Medical Biochemistry Commons^™

Investigating Gαs Pepducin’S Effect On Β2ar Signaling For Chf Pharmacology, Nida Bajwa, Nathan Hopfinger, Charles Scott

Phase 1

Introduction: Congestive heart failure affects nearly six million Americans and significantly impairs their quality of life. New and better interventions are needed to improve HF patients’ survival and outcomes. Pharmacologics that bias β2AR signaling towards arrestin, which promotes cardiomyocyte survival and contractility, may offer advantages over traditional β-blockers.

Objective: It has been demonstrated that peptides mimicking the C-terminus of the Gα_s subunit block downstream signaling of GPCRs. The study’s objective is to determine if a pepducin derived from the C-terminus of the Gα_s subunit of the β2AR could block G_s signaling but maintain arrestin-recruitment, thereby producing a …

Impaired Nuclear Export Of Polyglutamine-Expanded Androgen Receptor In Spinal And Bulbar Muscular Atrophy., Frederick J. Arnold, Anna Pluciennik, Diane E. Merry

Department of Biochemistry and Molecular Biology Faculty Papers

Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease caused by polyglutamine (polyQ) expansion in the androgen receptor (AR). Prior studies have highlighted the importance of AR nuclear localization in SBMA pathogenesis; therefore, in this study, we sought to determine the role of AR nuclear export in the pathological manifestations of SBMA. We demonstrate here that the nuclear export of polyQ-expanded AR is impaired, even prior to the formation of intranuclear inclusions of aggregated AR. Additionally, we find that promoting AR export with an exogenous nuclear export signal substantially reduces its aggregation and blocks hormone-induced toxicity. Moreover, we show …

Novel Hybrid Analogs Of Estrone Origin Exhibits Cytotoxic Effects Against Egfr-Dependent Cancers, Felix Acheampong

Electronic Theses and Dissertations

Cancer is second only to cardiovascular illnesses as the deadliest human disease globally. Currently, non-small cell lung cancer (NSCLC) and triple negative breast carcinoma (TNBC) are the most frequent types of cancer and have the highest mortalities. Epidermal growth factor receptor (EGFR), a central regulator of tumor progression, is frequently overexpressed in both cancers and is a key clinical target for therapeutic intervention. Natural products and their synthetic analogs have been utilized as EGFR tyrosine kinase inhibitors (TKIs) with potent antitumor effects. However, acquired resistance limits the long-term efficacy of these drugs. Estrone has been used as a scaffold in …

Metabolism Reprogramming In Hexavalent Chromium-Induced Human Lung Carcinogenesis, James Tate Fortin Wise

Theses and Dissertations--Pharmacology and Nutritional Sciences

Hexavalent chromium, Cr(VI), is an established human carcinogen that is a worldwide environmental health concern. It is well understood that reactive oxygen species, genomic instability, and DNA damage repair deficiency are important contributors to Cr(VI)-induced carcinogenesis. After decades of research some cancer hallmarks remain understudied for the mechanism of Cr(VI) carcinogenesis. Dysregulated cellular energetics have been established as a hallmark of cancer. Energy pathways that become dysregulated in cancer include mitochondrial respiration, lipogenesis, pentose phosphate pathway, one carbon metabolism, and increased anaerobic glycolysis in the presence of oxygen or ‘Warburg effect’.

To investigate metabolism changes in Cr(VI) carcinogenesis, we exposed …

Inhibition Of Cancer Stem Cells By Glycosaminoglycan Mimetics, Connor P. O'Hara

Theses and Dissertations

Connor O’Hara July 29, 2019

Inhibition of Cancer Stem Cells by Glycosaminoglycan Mimetics

In the United States cancer is the second leading cause of death, with colorectal cancer (CRC) being the third deadliest cancer and expected to cause over 51,000 fatalities in 2019 alone.¹ The current standard of care for CRC depends largely on the staging, location, and presence of metastasis.² As the tumor grows and invades nearby lymph tissue and blood vessels, CRC has the opportunity to invade not only nearby tissue but also metastasize into the liver and lung (most commonly).³ The 5-year survival rate …

Afatinib And Temozolomide Combination Inhibits Tumorigenesis By Targeting Egfrviii-Cmet Signaling In Glioblastoma Cells, Raghupathy Vengoji, Muzafar A. Macha, Rama Krishna Nimmakayala, Satyanarayana Rachagani, Jawed A. Siddiqui, Kavita Mallya, Santhi Gorantla, Maneesh Jain, Moorthy P. Ponnusamy, Surinder K. Batra, Nicole Shonka

Journal Articles: Biochemistry & Molecular Biology

BACKGROUND: Glioblastoma (GBM) is an aggressive brain tumor with universal recurrence and poor prognosis. The recurrence is largely driven by chemoradiation resistant cancer stem cells (CSCs). Epidermal growth factor receptor (EGFR) and its mutant EGFRvIII are amplified in ~ 60% and ~ 30% of GBM patients, respectively; however, therapies targeting EGFR have failed to improve disease outcome. EGFRvIII-mediated cross-activation of tyrosine kinase receptor, cMET, regulates GBM CSC maintenance and promote tumor recurrence. Here, we evaluated the efficacy of pan-EGFR inhibitor afatinib and Temozolomide (TMZ) combination on GBM in vitro and in vivo.

