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Epigallocatechin-3-Gallate in Alzheimer’s Disease
Published in Atanu Bhattacharjee, Akula Ramakrishna, Magisetty Obulesu, Phytomedicine and Alzheimer’s Disease, 2020
Khaleel Pasha Md, Magisetty Obulesu
When inhibited, neprilysin (NEP), a vital Aβ-degrading enzyme, induces Aβ aggregation in sporadic late-onset AD patients (Marr et al., 2003; Hama et al., 2004; Miners et al., 2006; Polito et al., 2018). Treatment with EGCG enhanced the degradation of Aβ by initiating extracellular signal-regulated kinase (ERK) activity, indicating a potential therapeutic effect of EGCG against AD (Yamamoto et al., 2017; Polito et al., 2018). EGCG administration also enhanced NEP activity in blood plasma, the hippocampus, and the cortex, as well as ameliorating memory loss in the 8-arm maze and object recognition tests (Zhuvarin et al., 2019).
Circulatory controls
Published in Burt B. Hamrell, Cardiovascular Physiology, 2018
Patients with aortic valvular stenosis and left ventricular hypertrophy eventually develop heart failure that is characterized by myocardial and vascular remodeling, and myocardial apoptosis and fibrosis. Relatively recent findings show that ANP and BNP act to reduce these adverse myocardial and vascular changes in heart failure. The clinical use of these beneficial effects of ANP and BNP is currently being investigated. The action of natriuretic peptides, particularly ANP, is terminated by enzymatic degradation by neprilysin. Neprilysin is produced in vascular endothelial cells and the tubular cells of the kidney. Clinical testing of neprilysin inhibitors have been carried out recently and show promise for heart failure treatment.
The Ayurvedic Treatment of Neurodegenerative Diseases
Published in Anne George, K. S. Joshy, Mathew Sebastian, Oluwatobi Samuel Oluwafemi, Sabu Thomas, Holistic Approaches to Infectious Diseases, 2017
Another interesting action of Withania somnifera against AD was recently defined, not in the central nervous system, but in the periphery. There is a degrading protease in the periphery, namely in the liver, called neprilysin that can potently destroy Aβ plaques. Withania somnifera was found not only to upregulate the processivity of neprilysin, but to also enhance the trafficking of Aβ plaques out of the brain via the lipoprotein receptor-related protein. Hence, Withania somnifera can be used to directly reduce the number of Aβ plaques and thus pharmacologically eliminate AD (Sehgai et al., 2012).
Safety and efficacy considerations amongst the elderly population in the updated treatment of heart failure: a review
Published in Expert Review of Cardiovascular Therapy, 2022
Further, within the ARNI, valsartan is partnered with another active chemical that promotes other beneficial effects, sacubitril. Sacubitril is classified as a prodrug that is activated by blood proteins called esterases [12]. The activated metabolite of sacubitril is then able to inhibit the enzyme, neprilysin [12]. Neprilysin is a neutral endopeptidase located on the surface of the cells where this enzyme can degrade natriuretic peptides, bradykinin and adrenomedullin [13]. Neprilysin also breaks down angiotensin II, so blocking neprilysin leads to an increase in angiotensin II [3]. Therefore, valsartan is added to counteract this increase. By inhibiting neprilysin activity, sacubitril indirectly increases brain natriuretic peptide (BNP), and the vasodilators, bradykinin and adrenomedullin [12]. BNP is the main endocrine peptide in the pathophysiology of heart failure [13]. BNP is created and processed and made in the cardiac muscle cells of the ventricles [13]. Once released, the peptide causes dilation in the arteries and veins, increased excretion of sodium and chloride, followed by increased excretion of water; thus, reducing the blood volume [13]. This is completed by BNP binding to the natriuretic peptide receptor A: upon binding, an increase in the levels of the secondary messenger cyclic guanosine monophosphate carries out the previously explained diuretic effect [13]. To conclude, sacubitril provides benefits in treating heart failure by increasing BNP and reducing the volume of blood required for the heart to pump.
New pharmacotherapy for heart failure with reduced ejection fraction
Published in Expert Review of Cardiovascular Therapy, 2020
Sara Sotirakos, Peter Wheen, James Spiers, Richard Armstrong
Atrial Natriuretic Peptide (ANP), or A-type, and Brain Natriuretic Peptide (BNP), or B-type, originate within myocardial cells and act antagonistically to the ANG-II mediated effects of the RAAS [5]. C-type Natriuretic Peptide (CNP) originates within the endothelium of blood vessels [5]. Activity of the RAAS system and circulating levels of ANP are both elevated in HF [5,9]. To note, the levels of natriuretic peptides are often assessed by measuring the N-terminus Pro-ANP (NT-proANP) or N-terminus Pro-BNP (NT-proBNP), which are the non-active prohormones that circulate longer and serve as an estimate of ANP or BNP levels [9]. Why would we want to increase levels of natriuretic peptides further using sacubitril/valsartan? As shown in Figure 1, natriuretic peptides mediate anti-RAAS effects such as vasodilation, lowered sympathetic tone, and natriuresis. Neprilysin is one of the key enzymes in the breakdown of these peptides [10]. Neprilysin has the highest affinity for ANP, CNP, ANG-I, and ANG-II; and lower affinities for BNP, endothelin-1, and bradykinin [11]. Inhibition of the breakdown of these natriuretic peptides allows this system to run at a higher capacity to the RAAS system. However, inhibition of neprilysin as a monotherapy has shown ineffective as neprilysin also breaks down ANG-II [10]. Sacubitril is therefore used in combination with valsartan, achieving an enhanced effect by decreasing activity of the RAAS system via the ARB valsartan and increasing activity of the natriuretic peptides via the NEP-I Sacubitril [12].
Advanced heart failure with reduced ejection fraction
Published in Baylor University Medical Center Proceedings, 2020
Albert Hicks, Jorge F. Velazco, Salman Gohar, Ahmed Seliem, Shelley A. Hall, Jeffrey B. Michel
Endogenous peptides such as brain natriuretic peptide (BNP) have vasodilatory and preload-reducing properties and are released in response to elevated left ventricular pressures, making them attractive targets for heart failure therapy. Neprilysin is a naturally occurring enzyme that degrades BNP. In 2002 omapatrilat, a combination of an ACEI and a neprilysin inhibitor, was compared to enalapril in the OVERTURE trial for treatment of heart failure.11 The primary endpoint was a composite of death and heart failure hospitalization. Omapatrilat was found to be noninferior to enalapril but demonstrated worse outcomes in black patients and higher rates of angioedema compared to the enalapril group. In 2005 nesiritide, a recombinant form of human BNP, in a meta-analysis demonstrated an increased risk of mortality in acutely decompensated heart failure patients compared to the control group.12 Despite the negative results of these endogenous peptide trials, further attempts to utilize this treatment pathway continued. To reduce the risk of angioedema, a neprilysin inhibitor in combination with an angiotensin receptor blocker (ARB) was studied.