a second messenger responsive to many external stimuli, playing an important role in cellular gene expression, metabolism, migration, differentiation, hypertrophy, apoptosis and secretion. All of these cellular functions are important in many diseases including cancer. Most of its effects were initially attributed to the classical protein kinase A (PKA) protein, but cellular functions such as proliferation and migration were found to be PKA independent and dependent on the newly discovered exchange proteins directly activated by cAMP (EPACs). EPACs are single polypeptides that primarily function as guanine exchange factors (GEFs) for Rap proteins that allow the …

Systemic Insulin Sensitivity And Skeletal Muscle Akt Signaling In Rats Artificially Selected For Low And High Aerobic Capacity, Kyle Levi Fulghum

Graduate Theses/Dissertations

The mechanism(s) linking physical inactivity, obesity, and type-II diabetes are unclear. I hypothesized low intrinsic aerobic capacity is associated with reduced systemic insulin sensitivity via skeletal muscle insulin signaling. After 34 generations of selective breeding, high aerobic capacity (HCR) rats exhibited an 8-fold increase in running distance vs low aerobic capacity (LCR) rats (n=14 per group). LCR rats had higher rates of weight gain vs HCR (p<0.05) though food consumption was constant (p=0.86) over a 12-week study. Rats were divided into 4 groups: 1) LCR-Sham Surgery, 2) LCR-Catheterization, 3) HCR-Sham Surgery or 4) HCR-Catheterization (n=7 per group). Euglycemic-hyperinsulinemic clamps on catheterized rats tested insulin sensitivity while sham LCR and HCR were used for basal tissue analysis. Plasma insulin levels did not differ during the clamps, but LCR required lower glucose infusion rates than HCR (p<0.05). Upon insulin stimulation, both absolute and normalized phospho-Akt(Ser473) of soleus muscle were significantly increased in HCR above basal group (p<0.05), but not in LCR. No difference was observed between insulin-stimulated phospho-Akt(Ser473) of HCR and LCR groups . These data support that LCR is linked to a reduction in insulin sensitivity in vivo without impairments of insulin-stimulated skeletal muscle phospho-Akt(Ser473) vs HCR rats.

Targeting Oncogenic Mirnas With Small Molecules For Breast Cancer Therapy, Paloma Del C. Monroig

Dissertations and Theses (Open Access)

The crucial role of microRNAs (miRNAs) in cancer pathobiology has driven the introduction of new drug development approaches such as miRNA inhibition. In order to advance miRNA-therapeutics, there is a need to develop screening strategies that can target tumors in a specific way. Small molecule inhibitors represent an attractive approach to pursue this. However, the absence of molecular structures for most of the miRNAs makes it very difficult to predict which inhibitors can bind to them. Herein we designed a strategy to screen for small molecules by assesing whether they could directly bind/ interact with miR-10b/miR-21. As part of our …

Reprogramming To Pluripotency Using Small Molecule Compounds, Brittany E. Greenberg

Theses and Dissertations (ETD)

The generation of induced pluripotent stem cells (iPSCs) through the use of small molecule compounds has evolved as a potential cellular reprogramming strategy. Individually, specific small molecule compounds have previously been shown to replace reprogramming transcription factors or enhance the efficiency of cellular reprogramming. More recently, a combination of small molecule compounds can replace all of the reprogramming factors. In this review, we describe in detail the generation of chemically induced pluripotent stem cells using small molecule inhibitors and activators that target either downstream protein kinases or modify chromatin structure to promote somatic cell reprogramming. In addition, epigenetic modulating small …

Non-Specific Blocking Of Mir-17-5p Guide Strand In Triple Negative Breast Cancer Cells By Amplifying Passenger Strand Activity., Yuan-Yuan Jin, Jade Andrade, Eric Wickstrom

Department of Biochemistry and Molecular Biology Faculty Papers

Conventional wisdom holds that only one of the two strands in a micro ribonucleic acid (miRNA) precursor duplex is selected as the active miRNA guide strand. The complementary miRNA passenger strand, however, is thought to be inactive. High levels of the oncogenic miRNA (oncomiR) guide strand called miR-17-5p is overexpressed in triple negative breast cancer (TNBC) and can inhibit ribosomal translation of tumor suppressor gene mRNAs, such as programmed cell death 4 (PDCD4) or phosphatase and tensin homolog (PTEN). We hypothesized that knocking down the oncogenic microRNA (oncomiR) miR-17-5p might restore the expression levels of PDCD4 and PTEN tumor suppressor …

Role Of Micrornas In Alcohol-Induced Multi-Organ Injury., Sathish Kumar Natarajan, Joseph M. Pachunka, Justin L. Mott

Journal Articles: Biochemistry & Molecular Biology

Alcohol consumption and its abuse is a major health problem resulting in significant healthcare cost in the United States. Chronic alcoholism results in damage to most of the vital organs in the human body. Among the alcohol-induced injuries, alcoholic liver disease is one of the most prevalent in the United States. Remarkably, ethanol alters expression of a wide variety of microRNAs that can regulate alcohol-induced complications or dysfunctions. In this review, we will discuss the role of microRNAs in alcoholic pancreatitis, alcohol-induced liver damage, intestinal epithelial barrier dysfunction, and brain damage including altered hippocampus structure and function, and neuronal loss, …

