Chemicals and Drugs Commons^™

Cord Blood Troponin I Levels: Biomarker Evidence Of Fetal Cardiac Injury In Intrahepatic Cholestasis Of Pregnancy, Itamar Futterman, Hitangee Jain, Rodney Mclaren, Jonathan Mays

Department of Obstetrics and Gynecology Faculty Papers

BACKGROUND: Intrahepatic cholestasis of pregnancy has been linked to sudden stillbirth. The suddenness of the stillbirths in these cases have led clinicians to suspect that the pathogenesis of stillbirth in women with intrahepatic cholestasis of pregnancy is not related to asphyxia but rather to an undefined etiology. One leading hypothesis relates certain bile acid metabolites to myocardial injury. OBJECTIVE: The purpose of this study was to determine whether cord blood troponin I levels are increased in fetuses born to mothers with a diagnosis of intrahepatic cholestasis of pregnancy. STUDY DESIGN: A prospective, case-control study was performed at a single institution …

Expression Of The Αvβ3 Integrin Affects Prostate Cancer Sev Cargo And Density And Promotes Sev Pro-Tumorigenic Activity In Vivo Through A Gpi-Anchored Receptor, Ngr2, Cecilia Verrillo, Fabio Quaglia, Christopher Shields, Stephen Lin, Andrew Kossenkov, Hsin-Yao Tang, David Speicher, Nicole Naranjo, Anna Testa, William Kelly, Qin Liu, Benjamin Leiby, Luca Musante, Khalid Sossey-Alaoui, Navneet Dogra, Tzu-Yi Chen, Dario Altieri, Lucia Languino

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

It is known that small extracellular vesicles (sEVs) are released from cancer cells and contribute to cancer progression via crosstalk with recipient cells. We have previously reported that sEVs expressing the αVβ3 integrin, a protein upregulated in aggressive neuroendocrine prostate cancer (NEPrCa), contribute to neuroendocrine differentiation (NED) in recipient cells. Here, we examine the impact of αVβ3 expression on sEV protein content, density and function. sEVs used in this study were isolated by iodixanol density gradients and characterized by nanoparticle tracking analysis, immunoblotting and single vesicle analysis. Our proteomic profile of sEVs containing αVβ3 shows downregulation of typical effectors involved …

Evaluation Of Myogenic Differentiation Potential Of Bmd Ipscs In Vitro And The Effect Of Ubiquitination Inhibitors On Dystrophin Stability In Vivo, Muchen Liu

Dissertations and Theses (Open Access)

Background: Muscular dystrophies are heterogeneous groups of inherited diseases leading to progressive muscular weakness and degeneration. In the case of Becker muscular dystrophy (BMD), non-disrupting mutations of the DMD gene reading frame is the causative defect. By the age of 30s, about 60 to 70% of BMD patients develop cardiomyopathy, which is often lethal. Unfortunately, there is currently no cure for BMD. Meanwhile, improvement of dystrophin stability by repressing polyubiquitination is a promising strategy. The application of human iPSCs in tissue regeneration also serves as a potential therapeutic strategy. This study aims to test the efficacy of selected drugs interfering …

Experimental And Theoretical Investigation Of The Coordination Of 8-Hydroxquinoline Inhibitors To Biomimetic Zinc Complexes And Histone Deacetylase 8 (Hdac8), Anthony M. Baudino, Harris F. Ciaccio, Michael J. Turski, Xavier A. Akins, Phoebus Sun Cao, Elisa Morales, Roger D. Sommer, Adam R. Johnson, Donald J. Wink, Kyle A. Grice, Kari Stone