METHODS: We analyzed the effect of afatinib and …

Trefoil Factor(S) And Ca19.9: A Promising Panel For Early Detection Of Pancreatic Cancer, Rahat Jahan, Koelina Ganguly, Lynette M. Smith, Pranita Atri, Joseph Carmicheal, Yuri Sheinin, Satyanarayana Rachagani, Gopalakrishnan Natarajan, Randall E. Brand, Muzafar A. Macha, Paul M. Grandgenett, Sukhwinder Kaur, Surinder K. Batra

Journal Articles: Biochemistry & Molecular Biology

BACKGROUND: Trefoil factors (TFF1, TFF2, and TFF3) are small secretory molecules that recently have gained significant attention in multiple studies as an integral component of pancreatic cancer (PC) subtype-specific gene signature. Here, we comprehensively investigated the diagnostic potential of all the member of trefoil family, i.e., TFF1, TFF2, and TFF3 in combination with CA19.9 for detection of PC.

METHODS: Trefoil factors (TFFs) gene expression was analyzed in publicly available cancer genome datasets, followed by assessment of their expression in genetically engineered spontaneous mouse model (GEM) of PC (KrasG12D; Pdx1-Cre (KC)) and in human tissue microarray consisting of normal pancreas adjacent …

Leucine Supplementation In Cuprizone-Induced Oligodendrocyte Toxicity, Michael Ley

Williams Honors College, Honors Research Projects

Cuprizone is a copper chelator that induces demyelination in the central nervous system when fed to mice. This compound is thought to target Complex IV and disrupt mitochondrial metabolism leading to loss of myelin-producing oligodendrocytes. In this proposal, we further examine the chemical and toxicological properties of cuprizone. Immunofluorescence imaging and microarray data on MO3.13 cells treated with cuprizone revealed the possibility of alterations in lysosomal function, as well as mitochondrial disruption via mTOR and Electron Transport Chain (ETC) related pathways. Cell viability assays conducted suggest that addition of Branched-Chain Amino Acids, most commonly used from literature, leucine, can increase …

Vitamin E Δ-Tocotrienol Sensitizes Human Pancreatic Cancer Cells To Trail-Induced Apoptosis Through Proteasome-Mediated Down-Regulation Of C-Flip, Rony A. Francois, Anying Zhang, Kazim Husain, Chen Wang, Sean Hutchinson, Michael Kongnyuy, Surinder K. Batra, Domenico Coppola, Said M. Sebti, Mokenge P. Malafa

Journal Articles: Biochemistry & Molecular Biology

Background: Vitamin E δ-tocotrienol (VEDT), a vitamin E compound isolated from sources such as palm fruit and annatto beans, has been reported to have cancer chemopreventive and therapeutic effects.

Methods: We report a novel function of VEDT in augmenting tumor necrosis factor-related apoptosis-inducing ligand- (TRAIL-) induced apoptosis in pancreatic cancer cells. The effects of VEDT were shown by its ability to trigger caspase-8-dependent apoptosis in pancreatic cancer cells.

Results: When combined with TRAIL, VEDT significantly augmented TRAIL-induced apoptosis of pancreatic cancer cells. VEDT decreased cellular FLICE inhibitory protein (c-FLIP) levels without consistently modulating the expression of decoy death receptors 1, …

Uncovering And Characterizing Splice Variants Associated With Survival In Lung Cancer Patients, Sean West, Sushil Kumar, Surinder K. Batra, Hesham Ali, Dario Ghersi

Journal Articles: Biochemistry & Molecular Biology

Splice variants have been shown to play an important role in tumor initiation and progression and can serve as novel cancer biomarkers. However, the clinical importance of individual splice variants and the mechanisms by which they can perturb cellular functions are still poorly understood. To address these issues, we developed an efficient and robust computational method to: (1) identify splice variants that are associated with patient survival in a statistically significant manner; and (2) predict rewired protein-protein interactions that may result from altered patterns of expression of such variants. We applied our method to the lung adenocarcinoma dataset from TCGA …

