Medical Biochemistry Commons^™

Mechanistic And Functional Shades Of Mucins And Associated Glycans In Colon Cancer, Ramesh Pothuraju, Shiv Ram Krishn, Shailendra K. Gautam, Priya Pai, Koelina Ganguly, Sanjib Chaudhary, Satyanarayana Rachagani, Sukhwinder Kaur, Surinder K. Batra

Journal Articles: Biochemistry & Molecular Biology

Mucus serves as the chief protective barrier against pathogenic and mechanical insults in respiratory, gastrointestinal, and urogenital tracts. Altered mucin expression, the major component of mucus, in conjunction with differential glycosylation has been strongly associated with both benign and malignant pathologies of colon. Mucins and their associated glycans arbitrate their impact sterically as well as mechanically by altering molecular and microbial spectrum during pathogenesis. Mucin expression in normal and pathological conditions is regulated by nonspecific (dietary factors and gut microbiota) and specific (epigenetic and transcriptional) modulators. Further, recent studies highlight the impact of altering mucin glycome (cancer-associated carbohydrate antigens including …

Micrornas Orchestrate Pathophysiology Of Breast Cancer Brain Metastasis: Advances In Therapy, Ranjana K. Kanchan, Jawed A. Siddiqui, Sidharth Mahapatra, Surinder K. Batra, Mohd W. Nasser

Journal Articles: Biochemistry & Molecular Biology

Brain metastasis (BM) predominantly occurs in triple-negative (TN) and epidermal growth factor 2 (HER2)-positive breast cancer (BC) patients, and currently, there is an unmet need for the treatment of these patients. BM is a complex process that is regulated by the formation of a metastatic niche. A better understanding of the brain metastatic processes and the crosstalk between cancer cells and brain microenvironment is essential for designing a novel therapeutic approach. In this context, the aberrant expression of miRNA has been shown to be associated with BM. These non-coding RNAs/miRNAs regulate metastasis through modulating the formation of a metastatic niche …

Molecular Implications Of Muc5ac-Cd44 Axis In Colorectal Cancer Progression And Chemoresistance, Ramesh Pothuraju, Satyanarayana Rachagani, Shiv Ram Krishn, Sanjib Chaudhary, Rama Krishna Nimmakayala, Jawed A. Siddiqui, Koelina Ganguly, Imayavaramban Lakshmanan, Jesse L. Cox, Kavita Mallya, Sukhwinder Kaur, Surinder K. Batra

Journal Articles: Biochemistry & Molecular Biology

BACKGROUND: Differential expression of mucins has been associated with several cancers including colorectal cancer (CRC). In normal physiological conditions, secretory mucin MUC5AC is not expressed in the colonic mucosa, whereas its aberrant expression is observed during development of colon cancer and its precursor lesions. To date, the molecular mechanism of MUC5AC in CRC progression and drug resistance remains obscure.

METHODS: MUC5AC expression was determined in colon tissue microarray by immunohistochemistry. A RNA interference and CRISPR/Cas9-mediated system was used to knockdown/knockout the MUC5AC in CRC cell lines to delineate its role in CRC tumorigenesis using in vitro functional assays and in …

Pneumovirus Infections: Understanding Rsv And Hmpv Entry, Replication, And Spread, Jonathan T. Kinder

Theses and Dissertations--Molecular and Cellular Biochemistry

Pneumoviruses including human metapneumovirus (HMPV) and respiratory syncytial virus (RSV) are significant causes of respiratory tract infections globally. Children, elderly, and immunocompromised patients are at the greatest risk for developing severe infections, which can have devastating outcomes. Although these viruses are ubiquitous with significant impacts on human health, there are no antivirals or vaccines available. The only FDA approved therapy is a monoclonal antibody for RSV, given prophylactically during the infectious season, and this treatment is only available for high risk infants. The work presented in this thesis aims to increase our understanding of how these viruses enter, replicate, and …

Obese Zucker Rats As A Reverse Translational Model Of Human Left Ventricular Hypertrophy, Mackenzie Shelby Newman

Graduate Theses, Dissertations, and Problem Reports (ETD)