Chemistry Department Faculty Articles

Zinc is integral to diverse biological functions, acting catalytically, structurally, and supportively in essential enzyme cycles, despite its limited amounts in the body. Targeting zinc enzymes with potent drugs, such as Vorinostat, demonstrates the therapeutic efficacy of zinc-binding ligands, notably in cutaneous T-cell lymphoma treatments. Our study merges experimental and theoretical approaches to analyze the coordination of 8-hydroxylquinoline (8HQ) inhibitors with biomimetic zinc complexes and human histone deacetylase 8 (HDAC8), a monozinc hydrolase enzyme. Assessing 10 8HQ derivatives for structural and electronic characteristics against these models, we observe minimal inhibition efficacy, corroborated through protein–ligand docking analyses, highlighting the complexities of …

Molecular Mechanisms Of Exercise-Stimulated Resolution Of Inflammation And Its Dietary Dependence., Ernesto H. Pena Calderin

Electronic Theses and Dissertations

Diet-induced obesity and adipose tissue (AT) inflammation that ensues sets the stage for systemic metabolic inflammation, disrupted insulin signaling, and eventual type 2 diabetes (T2D) development. At the center of this pathology lies a disruption in endogenous inflammation resolution pathways characterized by an imbalance in lipid mediator production (greater abundance of pro-inflammatory to pro-resolving lipids). Additionally, obese states are characterized by adrenergic deficiency, especially in response to physical activity. Inflammatory processes have been experimentally mitigated by either the pharmacological inhibition of pro-inflammatory signals (i.e., Leukotriene B₄ (LTB₄) and its receptor BLT1, which establishes a potent chemotactic stimulus …

Molecular Insights Into Propylthiouracil As A Thyroid Peroxidase Inhibitor: A Computational Study Approach, Dwi Anita Suryandari, Luluk Yunaini, Hadi Sunaryo, Khaerunissa Anbar Istiadi, Irandi Putra Pratomo

Indonesian Journal of Medical Chemistry and Bioinformatics

Thyroid peroxidase (TPO) is a crucial enzyme in the biosynthesis of thyroid hormones, catalyzing the iodination of tyrosine residues in thyroglobulin and the coupling of iodotyrosines to form thyroxine (T4) and triiodothyronine (T3). Propylthiouracil (PTU) is an antithyroid drug commonly used to manage hyperthyroidism by inhibiting TPO. Understanding the molecular interactions between TPO and PTU can provide insights into the inhibitory mechanisms and guide the design of more effective antithyroid medications. Objective: This study aims to elucidate the binding interactions between TPO and PTU through molecular docking, providing a detailed understanding of how PTU inhibits TPO activity. Methods: …

Liposomal Fba And Met6 Peptide Vaccination Protects Mice From Disseminated Candidiasis, Wei-Chiao Huang, Karen Eberle, Jonothan Rosario Colon, Jonathan F. Lovell, Hong Xin

School of Graduate Studies Faculty Publications

UNLABELLED: Epitopes from the cell surface proteins Fba and Met6 are putative vaccine targets for invasive candidiasis. Here, we describe a vaccine approach in which short peptides derived from Fba and Met6 are used in spontaneous nanoliposome antigen particle (SNAP) format. SNAP was enabled by the interaction of cobalt porphyrin phospholipid in liposomes with three histidine residues on the N-terminus of synthetic short peptide immunogens from Fba (F-SNAP), Met6 (M-SNAP), or bivalent Fba and Met6 (FM-SNAP). Liposomes were adjuvanted with synthetic monophosphoryl lipid and QS-21. In mice, immunization with F-SNAP, M-SNAP, or FM-SNAP induced antigen-specific IgG responses and mixed Th1/Th2 …

Csf1r Inhibition Depletes Brain Macrophages And Reduces Brain Virus Burden In Siv-Infected Macaques, Diana G. Bohannon, Laurent D. Zablocki-Thomas, Evan S. Leung, Jinbum K. Dupont, Julian B. Hattler, Jolanta Kowalewska, Miaoyun Zhao, Jiangtao Luo, Marco Salemi, Angela M. Amedee, Qingsheng Li, Marcelo J. Kuroda, Woong-Ki Kim

