Journal: Pharmacology & therapeutics

Article Title: Sirtuin activators and inhibitors: Promises, achievements, and challenges

doi: 10.1016/j.pharmthera.2018.03.004

Figure Lengend Snippet: Chemical structures for examples of activators and inhibitors for Sirt1 and Sirt6 as isoforms with examples for prospective therapeutic applications.

Article Snippet: Three small molecule SIRT1 activators (SRT2104, SRT2379, SRT3025) have been taken into the clinic by GlaxoSmithKline.

Techniques:

Journal: Pharmacology & therapeutics

Article Title: Sirtuin activators and inhibitors: Promises, achievements, and challenges

doi: 10.1016/j.pharmthera.2018.03.004

Figure Lengend Snippet: (a) Sirtuin catalytic core structure. The crystal structure of human SIRT3 in complex with substrate peptide (magenta) and non-hydrolysable NAD+ analog (gray; PDB ID 4FVT) illustrates the substrate binding sites. (b) Mechanism of Sirtuin-catalyzed NAD+-dependent protein Lys deacylation. (c) Crystal structure of human SIRT1 in complex with FdL substrate peptide (cyan) and three molecules of the STAC resveratrol (green; PDB ID 5BTR). The SIRT1-specific N-terminal STAC binding domain (SBD) and C-terminal regulatory (CTR) segment are indicated. (d) Crystal structure of human SIRT5 in complex with FdL substrate peptide (blue) and the STAC resveratrol (gray; PDB ID 4HDA). (e) Crystal structures of SIRT1 complexes with three different synthetic STACS (green [PDB ID 4ZZH], magenta [PDB ID 4ZZI], orange [PDB ID 4ZZJ]), illustrating that the linker to the SBD allows varying relative orientations of the two domains. Acetyl-peptide and non-hydrolysable NAD+ analog (orange) respective a competitive ELT inhibitor (magenta) are also bound and indicate substrate binding sites. (f) Model for transition of the apo SIRT1 open conformation (left) to the “closed” conformation of SIRT1 (right), with the STAC-bound SBD placed on top of the substrate-bound catalytic core. The important electrostatic interaction between Arg446 and Glu230 is indicated. (g) Crystal structure of human SIRT6 in complex with the NAD+ fragment ADP-ribose (gray) and the STAC UBCS039 (blue; PDB ID 5MF6).

Article Snippet: Three small molecule SIRT1 activators (SRT2104, SRT2379, SRT3025) have been taken into the clinic by GlaxoSmithKline.

Techniques: Binding Assay

Journal: Pharmacology & therapeutics

Article Title: Sirtuin activators and inhibitors: Promises, achievements, and challenges

doi: 10.1016/j.pharmthera.2018.03.004

Figure Lengend Snippet: Selected Sirtuin activators and inhibitors.

Article Snippet: Three small molecule SIRT1 activators (SRT2104, SRT2379, SRT3025) have been taken into the clinic by GlaxoSmithKline.

Techniques: In Vitro, In Vivo, Activity Assay

Journal: Oxidative Medicine and Cellular Longevity

Article Title: SIRT1 Modulators in Experimentally Induced Liver Injury

doi: 10.1155/2019/8765954

Figure Lengend Snippet: Effects of resveratrol and EX-527 pretreatment in lipopolysaccharide-induced acute hepatitis in D-galactosamine-sensitized rats (D-GalN/LPS) on the levels of (a) plasma ALT, (b) TBARS in homogenate and (c) SIRT1 expression. CO: control group; RES: 2.3 mg/kg resveratrol; D-GalN + LPS: 400 mg/kg D-galactosamine with 10 μ g/kg lipopolysaccharide; RES + D-GalN + LPS: 2.3 mg/kg resveratrol + D-GalN + LPS; EX − 527 + RES + D-GalN + LPS: 1 mg/kg EX-527 plus a combination of previous substances. Data are expressed as means ± SEM ( n = 6). a P < 0.05 versus CO. b P < 0.05 versus RES. c P < 0.05 versus D-GalN + LPS. d P < 0.05 versus RES + D-GalN + LPS (courtesy of Physiological Research , reference ).

Article Snippet: To address the ambiguity surrounding “resveratrol and similar polyphenols” and sirtuins, Sirtris Pharmaceuticals Inc. developed a number of synthetic SIRT1 activators: SRT1460, SRT1720, SRT2183, and SRT2104.

