doi:10.1016/j.fct.2014.08.005, Muthian, G., Bright, J. J. Given the experimental efficacy of the antidiabetic and antidyslipidemia action of BBR, most of the 18 completed or terminated clinical trials focused on these properties.
Many of them even inhibit Sirtuin 6, which is why we had to protect the ingredient Its laborious, complex and painful to produce, which means supply is limited. 750 (1), 6082. Oxid. Another phase 2 clinical study (NCT03325322) intends to evaluate the effects of oral fisetin on adipose tissue-derived mesenchymal stem/stromal cell function, kidney function, inflammation, and physical function in subjects with chronic kidney diseases and diabetes. The role of RSV as an immune response modulator was demonstrated in both in vitro and in vivo studies, where it reversed immune senescence in older rats, reduced inflammatory responses in rodents, and improved immunological activity against cancer cells (Malaguarnera, 2019). Bioactive compounds in the diet can act as antioxidant and anti-inflammatory agents, thereby reducing the negative effects of oxidative stress and the incidence of chronic diseases such as obesity, diabetes, and cardiovascular disorders (Wang et al., 2014). Annu. Recent research showed that oxidized LDL (oxLDL) induces oxidative stress (Lara-Guzman et al., 2018). Brain Res. doi:10.3390/molecules19010291, de Boer, V. C., de Goffau, M. C., Arts, I. C., Hollman, P. C., Keijer, J. Taken together, these findings highlight the beneficial effects of RSV against oxidative stress, which is involved in major pathologies such as heart and metabolic disorders. A recent study reported that fisetin reduces myocardial tissue damage in a reperfusion ischemia model by suppressing mitochondrial oxidative stress and inhibiting glycogen synthase kinase 3 (Shanmugam et al., 2018). 80 (2), 6273. After we showed that not all harvests of this ingredient activate Sirtuin 6, we set about finding those that did. Pharmacol. Mitochondrial Dynamic Dysfunction as a Main Triggering Factor for Inflammation Associated Chronic Non-Communicable Diseases. Cell Longev. SIRT1 and PGC-1 expression levels were decreased in rat MI/R groups, but were significantly increased after treatment with Que (Tang et al., 2019). showed an increase in AMPK phosphorylation and SIRT1 expression levels, while in vitro results revealed a reduction in lipid accumulation and an increase in lipolysis. Ther. Nutr. (2013). Lett. Further investigations will be required to provide a more detailed understanding. 72 (3), 371380.
doi:10.1007/s11684-019-0724-6, Sun, T., Zhang, Y., Zhong, S., Gao, F., Chen, Y., Wang, B., et al. Med. The data reported by Liou et al. doi:10.1002/mnfr.201801390, Geraets, L., Moonen, H. J., Brauers, K., Wouters, E. F., Bast, A., Hageman, G. J.
24 (5), 542552. Various supplements use a mixture of macroalgae, others stick to one and some products combine fucoidan with vitamins or other ingredients; as with all supplements, customers should examine provenance, purity and efficacy before deciding on a regimen, and luckily there is a wealth of academic evidence on the effects of fucoidan out there for the interested reader. It was very recently shown that Que (70 mg/kg) can reduce insulin resistance and improve glucose metabolism by reducing sensitivity to T2D/insulin resistance in ob/ob mice via SIRT1 activation (Hu et al., 2020). Berberine Ameliorates Doxorubicin-Induced Cardiotoxicity via a SIRT1/p66Shc-Mediated Pathway. Specifically, in a study to develop a therapeutic strategy for osteoarthritis, Que was shown to increase expression levels of SIRT1, PGC-1, NRF1 and NFR2, TFAM, and phospho-AMPK in osteoarthritis rats, confirming the hypothesis that Que might act via the AMPK/SIRT1 signaling pathway (Qiu et al., 2018). In contrast, under stress conditions Keap1 activity is inhibited by phosphorylation and free