Heart failure is a lifelong disability that for over half of those affected leads to mortality within five years after initial diagnosis. Left ventricular hypertrophy (LVH) is one of the most reliable independent predictors of heart failure. Pathological LVH is irreversible, but early diagnosis is often missed due to its asymptomatic nature. Obese Zucker rats (OZR), which develop obesity due to dysfunctional leptin signaling, naturally exhibit a LVH that mimics the obese human condition. Animal models are necessary because human donor tissue is scarce. The central hypothesis is that genes and proteins that are differentially expressed during development of LVH, …

การแสดงออกของยีนและคุณลักษณะของเซลล์ต้นกำเนิดมะเร็งในประชากรเซลล์ไลน์ U87mg Glioblastoma, รุ่งนภา บุตรศรี

Chulalongkorn University Theses and Dissertations (Chula ETD)

มะเร็งสมองชนิดกลัยโอบลาสโตมา (Glioblastoma หรือ GBM) เป็นมะเร็งสมองชนิดที่พบมากที่สุด มีความรุนแรงและมีอัตราการเสียชีวิตสูง ทำให้คนไข้โดยเฉลี่ยเสียชีวิตภายในหนึ่งปี นอกจากนี้เซลล์ GBM ยังมีความหลากหลายทางสัณฐาน ดังนั้นผู้วิจัยจึงเล็งเห็นความสำคัญของเซลล์ต้นกำเนิดมะเร็งที่เป็นประชากรที่มีความสำคัญในแง่ของการตอบสนองต่อการรักษาและการกลับมาเป็นซ้ำของโรคมะเร็ง การที่จะสามารถพัฒนาการรักษาที่มีความจำเพาะในการกำจัดเซลล์ต้นกำเนิดมะเร็งนี้ จะต้องมีกระบวนการในการระบุเซลล์ต้นกำเนิดมะเร็ง (identification) ที่มีความจำเพาะและแม่นยำ ผู้วิจัยจึงต้องการค้นคว้าในเชิงลึกเพื่อหาการแสดงออกของยีนและโปรตีนที่เกี่ยวข้องกับความเป็นเซลล์ต้นกำเนิดมะเร็ง โดยทำการแยกประชากรเซลล์ U87MG ออกเป็น 3 กลุ่ม ได้แก่ ประชากรเซลล์รวม ประชากรเซลล์ใหญ่ และประชากรเซลล์เล็กออกจากกัน โดยใช้ความแตกต่างของขนาดเซลล์ ด้วยเทคนิค Fluorescence-activated cell sorting (FACS) จากนั้นนำประชากรดังกล่าวมาเลี้ยงแยกกัน โดยทำการศึกษาประชากรทั้งหมด ประชากรขนาดใหญ่และประชากรขนาดเล็ก แล้วศึกษาความเป็นเซลล์ต้นกำเนิดในระดับอาร์เอ็นเอด้วยเทคนิค Real-Time PCR โดยมุ่งเน้นไปที่การศึกษา (1) pluripotency markers/ transcription factor ได้แก่ OCT4, SOX2, NANOG และ c-MYC (2) cancer stem cell signalling ได้แก่ mTOR pathway โดยเน้นไปที่ mTORC2 และ LIN28/let-7 pathway และ (3) cellular phenotypes ได้แก่ วัฏจักรของเซลล์ (cell cycle) การแบ่งตัวของเซลล์ (cell proliferation) และการเคลื่อนที่ของเซลล์ (cell migration) งานวิจัยนี้เป็นรายงานแรกที่ศึกษาความเป็นเซลล์ต้นกำเนิดมะเร็ง GBM ใน U87MG โดยการแยกเซลล์ออกเป็นประชากรเซลล์ใหญ่และประชากรเซลล์เล็กด้วย FACS โดยพบว่าเซลล์ U87MG มีการแสดงออกของยีนที่บ่งชี้ความเป็นเซลล์ต้นกำเนิด ได้แก่ OCT4, SOX2, LIN28B,c-MYC, ZWINT, TYMS และ RCF4 ยีนที่เกี่ยวข้องกับ GBM ที่ทำการศึกษาการแสดงออก ได้แก่ SPARCL1, GDF15, LAMA1, …