School of Graduate Studies Faculty Publications

Perivascular macrophages (PVMs) and, to a lesser degree, microglia are targets and reservoirs of HIV and simian immunodeficiency virus (SIV) in the brain. Previously, we demonstrated that colony-stimulating factor 1 receptor (CSF1R) in PVMs was upregulated and activated in chronically SIV-infected rhesus macaques with encephalitis, correlating with SIV infection of PVMs. Herein, we investigated the role of CSF1R in the brain during acute SIV infection using BLZ945, a brain-penetrant CSF1R kinase inhibitor. Apart from three uninfected historic controls, nine Indian rhesus macaques were infected acutely with SIVmac251 and divided into three groups (n = 3 each): an untreated control and …

Genome-Wide Methylation Patterns In Primary Uveal Melanoma: Development Of Methylsig-Um, An Epigenomic Prognostic Signature To Improve Patient Stratification, Emilie Lalonde, Dong Li, Kathryn Ewens, Carol L. Shields, Arupa Ganguly

Wills Eye Hospital Papers

Despite studies highlighting the prognostic utility of DNA methylation in primary uveal melanoma (pUM), it has not been translated into a clinically useful tool. We sought to define a methylation signature to identify newly diagnosed individuals at high risk for developing metastasis. Methylation profiling was performed on 41 patients with pUM with stage T2-T4 and at least three years of follow-up using the Illumina Infinium HumanMethylation450K BeadChip (N = 24) and the EPIC BeadChip (N = 17). Findings were validated in the TCGA cohort with known metastatic outcome (N = 69). Differentially methylated probes were identified in patients who developed …

Remimazolam And Its Place In The Current Landscape Of Procedural Sedation And General Anesthesia, Matthew Brohan, Janette Brohan, Basavana Goudra

Department of Anesthesiology Faculty Papers

Remimazolam was derived from its parent compound by adding an ester linkage into its structure so that the drug becomes a substrate for ester metabolism. As a result, it undergoes organ-independent ester hydrolysis, although the clinical benefits in terms of shorter recovery are not uniformly observed in clinical practice. Remimazolam is mainly tested in procedural sedation. In comparison to propofol, the current gold standard for procedural sedation, its proposed attractiveness is shorter wake-up times and a clear-headed recovery. Its clear advantages over propofol are better hemodynamic stability, lack of pain on injection and availability of a reversal agent in the …

Diesel Exhaust Particles Alter Mitochondrial Bioenergetics And Camp Producing Capacity In Human Bronchial Epithelial Cells, Isabella Cattani-Cavalieri, Marina Trombetta-Lima, Hong Yan, Ana L. Manzano-Covarrubias, Hoeke A. Baarsma, Asmaa Oun, Melissa Mol Van Der Veen, Emily Oosterhout, Amalia M. Dolga, Rennolds S. Ostrom, Samuel Santos Valenca, Martina Schmidt

Pharmacy Faculty Articles and Research

Introduction: Air pollution from diesel combustion is linked in part to the generation of diesel exhaust particles (DEP). DEP exposure induces various processes, including inflammation and oxidative stress, which ultimately contribute to a decline in lung function. Cyclic AMP (cAMP) signaling is critical for lung homeostasis. The impact of DEP on cAMP signaling is largely unknown.

Methods: We exposed human bronchial epithelial (BEAS-2B) cells to DEP for 24–72 h and evaluated mitochondrial bioenergetics, markers of oxidative stress and inflammation and the components of cAMP signaling. Mitochondrial bioenergetics was measured at 72 h to capture the potential and accumulative effects of …

Innovation Path At Institute For Protein Design Of Washington University And Its Enlightenment For Construction Of New Life Sciences R&D Institutions, Runzhou Zhao, Ming Ni, Yunzhi Fa, Xiaochen Bo, Jian Jiao

Bulletin of Chinese Academy of Sciences (Chinese Version)