Lactate-Mediated Epigenetic Reprogramming Regulates Formation Of Human Pancreatic Cancer-Associated Fibroblasts, Tushar D. Bhagat, Dagny Von Ahrens, Meelad Dawlaty, Yiyu Zou, Joelle Baddour, Abhinav Achreja, Hongyun Zhao, Lifeng Yang, Brijesh Patel, Changsoo Kwak, Gaurav S. Choudhary, Shanisha Gordon-Mitchell, Srinivas Aluri, Sanchari Bhattacharyya, Srabani Sahu, Yiting Yu, Matthias Bartenstein, Orsi Giricz, Masako Suzuki, Davendra Sohal, Sonal Gupta, Paola A. Guerrero, Surinder K. Batra, Michael Goggins, Ulrich Steidl, John Greally, Beamon Agarwal, Kith Pradhan, Debabrata Banerjee, Deepak Nagrath, Anirban Maitra, Amit Verma

Journal Articles: Biochemistry & Molecular Biology

Even though pancreatic ductal adenocarcinoma (PDAC) is associated with fibrotic stroma, the molecular pathways regulating the formation of cancer associated fibroblasts (CAFs) are not well elucidated. An epigenomic analysis of patient-derived and de-novo generated CAFs demonstrated widespread loss of cytosine methylation that was associated with overexpression of various inflammatory transcripts including CXCR4. Co-culture of neoplastic cells with CAFs led to increased invasiveness that was abrogated by inhibition of CXCR4. Metabolite tracing revealed that lactate produced by neoplastic cells leads to increased production of alpha-ketoglutarate (aKG) within mesenchymal stem cells (MSCs). In turn, aKG mediated activation of the …

Pr55Α Regulatory Subunit Of Pp2a Inhibits The Mob1/Lats Cascade And Activates Yap In Pancreatic Cancer Cells, Ashley L. Hein, Nichole D. Brandquist, Caroline Y. Ouellette, Parthasarathy Seshacharyulu, Charles A. Enke, Michel M. Ouellette, Surinder K. Batra, Ying Yan

Journal Articles: Biochemistry & Molecular Biology

PP2A holoenzyme complexes are responsible for the majority of Ser/Thr phosphatase activities in human cells. Each PP2A consists of a catalytic subunit (C), a scaffold subunit (A), and a regulatory subunit (B). While the A and C subunits each exists only in two highly conserved isoforms, a large number of B subunits share no homology, which determines PP2A substrate specificity and cellular localization. It is anticipated that different PP2A holoenzymes play distinct roles in cellular signaling networks, whereas PP2A has only generally been defined as a putative tumor suppressor, which is mostly based on the loss-of-function studies using pharmacological or …

Codon-Specific Translation By M1g37 Methylation Of Trna, Ya-Ming Hou, Isao Masuda, Howard Gamper

Department of Biochemistry and Molecular Biology Faculty Papers

Although the genetic code is degenerate, synonymous codons for the same amino acid are not translated equally. Codon-specific translation is important for controlling gene expression and determining the proteome of a cell. At the molecular level, codon-specific translation is regulated by post-transcriptional epigenetic modifications of tRNA primarily at the wobble position 34 and at position 37 on the 3′-side of the anticodon. Modifications at these positions determine the quality of codon-anticodon pairing and the speed of translation on the ribosome. Different modifications operate in distinct mechanisms of codon-specific translation, generating a diversity of regulation that is previously unanticipated. Here we …

Studies Of Oxidative Damage, Brain Proteome, And Neurochemical Metabolites In Cognitive And Neurodegenerative Disorders: (1) Chemotherapy-Induced Cognitive Impairment; (2) Parkinson Disease Rat Model, Xiaojia Ren

Theses and Dissertations--Chemistry

The rate of cancer patients is increasing as the development of science and technology. Twenty million cancer survivors are estimated living in the United States by 2025. However, many cancer survivors show cognitive dysfunction, negatively affecting the quality of life. These cognitive impairments are recognized as chemotherapy-induced cognitive impairment (CICI), also called "chemo brain" by cancer survivors, including the diminished ability of memory and learning, hard to concentrate and focus, as well as diminution of executive function and processing speed. The etiologies and pathologies of CICI are complicated, especially in most cases the anti-cancer drug cannot cross the blood-brain barrier …

Roles Of Lin28 Proteins In Cholangiocarcinoma, Nattapong Puthdee

Chulalongkorn University Theses and Dissertations (Chula ETD)

LIN28 is an RNA-binding protein, a known as regulator of microRNAs biogenesis and play a role in multiple cellular functions such as stem cell maintenance, cell metabolism and implicated in oncogenesis. In cancer study, LIN28 protein is frequently expressed and associated with tumor aggressiveness and poor disease outcome. Previous studies have shown that paralog-LIN28B was upregulated in during CCA development. However, the role of LIN28B in cholangiocarcinogenesis remains largely unknown. The present study, we found LIN28B is overexpressed in CCA patients' tissues. Overexpression of LIN28B in cholangiocytes-MMNK-1 cells showed that LIN28B enhanced cell proliferation, clonogenic potential, and promoted epithelial-to mesenchymal …