Nrf2 moves to the nucleus, where it binds to ARE in the regulatory regions of cytoprotective proteins and promotes transcription of antioxidant genes such as SOD, glutathione peroxidase (GPx), and GSH, and of phase II detoxifying enzymes such as heme oxygenase-1 (HO-1), glutathione transferases (GST), nicotinamide adenine dinucleotide phosphate (NADPH), and NAD(P)H dehydrogenase [quinone] 1 (NQO1) (Serafini et al., 2019). In particular, two phase 4 clinical trials (NCT02422927 and NCT03470376) tested the ability of a nutraceutical combination containing 500 mg BBR to ameliorate inflammation lipid profile and endothelial injury markers in patients with elevated levels of high-sensitivity C-reactive protein and in HIV-infected patients receiving stable antiretroviral therapy. Cur-induced SIRT1 upregulation has beneficial effects against a range of diseases including cardiac fibrosis, diabetes, and ischemia/reperfusion injury (Zendedel et al., 2018 #7; Yang et al., 2013 #5). Front. Fisetin Protects Against Hepatic Steatosis Through Regulation of the Sirt1/AMPK and Fatty Acid beta-Oxidation Signaling Pathway in High-Fat Diet-Induced Obese Mice. Health promotion by flavonoids, tocopherols, tocotrienols, and other phenols: direct or indirect effects? 19 (12), 3903. doi:10.3390/ijms19123903, Zordoky, B. N., Robertson, I. M., Dyck, J. R. (2015). (2017). Impact of curcumin on sirtuins: A review. J. Nutr. 2015:905749. doi:10.1155/2015/905749, Piotrowska, H., Kucinska, M., Murias, M. (2012). J. Clin. 65, 667679. Under normal conditions, the cystine-rich zinc Keap1 metalloprotein binds Nrf2 inside the cytoplasm, promoting ubiquitination and consequent proteasomal degradation and preventing Nrf2 nuclear translocation (Serafini et al., 2019). Protective effect of resveratrol against pressure overload-induced heart failure. Curcumin improves exercise performance of mice with coronary artery ligation-induced HFrEF: Nrf2 and antioxidant mechanisms in skeletal muscle. BBR in combination with RSV displayed hypolipidemic effects likely mediated by SIRT1 expression regulation. Here, we focus on the natural molecules resveratrol, quercetin, fisetin, curcumin, and berberine, and elucidate their effect on SIRT1 activation and their potential to treat and/or prevent several human pathologies, mainly associated with metabolic disorders (Figure 2). BioMed. EMBO J. It is also evident that a more robust correlation between health effects and administration of the bioactive compounds needs to be established in order to understand their biological impact and their direct association with SIRT activation. Although RSV is beneficial in many contexts, its pleiotropic actions need to be better studied in order to understand which of its described activities are directly due to SIRT1 modulation and whether this effect is always direct. 23 (12), 23692380. J. Diabetes Res. After ingestion, these compounds are in fact detected as phase II metabolites and their blood level does not exceed concentrations in the nM range. SIRT1 regulates metabolic pathways, cell survival, cellular senescence, and inflammation, and acts in the pathogenesis of chronic conditions such as diabetes as well as pulmonary, neurodegenerative, and cardiovascular diseases. Nutr. New SIRT6 activator supplement hits the market, Copyright 2022 FIRST LONGEVITY Limited. B. Nutrients 10 (11), 1651. doi:10.3390/nu10111651, Chassot, L. N., Scolaro, B., Roschel, G. G., Cogliati, B., Cavalcanti, M. F., Abdalla, D. S. P., et al. 2016:1689602. doi:10.1155/2016/1689602, Yu, Y., Sun, J., Wang, R., Liu, J., Wang, P., Wang, C. (2019). Sirtuins are class III histone deacetylases, whose enzymatic activity is dependent on NAD+ as a cofactor. The authors hypothesized that Que might improve MI/R-induced myocardial damage via regulation of SIRT1/PGC-1 and Bcl-2/Bax pathways (Tang et al., 2019). The