Medicine and Health Sciences Commons^™

Evidence For Paracrine Protective Role Of Exogenous Αa-Crystallin In Retinal Ganglion Cells, Madhu Nath, Zachary B Sluzala, Ashutosh S Phadte, Yang Shan, Angela M Myers, Patrice E Fort

Department of Biochemistry and Molecular Biology Faculty Papers

Expression and secretion of neurotrophic factors have long been known as a key mechanism of neuroglial interaction in the central nervous system. In addition, several other intrinsic neuroprotective pathways have been described, including those involving small heat shock proteins such as α-crystallins. While initially considered as a purely intracellular mechanism, both αA-crystallins and αB-crystallins have been recently reported to be secreted by glial cells. While an anti-apoptotic effect of such secreted αA-crystallin has been suggested, its regulation and protective potential remain unclear. We recently identified residue threonine 148 (T148) and its phosphorylation as a critical regulator of αA-crystallin intrinsic neuroprotective …

Evaluation Of Hippocampal Allostatic Load-Associated Factors In Animal Models Of Post-Traumatic Stress Disorder: Relevance To Human Ptsd, Dennis Parker Kelley

LSU Doctoral Dissertations

Post-traumatic stress disorder (PTSD) is associated with elevated allostatic load, nearly double the risk for metabolic syndrome, reduced hippocampal volume, and contextual memory processing deficits. Emerging evidence suggests that these stress effects may predispose individuals to the development of PTSD, and there is a known relationship between chronic stress and metabolic dysfunction. In this work, we utilized two rat models of PTSD to explore these connections. We used an acute predator odor stressor to investigate the relationship between PTSD-like behaviors and mitochondrial dysfunction in the hippocampus of rats, and we observed that conditioned place avoidance was associated with reduced mitochondrial …

Viral Ejection Proteins: Mosaically Conserved, Conformational Gymnasts, Nicholas A. Swanson, Chun-Feng Hou, Gino Cingolani

Department of Biochemistry and Molecular Biology Faculty Papers

Bacterial viruses (or bacteriophages) have developed formidable ways to deliver their genetic information inside bacteria, overcoming the complexity of the bacterial-cell envelope. In short-tailed phages of the Podoviridae superfamily, genome ejection is mediated by a set of mysterious internal virion proteins, also called ejection or pilot proteins, which are required for infectivity. The ejection proteins are challenging to study due to their plastic structures and transient assembly and have remained less characterized than classical components such as the phage coat protein or terminase subunit. However, a spate of recent cryo-EM structures has elucidated key features underscoring these proteins’ assembly and …

Therapeutic Approaches To Alter Mineral Formation And Growth In Vascular Calcification, Amirala Bakhshiannik

FIU Electronic Theses and Dissertations

Cardiovascular diseases represent the global leading cause of morbidity and mortality. Cardiovascular calcification is the most significant predictor of cardiovascular events, but no therapeutic options exist to prevent or treat mineral formation in the vasculature. The presence of bone-like mineral increases cardiac work required to move blood through systemic circulation and can lead to mechanical stress in atherosclerotic plaques, promoting plaque rupture events that cause heart attacks. Clinical trials correlated bisphosphonates (BiPs), common anti-osteoporosis pharmaceuticals, with contradicting cardiovascular outcomes. Here, we demonstrated the importance of treatment timing in BiP-induced mineral disruption or promotion. We showed that BiPs can alter morphological …

Positive Selection And Enhancer Evolution Shaped Lifespan And Body Mass In Great Apes, Daniela Tejada-Martinez, Roberto A Avelar, Inês Lopes, Bruce Zhang, Guy Novoa, João Pedro De Magalhães, Marco Trizzino

Department of Biochemistry and Molecular Biology Faculty Papers

Within primates, the great apes are outliers both in terms of body size and lifespan, since they include the largest and longest-lived species in the order. Yet, the molecular bases underlying such features are poorly understood. Here, we leveraged an integrated approach to investigate multiple sources of molecular variation across primates, focusing on over 10,000 genes, including approximately 1,500 previously associated with lifespan, and additional approximately 9,000 for which an association with longevity has never been suggested. We analyzed dN/dS rates, positive selection, gene expression (RNA-seq), and gene regulation (ChIP-seq). By analyzing the correlation between dN/dS, maximum lifespan, and body …

Liquid-Liquid Phase Separation Of Tdp-43 And Fus In Physiology And Pathology Of Neurodegenerative Diseases, Jenny L Carey, Lin Guo

