Medical Biochemistry Commons^™

Effects Of Localized Oxygen Production By Electrolysis On The First-Generation Glucose Sensor Response, Nandita Halder

Graduate Theses and Dissertations

Glucose sensors are very important for detecting blood glucose both in vitro and in vivo. First-generation glucose biosensors were based on the glucose oxidase (GOx) enzyme using molecular oxygen as the electron acceptor and therefore oxygen dependent. Unfortunately for in-vivo work, oxygen in the body is variable and limited. Alternative approaches to overcome the oxygen dependency came with their own limitations. The widely used and commercially available ex-vivo glucose test strip uses a mediator in place of oxygen to free it from oxygen dependency. The mediator-based technology, in most cases cannot be transferred to in vivo applications due to the …

Physiological Roles Of Mammalian Transmembrane Adenylyl Cyclase Isoforms, Katrina F. Ostrom, Justin E. Lavigne, Tarsis F. Brust, Roland Seifert, Carmen Dessauer, Val J. Watts, Rennolds S. Ostrom

Pharmacy Faculty Articles and Research

Adenylyl cyclases (ACs) catalyze the conversion of ATP to the ubiquitous second messenger cAMP. Mammals possess nine isoforms of transmembrane ACs, dubbed AC1-9, that serve as major effector enzymes of G protein-coupled receptors. The transmembrane ACs display varying expression patterns across tissues, giving potential for them having a wide array of physiologic roles. Cells express multiple AC isoforms, implying that ACs have redundant functions. Furthermore, all transmembrane ACs are activated by Gα_s so it was long assumed that all ACs are activated by Gα_s-coupled GPCRs. AC isoforms partition to different microdomains of the plasma membrane and form …

Targeting The Cdk6 Dependence Of Ph+ Acute Lymphoblastic Leukemia, Patrizia Porazzi, Marco De Dominici, Joseph Salvino, Bruno Calabretta

Department of Cancer Biology Faculty Papers

Ph+ ALL is a poor-prognosis leukemia subtype driven by the BCR-ABL1 oncogene, either the p190-or the p210-BCR/ABL isoform in a 70:30 ratio. Tyrosine Kinase inhibitors (TKIs) are the drugs of choice in the therapy of Ph+ ALL. In combination with standard chemotherapy, TKIs have markedly improved the outcome of Ph+ ALL, in particular if this treatment is followed by bone marrow transplantation. However, resistance to TKIs develops with high frequency, causing leukemia relapse that results in

Nucleotide P2y₂ Receptor-Dependent Leukocyte-Endothelial Interaction, Spencer E. Thomas

Graduate Theses/Dissertations

Extracellular nucleotides (ATP, UTP) released from cells act on nucleotide receptors to promote vascular inflammation. Increased leukocyte-endothelial interaction is a hallmark of vascular inflammation. The nucleotide P2Y₂ receptor (P2Y₂R), activated by extracellular ATP≈UTP, plays a role in cardiovascular homeostasis and immune regulation. Moreover, accumulating evidence from studies in vitro and in vivo models have implicated the P2Y₂R in the inflammatory response significantly contributing to the progression and pathogenesis of asthma, atherosclerosis, sepsis, and ischemia. I hypothesized that P2Y₂R activation by UTP, an agonist of the receptor, increased leukocyte rolling and adhesion in the microvasculature from baseline. To test the hypothesis, …

Biochemical Characterization Of Small Molecule Inhibitor Binding On A Ras Related Gtpase And Its Effector Interactions, Djamali Muhoza

Graduate Theses and Dissertations

The Ras superfamily of GTPases has 167 proteins that are involved in various cellular processes such as proliferation, transformation, migration, and inhibition of cell death. Mutations, abnormal expression, and function of these proteins are observed in many diseases, including several forms of cancer. Even though these GTPases were among the first discovered oncogenes, no successful Ras drug candidate has successfully passed clinical trials. Drugs targeting these proteins have failed mainly because of the complexity of their regulation, their high affinity to GTP, and their structure’s dynamic nature. Recently, novel promising targeting approaches have renewed interest in the Ras drug discovery …

