scholarly journals Discovery of novel compounds as potent activators of Sirt3

2022 ◽  
Author(s):  
Celina Reverdy ◽  
Gaetan Gitton ◽  
Xiangying Guan ◽  
Indranil Adhya ◽  
Rama Dumpati ◽  
...  
Keyword(s):  
Heart Disease ◽  
Metabolic Diseases ◽  
Docking Studies ◽  
Human Diseases ◽  
Multiple Organs ◽  
Age Related ◽  
Library Technology ◽  
Direct Activator

Among the sirtuin members, Sirt3 is one of the most important deacetylases as it regulates acetylation levels in mitochondria, which are linked to the metabolism of multiple organs and therefore involved in many types of human diseases such as age-related diseases, cancer, heart disease and metabolic diseases. In the current absence of any direct activator of Sirt3, the identification of new modulators could be a key step in the development of new therapeutics. Here we report the discovery of Sirt3 modulators thanks to DNA encoded library technology (ELT). The most enriched compounds after DEL selection against SIRT3 were evaluated according to their activity and affinity. Our best activator seems at least as potent as Honokiol (HKL) while the docking studies tend to show that our modulators probably interact with Sirt3 at an atypical site.

scholarly journals Mitophagy in Human Diseases

2021 ◽  
Vol 22 (8) ◽  
pp. 3903
Author(s):  
Laura Doblado ◽  
Claudia Lueck ◽  
Claudia Rey ◽  
Alejandro K. Samhan-Arias ◽  
Ignacio Prieto ◽  
...  
Keyword(s):  
Myocardial Injury ◽  
Metabolic Diseases ◽  
Vascular Complications ◽  
Human Diseases ◽  
Dietary Interventions ◽  
Age Related ◽  
Autophagic Process ◽  
Preclinical Animal Models ◽  
Potential Use

Mitophagy is a selective autophagic process, essential for cellular homeostasis, that eliminates dysfunctional mitochondria. Activated by inner membrane depolarization, it plays an important role during development and is fundamental in highly differentiated post-mitotic cells that are highly dependent on aerobic metabolism, such as neurons, muscle cells, and hepatocytes. Both defective and excessive mitophagy have been proposed to contribute to age-related neurodegenerative diseases, such as Parkinson’s and Alzheimer’s diseases, metabolic diseases, vascular complications of diabetes, myocardial injury, muscle dystrophy, and liver disease, among others. Pharmacological or dietary interventions that restore mitophagy homeostasis and facilitate the elimination of irreversibly damaged mitochondria, thus, could serve as potential therapies in several chronic diseases. However, despite extraordinary advances in this field, mainly derived from in vitro and preclinical animal models, human applications based on the regulation of mitochondrial quality in patients have not yet been approved. In this review, we summarize the key selective mitochondrial autophagy pathways and their role in prevalent chronic human diseases and highlight the potential use of specific interventions.

scholarly journals Autophagy in Metabolic Age-Related Human Diseases

Cells ◽  
2018 ◽  
Vol 7 (10) ◽  
pp. 149 ◽  
Author(s):  
Manon Moulis ◽  
Cecile Vindis
Keyword(s):  
Metabolic Diseases ◽  
Therapeutic Potential ◽  
Current Knowledge ◽  
Protein Aggregates ◽  
Cellular Mechanism ◽  
Human Diseases ◽  
Age Related ◽  
Metabolic Age ◽  
Dependent Pathway

Autophagy is a highly conserved homeostatic cellular mechanism that mediates the degradation of damaged organelles, protein aggregates, and invading pathogens through a lysosome-dependent pathway. Over the last few years, specific functions of autophagy have been discovered in many tissues and organs; however, abnormal upregulation or downregulation of autophagy has been depicted as an attribute of a variety of pathologic conditions. In this review, we will describe the current knowledge on the role of autophagy, from its regulation to its physiological influence, in metabolic age-related disorders. Finally, we propose to discuss the therapeutic potential of pharmacological and nutritional modulators of autophagy to treat metabolic diseases.