Department of Biochemistry and Molecular Biology Faculty Papers

Liquid-liquid phase separation of RNA-binding proteins mediates the formation of numerous membraneless organelles with essential cellular function. However, aberrant phase transition of these proteins leads to the formation of insoluble protein aggregates, which are pathological hallmarks of neurodegenerative diseases including ALS and FTD. TDP-43 and FUS are two such RNA-binding proteins that mislocalize and aggregate in patients of ALS and FTD. They have similar domain structures that provide multivalent interactions driving their phase separation in vitro and in the cellular environment. In this article, we review the factors that mediate and regulate phase separation of TDP-43 and FUS. We also …

Synthesis, Characterization And Physicochemical Properties Of Biogenic Silver Nanoparticle-Encapsulated Chitosan Bionanocomposites, Sreelekha Ediyilyam, Mahesh M Lalitha, Bini George, Sarojini Sharath Shankar, Stanisław Wacławek, Miroslav Černík, Vinod Vellora Thekkae Padil

Department of Medicine Faculty Papers

Green bionanocomposites have garnered considerable attention and applications in the pharmaceutical and packaging industries because of their intrinsic features, such as biocompatibility and biodegradability. The work presents a novel approach towards the combined effect of glycerol, tween 80 and silver nanoparticles (AgNPs) on the physicochemical properties of lyophilized chitosan (CH) scaffolds produced via a green synthesis method.The produced bionanocomposites were characterized with the help of Fourier transform infrared spectroscopy (FTIR) and Scanning electron microscopy (SEM). The swelling behavior, water vapor transmission rate, moisture retention capability, degradation in Hanks solution, biodegradability in soil, mechanical strength and electrochemical performance of the composites …

Interplay Between An Atp-Binding Cassette F Protein And The Ribosome From Mycobacterium Tuberculosis, Zhicheng Cui, Xiaojun Li, Joonyoung Shin, Howard Gamper, Ya-Ming Hou, James C Sacchettini, Junjie Zhang

Department of Biochemistry and Molecular Biology Faculty Papers

EttA, energy-dependent translational throttle A, is a ribosomal factor that gates ribosome entry into the translation elongation cycle. A detailed understanding of its mechanism of action is limited due to the lack of high-resolution structures along its ATPase cycle. Here we present the cryo-electron microscopy (cryo-EM) structures of EttA from Mycobacterium tuberculosis (Mtb), referred to as MtbEttA, in complex with the Mtb 70S ribosome initiation complex (70SIC) at the pre-hydrolysis (ADPNP) and transition (ADP-VO4) states, and the crystal structure of MtbEttA alone in the post-hydrolysis (ADP) state. We observe that MtbEttA binds the E-site of the Mtb 70SIC, remodeling the …

Impact Of Pooling Samples On Analytic Sensitivity Of A Real-Time Reverse Transcriptase Pcr Assay For Sars Cov-2, Subathra Marimuthu, Stephen P. Furmanek, Holly Aliesky, Leslie A. Wolf

The University of Louisville Journal of Respiratory Infections

During the COVID-19 pandemic, laboratories experienced periods of shortages for certain critical materials required to meet the high demand for SARS-CoV-2 testing. The U.S. Food & Drug Administration provided a template for molecular diagnostic testing, including guidance for a specimen pooling process in order to evaluate performance of the SARS-CoV-2 nucleic acid amplification assay. This study aimed to evaluate the testing of pooled specimens consisting of four nasopharyngeal swab specimens using the Luminex ARIES^® nucleic acid amplification platform. Results indicated that there was a loss of analytic sensitivity with pooled nasopharyngeal swab samples, demonstrating that this approach should be …

Ubiquitous Aberration In Cholesterol Metabolism Across Pancreatic Ductal Adenocarcinoma, Venugopal Gunda, Thiago C. Genaro-Mattos, Jyoti B. Kaushal, Ramakanth C. Venkata, Gopalakrishnan Natarajan, Kavita Mallya, Paul M. Grandgenett, Karoly Mirnics, Surinder K. Batra, Zeljka Korade, Satyanarayana Rachagani

Journal Articles: Biochemistry & Molecular Biology

Pancreatic cancer (PC) is characterized by metabolic deregulations that often manifest as deviations in metabolite levels and aberrations in their corresponding metabolic genes across the clinical specimens and preclinical PC models. Cholesterol is one of the critical metabolites supporting PC, synthesized or acquired by PC cells. Nevertheless, the significance of the de novo cholesterol synthesis pathway has been controversial in PC, indicating the need to reassess this pathway in PC. We utilized preclinical models and clinical specimens of PC patients and cell lines and utilized mass spectrometry-based sterol analysis. Further, we also performed in silico analysis to corroborate the significance …

Tumor Microenvironment Enriches The Stemness Features: The Architectural Event Of Therapy Resistance And Metastasis, Palanisamy Nallasamy, Rama Krishna Nimmakayala, Seema Parte, Abhirup C. Are, Surinder K. Batra, Moorthy P. Ponnusamy