Techniques: Clinical Proteomics, Expressing, Control

Journal: Oxidative Medicine and Cellular Longevity

Article Title: SIRT1 Modulators in Experimentally Induced Liver Injury

doi: 10.1155/2019/8765954

Figure Lengend Snippet: Effects of quercetin and SRT1720 pretreatments on (a) SIRT1 and (b) HO-1 protein expressions in lipopolysaccharide-induced hepatitis in D-galactosamine-sensitized (D-GalN/LPS) rats after 24 hours. Beta-actin was used as an endogenous control. CO: negative control, vehicle only; Q: quercetin 50 mg/kg; SRT1720: SRT1720 5 mg/kg; D-GalN/LPS: D-galactosamine 400 mg/kg + lipopolysaccharide 10 μ g/kg; Q + D-GalN/LPS: combination of Q and D-GalN/LPS; SRT1720 + D-GalN/LPS: combination of SRT1720 and D-GalN/LPS. ∗ indicates significant values ( P ≤ 0.05) compared to the negative control group (vehicle only); # indicates significant values ( P ≤ 0.05) compared to the D-GalN/LPS group. The results are expressed as means ± SEM, n = 5 (courtesy of Physiological Research , reference ).

Article Snippet: To address the ambiguity surrounding “resveratrol and similar polyphenols” and sirtuins, Sirtris Pharmaceuticals Inc. developed a number of synthetic SIRT1 activators: SRT1460, SRT1720, SRT2183, and SRT2104.

Techniques: Control, Negative Control

Journal: Oxidative Medicine and Cellular Longevity

Article Title: SIRT1 Modulators in Experimentally Induced Liver Injury

doi: 10.1155/2019/8765954

Figure Lengend Snippet: Effects of quercetin and carbon tetrachloride treatments on SIRT1 and heme oxygenase-1 (HO-1) expressions. (a) Representative Western blot image. (b) Quantification of SIRT1 expression by densitometry. (c) Quantification of HO-1 protein expression by densitometry. Beta-actin was used as an endogenous control. CO: negative control, vehicle only; Q: quercetin; CTC: carbon tetrachloride; Q + CTC: quercetin plus carbon tetrachloride. Data are presented as mean ± SEM, n = 6. ∗ P < 0.05, ∗∗ P < 0.01, or ∗∗∗ P < 0.001 relative to the CO group (vehicle only). ## P < 0.01 relative to the CTC group (courtesy of Elsevier , reference ).

Article Snippet: To address the ambiguity surrounding “resveratrol and similar polyphenols” and sirtuins, Sirtris Pharmaceuticals Inc. developed a number of synthetic SIRT1 activators: SRT1460, SRT1720, SRT2183, and SRT2104.

Techniques: Western Blot, Expressing, Control, Negative Control

Journal: Oxidative Medicine and Cellular Longevity

Article Title: SIRT1 Modulators in Experimentally Induced Liver Injury

doi: 10.1155/2019/8765954

Figure Lengend Snippet: Effects of sirtuin 1-activating compounds (STACs) and inhibitors on chemically induced hepatotoxicity. Hepatotoxins, like D-GalN/LPS and CTC, induce the formation of ROS/RNS in hepatocytes leading to oxidative stress, inflammation, and cell death. SIRT1 is activated and inhibited by stress-responsive factors and plays a dynamic role in regulating cytoprotection and apoptosis depending on the dosing schedule. SIRT1 activation by STACs results to a decrease of cell death and an increase in stress adaptation of hepatocytes due to the activation (↑) or the inhibition (↓) of various signaling and antioxidant molecules (not all included). These hepatoprotective effects can be blocked by administration of SIRT1 inhibitors. Blue →: activation; red ─●: inhibition; AMPK: AMP-activated protein kinase; CTC: carbon tetrachloride; D-GalN: D-galactosamine; FOXOs: forkhead homeobox type O family including FoxO1, FoxO3, and FoxO4; GADD45: growth arrest and DNA damage-inducible protein; GCL: glutamate cysteine ligase; GST: glutathione transferase; HO-1: heme oxygenase-1; IL-1/6: interleukin-1/6; iNOS: inducible nitric oxide synthase; JNK: c-Jun N-terminal kinase; LPS: lipopolysaccharide; miR-34a: microRNA-34a; NAD + : nicotinamide adenine dinucleotide; p53: tumor suppressor protein p53; PGC-1 α : peroxisome proliferator-activated receptor gamma coactivator 1 alpha; Prx: peroxiredoxins; RelA/p65/NF- κ B: RelA/p65 subunit of nuclear factor kappa-B; ROS: reactive oxygen species; RNS: reactive nitrogen species; SIRT1: silent information regulator (two) 1 (sirtuin 1); SOD2: superoxide dismutase 2; TNF- α : tumor necrosis factor-alpha.

Article Snippet: To address the ambiguity surrounding “resveratrol and similar polyphenols” and sirtuins, Sirtris Pharmaceuticals Inc. developed a number of synthetic SIRT1 activators: SRT1460, SRT1720, SRT2183, and SRT2104.

Techniques: Activation Assay, Inhibition