Conservation Of Inner Nuclear Membrane Targeting Sequences In Mammalian Pom121 And Yeast Heh2 Membrane Proteins., Annemarie Kralt, Noorjahan B Jagalur, Vincent Van Den Boom, Ravi K Lokareddy, Anton Steen, Gino Cingolani, Maarten Fornerod, Liesbeth M Veenhoff

Department of Biochemistry and Molecular Biology Faculty Papers

Endoplasmic reticulum-synthesized membrane proteins traffic through the nuclear pore complex (NPC) en route to the inner nuclear membrane (INM). Although many membrane proteins pass the NPC by simple diffusion, two yeast proteins, ScSrc1/ScHeh1 and ScHeh2, are actively imported. In these proteins, a nuclear localization signal (NLS) and an intrinsically disordered linker encode the sorting signal for recruiting the transport factors for FG-Nup and RanGTP-dependent transport through the NPC. Here we address whether a similar import mechanism applies in metazoans. We show that the (putative) NLSs of metazoan HsSun2, MmLem2, HsLBR, and HsLap2β are not sufficient to drive nuclear accumulation of …

High Throughput Sequencing Identifies Micrornas Mediating Α-Synuclein Toxicity By Targeting Neuroactive-Ligand Receptor Interaction Pathway In Early Stage Of Drosophila Parkinson's Disease Model., Yan Kong, Xijun Liang, Lin Liu, Dongdong Zhang, Chao Wan, Zhenji Gan, Liudi Yuan, Bing-Hua Jiang

Department of Medicine Faculty Papers

Parkinson's disease (PD) is a prevalent neurodegenerative disorder with pathological features including death of dopaminergic neurons in the substantia nigra and intraneuronal accumulations of Lewy bodies. As the main component of Lewy bodies, α-synuclein is implicated in PD pathogenesis by aggregation into insoluble filaments. However, the detailed mechanisms underlying α-synuclein induced neurotoxicity in PD are still elusive. MicroRNAs are ~20nt small RNA molecules that fine-tune gene expression at posttranscriptional level. A plethora of miRNAs have been found to be dysregulated in the brain and blood cells of PD patients. Nevertheless, the detailed mechanisms and their in vivo functions in PD …

Investigation Of Behavioral And Cellular Changes In The Maternal Immune Activation Model Of Autism Spectrum Disorders, Shreya Roy

Theses & Dissertations

Maternal infection during pregnancy, which leads to maternal immune activation (MIA), is an environmental risk factor for autism spectrum disorders (ASD). MIA can be induced in mice and their offspring exhibit behaviors that model the core symptoms of ASD. One of the core behavioral symptoms in ASD patients is presence of increased repetitive behavior, which is modeled by an increase in marble burying in MIA mice. It has been shown that the deficits seen in MIA mice are associated with the dysregulation of cytokine levels in the developing brain, specifically an increase in pro-inflammatory cytokines. In this thesis, I tested …

Methylation Of Egfr By Arginine Methyltransferase Prmt1 Enhances Egfr Signaling And Cetuximab Resistance, Hsin-Wei Liao

Dissertations and Theses (Open Access)

Protein modifications of epidermal growth factor receptor (EGFR) intracellular domain are well known regulators of EGFR functions whereas those of its extracellular domain remain relatively unexplored. Here, we report that methylation at R198 and R200 of EGFR extracellular domain by protein arginine methyltransferase 1 (PRMT1) upregulates its binding to EGF and subsequent receptor dimerization and signaling activation. Methylation-defective EGFR mutant reduced tumor growth in mouse orthotopic xenograft model. Importantly, increased EGFR methylation sustains its signaling activation and cell proliferation in the presence of therapeutic EGFR monoclonal antibody, cetuximab. EGFR methylation level also correlates with higher recurrence rate after cetuximab treatment …

Cellular Prostatic Acid Phosphatase (Cpacp) Serves As A Useful Biomarker Of Histone Deacetylase (Hdac) Inhibitors In Prostate Cancer Cell Growth Suppression., Yu-Wei Chou, Fen-Fen Lin, Sakthivel Muniyan, Frank C. Lin, Ching-Shih Chen, Jue Wang, Chao-Cheng Huang, Ming-Fong Lin

Journal Articles: Biochemistry & Molecular Biology

BACKGROUND: Prostate cancer (PCa) is the most commonly diagnosed solid tumor and the second leading cancer death in the United States, and also one of the major cancer-related deaths in Chinese. Androgen deprivation therapy (ADT) is the first line treatment for metastatic PCa. PCa ultimately relapses with subsequent ADT treatment failure and becomes castrate-resistant (CR). It is important to develop effective therapies with a surrogate marker towards CR PCa.