Biological Activity And Solubility Of 5-Methoxy-1,4-Benzoquinone Having Bromoheptyl And Bromodecyl Substituents In The N-Octanol/Water System, Siti Mariyah Ulfa, Fath Dwisari, Laras Pangesti, Mohammad Farid Rahman

Makara Journal of Science

The biological activity and solubility of compounds are influenced by its chemical structure. These properties can be improved by substituting alkyl, alkoxy, and/or haloalkane in the parent skeleton. In this research, the synthesis of 3-(7-bromoheptyl)-2-methyl-5-methoxy-1,4-benzoquinone (3a) and 3-(10-bromodecyl)-2-methyl-5-methoxy-1,4-benzoquinone (3b) was achieved through the decarboxylation reaction. The solubility and biological activity of 3a and 3b were compared with that of thymoquinone (TQ), which acts as an anti-inflammatory agent. Compounds 3a and 3b were successfully synthesized and analyzed using Fourier Transform Infra-Red (FTIR) and Nuclear Magnetic Resonance (NMR). The FTIR spectrum showed the increasing intensity of …

Characterization Of Cucurbitacin-Inspired Estrone Analogues As Novel Inhibitors Of Human Atp- Binding Cassette Proteins (Abcb1 And Abcc1), Jennifer Kyeremateng

Electronic Theses and Dissertations

ATP-binding cassette (ABC) transporters are a large class of integral membrane proteins that contribute to key physiological functions in all organisms by utilizing ATP binding and hydrolysis to transport diverse substrates across membrane barriers. P-glycoprotein (P-gp/ ABCB1) and Multidrug Resistance protein 1 (MRP1/ABCC1) are widely reported ABC transporters associated with multidrug resistance in cancer. Multidrug resistance (MDR) mediated by P-gp and MRP1 is responsible for treatment failures of many metastatic cancers as a result of reduced accumulation, bioavailability and diminished potency of anticancer drugs. Currently, known P-gp and MRP1 inhibitors are limited due to toxicity, lack of selectivity and low …

Open Problems In Extracellular Rna Data Analysis: Insights From An Ercc Online Workshop, Roger P Alexander, Robert R Kitchen, Juan Pablo Tosar, Matthew Roth, Pieter Mestdagh, Klaas E A Max, Joel Rozowsky, Karolina Elżbieta Kaczor-Urbanowicz, Justin Chang, Leonora Balaj, Bojan Losic, Eric L Van Nostrand, Emily Laplante, Bogdan Mateescu, Brian S White, Rongshan Yu, Aleksander Milosavljevic, Gustavo Stolovitzky, Ryan M Spengler

Faculty, Staff and Students Publications

We now know RNA can survive the harsh environment of biofluids when encapsulated in vesicles or by associating with lipoproteins or RNA binding proteins. These extracellular RNA (exRNA) play a role in intercellular signaling, serve as biomarkers of disease, and form the basis of new strategies for disease treatment. The Extracellular RNA Communication Consortium (ERCC) hosted a two-day online workshop (April 19–20, 2021) on the unique challenges of exRNA data analysis. The goal was to foster an open dialog about best practices and discuss open problems in the field, focusing initially on small exRNA sequencing data. Video recordings of workshop …

Design Of Hfgf1 Variant(S) With Increased Stability And Enhanced Bioactivity, Shilpi P. Agrawal

Graduate Theses and Dissertations

Fibroblast growth factors (FGFs) are involved in various cellular processes such as cell growth,proliferation, differentiation, migration, angiogenesis, wound healing and embryonic development. Human acidic fibroblast growth factor (hFGF1) binds non-selectively to all the four FGF-receptors and is therefore considered as a powerful mitogen with broadest specificity. However, pharmacological applications of hFGF1 are restricted due to the low thermal stability of the growth factor. hFGF1 has low thermodynamic stability under physiological temperatures which leads to impairment of cellular signaling process thereby preventing its potential mitogenic properties. hFGF1 has a heparin binding pocket at the C-terminus which comprises of positively charges residues. …