immunostimulating effect of Que is due to induction of the expression of interferon- (IFN-) derived from Th-1 and inhibition of IL-4 derived from Th-2 in normal peripheral blood mononuclear cells (Nair et al., 2002). Adv. Via regulation of p53 deacetylation and modulation of autophagy, SIRT1 is implicated in cellular response to caloric restriction and lifespan extension. (2016). Sirtuins at the crossroads of stemness, aging, and cancer. (2015). Most of the evidence supporting the beneficial effects of phytochemical compounds comes from in vitro or animal studies, while human studies evaluating the long-term impact of phytomolecules are particularly few or inconsistent. Res. Life Sci. 24, 36. doi:10.1186/s11658-019-0158-9, Rodgers, J. T., Lerin, C., Haas, W., Gygi, S. P., Spiegelman, B. M., Puigserver, P. (2005). Caloric restriction and its mimetics. Berberine Protects Secondary Injury in Mice with Traumatic Brain Injury Through Anti-oxidative and Anti-inflammatory Modulation. A recent in vitro study showed that RSV reduces hypoxia-induced apoptosis in H9C2 cells through activation of SIRT1/miR-30d-5p/NF-B axis (Han et al., 2020). M. Lamprecht (Boca Raton, FL: CRC Press/Taylor & Francis), Kris-Etherton, P. M., Hecker, K. D., Bonanome, A., Coval, S. M., Binkoski, A. E., Hilpert, K. F., et al. Evidence for novel mechanisms involving SOCS-1, -3 and p38 MAPK. Rep. 8 (1), 15726. doi:10.1038/s41598-018-33879-w, Serafini, M. M., Catanzaro, M., Fagiani, F., Simoni, E., Caporaso, R., Dacrema, M., et al. Table 1 Classification of nutraceuticals based on their action and food source. A greater insight into the selectivity and specificity of natural SIRT activators may help understand the myriad beneficial effects described to date. Exp. (1985) 126 (2), 477486. Because of the pleiotropic actions of RSV, clinical trials are currently testing its therapeutic potential in a wide range of human diseases. However, some studies highlighted the potential ability of BBR to prevent oxidative stress-induced senescence by activating AMPK and restoring NAD+ levels (Song et al., 2020). These findings show that Cur-induced cardio-protection was mediated by SIRT1 (Yang et al., 2013). 25 (1), 118. Cardioprotective effect of a moderate and prolonged exercise training involves sirtuin pathway. Identification of a SIRT1 mutation in a family with type 1 diabetes. Clin. J. Chin. Cur is able to activate Nrf2/Keap1/ARE signaling pathway by Michael reaction with thiol residues in Keap1, inducing the release and activation of Nrf2 and promoting antioxidant effects (Wafi et al., 2019; Yu et al., 2019). Endale, M., Park, S. C., Kim, S., Kim, S. H., Yang, Y., Cho, J. Y., et al. 8 (4), 542547. In different organisms (S. cerevisiae, C. elegans, and D. melanogaster) expressing SIRT1 (or its homologous genes), RSV treatment is able to extend life span. Fisetin: a dietary antioxidant for health promotion. doi:10.1016/j.biopha.2017.03.102, Jimenez-Flores, L. M., Lopez-Briones, S., Macias-Cervantes, M. H., Ramirez-Emiliano, J., Perez-Vazquez, V. (2014). Cardiovasc. Sirtuins are reported to modulate numerous activities by controlling gene expression, DNA repair, metabolism, oxidative stress response, mitochondrial function, and biogenesis. 3 (4), 437441. Que can also act as both an antioxidant and pro-oxidant agent. Discovery of curcumin, a component of golden spice, and its miraculous biological activities. As well as activating SIRT1, BBR is also able to decrease FOXO1 acetylation, triggering anti-apoptotic signaling pathways via Bcl-2 expression, and Bax and caspase-3 downregulation (Yu et al., 2016). doi:10.1016/j.cmet.2013.02.001, Brasnyo, P., Molnar, G. A., Mohas, M., Marko, L., Laczy, B., Cseh, J., et al. Biofactors 46 (1), 168179. 