Circulating-Tumor Dna And Cancer-Induced Gene Expression As Novel Liquid Biomarkers Of Liver Cancers, Pattapon Kunadirek

Chulalongkorn University Theses and Dissertations (Chula ETD)

Liver cancer is one of the most cancer-related mortality with high incidence worldwide. Hepatocellular carcinoma (HCC) is the most common liver cancer type. Currently, Liquid biopsy is known as a non-invasive biomarker tool that specifically represents tumor appearance, leading to improved patient outcomes. Therefore, the novel biomarkers of liquid biopsy in Thai HCC patients are still unexplored and needed for precision medicine. The main aims of this study were First, to explore genetic profiles from liquid biopsies of circulating cell-free DNA (cfDNA) and peripheral blood mononuclear cells (PBMCs) using next-generation sequencing (NGS) and identify novel biomarkers for HCC from these …

Educational Needs Of Newly Diagnosed Cancer Patients In Learning About Cancer: A Qualitative Study In The Malaysian Urban Setting, Munisamy Murallitharan

Student Works (2020-2029)

Patients with chronic diseases such as cancer are able to have better outcomes if they understand about all aspects of the disease, develop the correct attitude to manage themselves and their disease better; and engage in preventive practices that can help them prevent worsening of disease or recurrence. Patient education is an intervention that has proven to be effective in different settings for this. However in the Malaysian cancer setting, the educational needs of patients are poorly understood. The aim of this study was to explore and understand the educational needs of newly diagnosed cancer patients in learning about cancer …

Evaluation Of The Diagnostic Accuracy And Utility Of A New Dengue Rapid Diagnostic Test In Malaysia, Zhuo Lin Chong

Student Works (2020-2029)

Dengue is an emerging arboviral disease endemic to many tropical countries including Malaysia. Due to its unspecific symptoms, dengue diagnosis can only be confirmed through diagnostic tests. Existing laboratory-based dengue diagnostics like enzyme linked immunosorbent assay (ELISA) is accurate in detecting dengue non-structural protein-1 (NS1), and anti-dengue immunoglobulin M (IgM) and G (IgG); but is also more complicated and time-consuming. Commercially available dengue rapid immunochromatographic test (RIT) is efficient but less sensitive. A new dengue rapid diagnostic rest (RDT) using biosensors may be both efficient and accurate in diagnosing acute dengue. This study evaluated this new dengue NS1-based RDT and …

G6pd Activity, Oxidative Stress, And Alu Methylation In Hbv-Related Hepatocellular Carcinoma, Watcharapong Jugnam-Ang

Chulalongkorn University Theses and Dissertations (Chula ETD)

Hepatocellular carcinoma (HCC) is the third leading caused cancer death in worldwide. The effective diagnosis markers are needed because of the late diagnosis and low survival time. G6PD is the rate-limiting enzyme in pentose phosphate pathway (PPP) that elevated in several cancers including HCC. Alu element is a common repetitive sequence in human genome, that its methylation alteration has been reported in cancers. In this study, we aimed to investigate the level of blood G6PD activity, the expression of G6PD in HCC liver tissues, the level of Alu methylation in PBMCs and clinicopathological parameters of HCC patients. Blood G6PD activity …

Telomere Shortening And Cellular Senescence Induced By Oxalate And Nephrolithiasis Urine In Hk-2 Cells, Kamonchanok Chuenwisad

Chulalongkorn University Theses and Dissertations (Chula ETD)

Kidney stone disease is a common urologic problem worldwide, especially in the tropics such as Thailand. It is known as a multifactorial condition, and aging increases the risk of stone development. The major type of stones is calcium oxalate (CaOx), and its formation is driven by increased urinary oxalate excretion and calcium oxalate monohydrate (COM) crystallization. Both oxalate and COM are known to induce reactive oxygen species (ROS) production and cause oxidative stress. Furthermore, patients with CaOx stone have increased extent of oxidative stress. In this study, we investigated the induction of cellular senescence and telomere shortening through oxidative stress …