The Role Of Liver Sinusoidal Endothelial Cells In Liver Malady Homeostasis, Fatima Cabral

Department of Biochemistry: Dissertations, Theses, and Student Research

Current literature described techniques for the purification of liver cell types through text alone. The techniques described for the isolation of liver sinusoidal endothelial cells as well as hepatocytes described here are modified from a published article in the Journal of Visualized experiments. The video protocol allows for the user to successfully isolate cells as the most difficult parts of the procedure are demonstrated visually. The detection of liver maladies such as the non-alcoholic fatty liver disease, the stage if this disease and differentiation between non-alcoholic and alcoholic fatty liver disease is demonstrated in the development of a unique panel …

Role For Carbohydrate Response Element-Binding Protein (Chrebp) In High Glucose-Mediated Repression Of Long Noncoding Rna Tug1, Jianyin Long, Daniel L Galvan, Koki Mise, Yashpal S Kanwar, Li Li, Naravat Poungavrin, Paul A Overbeek, Benny H Chang, Farhad R Danesh

Faculty, Staff and Students Publications

Long noncoding RNAs (lncRNAs) have been shown to play key roles in a variety of biological activities of the cell. However, less is known about how lncRNAs respond to environmental cues and what transcriptional mechanisms regulate their expression. Studies from our laboratory have shown that the lncRNA Tug1 (taurine upregulated gene 1) is crucial for the progression of diabetic kidney disease, a major microvascular complication of diabetes. Using a combination of proximity labeling with the engineered soybean ascorbate peroxidase (APEX2), ChIP-qPCR, biotin-labeled oligonucleotide pulldown, and classical promoter luciferase assays in kidney podocytes, we extend our initial observations in the current …

Polydopamine Antioxidant Hydrogels For Wound Healing Applications, Naphtali A. O'Connor, Abdulhaq Syed, Madeline Wong, Josiah Hicks, Greisly Nunez, Andrei Jitianu, Zach Siler, Marnie Peterson

Publications and Research

Antioxidants are known to improve the wound healing process and are researched as a therapeutic strategy to treat chronic wounds. Dopamine is a known neurotransmitter with antioxidant properties that can be polymerized to form polydopamine (PDA). Herein, polydopamine is demonstrated as an antioxidant biomaterial. In prior work, we developed methodology to prepare hydrogels by crosslinking polysaccharides with polyamines via epichlorohydrin and NaOH. Using this previously developed methodology, dextran hydrogels crosslinked with polydopamine were prepared. Darkening of the gels indicated the increasing incorporation of polydopamine within the hydrogels. In addition to basic pH, polydopamine can be formed by reaction with polyethylene …

Characterization Of Retinal Biomechanical Properties Using Brillouin Microscopy, Yogeshwari S Ambekar, Manmohan Singh, Giuliano Scarcelli, Elda M Rueda, Benjamin M Hall, Ross A Poché, Kirill V Larin

Faculty, Staff and Students Publications

SIGNIFICANCE: The retina is critical for vision, and several diseases may alter its biomechanical properties. However, assessing the biomechanical properties of the retina nondestructively is a challenge due to its fragile nature and location within the eye globe. Advancements in Brillouin spectroscopy have provided the means for nondestructive investigations of retina biomechanical properties.

AIM: We assessed the biomechanical properties of mouse retinas using Brillouin microscopy noninvasively and showed the potential of Brillouin microscopy to differentiate the type and layers of retinas based on stiffness.

APPROACH: We used Brillouin microscopy to quantify stiffness of fresh and paraformaldehyde (PFA)-fixed retinas. As further …

Capsaicin Is A Negative Allosteric Modulator Of The 5-Ht3 Receptor, Eslam El Nebrisi, Tatiana Prytkova, Dietrich Ernst Lorke, Luke Howarth, Asma Hassan Alzaabi, Keun-Hang Susan Yang, Frank Christopher Howarth, Murat Oz

