Browsing by Subject "Arginine"

Now showing 1 - 7 of 7
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    A new perspective on NO pathway in sepsis and ADMA lowering as a potential therapeutic approach
    (BMC, 2022-08-12) Singh, Jaipal; Lee, Young; Kellum, John A.; Cellular and Integrative Physiology, School of Medicine
    The nitric oxide pathway plays a critical role in vascular homeostasis. Increased levels of systemic nitric oxide (NO) are observed in preclinical models of sepsis and endotoxemia. This has led to the postulation that vasodilation by inducible nitric oxide synthase (iNOS) generated NO may be a mechanism of hypotension in sepsis. However, contrary to the expected pharmacological action of a nitric oxide synthase (NOS) inhibitor, clinical studies with L-NAME produced adverse cardiac and pulmonary events, and higher mortality in sepsis patients. Thus, the potential adverse effects of NO in human sepsis and shock have not been fully established. In recent years, the emerging new understanding of the NO pathway has shown that an endogenously produced inhibitor of NOS, asymmetric dimethylarginine (ADMA), a host response to infection, may play an important role in the pathophysiology of sepsis as well as organ damage during ischemia-reperfusion. ADMA induces microvascular dysfunction, proinflammatory and prothrombotic state in endothelium, release of inflammatory cytokines, oxidative stress and mitochondrial dysfunction. High levels of ADMA exist in sepsis patients, which may produce adverse effects like those observed with L-NAME. Several studies have demonstrated the association of plasma ADMA levels with mortality in sepsis patients. Preclinical studies in sepsis and ischemia-reperfusion animal models have shown that lowering of ADMA reduced organ damage and improved survival. The clinical finding with L-NAME and the preclinical research on ADMA "bed to bench" suggest that ADMA lowering could be a potential therapeutic approach to attenuate progressive organ damage and mortality in sepsis. Testing of this approach is now feasible by using the pharmacological molecules that specifically lower ADMA.
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    Analyses of the Effects of Arginine, Nicotine, Serotype and Collagen-Binding Proteins on Biofilm Development by 33 Strains of Streptococcus mutans
    (Frontiers Media, 2021-11-25) Wagenknecht, Dawn R.; Gregory, Richard L.; Biomedical and Applied Sciences, School of Dentistry
    Streptococcus mutans serotype k strains comprise <3% of oral isolates of S. mutans but are prominent in diseased cardiovascular (CV) tissue. Collagen binding protein (CBP) genes, cbm and cnm, are prevalent in serotype k strains and are associated with endothelial cell invasion. Nicotine increases biofilm formation by serotype c strains of S. mutans, but its effects on serotype k strains and strains with CBP are unknown. Saliva contains arginine which alters certain properties of the extracellular polysaccharides (EPS) in S. mutans biofilm. We examined whether nicotine and arginine affect sucrose-induced biofilm of S. mutans serotypes k (n = 23) and c (n = 10) strains with and without CBP genes. Biofilm mass, metabolism, bacterial proliferation, and EPS production were assessed. Nicotine increased biomass and metabolic activity (p < 0.0001); arginine alone had no effect. The presence of a CBP gene (either cbm or cnm) had a significant effect on biofilm production, but serotype did not. Nicotine increased bacterial proliferation and the effect was greater in CBP + strains compared to strains lacking CBP genes. Addition of arginine with nicotine decreased both bacterial mass and EPS compared to biofilm grown in nicotine alone. EPS production was greater in cnm + than cbm + strains (p < 0.0001). Given the findings of S. mutans in diseased CV tissue, a nicotine induced increase in biofilm production by CBP + strains may be a key link between tobacco use and CV diseases.
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    A Modified Adhesive System for Use in Treatment of Dentin Hypersensitivity
    (2020-08) AlShehri, Aram Mushabbab; Sochacki, Sabrina Feitosa; Hara, Anderson; Platt, Jeffrey A.; Windsor, L. Jack
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    NF-κB: Regulation by Methylation
    (American Association for Cancer Research, 2015-09-15) Lu, Tao; Stark, George R.; Department of Pharmacology and Toxicology, IU School of Medicine
    In normal cells exposed to stress, the central transcription factor NF-κB is activated only transiently, to modulate the activation of downstream immune responses. However, in most cancers, NF-κB is abnormally activated constitutively, contributing thus to oncogenesis and tumor progression. Therefore, downregulating NF-κB activity is an important goal of cancer treatment. In order to control NF-κB activity therapeutically, it is helpful to understand the molecular mechanisms that normally govern its activation and how dysregulated NF-κB activity may aid the development of disease. Recent evidence from our laboratories and others indicates that, in addition to various posttranslational modifications of NF-κB that have been observed previously, including phosphorylation, ubiquitination, and acetylation, NF-κB can be methylated reversibly on lysine or arginine residues by histone-modifying enzymes, including lysine and arginine methyl transferases and demethylases. Furthermore, these methylations are required to activate many downstream genes. Interestingly, amplifications and mutations of several such enzymes have been linked to cancer. We propose that some of these mutations may alter the methylation not only of histones but also of NF-κB, making them attractive therapeutic targets.