Journal Articles: Biochemistry & Molecular Biology

Cancer divergence has many facets other than being considered a genetic term. It is a tremendous challenge to understand the metastasis and therapy response in cancer biology; however, it postulates the opportunity to explore the possible mechanism in the surrounding tumor environment. Most deadly solid malignancies are distinctly characterized by their tumor microenvironment (TME). TME consists of stromal components such as immune, inflammatory, endothelial, adipocytes, and fibroblast cells. Cancer stem cells (CSCs) or cancer stem-like cells are a small sub-set of the population within cancer cells believed to be a responsible player in the self-renewal, metastasis, and therapy response of …

Liquid Biopsy: A Step Closer To Transform Diagnosis, Prognosis And Future Of Cancer Treatments, Saife N. Lone, Sabah Nisar, Tariq Masoodi, Mayank Singh, Arshi Rizwan, Sheema Hashem, Wael El-Rifai, Davide Bedognetti, Surinder K. Batra, Mohammad Haris, Ajaz A. Bhat, Muzafar A. Macha

Journal Articles: Biochemistry & Molecular Biology

Over the past decade, invasive techniques for diagnosing and monitoring cancers are slowly being replaced by non-invasive methods such as liquid biopsy. Liquid biopsies have drastically revolutionized the field of clinical oncology, offering ease in tumor sampling, continuous monitoring by repeated sampling, devising personalized therapeutic regimens, and screening for therapeutic resistance. Liquid biopsies consist of isolating tumor-derived entities like circulating tumor cells, circulating tumor DNA, tumor extracellular vesicles, etc., present in the body fluids of patients with cancer, followed by an analysis of genomic and proteomic data contained within them. Methods for isolation and analysis of liquid biopsies have rapidly …

Depletion Of Transmembrane Mucin 4 (Muc4) Alters Intestinal Homeostasis In A Genetically Engineered Mouse Model Of Colorectal Cancer, Ramesh Pothuraju, Priya Pai, Sanjib Chaudhary, Jawed A. Siddiqui, Jesse L. Cox, Sukhwinder Kaur, Satyanarayana Rachagani, Hemant K. Roy, Michael Bouvet, Surinder K. Batra

Journal Articles: Biochemistry & Molecular Biology

Mucins are components of the mucus layer overlying the intestinal epithelial cells, which maintains physiological homeostasis. Altered mucin expression is associated with disease progression. Expression of MUC4 decreases in colorectal cancer (CRC); however, its functional role and implications in the intestinal pathology in CRC are not studied well. Therefore, we generated a genetically engineered Muc4 knockout (Muc4^-/-) CRC mouse model by crossing with Muc4^-/- and Apc^flox/flox mice in the presence of colon-specific inducible Cre. We observed that deficiency of Muc4 results in an increased number of macroscopic tumors in the colon and rectal region and leads …

The Gsk3 Kinase And Lztr1 Protein Regulate The Stability Of Ras Family Proteins And The Proliferation Of Pancreatic Cancer Cells, Chitra Palanivel, Neha Chaudhary, Parthasarathy Seshacharyulu, Jesse L. Cox, Ying Yan, Surinder K. Batra, Michel M. Ouellette

Journal Articles: Biochemistry & Molecular Biology

Ras family proteins are membrane-bound GTPases that control proliferation, survival, and motility. Many forms of cancers are driven by the acquisition of somatic mutations in a RAS gene. In pancreatic cancer (PC), more than 90% of tumors carry an activating mutation in KRAS. Mutations in components of the Ras signaling pathway can also be the cause of RASopathies, a group of developmental disorders. In a subset of RASopathies, the causal mutations are in the LZTR1 protein, a substrate adaptor for E3 ubiquitin ligases that promote the degradation of Ras proteins. Here, we show that the function of LZTR1 is regulated …

Liquid Biopsies To Occult Brain Metastasis, Asad Ur Rehman, Parvez Khan, Shailendra K. Maurya, Jawed A. Siddiqui, Juan A. Santamaria-Barria, Surinder K. Batra, Mohd W. Nasser

Journal Articles: Biochemistry & Molecular Biology

Brain metastasis (BrM) is a major problem associated with cancer-related mortality, and currently, no specific biomarkers are available in clinical settings for early detection. Liquid biopsy is widely accepted as a non-invasive method for diagnosing cancer and other diseases. We have reviewed the evidence that shows how the molecular alterations are involved in BrM, majorly from breast cancer (BC), lung cancer (LC), and melanoma, with an inception in how they can be employed for biomarker development. We discussed genetic and epigenetic changes that influence cancer cells to breach the blood-brain barrier (BBB) and help to establish metastatic lesions in the …

