scholarly journals Macrocyclic Peptides as Allosteric Inhibitors of Nicotinamide N-Methyltransferase (NNMT)

2021 ◽  
Author(s):  
Matthijs van Haren ◽  
Yurui Zhang ◽  
Vito Thijssen ◽  
Ned Buijs ◽  
Yongzhi Gao ◽  
...  
Keyword(s):  
Allosteric Inhibitors ◽  
Methyl Donor ◽  
Disease States ◽  
Macrocyclic Peptides

Nicotinamide N-methyltransferase (NNMT) methylates nicotinamide to form 1-methylnicotinamide (MNA) using S-adenosyl-L-methionine (SAM) as the methyl donor. The complexity of the role of NNMT in healthy and disease states is slowly...

scholarly journals Macrocyclic Peptides as Allosteric Inhibitors of Nicotinamide N-Methyltransferase (NNMT)

2020 ◽  
Author(s):  
Matthijs J. van Haren ◽  
Yurui Zhang ◽  
Ned Buijs ◽  
Vito Thijssen ◽  
Davide Sartini ◽  
...  
Keyword(s):  
Cyclic Peptides ◽  
Cyclic Peptide ◽  
Peptide Inhibitors ◽  
Allosteric Inhibitors ◽  
Disease States ◽  
Potent Inhibition ◽  
Macrocyclic Peptides ◽  
Diabetes And Obesity ◽  
Substrate Competition

<p>Nicotinamide <i>N</i>-methyltransferase (NNMT) methylates nicotinamide to form 1-methylnicotinamide using <i>S</i>-adenosyl-l-methionine (SAM) as the methyl donor. The complexity of the role of NNMT in healthy and disease states is slowly being elucidated and provides indication that NNMT may be an interesting therapeutic target for a variety of diseases including cancer, diabetes, and obesity. Most inhibitors of NNMT described to date are structurally related to one or both of its substrates. In search of structurally diverse NNMT inhibitors, an mRNA display screening technique was used to identify macrocyclic peptides which bind to NNMT. Several of the cyclic peptides identified in this manner show potent inhibition of NNMT with IC<sub>50</sub> values as low as 229 nM. Interestingly, substrate competition experiments reveal that these cyclic peptide inhibitors are noncompetitive with either SAM or NA indicating they may be the first allosteric inhibitors reported for NNMT.</p>

scholarly journals Macrocyclic Peptides as Allosteric Inhibitors of Nicotinamide N-Methyltransferase (NNMT)

2020 ◽  
Author(s):  
Matthijs J. van Haren ◽  
Yurui Zhang ◽  
Ned Buijs ◽  
Vito Thijssen ◽  
Davide Sartini ◽  
...  
Keyword(s):  
Cyclic Peptides ◽  
Cyclic Peptide ◽  
Peptide Inhibitors ◽  
Allosteric Inhibitors ◽  
Disease States ◽  
Potent Inhibition ◽  
Macrocyclic Peptides ◽  
Diabetes And Obesity ◽  
Substrate Competition

<p>Nicotinamide <i>N</i>-methyltransferase (NNMT) methylates nicotinamide to form 1-methylnicotinamide using <i>S</i>-adenosyl-l-methionine (SAM) as the methyl donor. The complexity of the role of NNMT in healthy and disease states is slowly being elucidated and provides indication that NNMT may be an interesting therapeutic target for a variety of diseases including cancer, diabetes, and obesity. Most inhibitors of NNMT described to date are structurally related to one or both of its substrates. In search of structurally diverse NNMT inhibitors, an mRNA display screening technique was used to identify macrocyclic peptides which bind to NNMT. Several of the cyclic peptides identified in this manner show potent inhibition of NNMT with IC<sub>50</sub> values as low as 229 nM. Interestingly, substrate competition experiments reveal that these cyclic peptide inhibitors are noncompetitive with either SAM or NA indicating they may be the first allosteric inhibitors reported for NNMT.</p>