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    Specific Lowering of Asymmetric Dimethylarginine by Pharmacological Dimethylarginine Dimethylaminohydrolase Improves Endothelial Function, Reduces Blood Pressure and Ischemia-Reperfusion Injury
    (American Society for Pharmacology and Experimental Therapeutics, 2021) Lee, Young; Mehrotra, Purvi; Basile, David; Ullah, Mahbub; Singh, Arshnoor; Skill, Nicholas; Younes, Subhi Talal; Sasser, Jennifer; Shekhar, Anantha; Singh, Jaipal; Cellular and Integrative Physiology, School of Medicine
    Multiple clinical and preclinical studies have demonstrated that plasma levels of asymmetric dimethylarginine (ADMA) are strongly associated with hypertension, diabetes, and cardiovascular and renal disease. Genetic studies in rodents have provided evidence that ADMA metabolizing dimethylarginine dimethylaminohydrolase (DDAH)-1 plays a role in hypertension and cardiovascular disease. However, it remains to be established whether ADMA is a bystander, biomarker, or sufficient contributor to the pathogenesis of hypertension and cardiovascular and renal disease. The goal of the present investigation was to develop a pharmacological molecule to specifically lower ADMA and determine the physiologic consequences of ADMA lowering in animal models. Further, we sought to determine whether ADMA lowering will produce therapeutic benefits in vascular disease in which high ADMA levels are produced. A novel long-acting recombinant DDAH (M-DDAH) was produced by post-translational modification, which effectively lowered ADMA in vitro and in vivo. Treatment with M-DDAH improved endothelial function as measured by increase in cGMP and in vitro angiogenesis. In a rat model of hypertension, M-DDAH significantly reduced blood pressure (vehicle: 187 ± 19 mm Hg vs. M-DDAH: 157 ± 23 mm Hg; P < 0.05). Similarly, in a rat model of ischemia-reperfusion injury, M-DDAH significantly improved renal function as measured by reduction in serum creatinine (vehicle: 3.14 ± 0.74 mg/dl vs. M-DDAH: 1.1 ± 0.75 mg/dl; P < 0.01), inflammation, and injured tubules (vehicle: 73.1 ± 11.1% vs. M-DDAH: 22.1 ± 18.4%; P < 0.001). These pharmacological studies have provided direct evidence for a pathologic role of ADMA and the therapeutic benefits of ADMA lowering in preclinical models of endothelial dysfunction, hypertension, and ischemia-reperfusion injury. SIGNIFICANCE STATEMENT: High levels of ADMA occur in patients with cardiovascular and renal disease. A novel modified dimethylarginine dimethylaminohydrolase by PEGylation effectively lowers ADMA, improves endothelial function, reduces blood pressure and protects from ischemia-reperfusion renal injury.
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    Starve Cancer Cells of Glutamine: Break the Spell or Make a Hungry Monster?
    (MDPI, 2019-06-11) Jiang, Jie; Srivastava, Sankalp; Zhang, Ji; Biochemistry & Molecular Biology, IU School of Medicine
    Distinct from normal differentiated tissues, cancer cells reprogram nutrient uptake and utilization to accommodate their elevated demands for biosynthesis and energy production. A hallmark of these types of reprogramming is the increased utilization of, and dependency on glutamine, a nonessential amino acid, for cancer cell growth and survival. It is well-accepted that glutamine is a versatile biosynthetic substrate in cancer cells beyond its role as a proteinogenic amino acid. In addition, accumulating evidence suggests that glutamine metabolism is regulated by many factors, including tumor origin, oncogene/tumor suppressor status, epigenetic alternations and tumor microenvironment. However, despite the emerging understanding of why cancer cells depend on glutamine for growth and survival, the contribution of glutamine metabolism to tumor progression under physiological conditions is still under investigation, partially because the level of glutamine in the tumor environment is often found low. Since targeting glutamine acquisition and utilization has been proposed to be a new therapeutic strategy in cancer, it is central to understand how tumor cells respond and adapt to glutamine starvation for optimized therapeutic intervention. In this review, we first summarize the diverse usage of glutamine to support cancer cell growth and survival, and then focus our discussion on the influence of other nutrients on cancer cell adaptation to glutamine starvation as well as its implication in cancer therapy.