Gdf15 Promotes Prostate Cancer Bone Metastasis And Colonization Through Osteoblastic Ccl2 And Rankl Activation, Jawed A. Siddiqui, Parthasarathy Seshacharyulu, Sakthivel Muniyan, Ramesh Pothuraju, Parvez Khan, Raghupathy Vengoji, Sanjib Chaudhary, Shailendra K. Maurya, Subodh M. Lele, Maneesh Jain, K Datta, Mohd W. Nasser, Surinder K. Batra

Journal Articles: Biochemistry & Molecular Biology

Bone metastases occur in patients with advanced-stage prostate cancer (PCa). The cell-cell interaction between PCa and the bone microenvironment forms a vicious cycle that modulates the bone microenvironment, increases bone deformities, and drives tumor growth in the bone. However, the molecular mechanisms of PCa-mediated modulation of the bone microenvironment are complex and remain poorly defined. Here, we evaluated growth differentiation factor-15 (GDF15) function using in vivo preclinical PCa-bone metastasis mouse models and an in vitro bone cell coculture system. Our results suggest that PCa-secreted GDF15 promotes bone metastases and induces bone microarchitectural alterations in a preclinical xenograft model. Mechanistic studies …

Phytochemical Constituents Of Aquilaria Malaccensis Leaf Extract And Their Anti-Inflammatory Activity Against Lps/Ifn-Γ-Stimulated Raw 264.7 Cell Line, Eman Ramadan, Manar A. Eissa, Yumi Z. H-Y Hashim, Dina M. El-Kersh

Pharmacy

This study aims to identify the major phytochemical constituents in Aquilaria malaccensis (Thymelaeaceae) ethanolic leaf extract (ALEX-M) and elucidate their ability to suppress nitric oxide (NO) production from a murine macrophage-like cell line (RAW 264.7) stimulated by lipopolysaccharide (LPS) and interferon-γ (IFN-γ). Dichloromethane (DCM) and ethyl acetate (EtOAc) fractions of ALEX-M were subjected to column chromatography. Eight known compounds were isolated for the first time from this species. Compounds were identified using spectroscopic techniques (IR, UV, HRESIMS, and 1D and 2D NMR). Anti-inflammatory activity of both extract and isolated compounds were investigated in vitro. The fractions offered the isolation of …

Further Decoding The Molecular Relationship Between Pancreatic Adenocarcinoma And Diabetes Mellitus, Russell H. Moreland Iii, Sheema Khan

MEDI 9331 Scholarly Activities Clinical Years

Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy, especially as there are no current reliable methods of screening. Recently literature reports a significant relationship with pancreatic ductal adenocarcinoma and diabetes mellitus (DM). The pathologic molecular mechanism is not completely understood but it may hold insights into the development of novel screening and treatment options. In our study we compiled a list of 74 proteins involved in the PDAC and DM pathway, with 47 showing increased expression levels and 11 with decreased expression levels. These proteins are currently undergoing further computational analysis to identify their pathway interactions.

Anthracyclines Attenuate The Nrf1-Mediated Bounce-Back Response, Bader Albalawi

Theses and Dissertations

Proteasome inhibitors, such as carfilzomib, are FDA-approved to treat multiple myeloma and mantle cell lymphoma. Unfortunately, proteasome inhibitors have only produced clinically significant results in patients with hematologic cancers, despite their predicted pan-cancer utility, and even hematologic cancer types frequently show intrinsic and acquired resistance.

One proposed mechanism responsible for the proteasome inhibitors' shortcomings is the NRF1-mediated bounce-back response. Identification of drugs that can potentiate the action of proteasome inhibitors could overcome resistance in patients with hematologic cancers and expand proteasome inhibitors' use to treat solid tumors. Our previous studies have identified anthracyclines as potential compounds that interfere with the …

Soluble Guanylyl Cyclase: Molecular Basis For Ligand Selectivity And Action In Vitro And In Vivo, Gang Wu, Iraida Sharina, Emil Martin

Journal Articles

Nitric oxide (NO), carbon monoxide (CO), oxygen (O2), hydrogen sulfide (H2S) are gaseous molecules that play important roles in the physiology and pathophysiology of eukaryotes. Tissue concentrations of these physiologically relevant gases vary remarkable from nM range for NO to high μM range of O2. Various hemoproteins play a significant role in sensing and transducing cellular signals encoded by gaseous molecules or in transporting them. Soluble guanylyl cyclase (sGC) is a hemoprotein that plays vital roles in a wide range of physiological functions and combines the functions of gaseous sensor and signal transducer. sGC uniquely evolved to sense low non-toxic …