METHOD: Histone deacetylase (HDAC) inhibitors were examined to determine their effects in androgen receptor (AR)/cellular prostatic acid phosphatase (cPAcP)-positive PCa cells, including LNCaP C-33, C-81, C4-2 and C4-2B and MDA PCa2b …

Novel Imidazopyridine Derivatives Possess Anti-Tumor Effect On Human Castration-Resistant Prostate Cancer Cells., Matthew A. Ingersoll, Anastesia S. Lyons, Sakthivel Muniyan, Napoleon D'Cunha, Tashika Robinson, Kyle Hoelting, Jennifer G. Dwyer, Xiu R. Bu, Surinder K. Batra, Ming-Fong Lin

Journal Articles: Biochemistry & Molecular Biology

Prostate cancer (PCa) is the second leading cause of cancer-related death afflicting United States males. Most treatments to-date for metastatic PCa include androgen-deprivation therapy and second-generation anti-androgens such as abiraterone acetate and enzalutamide. However, a majority of patients eventually develop resistance to these therapies and relapse into the lethal, castration-resistant form of PCa to which no adequate treatment option remains. Hence, there is an immediate need to develop effective therapeutic agents toward this patient population. Imidazopyridines have recently been shown to possess Akt kinase inhibitory activity; thus in this study, we investigated the inhibitory effect of novel imidazopyridine derivatives HIMP, …

Caspase-8 Scaffolding Function And Mlkl Regulate Nlrp3 Inflammasome Activation Downstream Of Tlr3., Seokwon Kang, Teresa Fernandes-Alnemri, Corey Rogers, Lindsey Mayes, Ying Wang, Christopher Dillon, Linda Roback, William Kaiser, Andrew Oberst, Junji Sagara, Katherine A Fitzgerald, Douglas R Green, Jianke Zhang, Edward S Mocarski, Emad S Alnemri

Department of Biochemistry and Molecular Biology Faculty Papers

TLR2 promotes NLRP3 inflammasome activation via an early MyD88-IRAK1-dependent pathway that provides a priming signal (signal 1) necessary for activation of the inflammasome by a second potassium-depleting signal (signal 2). Here we show that TLR3 binding to dsRNA promotes post-translational inflammasome activation through intermediate and late TRIF/RIPK1/FADD-dependent pathways. Both pathways require the scaffolding but not the catalytic function of caspase-8 or RIPK1. Only the late pathway requires kinase competent RIPK3 and MLKL function. Mechanistically, FADD/caspase-8 scaffolding function provides a post-translational signal 1 in the intermediate pathway, whereas in the late pathway it helps the oligomerization of RIPK3, which together with …

Membrane Proximal Ectodomain Cleavage Of Muc16 Occurs In The Acidifying Golgi/Post-Golgi Compartments., Srustidhar Das, Prabin D. Majhi, Mona H. Al-Mugotir, Satyanarayana Rachagani, Paul Sorgen, Surinder K. Batra

Journal Articles: Biochemistry & Molecular Biology

MUC16, precursor of the most widely used ovarian cancer biomarker CA125, is up regulated in multiple malignancies and is associated with poor prognosis. While the pro-tumorigenic and metastatic roles of MUC16 are ascribed to the cell-associated carboxyl-terminal MUC16 (MUC16-Cter), the exact biochemical nature of MUC16 cleavage generating MUC16-Cter has remained unknown. Using different lengths of dual-epitope (N-terminal FLAG- and C-terminal HA-Tag) tagged C-terminal MUC16 fragments, we demonstrate that MUC16 cleavage takes place in the juxta-membrane ectodomain stretch of twelve amino acids that generates a ~17 kDa cleaved product and is distinct from the predicted sites. This was further corroborated by …

Molecular Mechanisms That Govern Human Cardiac Stem Cell Age Disparity, Tania Fuentes

Loma Linda University Electronic Theses, Dissertations & Projects

Transplantation of adult endogenous cardiovascular progenitor cells for heart repair results in some clinical benefit, however these stem cells lack the regenerative capacity unique to neonatal cardiovascular stem cells. The goal of this work was to identify mechanisms that contribute to the decline of cardiac stem cell regenerative ability with age and investigate novel therapeutic strategies to improve cardiac stem cell function. When comparing neonatal and adult cardiovascular stem cell clones, both cell types were capable of cardiomyogenic differentiation. However, the expression levels of forty-one microRNAs were significantly altered with age. Expression differences were correlated with reduced proliferation and a …

Multilevel Deregulation Of Survival Mechanisms In Npm-Alk+ T-Cell Lymphoma, Deeksha Vishwamitra

Dissertations and Theses (Open Access)

The anaplastic lymphoma kinase (ALK) is a single chain transmembrane receptor tyrosine kinase that belongs to the insulin receptor superfamily. Other members of this superfamily include the insulin receptor (IR), type I insulin-like growth factor receptor (IGF-IR), and the leukocyte tyrosine kinase. The common structural finding among these tyrosine kinases is the YXXXYY motif present within their respective tyrosine kinase domains. Binding of its ligands causes ALK receptor homodimerization and protein kinase activation. ALK has been previously shown to play a significant role during early developmental stages. In human embryos, the expression of ALK is mainly seen in …