The Histone Deacetylase Inhibitor Tubacin Mitigates Endothelial Dysfunction By Up-Regulating The Expression Of Endothelial Nitric Oxide Synthase., Jihui Chen, Jian Zhang, Noor F. Shaik, Bing Yi, Xin Wei, Xiao-Feng Yang, Ulhas P. Naik, Ross Summer, Guijun Yan, Xinyun Xu, Jianxin Sun

Center for Translational Medicine Faculty Papers

Endothelial nitric oxide (NO) synthase (eNOS) plays a critical role in the maintenance of blood vessel homeostasis. Recent findings suggest that cytoskeletal dynamics play an essential role in regulating eNOS expression and activation. Here, we sought to test whether modulation of cytoskeletal dynamics through pharmacological regulation of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation affects eNOS expression and endothelial function in vitro and in vivo.Wefound that tubulin acetylation inducer (tubacin), a compound that appears to selectively inhibit HDAC6 activity, dramatically increased eNOS expression in several different endothelial cell lines, as determined by both immunoblotting and NO production assays. Mechanistically, we found …

Gasdermins In Apoptosis: New Players In An Old Game., Corey Rogers, Emad S. Alnemri

Department of Biochemistry and Molecular Biology Faculty Papers

Apoptosis is a form of programmed cell death (PCD) that plays critical physiological roles in removing superfluous or dangerous cell populations that are unneeded or threatening to the health of the host organism. Although the molecular pathways leading to activation of the apoptotic program have been extensively studied and characterized starting in the 1970s, new evidence suggests that members of the gasdermin superfamily are novel pore-forming proteins that augment apoptosis by permeabilizing the mitochondria and participate in the final stages of the apoptotic program by inducing secondary necrosis/pyroptosis. These findings may explain outstanding questions in the field such as why …

An In-Depth Review Of Retinitis Pigmentosa Development And Pathologies Overtime In Patients, Abdul Harris

Honors College Theses

Retinitis Pigmentosa is a disease which can cause blindness and affects around 2.5 million people worldwide. It is a disorder that has a multitude of ways of being inherited, such as autosomal dominant, autosomal recessive as well as X-linked and mitochondrial linked disorder. While some versions of RP may be syndromic (20%-30%), a majority of cases are in fact non-syndromic. The majority of non-syndromic cases inherited via autosomal dominant RP having RHO gene mutations, and X-linked means of inheritance having majority of patients with RPGR gene mutations. Ushers Syndrome, a syndromic version of retinitis pigmentosa and autosomal recessive RP having …

Alzheimer's And Amyloid Beta: Amyloidogenicity And Tauopathy Via Dyshomeostatic Interactions Of Amyloid Beta, Jordan Tillinghast

Senior Honors Theses

This paper reviews functions of Amyloid-β (Aβ) in healthy individuals compared to the consequences of aberrant Aβ in Alzheimer’s disease (AD). As extraneuronal Aβ accumulation and plaque formation are characteristics of AD, it is reasonable to infer a pivotal role for Aβ in AD pathogenesis. Establishing progress of the disease as well as the mechanism of neurodegeneration from AD have proven difficult (Selkoe, 1994). This thesis provides evidence suggesting the pathogenesis of AD is due to dysfunctional neuronal processes involving Aβ’s synaptic malfunction, abnormal interaction with tau, and disruption of neuronal homeostasis. Significant evidence demonstrates that AD symptoms are partially …

Allele-Specific Rna Interference Prevents Neuropathy In Charcot-Marie-Tooth Disease Type 2d Mouse Models., Kathryn H Morelli, Laurie B Griffin, Nettie K Pyne, Lindsay M Wallace, Allison M Fowler, Stephanie N Oprescu, Ryuichi Takase, Na Wei, Rebecca Meyer-Schuman, Dattatreya Mellacheruvu, Jacob O Kitzman, Samuel G Kocen, Timothy J Hines, Emily L Spaulding, James R Lupski, Alexey Nesvizhskii, Pedro Mancias, Ian J Butler, Xiang-Lei Yang, Ya-Ming Hou, Anthony Antonellis, Scott Q Harper, Robert W Burgess