17 (3), 448455. In vivo and in vitro experiments on rat heart and cardiomyocytes showed that Cur pre-treatment had protective effects, decreasing myocardial infarct size (Yang et al., 2013). Fisetin targets YB-1/RSK axis independent of its effect on ERK signaling: insights from in vitro and in vivo melanoma models. Maternal quercetin administration during gestation and lactation decrease endoplasmic reticulum stress and related inflammation in the adult offspring of obese female rats. Protective Effect of Resveratrol against Ischemia-Reperfusion Injury via Enhanced High Energy Compounds and eNOS-SIRT1 Expression in Type 2 Diabetic Female Rat Heart. The most studied member of this enzymatic class is SIRT1. Cell Physiol. J. 5, 253295. The dietary flavonoid fisetin (3,3,4,7-tetra-hydroxyflavone) is a natural polyphenol present in plants and fruits such as apples, persimmons, grapes, onions, kiwi, kale, and strawberries, whose daily intake is estimated to be about 0.4mg (Khan et al., 2013). A., Kim, C. W. (2008). Fisetin treatment in NAFLD mice reduced epididymal adipose tissue, hepatocyte steatosis, and fatty acid synthesis. The effect of hesperidin and quercetin on oxidative stress, NF-kappaB and SIRT1 levels in a STZ-induced experimental diabetes model. doi:10.1080/13813455.2019.1662452, Song, D., Hao, J., Fan, D. (2020). Indeed, SIRT1 has been reported to play a key role in tumorigenesis, as an oncogene or tumor suppressor depending on the context specificity (Biason-Lauber et al., 2013). In vivo data showed that BBR combined with RSV lowered total cholesterol, triglyceride, and LDL cholesterol levels in mice. Neurochem. Sci. The main mechanisms of action common to polyphenol and non-polyphenol molecules that lead to antioxidant and anti-inflammatory effects via SIRT1 activation are reported in Figure 1.
(2019). J. Nutr. Biochem. Front. In oral carcinoma cell lines and in SCC-4 cells, BBR inhibits expression of COX2 and AP-1 bond, decreases prostaglandin E2 (PGE2) production, and suppresses NF-B, IKK, ERK, and JNK activities. doi:10.18632/aging.103059, Huang, S. X., Qiu, G., Cheng, F. R., Pei, Z., Yang, Z., Deng, X. H., et al. Numerous studies have provided evidence of the protective effects of natural polyphenolic substances such as resveratrol, quercetin, curcumin, and fisetin, and of natural non-polyphenolic substances such as berberine (McCubrey et al., 2017). Med. Silent information regulator 1 protects the heart from ischemia/reperfusion. doi:10.1016/j.cellsig.2013.06.007, Khan, N., Syed, D. N., Ahmad, N., Mukhtar, H. (2013). Fucoidan supplements are widely available, and claim to aid digestion, strengthen the immune system, support chemotherapy by reducing cancer-related inflammation and improve circulation [5]. Data obtained in a rat model and in rat H9c2 cardiac cells showed that BBR treatment leads to upregulation of SIRT1 and downregulation of p66shc expression both in vivo and in vitro, resulting in suppression of ROS production, apoptosis, and mitochondrial damage, and improving cardiac dysfunction. doi:10.2337/db12-0117, Wafi, A. M., Hong, J., Rudebush, T. L., Yu, L., Hackfort, B., Wang, H., et al.
(2015). (2013). RSV treatment decreased cortical and hippocampal malondialdehyde levels while increasing SOD activity and SIRT1 expression in a diabetic rat model (Ma et al., 2019). 2019:8278454. doi:10.1155/2019/8278454, Yu, L., Li, Q., Yu, B., Yang, Y., Jin, Z., Duan, W., et al. Front. doi:10.1007/s00394-014-0673-4, Wu, Y. Antagonistic crosstalk between NF-kappaB and SIRT1 in the regulation of inflammation and metabolic disorders. Med. Berberine Attenuates Myocardial Ischemia/Reperfusion Injury by Reducing Oxidative Stress and Inflammation Response: Role of Silent Information Regulator 1. Rev. A previous study had also shown that SIRT1 activation promotes antioxidant molecule production and decreases pro-apoptotic proteins through FOXO1 activation, thus protecting against MI/R lesions (Hsu et al., 2010).
