Sirtuin Modulators in Cellular and Animal Models of Human Diseases

Hong, Jun Young; Lin, Hening

doi:10.3389/fphar.2021.735044

Cited by 23 publications

(14 citation statements)

References 211 publications

(350 reference statements)

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“…Among the seven human sirtuins (SIRT1-7), a growing body of evidence suggests that SIRT1 modulates many signaling pathways by deacetylating substrate proteins involved in metabolic diseases, neurodegeneration, cancer and inflammation, thus linking SIRT1 to several diseases [ 24 ]. Many activators and inhibitors have been discovered to modulate SIRT1 activity [ 25 ] and, in this context, we identified a new chemical class of SIRT1 activators. The design of the newly synthesized derivatives reported in this work was inspired by the common general polyphenolic structure of natural SIRT1 activators such as resveratrol, quercetin and naringenin.…”

Section: Discussionmentioning

confidence: 99%

New Synthetic Analogues of Natural Polyphenols as Sirtuin 1-Activating Compounds

et al. 2022

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NAD+-dependent deacetylase SIRT1 regulates many different biological processes, thus being involved in pathogenic conditions such as metabolic diseases, neurogenerative disorders and cancer. Notably, experimental evidence underlined that the activation of SIRT1 had promising cardioprotective effects. Consequently, many efforts have been so far devoted to finding new SIRT1 activators, both derived from natural sources or prepared by synthetic procedures. Herein, we discovered new SIRT1-activating derivatives, characterized by phenolic rings spaced by sulfur, nitrogen or oxygen-based central linkers. The newly synthesized derivatives were analyzed in enzymatic assays to determine their ability to activate SIRT1, as compared with that of resveratrol. Among the tested molecules, bisarylaniline compound 10 proved to be the most efficient SIRT1 activator. An evaluation of the effects caused by focused structural variations revealed that its para-hydroxy-substituted diphenyl moiety of 10 was the fundamental structural requirement for achieving good SIRT1 activation. Compound 10 was further investigated in ex vivo studies in isolated and perfused rat hearts submitted to ischemia/reperfusion (I/R), where it showed significant protection of the myocardium against I/R injury. Molecular modeling studies suggest the binding mode of 10 within SIRT1 in the presence of the p53-AMC peptide. Our findings reveal that this chemical scaffold may be used as the starting point to develop a new class of more potent SIRT1 activators as cardioprotective agents.

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Section: Discussionmentioning

confidence: 99%

New Synthetic Analogues of Natural Polyphenols as Sirtuin 1-Activating Compounds

et al. 2022

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“…Overall, we uncovered a prominent role for in T-ALL generation and progression, as well as a novel therapeutic target in T-ALL. In this context, it is relevant to note the multiple efforts and compounds described to date to either pharmacologically activate or inhibit SIRT1 (68). Still, the field of SIRT1 pharmacological modulation has been mired in controversy, with many studies disputing the specificity of these compounds, most prominently resveratrol and other purported SIRT1 activators (69).…”

Section: Discussionmentioning

confidence: 99%

A therapeutically targetable NOTCH1-SIRT1-KAT7 axis in T-cell Leukemia

Lancho

Singh

Silva-Diz

et al. 2022

Preprint

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T-cell Acute Lymphoblastic Leukemia (T-ALL) is a NOTCH1-driven disease in need of novel therapies. Here, we identify a NOTCH1-SIRT1-KAT7 link as a therapeutic vulnerability in T-ALL, in which SIRT1 is overexpressed downstream of a novel NOTCH1-bound enhancer. SIRT1 loss impairs leukemia generation, while SIRT1 overexpression accelerates leukemia and confers resistance to NOTCH1 inhibition in a deacetylase-dependent manner. Moreover, secondary SIRT1 loss extends survival and synergizes with NOTCH1 inhibition. Global acetyl-proteomics upon SIRT1 loss uncovered hyperacetylation of KAT7 and BRD1, subunits of a histone acetyltransferase complex targeting H4K12. Metabolic and gene expression profiling revealed a metabolic crisis together with a transcriptional signature resembling KAT7 deletion. Consistently, SIRT1 loss resulted in reduced H4K12ac, and overexpression of a non-acetylatable KAT7 mutant partly rescued SIRT1 loss-induced proliferation defects. The newly unveiled NOTCH1-SIRT1-KAT7 axis uncovers novel therapeutic targets in T-ALL and reveals a circular feedback mechanism balancing deacetylase/acetyltransferase activation with potentially broad relevance in cancer.

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“…Nuclear SIRTs, including SIRT1, 2, 6, and 7, act as regulators of the inflammatory response [ 41 ]. Given the essential function of SIRTs in numerous biological pathways, their dysregulation and abnormal expression are, not surprisingly, associated with a variety of human diseases, including metabolic and neurodegenerative diseases, cardiovascular diseases, cancers, infection, and inflammatory diseases [ 42 , 43 , 44 , 45 ]. There is also a large body of evidence demonstrating a role for SIRTs in the epigenetic control of several target genes and proteins, by the modification of histone and non-histone proteins in both normal and transformed cells.…”

Section: Overview Of Sirtsmentioning

confidence: 99%

Sirtuin 1 in Host Defense during Infection

Kim

Silwal

2022

Cells

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Sirtuins (SIRTs) are members of the class III histone deacetylase family and epigenetically control multiple target genes to modulate diverse biological responses in cells. Among the SIRTs, SIRT1 is the most well-studied, with a role in the modulation of immune and inflammatory responses following infection. The functions of SIRT1 include orchestrating immune, inflammatory, metabolic, and autophagic responses, all of which are required in establishing and controlling host defenses during infection. In this review, we summarize recent information on the roles of SIRT1 and its regulatory mechanisms during bacterial, viral, and parasitic infections. We also discuss several SIRT1 modulators, as potential antimicrobial treatments. Understanding the function of SIRT1 in balancing immune homeostasis will contribute to the development of new therapeutics for the treatment of infection and inflammatory disease.

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Sirtuin Modulators in Cellular and Animal Models of Human Diseases

Cited by 23 publications

References 211 publications

New Synthetic Analogues of Natural Polyphenols as Sirtuin 1-Activating Compounds

New Synthetic Analogues of Natural Polyphenols as Sirtuin 1-Activating Compounds

A therapeutically targetable NOTCH1-SIRT1-KAT7 axis in T-cell Leukemia

Sirtuin 1 in Host Defense during Infection

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