Mutations of mtDNA in some vascular and metabolic diseases

2020 ◽  
Vol 26 ◽  
Author(s):  
Margarita A. Sazonova ◽  
Anastasia I. Ryzhkova ◽  
Vasily V. Sinyov ◽  
Marina D. Sazonova ◽  
Tatiana V. Kirichenko ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Coronary Heart Disease ◽  
Type 2 Diabetes Mellitus ◽  
Heart Disease ◽  
Chronic Diseases ◽  
Metabolic Diseases ◽  
Present Review ◽  
Mtdna Mutations

Background: The present review article considers some chronic diseases of vascular and metabolic genesis, the causes of which may be mitochondrial dysfunction. Very often, in the long course of the disease, complications may occur, leading to myocardial infarction or ischemic stroke and as a result, death.In particular, a large percentage of human deaths nowadays belongs to cardiovascular diseases such as coronary heart disease (CHD), arterial hypertension, cardiomyopathies and type 2 diabetes mellitus. Objective: The aim of the present review was the analysis of literature sources, devoted to an investigation of a link of mitochondrial DNA mutations with chronic diseases of vascular and metabolic genesis, Results: The analysis of literature indicates the association of the mitochondrial genome mutations with coronary heart disease, type 2 diabetes mellitus, hypertension and various types of cardiomyopathies. Conclusion: The detected mutations can be used to analyze the predisposition to chronic diseases of vascular and metabolic genesis. They can also be used to create molecular-cell models necessary to evaluate the effectiveness of drugs developed for treatment of these pathologies. MtDNA mutations associated withthe absence of diseases of vascular and metabolic genesis could be potential candidates for gene therapy of diseases of vascular and metabolic genesis.

scholarly journals The ATP Synthase Deficiency in Human Diseases

Life ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 325
Author(s):  
Chiara Galber ◽  
Stefania Carissimi ◽  
Alessandra Baracca ◽  
Valentina Giorgio
Keyword(s):  
Oxidative Phosphorylation ◽  
Atp Synthase ◽  
Mitochondrial Protein ◽  
High Energy ◽  
Neurocognitive Disorders ◽  
Human Diseases ◽  
Age Related ◽  
Muscle Tissues ◽  
Mitochondrial Atp Synthase ◽  
Genes Encoding

Human diseases range from gene-associated to gene-non-associated disorders, including age-related diseases, neurodegenerative, neuromuscular, cardiovascular, diabetic diseases, neurocognitive disorders and cancer. Mitochondria participate to the cascades of pathogenic events leading to the onset and progression of these diseases independently of their association to mutations of genes encoding mitochondrial protein. Under physiological conditions, the mitochondrial ATP synthase provides the most energy of the cell via the oxidative phosphorylation. Alterations of oxidative phosphorylation mainly affect the tissues characterized by a high-energy metabolism, such as nervous, cardiac and skeletal muscle tissues. In this review, we focus on human diseases caused by altered expressions of ATP synthase genes of both mitochondrial and nuclear origin. Moreover, we describe the contribution of ATP synthase to the pathophysiological mechanisms of other human diseases such as cardiovascular, neurodegenerative diseases or neurocognitive disorders.

scholarly journals Visible Age-Related Signs and Risk of Ischemic Heart Disease in the General Population

Circulation ◽  
2014 ◽  
Vol 129 (9) ◽  
pp. 990-998 ◽  
Author(s):  
Mette Christoffersen ◽  
Ruth Frikke-Schmidt ◽  
Peter Schnohr ◽  
Gorm B. Jensen ◽  
Børge G. Nordestgaard ◽  
...  
Keyword(s):  
Heart Disease ◽  
General Population ◽  
Ischemic Heart Disease ◽  
Ischemic Heart ◽  
Age Related

SGLT2 inhibitors as calorie restriction-mimetics: insights on longevity pathways and age-related diseases

Endocrinology ◽  
2021 ◽  
Author(s):  
Caroline W S Hoong ◽  
Marvin W J Chua
Keyword(s):  
Calorie Restriction ◽  
Stress Resistance ◽  
Target Genes ◽  
Metabolic Diseases ◽  
Vascular Inflammation ◽  
Sglt2 Inhibitors ◽  
Acid Oxidation ◽  
The Metabolic Syndrome ◽  
Age Related ◽  
Energy Deprivation