The Institute for Protein Design (IPD) at the University of Washington is a pioneering local and state-supported non-profit scientific research institution. Since its establishment in 2012, IPD has seized the opportunity of AI for Science and open science, and continuously enhanced its capabilities of fundamental innovations, breakthrough technologies, and industrial impact. We summarized five factors contributing to IPD’s development, including focusing on the cutting-edge issues of basic scientific research to gain a first-mover advantage and then further expand, integrating AI-enhanced digital tools and solid experimental validations, facilitating the integrated development of innovation and industrial chains, giving full play to the …

Roles Of Hydrogen Sulfide (H2s) As A Potential Therapeutic Agent In Cardiovascular Diseases: A Narrative Review, Kazi N. Islam, Ivan D. Nguyen, Rahib Islam, Humza Pirzadah, Hassan Malik

School of Medicine Faculty Publications

Cardiovascular disease (CVD) stands as one of the leading causes of morbidity and mortality worldwide, and the continued search for novel therapeutics is vital for addressing this global health challenge. Over the past decade, hydrogen sulfide (H₂S) has garnered significant attention in the field of medical research, as it has been proven to be a cardioprotective gaseous signaling molecule. It joins nitric oxide and carbon monoxide as endogenously produced gasotransmitters. As for its mechanism, H₂S functions through the posttranslational addition of a sulfur group to cysteine residues on target proteins in a process called sulfhydration. As a result, the observed …

Association Of High Fibrinogen To Albumin Ratio With Long-Term Mortality In Patients With Spontaneous Intracerebral Hemorrhage, Shiping Chen, Yu Zhang, Yangchun Xiao, Xin Cheng, Liyuan Peng, Yixin Tian, Tiangui Li, Jialing He, Pengfei Hao, Weelic Chong, Yang Hai, Chao You, Fang Fang

Department of Medical Oncology Faculty Papers

BACKGROUND: The association between fibrinogen-to-albumin ratio (FAR) and in-hospital mortality in patients with spontaneous intracerebral hemorrhage (ICH) has been established. However, the association with long-term mortality in spontaneous ICH remains unclear. This study aims to investigate the association between FAR and long-term mortality in these patients.

METHODS: Our retrospective study involved 3,538 patients who were diagnosed with ICH at West China Hospital, Sichuan University. All serum fibrinogen and serum albumin samples were collected within 24 h of admission and participants were divided into two groups according to the FAR. We conducted a Cox proportional hazard analysis to evaluate the association …

Allopurinol: Clinical Considerations In The Development And Treatment Of Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis, And Other Associated Drug Reactions, Kathryn M. Dillman, Alison M. Hawkins, Amanda R. Ragland, Grace C. Wester, Driskell R. Greene, Giustino Varrassi, Peyton Moore, Raju Behara, Shahab Ahmadzadeh, Harish Siddaiah, Sahar Shekoohi, Alan D. Kaye

School of Medicine Faculty Publications

Allopurinol lowers urate production through the inhibition of xanthine oxidase. It is oxidatively hydroxylated to oxypurinol and is the most prescribed medication for gout treatment. Although it has a beneficial effect in the treatment of this common disease, like many medications, it is also known for having numerous adverse effects. Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), diseases that exist on a spectrum, are two of the most dangerous adverse effects associated with allopurinol use. These immune-mediated disease processes involve almost every organ system. They are essential to recognize as early as possible, as they could potentially be deadly, …

Cholesterol Drugs May Improve Periodontal Disease

New Orleans Dental Association News

Recently, statin treatment applied locally into tissues during both surgical and nonsurgical procedures exhibiting a positive effect on various parameters of periodontal tissue health. When looking at this novel, not yet commonly utilized approach to the local application of statins as an adjunct to periodontal treatment, early studies have shown significant improvement in clinical parameters, such as probing depth and clinical attachment levels. This method of local statin delivery into the tissue shows promise, and should be explored by further research.

