Medicine and Health Sciences Commons^™

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 …

A Brief Review Of Fda’S Novel Tools For Ensuring Pharmaceutical Quality In The Human Drug Supply Chain, Heather R. Campbell, Robert A. Lodder

Pharmaceutical Sciences Faculty Publications

Purpose

Pharmaceutical manufacturers execute quality control operations and Good Manufacturing Practices (GMP) to provide safe drugs. The Federal Drug and Food Administration (FDA) is tasked with ensuring manufacturers are performing such procedures. Faced with limited resources the FDA has developed novel tools to aid pharmaceutical manufacturing oversight. This paper briefly reviews these tools.

Methods

Current inspection approaches employed by the FDA are identified by searching the FDA’s guidances, the Code of Federal Regulations, public reports and other online resources.

Outcomes

Industry

A risk-based site selection model (SSM) is used to prioritize on-site inspections for FDA investigators. Theoretically, the SSM allows …

Pharmaceutical Manufacturing In The 21st Century: Identification And Analysis Of Key Elements, Robert N. Mills

Honors Theses

The availability of quality pharmaceutical products impacts the lives of the global population on a daily basis. The importance of product availability and quality within pharmaceutical manufacturing requires that quality systems put into place are capable of accurately and robustly capturing the quality compliance, or lack thereof, of the various stages of production. This review intends to analyze current expert-recommended best practices within key elements of a pharmaceutical manufacturing quality control system and provide recommendations throughout. The quality elements discussed include Quality by Design method validation, necessary equipment determination, and equipment qualification, followed by documentation control and data flow.

The Guanylate Cyclase C-Cgmp Signaling Axis Opposes Intestinal Epithelial Injury And Neoplasia., Jeffrey A. Rappaport, Scott A. Waldman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Guanylate cyclase C (GUCY2C) is a transmembrane receptor expressed on the luminal aspect of the intestinal epithelium. Its ligands include bacterial heat-stable enterotoxins responsible for traveler's diarrhea, the endogenous peptide hormones uroguanylin and guanylin, and the synthetic agents, linaclotide, plecanatide, and dolcanatide. Ligand-activated GUCY2C catalyzes the synthesis of intracellular cyclic GMP (cGMP), initiating signaling cascades underlying homeostasis of the intestinal epithelium. Mouse models of GUCY2C ablation, and recently, human populations harboring GUCY2C mutations, have revealed the diverse contributions of this signaling axis to epithelial health, including regulating fluid secretion, microbiome composition, intestinal barrier integrity, epithelial renewal, cell cycle progression, responses …

Nitric Oxide And Cyclic Gmp Signaling In Cancer Therapy, Armond Dorsey, Ferid Murad, Md, Phd, Ka Bian, Md, Phd

Journal of Health Disparities Research and Practice

The nitric oxide-3’,5’-cyclic guanosine monophosphate signaling pathway (NO-cGMP signaling pathway) is a well-known signal transduction pathway which elicits several physiological processes including: cell proliferation, vasodilation, cardiac protection, etc. In this pathway, NO binds to the ferrous heme of histidine-105 on the prosthetic heme of the β₁ subunit of soluble guanylyl cyclase, resulting in the production of cGMP. This pathway, however, is inhibited in certain cancer cells—as observed in glioma cell lines. As a result, the production of cGMP is reduced. This mechanism may facilitate uncontrolled tumor cell growth.

The cancers under research—lung carcinoma, glioma, and pancreatic carcinoma—are all highly …

No-Independent Modulation Of Soluble Guanylyl Cyclase (Sgc) Activity And Function, George L. Britton Jr

Dissertations & Theses (Open Access)

Soluble guanylyl cyclase (sGC) plays a key role in the nitric oxide (NO) signaling pathway, where it functions as an NO receptor and generator of a secondary intracellular messenger, cGMP. In addition to NO, investigators have identified a number of proteins that interact with sGC and modulate its function. For example, the interaction of sGC with ADP-ribosylation factor GTPase activating protein 1 (AGAP1) governs sGC’s intracellular distribution and therefore mediates localized production of cGMP. Interactions of sGC with heat-shock protein 90 (HSP90) or HSP70 promote the extent of sGC activation upon NO stimulation, while interaction of sGC with the η …

Cgmp Pde As A Novel Molecular Target For The Prevention And Treatment Of Breast Cancer, Heather Nicole Tinsley

All ETDs from UAB

Breast cancer remains a major health concern, despite efforts to develop improved therapeutics. Chemoprevention is a promising strategy for reducing breast cancer-related morbidity and mortality. However, with the exception of the selective estrogen receptor modulators (SERMs), which have limited efficacy and severe toxicities, no drugs have been approved for breast cancer chemoprevention. Studies demonstrate that certain nonsteroidal anti-inflammatory drugs (NSAIDs) display promising chemopreventive efficacy. Unfortunately, the depletion of physiologically important prostaglandins due to inhibition of the cyclooxygenase (COX) enzymes results in potentially fatal toxicities, which exclude the use of NSAIDs and COX-2 selective inhibitors for chemoprevention. Ample data, however, suggest …

Ischemic Preconditioning Protects Adult Rat Cardiomyocytes Against Necrosis But Not Apoptosis, Via Activation Of Pkg, Marc J. Caligtan

Theses and Dissertations

The role of cyclic guanosine monophosphate (cGMP) dependent protein kinase (PKG) in necrotic and apoptotic pathways of many cell types is well established; however its role in the ischemic preconditioning (IPC) of cardiomyocytes is not clearly defined. In the current study, we assessed the hypothesis that PKG protects against cell death following ischemidreperfusion injury in myocytes subjected to IPC. Freshly isolated adult rat ventricular myocytes were subjected to IPC by incubating in ischemic buffer for 30 minutes (min) followed by incubation in normal medium for 30 min. Prolonged simulated ischemia (SI) was created by incubating myocytes in the ischemic buffer …

Canine Rod Photoreceptor Cgmp-Gated Channel Protein Α-Subunit: Studies On The Expression Of The Gene And Characterization Of The Cdna, Qi Zhang, Sue Pearce-Kelling, Gregory Acland, Gustavo Aguirre, Kunal Ray

Gustavo D. Aguirre, VMD, PhD