การเสริมผลิตภัณฑ์จากพืชเพื่อชะลอความเสื่อมของไตจากโรคเบาหวานในหนู, วิรินทร์ บวรสมสฤษดิ์

Chulalongkorn University Theses and Dissertations (Chula ETD)

โรคเบาหวาน (Diabetes mellitus, DM) เป็นภาวะผิดปกติที่ร่างกายมีระดับน้ำตาลในเลือดสูงกว่าปกติ จนนำไปสู่อาการแทรกซ้อนต่าง ๆ อาทิ โรคไตวายเรื้อรังระยะสุดท้าย และโรคไขมันพอกตับที่ไม่ได้เกิดจากแอลกอฮอล์ (Non-alcoholic fatty liver disease, NAFLD) เพื่อควบคุมระดับน้ำตาลในเลือด ผู้ป่วยโรคเบาหวานจะได้รับการแนะนำให้บริโภคอาหารในแต่ละมื้อลดลง และเพิ่มมื้ออาหารว่างเป็นอาหารที่มีค่าดัชนีอาหารต่ำ เป็นที่ทราบกันดีว่าพืชในตระกูลถั่วและงามีประโยชน์ต่อสุขภาพหลายประการ การศึกษาในพืชตระกูลถั่วพบว่าสามารถป้องกันภาวะไขมันในเลือดสูงรวมถึงบรรเทาภาวะโรคเบาหวานได้ และยังมีการศึกษาที่พบว่างา (Sesame) ช่วยลดคอเลสเตอรอล (Cholesterol) ในเลือด นอกจากนี้ถั่วเขียวทอดและงาคั่วเป็นหนึ่งในอาหารกินเล่นที่นิยมของคนไทย สมควรที่จะส่งเสริมผู้ป่วยโรคเบาหวานบริโภคถั่วเขียวทอดหรืองาคั่วเป็นอาหารว่าง หากแต่ในปัจจุบันยังไม่มีหลักฐานเพียงพอที่จะทำให้เชื่อมั่นได้ว่า ถั่วเขียวทอดและงาคั่ว สามารถลดความเสี่ยงในการเกิดภาวะแทรกซ้อนของโรคเบาหวานได้จริงหรือไม่ ในงานวิจัยครั้งนี้จึงมีจุดประสงค์ที่จะศึกษาผลของการบริโภคถั่วเขียวทอดและงาดำคั่วต่อการดำเนินโรคเบาหวานชนิดที่ 2 ในหนูทดลอง โดยการแบ่งหนูทดลองออกเป็น 4 กลุ่ม คือ หนูปกติกลุ่มควบคุม (Normal control group; NC) หนูเบาหวานกลุ่มควบคุม (Diabetes mellitus control group; DMC) หนูเบาหวานที่บริโภคถั่วเขียวทอด (Fried mung bean group; FMB) และหนูเบาหวานที่บริโภคงาดำคั่ว (Roasted black sesame group; RBS) หนูทดลองนอกเหนือจากกลุ่มปกติควบคุมจะถูกกระตุ้นให้เป็นเบาหวาน และบริโภคอาหารไขมันสูง พบว่าในสัปดาห์ที่ 12 ของการทดลอง ระดับน้ำตาล HbA1C ระดับไขมันและคริอะตินินในเลือดในหนูทดลองแต่ละกลุ่มไม่มีความแตกต่างกัน แต่เมื่อทำการศึกษาพยาธิสภาพของไตและตับด้วยกล้องจุลทรรศน์แบบแสง และกล้องจุลทรรศน์อิเล็กตรอนแบบส่องผ่าน พบว่าหนูเบาหวานกลุ่มควบคุมมีปริมาณไขมันสะสมในตับสูง และมีความหนาของเยื่อฐานโกลเมอรูลัส (Glomerular basement membrane) และความกว้างของขาเซลล์โพโดไซต์ (podocyte foot process) มากกว่าหนูปกติกลุ่มควบคุมอย่างมีนัยสำคัญ ซึ่งเป็นภาวะแทรกซ้อนระยะแรกของตับและไตในโรคเบาหวาน และพบว่าหนูที่ได้รับถั่วเขียวทอดและงาดำคั่ว ไม่พบความผิดปกติทางพยาธิสภาพของตับและไตดังกล่าว จากผลการทดลองทั้งหมดในการวิจัยครั้งนี้อาจกล่าวได้ว่าการบริโภคถั่วเขียวทอดหรืองาดำคั่วสามารถบรรเทาพยาธิสภาพของไตและตับที่เกิดจากโรคเบาหวานในหนูทดลองที่เป็นเบาหวานชนิดที่ 2 ได้