The Potential Anti-Arrhythmic Effect Of Sglt2 Inhibitors, Hong-Yi Duan, Hector Barajas-Martinez, Charles Antzelevitch, Dan Hu

Department of Medicine Faculty Papers

Sodium-glucose cotransporter type 2 inhibitors (SGLT2i) were initially recommended as oral anti-diabetic drugs to treat type 2 diabetes (T2D), by inhibiting SGLT2 in proximal tubule and reduce renal reabsorption of sodium and glucose. While many clinical trials demonstrated the tremendous potential of SGLT2i for cardiovascular diseases. 2022 AHA/ACC/HFSA guideline first emphasized that SGLT2i were the only drug class that can cover the entire management of heart failure (HF) from prevention to treatment. Subsequently, the antiarrhythmic properties of SGLT2i have also attracted attention. Although there are currently no prospective studies specifically on the anti-arrhythmic effects of SGLT2i. We provide clues from …

Toward The Development Of A Pan-Lyssavirus Vaccine, Sabrine Ben Hamed, Jacob Myers, Anisha Chandwani, Christoph Wirblich, Drishya Kurup, Nir Paran, Matthias Schnell

Department of Microbiology and Immunology Faculty Papers

In addition to the rabies virus (RABV), 16 more lyssavirus species have been identified worldwide, causing a disease similar to RABV. Non-rabies-related human deaths have been described, but the number of cases is unknown, and the potential of such lyssaviruses causing human disease is unpredictable. The current rabies vaccine does not protect against divergent lyssaviruses such as Mokola virus (MOKV) or Lagos bat virus (LBV). Thus, a more broad pan-lyssavirus vaccine is needed. Here, we evaluate a novel lyssavirus vaccine with an attenuated RABV vector harboring a chimeric RABV glycoprotein (G) in which the antigenic site I of MOKV replaces …

A Fungal Metabolic Regulator Underlies Infectious Synergism During Candida Albicans-Staphylococcus Aureus Intra-Abdominal Co-Infection, Saikat Paul, Olivia A. Todd, Kara R. Eichelberger, Christine Tkaczyk, Bret R. Sellman, Mairi C. Noverr, James E. Cassat, Paul L. Fidel, Brian M. Peters

School of Dentistry Faculty Publications

Candida albicans and Staphylococcus aureus are two commonly associated pathogens that cause nosocomial infections with high morbidity and mortality. Our prior and current work using a murine model of polymicrobial intra-abdominal infection (IAI) demonstrates that synergistic lethality is driven by Candida-induced upregulation of functional S. aureus α-toxin leading to polymicrobial sepsis and organ damage. In order to determine the candidal effector(s) mediating enhanced virulence, an unbiased screen of C. albicans transcription factor mutants was undertaken revealing that zcf13Δ/Δ fails to drive augmented α-toxin or lethal synergism during co-infection. A combination of transcriptional and phenotypic profiling approaches shows that ZCF13 regulates …

Conformational Alterations Of The Cell Surface Of Monomeric And Dimeric Β2m-Free Hla-I (Proto-Hla) May Enable Novel Immune Functions In Health And Disease, Mepur Ravindranath, Narendranath Ravindranath, Carly Amato-Menker, Fatiha El Hilali, Edward Filippone

Division of Nephrology Faculty Papers

Human leukocyte antigens (HLAs) are polymorphic glycoproteins expressed on the cell surface of nucleated cells and consist of two classes, HLA class I and HLA class II. In contrast, in mice, these molecules, known as H-2, are expressed on both nucleated cells and erythrocytes. HLA-I molecules (Face-1) are heterodimers consisting of a polypeptide heavy chain (HC) and a light chain, B2-microglobulin (B2m). The heterodimers bind to antigenic peptides and present them to the T-cell receptors of CD8+ cytotoxic T lymphocytes. The HCs can also independently emerge on the cell surface as B2m-free HC monomers without peptides (Face-2). Early investigators suggested …