Abstract SGLT2 inhibitors induce glycosuria, reduce insulin levels, promote fatty acid oxidation and ketogenesis. By promoting a nutrient deprivation state, SGLT2 inhibitors upregulate the energy deprivation sensors AMPK and SIRT1, inhibit the nutrient sensors mTOR and insulin/IGF-1, and modulate the closely-linked HIF-2α/HIF-1α pathways. Phosphorylation of AMPK and upregulation of adiponectin and PPAR-α favour a reversal of the metabolic syndrome which have been linked to suppression of chronic inflammation. Downregulation of insulin/IGF1 pathways and mTOR signalling from a reduction in glucose and circulating amino acids promote cellular repair mechanisms including autophagy and proteostasis which confer cellular stress resistance and attenuate cellular senescence. SIRT1, another energy sensor activated by NAD+ in nutrient-deficient states, is reciprocally activated by AMPK, and can deacetylate and activate transcription factors such as PCG-1α, TFAM and NRF2 that regulate mitochondrial biogenesis. FOXO3 transcription factor which target genes in stress resistance, is also activated by AMPK and SIRT1. Modulation of these pathways by SGLT2 inhibitors have been shown to alleviate metabolic diseases, attenuate vascular inflammation and arterial stiffness, improve mitochondrial function and reduce oxidative stress-induced tissue damage. Compared to other calorie restriction mimetics such as metformin, rapamycin, resveratrol and NAD+ precursors, SGLT2 inhibitors appear to be the most promising in the treatment of ageing-related diseases, due to its regulation of multiple longevity pathways that closely resemble that achieved by calorie restriction, and their established efficacy in reduction in cardiovascular events and all-cause mortality. Evidence is compelling for the role of SGLT2 inhibitors as a calorie restriction mimetic in anti-ageing therapeutics.

scholarly journals Predicting the risk of atherosclerosis in patients with cystic fibrosis – rationale and design of a prospective cohort study

2015 ◽  
Vol 84 (2) ◽  
pp. 126-128
Author(s):  
Edyta Mądry ◽  
Jan Nowak ◽  
Andrzej Wykrętowicz ◽  
Ewa Wenska-Chyży ◽  
Anna Miśkiewicz-Chotnicka ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Cohort Study ◽  
Heart Disease ◽  
Prospective Cohort Study ◽  
Prospective Cohort ◽  
Metabolic Diseases ◽  
Chronic Obstructive ◽  
Science Center ◽  
Obstructive Pulmonary Disease ◽  
Endogenous Factors

The project “Risk of atherosclerosis in cystic fibrosis in relation to the exogenous and endogenous factors that influence the course of the disease” ranked first in the OPUS2 Competition, as announced in May 2012 by the Polish National Science Center. The total value of the grant is 198,580 PLN (ca. 50,000 EUR). The grant was awarded jointly to the Department of Pediatric Gastroenterology and Metabolic Diseases and to the Department of Cardiac Intensive Care at Poznan University of Medical Sciences, Poland. The project will be focused on conducting a prospective cohort study in patients with cystic fibrosis (CF) and healthy controls. Cases of symptomatic and asymptomatic forms of coronary heart disease in patients with CF were reported [1, 2]; however, no data on the epidemiology of atherosclerosis in patients with CF were published so far. In the past, cardiovascular disease in patients with CF used to be limited to pulmonary heart disease as a consequence of end-stage chronic obstructive pulmonary disease [3]. Although hypertension has not yet been officially recognized as a major problem in this population [4], there are reports indicating that it is found in 20% of patients in adult CF care centers [5]. The project is innovative in nature and necessitates close co-operation between cardiology and basic science units.

scholarly journals Response to Letter Regarding Article, “Visible Age-Related Signs and Risk of Ischemic Heart Disease in the General Population: A Prospective Cohort Study”

Circulation ◽  
2014 ◽  
Vol 130 (24) ◽  
Author(s):  
Mette Christoffersen ◽  
Ruth Frikke-Schmidt ◽  
Peter Schnohr ◽  
Gorm B. Jensen ◽  
Børge G. Nordestgaard ◽  
...  
Keyword(s):  
Cohort Study ◽  
Heart Disease ◽  
General Population ◽  
Ischemic Heart Disease ◽  
Prospective Cohort Study ◽  
Prospective Cohort ◽  
Ischemic Heart ◽  
Age Related
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