Immune Disord. RSV was shown to be involved in the activation of macrophages, T cells, and natural killer cells, as well as in the suppression processes of CD4+ CD25+ regulatory T cells (Yang et al., 2008; Svajger and Jeras, 2012). Neuroprotective Effect of Resveratrol via Activation of Sirt1 Signaling in a Rat Model of Combined Diabetes and Alzheimers Disease. (2019). Nutr. 120 (6), 97479757. Cardiomyocytes treated by Cur displayed upregulation of SIRT1, COX, and succinate dehy-drogenase (SDH), and downregulation of Bax. Sci. (2013). Front. Bull. SIRT6Activator is a natural product derived from a strain of seaweed is called Fucus Vesiculosus. (2016). (2017). At low concentrations (1010 M), Que displayed a protective effect against oxidative DNA damage (in vitro) in human lymphocytes (Li et al., 2016). Pharmacol. BBR attenuated oxidative stress by increasing SOD1 levels through activation of SIRT1 and inhibition of miR-106b expression (Chen and Yang, 2017). Increased fatty acid synthesis and hepatocyte accumulation is associated with metabolic disorder (Liou et al., 2018). Exp. A list of completed studies using Que in different metabolic and inflammatory conditions is reported in Table 3. Ed. Interesting results from three phase 2/3 clinical studies showed that Cur (as capsules or gel) prevents or reduces radiation-induced dermatitis in breast cancer patients receiving radiotherapy, enhancing the function of normal tissues (NCT01246973, NCT01042938, NCT02556632). Food Res. Toxicol. doi:10.1016/j.jnutbio.2013.09.001, Wong, A., Woodcock, E. A. Received: 14 April 2020; Accepted: 27 July 2020;Published: 07 August 2020. Patients were subjected to five different Cur doses (500, 1,000, 2,000, 4,000, and 8,000 mg) every day for 3 months, and data showed that Cur treatment up to 8,000 mg/day is not toxic (Hsu and Cheng, 2007). Activated SIRT1 interrupts TLR4/NF-B/STAT axis, reduces cytokine production by inactivated immune cells, and inhibits pro-inflammatory factors derived from macrophages/mast cells, such as platelet-activating factor and TNF- (Capiralla et al., 2012). Nutrients 11 (5), 946. doi:10.3390/nu11050946, McCubrey, J. SIRT1-mediated FoxOs pathways protect against apoptosis by promoting autophagy in osteoblast-like MC3T3-E1 cells exposed to sodium fluoride. The fact that studies indicate that the majority of SIRT activators (or at least SIRT1-targeting activators) exert both direct activating effects and indirect effects via modulation of SIRT1 downstream pathways complicates the interpretation of results and, particularly, the mining of data specifically dependent on direct SIRT1 binding and activation. Physiol. doi:10.1017/S0007114511000316, Brunet, A., Sweeney, L. B., Sturgill, J. F., Chua, K. F., Greer, P. L., Lin, Y., et al. Quercetin improve ischemia/reperfusion-induced cardiomyocyte apoptosis in vitro and in vivo study via SIRT1/PGC-1alpha signaling. doi:10.1161/CIRCULATIONAHA.110.958033, Hu, T., Shi, J. J., Fang, J., Wang, Q., Chen, Y.
(2013). Biol. Resveratrol mitigates lipopolysaccharide- and Abeta-mediated microglial inflammation by inhibiting the TLR4/NF-kappaB/STAT signaling cascade. Mediterranean Diet and Prevention of Chronic Diseases. The beneficial effects of fisetin were also linked to its action as a caloric restriction mimetic (CRM) (Singh et al., 2018). Today 52 (5), 208222. (2017). Fisetin, a potential caloric restriction mimetic, modulates ionic homeostasis in senescence induced and naturally aged rats.
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