4.2 RES as activator of sirtuins and other biological target structures
There are several molecular activities discussed that should convey the health-promoting effects of RES. In one of the most important (if not the decisive one) study, it was shown that RES modulates the activity of the silent mating type information regulation 2 homolog 1 (SIRT1) (3). SIRT1 belongs to a protein family consisting of seven (SIRT1-SIRT7) individual members that are unique Nicotinamide adenine dinucleotide (NAD+)-deacetylases. They regulate cellular energy metabolism, mitochondrial function, and modulate stress responses by interacting with multiple signalling proteins, transcriptional factors and poly (ADP-ribose) polymerases (PARPs) (33). In the study by …show more content…
Particularly, several studies were initiated to unravel the structural basis for the observed allosteric, substrate-dependent stimulation of SIRT1 activity by the stilbenoid RES. In this regard, a crystal structure of SIRT1 in complex with RES and a 7-amino-4-methylcoumarin (AMC)-containing peptide provided valuable structural insights into the regulation of SIRT1 activity by RES (34). In the proposed model, each SIRT1 can bind to three RES molecules (Figure 5A). Two of these RES molecules make hydrogen bonds with both the extended N-terminal domain (NTD) and the p53-AMC, while the third RES molecule contacts the catalytic domain of SIRT1 (Figure 5B). The individual RES molecules are packed into preformed protein pockets in which a close network of hydrophobic and van de Waals interactions are possible (Figure 5C). Based on the proposed structure, it was suggested that RES serves as a molecular adapter bridging the NTD moiety and the peptide together by principally interacting with the peptidyl-AMC on one side and via specific NTD residues on the other side. These interactions provoke conformational changes that are responsible for lowering the Michaelis constant value between the peptide to be acetylated and …show more content…
In this study, patients receiving 0.5 g trans-RES for 12weeks showed a significant reduction in liver enzymes, inflammatory cytokines, NF-κB activity and hepatic steatosis grade as compared with those that received the same amount of a medium-chain triglyceride placebo. A rather similar study that enrolled 60 subjects with NAFLD that were given two 150 mg RES capsules twice daily for three months showed significantly improvement of several biomarkers including liver enzymes, glucose, low-density lipoprotein cholesterol, total cholesterol, and insulin resistance index (50). In contrast to these encouraging studies, another very recent, randomised, clinical trial from Denmark that enrolled 28 overweight patients found no indication that RES treatment (1.5 g RES/d for 6months) had any consistent therapeutic effect (51).
Since the number of clinical trials that test RES as a liver therapeutic are still scarce and those reported are rather contradictory, it is presently hard to estimate the beneficial effects for therapy of human liver disease. Therefore, it is too early to recommend therapeutic application of RES in human liver disease. There is a mandatory need for future clinical studies with appropriate design and higher numbers of patients. These are urgently needed to clarify the true impact of RES treatment in liver diseased
There are several molecular activities discussed that should convey the health-promoting effects of RES. In one of the most important (if not the decisive one) study, it was shown that RES modulates the activity of the silent mating type information regulation 2 homolog 1 (SIRT1) (3). SIRT1 belongs to a protein family consisting of seven (SIRT1-SIRT7) individual members that are unique Nicotinamide adenine dinucleotide (NAD+)-deacetylases. They regulate cellular energy metabolism, mitochondrial function, and modulate stress responses by interacting with multiple signalling proteins, transcriptional factors and poly (ADP-ribose) polymerases (PARPs) (33). In the study by …show more content…
Particularly, several studies were initiated to unravel the structural basis for the observed allosteric, substrate-dependent stimulation of SIRT1 activity by the stilbenoid RES. In this regard, a crystal structure of SIRT1 in complex with RES and a 7-amino-4-methylcoumarin (AMC)-containing peptide provided valuable structural insights into the regulation of SIRT1 activity by RES (34). In the proposed model, each SIRT1 can bind to three RES molecules (Figure 5A). Two of these RES molecules make hydrogen bonds with both the extended N-terminal domain (NTD) and the p53-AMC, while the third RES molecule contacts the catalytic domain of SIRT1 (Figure 5B). The individual RES molecules are packed into preformed protein pockets in which a close network of hydrophobic and van de Waals interactions are possible (Figure 5C). Based on the proposed structure, it was suggested that RES serves as a molecular adapter bridging the NTD moiety and the peptide together by principally interacting with the peptidyl-AMC on one side and via specific NTD residues on the other side. These interactions provoke conformational changes that are responsible for lowering the Michaelis constant value between the peptide to be acetylated and …show more content…
In this study, patients receiving 0.5 g trans-RES for 12weeks showed a significant reduction in liver enzymes, inflammatory cytokines, NF-κB activity and hepatic steatosis grade as compared with those that received the same amount of a medium-chain triglyceride placebo. A rather similar study that enrolled 60 subjects with NAFLD that were given two 150 mg RES capsules twice daily for three months showed significantly improvement of several biomarkers including liver enzymes, glucose, low-density lipoprotein cholesterol, total cholesterol, and insulin resistance index (50). In contrast to these encouraging studies, another very recent, randomised, clinical trial from Denmark that enrolled 28 overweight patients found no indication that RES treatment (1.5 g RES/d for 6months) had any consistent therapeutic effect (51).
Since the number of clinical trials that test RES as a liver therapeutic are still scarce and those reported are rather contradictory, it is presently hard to estimate the beneficial effects for therapy of human liver disease. Therefore, it is too early to recommend therapeutic application of RES in human liver disease. There is a mandatory need for future clinical studies with appropriate design and higher numbers of patients. These are urgently needed to clarify the true impact of RES treatment in liver diseased