Medical Molecular Biology Commons^™

Pcsk9 Inhibitors: A Review Of The Efficacy, Safety And Current Literature Recommendations, Lacey L. Jandrin

Physician Assistant Scholarly Project Posters

Atherosclerotic cardiovascular disease is the leading cause of morbidity and mortality in developed counties. It is estimated that 60 million Americans have LDL-C levels > 160 mg/dl. Only about 1/3 of these patients meet treated LDL cholesterol goals of < 70 mg/dl indicating a need for greater control. High dose statins have been the mainstay in treatment of dyslipidemia, however, up to 20% of patients are statin intolerant indicating a need for secondary treatment strategies. This lead to the development of monoclonal antibodies to proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. PCSK9 inhibitors result in decreased destruction of the low-density lipoprotein receptor (LDL-R) which leads to an increase in the transport of LDL-C to its destruction effectively reducing LDL-C levels in the blood. The purpose of this study is to analyze the literature available on the efficacy and safety of new PCSK9 inhibitors. The results of this literature review indicated that PCSK9 inhibitors effectively lowered LDL-C by an average of approximately 50%. The evidence reviewed by this analysis indicate that 70% of patients treated with PCSK9 inhibitors met LDL-C goals. The findings also indicate that the side effects associated with this new class of medications are comparable to current side effects seen with traditional cholesterol lowering agents. The largest side effect seen in up to 10% of patients were injection site reactions and did not require discontinuation of the medication. The results of this analysis indicate that PCSK9 inhibitors may be of benefit in patients who are statin intolerant, do not meet LDL-C goals on traditional statin therapy or have familial hypercholesterolemia. Education in use of injectables, cost and insurance coverage and dosing schedule are likely to be areas of continued research and may affect use of this new class of cholesterol lowering agents.

Identification And Characterization Of Dna Repair Snf2/Swi2 Atpases In Tetrahymena Thermophila, Andrew Francis Morin

MSU Graduate Theses

The Snf2/Swi2 ATPases Rad5 and Rad16 have been shown to play vital roles in a number of DNA repair pathways. In both Saccharomyces cerevisiae and human cell lines, Rad5 homologs (SHPRH, HLTF) have been shown to function in DNA double strand break (DSB) repair along with pathways that repair damage after replication. The function of Rad16, unlike Rad5, has been found only in lower eukaryotes such as Saccharomyces, despite the fact that it plays an essential role in nucleotide excision repair (NER), and more specifically in the repair of silenced areas of the genome. In order to more fully understand …

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

University of 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 …

Intracellular Trafficking Governs The Processing Of The Amyloid Precursor Protein And The Secretion Of Beta-Amyloid, Joshua Hoi Ki Tam

Electronic Thesis and Dissertation Repository

One of the hallmarks of Alzheimer’s disease (AD) is the pathological accumulation of β-amyloid (Aβ) in the brains of AD patients. Oligomeric and fibrillar aggregates of Aβ have been shown to be neurotoxic to neurons and hippocampal slices. Therefore, limiting Aβ production is an important area of research in order to delay or stop AD progression. Aβ is produced by amyloidogenic cleavage of amyloid precursor protein (APP). Amyloidogenic cleavage requires ectodomain removal by β-secretase and intramembrane γ-cleavage by γ-secretase to release Aβ products ranging from 38-43 residues. Work from our lab has shown that APP and γ-secretase are resident proteins …

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 …

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

Dissertations & 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 …

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

MSU Graduate Theses

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.

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 …

Kidney Injury Molecule-1 Signalling In Ischemic Acute Kidney Injury And Phagocytosis, Ola Z. Ismail

Electronic Thesis and Dissertation Repository

Acute kidney injury (AKI) is defined by the rapid loss of kidney function due to tissue damage. It affects 10-30 % of hospitalized patients and is independently associated with increased morbidity and mortality. Ischemia-reperfusion injury (IRI) is the most common pathoetiological mechanism of AKI, whereby tissue injury is mediated by reactive oxygen species. Ischemic AKI leads to the rapid upregulation of a transmembrane protein, kidney injury molecule-1 (KIM-1) on the apical membrane of proximal tubular epithelial cells (TECs). Previous work from our group and others demonstrated that the extracellular domain of KIM-1 specifically binds to phosphatidylserine on apoptotic cells, thereby …

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 …

Characterization Of The Nicotine-Induced Endoplasmic Reticulum Stress Response In The Rat Placenta In Vivo And In Vitro, Michael Ka Chun Wong

Electronic Thesis and Dissertation Repository

Nicotine exposure during pregnancy leads to adverse health outcomes, including compromised placental development. Although the molecular mechanisms remain elusive, recent studies identified that endoplasmic reticulum (ER) stress may underlie poor placentation. Therefore, we were interested in investigating the effects of nicotine exposure on the ER stress response in the placenta. A well-established maternal nicotine exposure rat model and Rcho-1 trophoblast giant cell model were utilized to address the research questions. Maternal nicotine exposure in vivo led to elevated ER stress in association with impaired disulfide bond formation and hypoxia. Nicotine exposure in vitro further differentiated that ER stress may be …

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

Dissertations & 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 …