Role of the NF-kB Pathway in the Pathogenesis of Human Disease States

2001 ◽  
Vol 1 (3) ◽  
pp. 287-296 ◽  
Author(s):  
Yumi Yamamoto ◽  
Richard Gaynor
Keyword(s):  
Human Disease ◽  
Disease States

A distinct role in breast cancer for two LIV-1 family zinc transporters

2008 ◽  
Vol 36 (6) ◽  
pp. 1247-1251 ◽  
Author(s):  
Kathryn M. Taylor
Keyword(s):  
Breast Cancer ◽  
Cancer Metastasis ◽  
Prognostic Indicator ◽  
Breast Cancer Metastasis ◽  
Zinc Transporters ◽  
Aberrant Expression ◽  
Disease States ◽  
Cancer Spread ◽  
Protein Transporters

Zinc, essential for normal cell growth, is tightly controlled in cells by two families of zinc transporters. The aberrant expression of zinc transporters from the LIV-1 family of ZIP (Zrt/Irt-like protein) transporters is increasingly being implicated in a variety of disease states. In the present paper, I describe a mechanism for the role of ZIP7 in the progression of breast cancer, identifying it as a new target in breast cancer. Furthermore, I document a link between another zinc transporter, LIV-1, and breast cancer metastasis, identifying it as a potential new prognostic indicator of breast cancer spread.

Defining the role of pharmacists in medication-related genetic counseling

2021 ◽  
Author(s):  
Nova A Chart ◽  
David F Kisor ◽  
Christopher L Farrell
Keyword(s):  
Genetic Risk ◽  
Pharmacy Practice ◽  
Interdisciplinary Team ◽  
Standard Of Care ◽  
Treatment Team ◽  
Multiple Cancer ◽  
Cancer Treatments ◽  
Disease States ◽  
Practice Approach

There is little question that precision medicine will eventually be the standard of care in treatment with algorithms designed for therapy selection and is already being used in some specialties such as cystic fibrosis and multiple cancer treatments. Genetic counselors are the heart of the treatment team in relation to counseling regarding genetic risk factors and disease states. A framework for treatment within the interdisciplinary team with more defined roles and areas of specialty will need to be in place as this practice approach expands with new data and treatments. Pharmacists are poised to be of great assistance in this matrix as many of these roles are merely an extension of current tasks and responsibilities of pharmacy practice.

Regulation of the Cerebral Circulation: Role of Endothelium and Potassium Channels

1998 ◽  
Vol 78 (1) ◽  
pp. 53-97 ◽  
Author(s):  
FRANK M. FARACI ◽  
DONALD D. HEISTAD
Keyword(s):  
Potassium Channels ◽  
Cerebral Circulation ◽  
Second Messengers ◽  
Chronic Hypertension ◽  
Major Mechanism ◽  
Disease States ◽  
Vasoactive Factors ◽  
New Concepts ◽  
Intracellular Second Messengers

Faraci, Frank M., and Donald D. Heistad. Regulation of the Cerebral Circulation: Role of Endothelium and Potassium Channels. Physiol. Rev. 78: 53–97, 1998. — Several new concepts have emerged in relation to mechanisms that contribute to regulation of the cerebral circulation. This review focuses on some physiological mechanisms of cerebral vasodilatation and alteration of these mechanisms by disease states. One mechanism involves release of vasoactive factors by the endothelium that affect underlying vascular muscle. These factors include endothelium-derived relaxing factor (nitric oxide), prostacyclin, and endothelium-derived hyperpolarizing factor(s). The normal vasodilator influence of endothelium is impaired by some disease states. Under pathophysiological conditions, endothelium may produce potent contracting factors such as endothelin. Another major mechanism of regulation of cerebral vascular tone relates to potassium channels. Activation of potassium channels appears to mediate relaxation of cerebral vessels to diverse stimuli including receptor-mediated agonists, intracellular second messengers, and hypoxia. Endothelial- and potassium channel-based mechanisms are related because several endothelium-derived factors produce relaxation by activation of potassium channels. The influence of potassium channels may be altered by disease states including chronic hypertension, subarachnoid hemorrhage, and diabetes.