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

In this study, effects of capsaicin, an active ingredient of the capsicum plant, were investigated on human 5-hydroxytryptamine type 3 (5-HT₃) receptors. Capsaicin reversibly inhibited serotonin (5-HT)-induced currents recorded by two-electrode voltage clamp method in Xenopus oocytes. The inhibition was time- and concentration-dependent with an IC₅₀ = 62 μM. The effect of capsaicin was not altered in the presence of capsazepine, and by intracellular BAPTA injections or trans-membrane potential changes. In radio-ligand binding studies, capsaicin did not change the specific binding of the 5-HT₃ antagonist [³H]GR65630, indicating that it is a noncompetitive inhibitor of …

Ionophoric Polyphenols Are Permeable To The Blood Brain Barrier, Interact With Human Serum Albumin And Calf Thymus Dna, And Inhibit Ache Enzymatic Activity, Alberto Martinez, Mai Zahran, Miguel Gomez, Johnny Guevara, Rosemary Pichardo-Bueno, Junaid Asim, Gabriel Ortiz, Yaa Andoh, Sinji Shibutani, Baljit Kaur

Publications and Research

Alzheimer’s disease (AD) is the most common form of dementia that affects more than 40 million people around the world. The incidence is expected to rapidly increase due to the lack of any effective treatment. In previous work we synthesized a family of five ionophoric polyphenols (compounds 1–5) that targeted important aspects related to AD, such as the toxic aggregation of amyloid-β peptides, the production of reactive oxygen species, or the excessive presence of Cu²⁺ ions. Here, in order to gain insights into their potential therapeutic value, we have tested the ability of compounds 1– …

Effects Of Nicotinamide Riboside And Beta-Hydroxybutyrate On C. Elegans Lifespan, Jeffery Peters

Undergraduate Honors Theses

The nicotinamide riboside (NR) form of vitamin B₃and the ketone body ß-hydroxybutyrate (BHB) are two of the most promising natural compounds yet identified for the treatment of aging and aging-related diseases. Forms of vitamin B₃are precursors for the synthesis of the coenzymes nicotinamide adenine dinucleotide (NAD(H)) and nicotinamide adenine dinucleotide phosphate (NADP(H)). In aged cells levels of NAD⁺decline, decreasing metabolism and decreasing activity of protective sirtuin protein deacetylases. In aged cells NR, but not more common forms of vitamin B3, boost NAD⁺levels. BHB is naturally produced by the body when individuals fast …

Alternative Polyadenylation Modulates Expression Of Pro-Fibrotic Proteins And Contributes To Lung Fibrosis, Junsuk Ko

Dissertations and Theses (Open Access)

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease which affects about 5 to 8 million individuals in the world. Despite the high prevalence, there is currently no cure for IPF, and the cause of this disease is still unclear. Our laboratory and collaborators have shown that nudix hydrolase 21 (NUDT21, which is also known as cleavage factor 25, CFIm25) is a key regulator of alternative polyadenylation (APA). NUDT21 depletion causes 3’UTR shortening via APA leading to enhanced mRNA stability and protein translation. This NUDT21 reduction promotes tumor growth in glioblastoma by enhancing expression of oncogenes. Cancer and IPF share …

Development And Characterization Of A Wee1 Kinase Degrader, Zhengnian Li, Benika J Pinch, Calla M Olson, Katherine A Donovan, Radosław P Nowak, Caitlin E Mills, David A Scott, Zainab M Doctor, Nicholas A Eleuteri, Mirra Chung, Peter K Sorger, Eric S Fischer, Nathanael S Gray

Faculty, Staff and Students Publications

The G1/S cell cycle checkpoint is frequently dysregulated in cancer, leaving cancer cells reliant on a functional G2/M checkpoint to prevent excessive DNA damage. Wee1 regulates the G2/M checkpoint by phosphorylating CDK1 at Tyr15 to prevent mitotic entry. Previous drug development efforts targeting Wee1 resulted in the clinical-grade inhibitor, AZD1775. However, AZD1775 is burdened by dose-limiting adverse events, and has off-target PLK1 activity. In an attempt to overcome these limitations, we developed Wee1 degraders by conjugating AZD1775 to the cereblon (CRBN)-binding ligand, pomalidomide. The resulting lead compound, ZNL-02-096, degrades Wee1 while sparing PLK1, induces G2/M accumulation at 10-fold lower doses …