Department of Biochemistry and Molecular Biology Faculty Papers

Gene therapy approaches are being deployed to treat recessive genetic disorders by restoring the expression of mutated genes. However, the feasibility of these approaches for dominantly inherited diseases - where treatment may require reduction in the expression of a toxic mutant protein resulting from a gain-of-function allele - is unclear. Here we show the efficacy of allele-specific RNAi as a potential therapy for Charcot-Marie-Tooth disease type 2D (CMT2D), caused by dominant mutations in glycyl-tRNA synthetase (GARS). A de novo mutation in GARS was identified in a patient with a severe peripheral neuropathy, and a mouse model precisely recreating the mutation …

Identification Of The Kaposi's Sarcoma-Associated Herpesvirus (Kshv) Surface Glycoprotein Targets Of Human Kshv-Specific Neutralizing Antibody Responses, Yasaman Mortazavi

School of Biological Sciences: Dissertations, Theses, and Student Research

Kaposi’s sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV-8), is the etiological agent of Kaposi’s sarcoma (KS), and is also associated with two B cell malignancies, primary effusion lymphoma and multicentric Castleman's disease. The distribution of KSHV varies globally with high prevalence in some areas of sub-Saharan Africa (SSA), where seroprevalence can be as high as 80%. It is estimated that nearly 44,000 new cases of KS emerge annually globally, with the highest incidents occurring in Africa, where KSHV is endemic. Currently, there is no prophylactic vaccine against KSHV, and efforts to develop prophylactic vaccines have been limited. …

Phenylethynyl-Substituted Benzenes And Heterocycles For The Treatment Of Cancer, David S. Watt, Chunming Liu, Vitaliy M. Sviripa, Wen Zhang, Markos Leggas

Molecular and Cellular Biochemistry Faculty Patents

Halogenated phenylethynyl-substituted heterocycles that possess either an N-alkylamino or N,N-dialkylamino group attached to the heterocycle or halogenated phenylethynyl-substituted benzenes that a nitrogen-containing heterocycle attached to the benzene inhibit the proliferation cancer cells and are useful antineoplastic agents.

Characterization Of Resistance To A Potent D-Peptide Hiv Entry Inhibitor., Amanda R Smith, Matthew T Weinstock, Amanda E Siglin, Frank G Whitby, J Nicholas Francis, Christopher P Hill, Debra M Eckert, Michael J Root, Michael S Kay

Department of Biochemistry and Molecular Biology Faculty Papers

BACKGROUND: PIE12-trimer is a highly potent D-peptide HIV-1 entry inhibitor that broadly targets group M isolates. It specifically binds the three identical conserved hydrophobic pockets at the base of the gp41 N-trimer with sub-femtomolar affinity. This extremely high affinity for the transiently exposed gp41 trimer provides a reserve of binding energy (resistance capacitor) to prevent the viral resistance pathway of stepwise accumulation of modest affinity-disrupting mutations. Such modest mutations would not affect PIE12-trimer potency and therefore not confer a selective advantage. Viral passaging in the presence of escalating PIE12-trimer concentrations ultimately selected for PIE12-trimer resistant populations, but required an extremely …

Structural And Functional Analysis Of Parameters Governing Tankyrase-1 Interaction With Telomeric Repeat-Binding Factor 1 And Gdp-Mannose 4,6-Dehydratase., Travis Eisemann, Marie-France Langelier, John M. Pascal

Department of Biochemistry and Molecular Biology Faculty Papers

Human tankyrase-1 (TNKS) is a member of the poly(ADPribose) polymerase (PARP) superfamily of proteins that posttranslationally modify themselves and target proteins with ADP-ribose (termed PARylation). The TNKS ankyrin repeat domain mediates interactions with a growing number of structurally and functionally diverse binding partners, linking TNKS activity to multiple critical cell processes, including Wnt signaling, Golgi trafficking, and telomere maintenance. However, some binding partners can engage TNKS without being modified, suggesting that separate parameters influence TNKS interaction and PARylation. Here, we present an analysis of the sequence and structural features governing TNKS interactions with two model binding partners: The PARylated partner …