scholarly journals The Matrisome, Inflammation, and Liver Disease

2020 ◽  
Vol 40 (02) ◽  
pp. 180-188 ◽  
Author(s):  
Christine E. Dolin ◽  
Gavin E. Arteel
Keyword(s):  
Extracellular Matrix ◽  
Liver Disease ◽  
Fatty Liver ◽  
Chronic Liver Disease ◽  
Fatty Liver Disease ◽  
Chronic Liver ◽  
Disease Development ◽  
Disease States ◽  
Ecm Proteins

AbstractChronic fatty liver disease is common worldwide. This disease is a spectrum of disease states, ranging from simple steatosis (fat accumulation) to inflammation, and eventually to fibrosis and cirrhosis if untreated. The fibrotic stage of chronic liver disease is primarily characterized by robust accumulation of extracellular matrix (ECM) proteins (collagens) that ultimately impairs the function of the organ. The role of the ECM in early stages of chronic liver disease is less well-understood, but recent research has demonstrated that several changes in the hepatic ECM in prefibrotic liver disease are not only present but may also contribute to disease progression. The purpose of this review is to summarize the established and proposed changes to the hepatic ECM that may contribute to inflammation during earlier stages of disease development, and to discuss potential mechanisms by which these changes may mediate the progression of the disease.

scholarly journals Endospores and other lysis-resistant bacteria comprise a widely shared core community within the human microbiota

2017 ◽  
Author(s):  
Sean M. Kearney ◽  
Sean M. Gibbons ◽  
Mathilde Poyet ◽  
Thomas Gurry ◽  
Kevin Bullock ◽  
...  
Keyword(s):  
Dietary Fatty Acids ◽  
Resistant Bacteria ◽  
Human Gut ◽  
Environmental Signals ◽  
Human Microbiota ◽  
Disease States ◽  
Culture Independent ◽  
Health And Disease ◽  
Over Time

AbstractEndospore-formers in the human microbiota are well adapted for host-to-host transmission, and an emerging consensus points to their role in determining health and disease states in the gut. The human gut, more than any other environment, encourages the maintenance of endospore formation, with recent culture-based work suggesting that over 50% of genera in the microbiome carry genes attributed to this trait. However, there has been limited work on the ecological role of endospores and other stress-resistant cellular states in the human gut. In fact, there is no data to indicate whether organisms with the genetic potential to form endospores actually form endosporesin situand how sporulation varies across individuals and over time. Here, we applied a culture-independent protocol to enrich for endospores and other stress-resistant cells in human feces to identify variation in these states across people and within an individual over time. We see that cells with resistant states are more likely than those without to be shared among multiple individuals, which suggests that these resistant states are particularly adapted for cross-host dissemination. Furthermore, we use untargeted fecal metabolomics in 24 individuals and within a person over time to show that these organisms respond to shared environmental signals, and in particular, dietary fatty acids, that likely mediate colonization of recently disturbed human guts.

scholarly journals Sugar substitutes and dental health

2018 ◽  
Vol 7 (9) ◽  
pp. 1667 ◽  
Author(s):  
Rohan Sachdev
Keyword(s):  
Dental Caries ◽  
Dental Health ◽  
Food Additives ◽  
Sweet Taste ◽  
Sugar Substitutes ◽  
Disease States ◽  
Fermentable Carbohydrates ◽  
Sweetening Agents ◽  
Day By Day

Sugar is one of the most widely consumed sweetening agents. Unfortunately, its use has been linked to various disease states, such as obesity, diabetes mellitus (DM) and dental caries. Dental caries is a chronic disease which can affect us at any age. The role of sugar (and other fermentable carbohydrates such as highly refined flour) as a risk factor in the initiation and progression of dental caries is increasing day by day. Sugar substitutes are food additives that provide a sweet taste more or less similar to that of sugar and plays important role in control of dental caries.

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