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 …

The Vimentin Rod Domain Blocks P-Selectin-P-Selectin Glycoprotein Ligand 1 Interactions To Attenuate Leukocyte Adhesion To Inflamed Endothelium, Fong Wilson Lam, Cameron August Brown, Christian Valladolid, Dabel Cynthia Emebo, Timothy Gerald Palzkill, Miguel Angel Cruz

Faculty, Staff and Students Publications

Acute inflammation begins with leukocyte P-selectin glycoprotein ligand-1 (PSGL-1) binding to P-selectin on inflamed endothelium and platelets. In pathologic conditions, this process may contribute to secondary organ damage, like sepsis-induced liver injury. Therefore, developing novel therapies to attenuate inflammation may be beneficial. We previously reported that recombinant human vimentin (rhVim) binds P-selectin to block leukocyte adhesion to endothelium and platelets. In this study, we used SPOT-peptide arrays to identify the rod domain as the active region within rhVim that interacts with P-selectin. Indeed, recombinant human rod domain of vimentin (rhRod) binds to P-selectin with high affinity, with in silico modeling …

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 …

Purification And Characterization Of A Nonspecific Lipid Transfer Protein 1 (Nsltp1) From Ajwain (Trachyspermum Ammi) Seeds, Meshal Nazeer, Humera Waheed, Maria Saeed, Saman Yousuf Ali, M. Iqbal Choudhary, Zaheer Ul-Haq, Aftab Ahmed

Pharmacy Faculty Articles and Research

Ajwain (Trachyspermum ammi) belongs to the family Umbelliferae, is commonly used in traditional, and folk medicine due to its carminative, stimulant, antiseptic, diuretic, antihypertensive, and hepatoprotective activities. Non-specific lipid transfer proteins (nsLTPs) reported from various plants are known to be involved in transferring lipids between membranes and in plants defense response. Here, we describe the complete primary structure of a monomeric non-specific lipid transfer protein 1 (nsLTP1), with molecular weight of 9.66 kDa, from ajwain seeds. The nsLTP1 has been purified by combination of chromatographic techniques, and further characterized by mass spectrometry, and Edman degradation. The ajwain nsLTP1 …

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 …

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 …

A Novel Exo-Proteomic Approach To The Study Of Traumatic Brain Injury, Ron B. Moyron

Loma Linda University Electronic Theses, Dissertations & Projects

Concussions and Traumatic Brain Injuries (TBI) are significant health concerns and affect a wide cross section of society. Current diagnostic criteria and modalities, such as brain imaging and subjective measures of consciousness such as the Glasgow Coma Scale (GCS) score, are insufficient to properly diagnose the full spectrum of head injuries. Assessment of injury severity and outcome are further complicated by the vast array of symptoms, many of which mimic those displayed by other disorders. It is important to possess a better diagnostic tool for head injury triage and outcome prediction. One current line of inquiry seeks to discover a …

A Cytotoxic Evaluation Of A Chalcone Derivative Library On A549 Cells, Mary Elaine Kuo

Undergraduate Theses

Chalcones, a precursor to flavonoids, are chemical compounds found naturally in plants. The chalcones’ structure consists of a ketone bridge attached to two aromatic rings. Varying substituents on the aromatic rings allow for different affects, including anti-cancer properties. As a Michael acceptor, chalcones interact with pathways that cause inhibition of the initiation, promotion, and progression of cancer tumors. We have screened 32 compounds for growth inhibition in lung cells that vary the flexibility and confirmation of the 3 carbon bridge between the two aromatic rings as well as the effects of electronic modifications to the aromatic ring. We have found …

Curcumin Potentiates The Function Of Human Α7-Nicotinic Acetylcholine Receptors Expressed In Sh-Ep1 Cells, Eslam El Nebrisi, Lina T. Al Kury, Keun-Hang Susan Yang, Petrilla Jayaprakash, Frank Christopher Howarth, Nadine Kabbani, Murat Oz

Mathematics, Physics, and Computer Science Faculty Articles and Research

Effects of curcumin, a biologically active ingredient of turmeric, were tested on the Ca²⁺transients induced by the activation of α₇ subunit of the human nicotinic acetylcholine (α₇nACh) receptor expressed in SH-EP1 cells. Curcumin caused a significant potentiation of choline (1 mM)-induced Ca²⁺ transients with an EC₅₀ value of 133 nM. The potentiating effect of curcumin was not observed in Ca²⁺ transients induced by high K⁺ (60 mM) containing solutions or activation of α₄β₂ nACh receptors and the extent of curcumin potentiation was not altered in the presence of …

Could A Common Mechanism Of Protein Degradation Impairment Underlie Many Neurodegenerative Diseases?, David M. Smith

Faculty & Staff Scholarship

At the cellular level, many neurodegenerative diseases (NDs), often considered proteinopathies, are characterized by the accumulation of misfolded and damaged proteins into large insoluble aggregates. Prominent species that accumulate early and play fundamental roles in disease pathogenesis are amyloid β (Aβ) and tau in Alzheimer disease, α-synuclein (α-syn) in Parkinson disease, and polyQ-expanded huntingtin (Htt) in Huntington disease. Although significant efforts have focused on how the cell deals with these protein aggregates, why is it that these misfolded proteins are not degraded normally in the first place? A vast body of literature supports the notion that the cell’s protein degradation …

Targeting Ovarian Cancer And Endothelium With An Allosteric Ptp4a3 Phosphatase Inhibitor, Kelley E. Mcqueeney, Joseph M. Salamoun, James C. Burnett, Nektarios Barabutis, Paula Pekic, Sophie L. Lewandowski, Danielle C. Llaneza, Robert Cornelison, Yunpeng Bai, Zhong-Yin Zhang, John D. Catravas

Bioelectrics Publications

Overexpression of protein tyrosine phosphatase PTP4A oncoproteins is common in many human cancers and is associated with poor patient prognosis and survival. We observed elevated levels of PTP4A3 phosphatase in 79% of human ovarian tumor samples, with significant overexpression in tumor endothelium and pericytes. Furthermore, PTP4A phosphatases appear to regulate several key malignant processes, such as invasion, migration, and angiogenesis, suggesting a pivotal regulatory role in cancer and endothelial signaling pathways. While phosphatases are attractive therapeutic targets, they have been poorly investigated because of a lack of potent and selective chemical probes. In this study, we disclose that a potent, …

Mitochondrial Reactive Oxygen Species In Lipotoxic Hearts Induces Post-Translational Modifications Of Akap121, Drp1 And Opa1 That Promote Mitochondrial Fission, Kensuke Tsushima, Heiko Bugger, Adam R. Wende, Jamie Soto, Gregory A. Jenson, Austin R. Tor, Rose Mcglauflin, Helena C. Kenny, Yuan Zhang, Rhonda Souvenir, Xiao X. Hu, Crystal L. Sloan, Renata O. Pereira, Vitor A. Lira, Kenneth W. Spitzer, Terry L. Sharp, Kooresh I. Shoghi, Genevieve C. Sparagna, Eva A. Rog-Zielinska, Peter Kohl, Oleh Khalimonchuk, Jean E. Schaffer, E. Dale Abel

Department of Biochemistry: Faculty Publications

Rationale: Cardiac lipotoxicity, characterized by increased uptake, oxidation and accumulation of lipid intermediates, contributes to cardiac dysfunction in obesity and diabetes. However, mechanisms linking lipid overload and mitochondrial dysfunction are incompletely understood.

Objective: To elucidate the mechanisms for mitochondrial adaptations to lipid overload in postnatal hearts in vivo.

Methods and Results: Using a transgenic mouse model of cardiac lipotoxicity overexpressing long-chain acyl-CoA synthetase 1 in cardiomyocytes, we show that modestly increased myocardial fatty acid uptake leads to mitochondrial structural remodeling with significant reduction in minimum diameter. This is associated with increased palmitoyl-carnitine oxidation and increased reactive oxygen species (ROS) generation …