Nutrients 11 (1), 105. doi:10.3390/nu11010105, Galleggiante, V., De Santis, S., Liso, M., Verna, G., Sommella, E., Mastronardi, M., et al. The antioxidant and anti-inflammatory effects of BBR were also investigated in heart (Yu et al., 2016). 2018:9173436. doi:10.1155/2018/9173436, Shentu, T. P., He, M., Sun, X., Zhang, J., Zhang, F., Gongol, B., et al. Preclinical and clinical evidence for the role of resveratrol in the treatment of cardiovascular diseases. Curcumin Management of Myocardial Fibrosis and its Mechanisms of Action: A Review. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). 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. J. Med. Due to its poor solubility, short half-life, and low bioavailability, its medical use is limited (Konrad and Nieman, 2015). Ed.
113 Suppl 9B, 71S88S. Effects of isoquinoline alkaloid berberine on lipid peroxidation, antioxidant defense system, and liver damage induced by lead acetate in rats. Oral. The overproduction of reactive oxygen species (ROS), including free radicals, and reactive nitrogen species (RNS) can lead to damage of cellular components, such as lipids, proteins, and DNA. doi:10.12659/MSM.911714, Zhu, X., Yang, J., Zhu, W., Yin, X., Yang, B., Wei, Y., et al. Cur can downregulate expression of growth factor receptors, transcription factors, TNFs, and nitric oxide synthase, and increase AMPK levels. J. Clin. J. Clin. Regulation of SIRT1 by oxidative stress-responsive miRNAs and a systematic approach to identify its role in the endothelium. Another study investigated Cur-mediated effects in patients with chronic non-alcoholic pancreatitis, showing that patients had a strong reversal of lipid peroxidation (Durgaprasad et al., 2005). 109, 21362144. Nat. doi:10.1038/onc.2017.296, Sampaio, S. F., Branco, A. F., Wojtala, A., Vega-Naredo, I., Wieckowski, M. R., Oliveira, P. J. Berberine induces apoptosis through a mitochondria/caspases pathway in human hepatoma cells. (2019). Dietary flavones and flavonoles are inhibitors of poly(ADP-ribose)polymerase-1 in pulmonary epithelial cells. Molecules 19 (12), 2009120112. 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). Neuroprotective Effect of Resveratrol via Activation of Sirt1 Signaling in a Rat Model of Combined Diabetes and Alzheimers Disease. 665, 7889. NF-B deregulation can influence other mechanisms in which SIRT1 and AMPK are involved, such as glucose absorption in skeletal muscle. 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). SIRT1 guards against oxidative stress by activating gene transcription of PGC-1 via deacetylation, and by regulating transcription of factors such as the nuclear receptor peroxisome proliferator-activated receptor (PPAR), nuclear respiratory factor (NRF), and mitochondrial transcription factor A (TFAM), involved in modulation of biogenesis and mitochondrial function (Ren et al., 2019), and metabolism of glucose and lipids (Rodgers et al., 2005). Life Sci. SIRT1 also increases the expression of MnSOD by deacetylating p53, thus enhancing cellular antioxidant capacity (Brunet et al., 2004; Zhang et al., 2017; Ren et al., 2019). 137 (10), 21902195. doi:10.1038/s41586-019-1411-0, Chang, H. C., Guarente, L. (2014). These findings show that Cur-induced cardio-protection was mediated by SIRT1 (Yang et al., 2013). doi:10.1007/s13105-016-0492-6, Lara-Guzman, O. J., Gil-Izquierdo, A., Medina, S., Osorio, E., Alvarez-Quintero, R., Zuluaga, N., et al. 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. 467 (4), 638644. Unfortunately, where it is grown and other conditions tend not to have an effect on the Sirtuin activating properties, so this means we just have to get multiple samples from multiple harvests all around the world. Nutr. (2017). 58 (10), 13091317. A phase 2 clinical study (NCT01925547) investigated the effect of Cur micelles on inflammation and lipid metabolism markers in subjects at risk for metabolic syndrome. This review will examine compounds of natural origin recently found to upregulate SIRT1 activity, such as polyphenolic products in fruits, vegetables, and plants including resveratrol, fisetin, quercetin, and curcumin. Table 4 Berberine in clinical trials for metabolic and inflammatory disorders. (2018). Natural compounds in epigenetics: a current view. 95 (9), E1E8. All these effects are due to its ability to remove ROS, inhibit cyclooxygenase (COX), and trigger anti-inflammatory pathways via SIRT1 activation (Miceli et al., 2014; Malaguarnera, 2019). doi:10.1016/j.bbrc.2015.10.094, Konrad, M., Nieman, D. C. (2015). Cur may have positive effects in T2D by mediating the reduction of NF-B expression in inflammatory pathway (Zendedel et al., 2018). Over the past few years, the ever-growing awareness that good health goes hand in hand with a healthy and balanced diet has encouraged people to eat more fruit and vegetables, and to take supplements to make up for any deficiency (DAngelo et al., 2019). SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. Med.
Med. An antiinflammatory and reactive oxygen species suppressive effects of an extract of Polygonum cuspidatum containing resveratrol. doi:10.1089/ars.2012.4581, Donniacuo, M., Urbanek, K., Nebbioso, A., Sodano, L., Gallo, L., Altucci, L., et al. Polyphenols Regulate Endothelial Functions and Reduce the Risk of Cardiovascular Disease. Increased fatty acid synthesis and hepatocyte accumulation is associated with metabolic disorder (Liou et al., 2018). Copyright 2020 Iside, Scafuro, Nebbioso and Altucci. doi:10.1002/jcb.26089, Chen, Z., Shentu, T. P., Wen, L., Johnson, D. A., Shyy, J. Y.
Diabetes 65 (8), 22822294. Several clinical studies investigated its effects on hyperlipidemia and hypercholesterolemia and relative disorders. Aging 12 (8), 70157029. doi:10.18632/aging.103059, Huang, S. X., Qiu, G., Cheng, F. R., Pei, Z., Yang, Z., Deng, X. H., et al. Increased nuclear NAD biosynthesis and SIRT1 activation prevent axonal degeneration. Am. Res. A phase 1 clinical trial (NCT01640197) tested the effects of chronic resveratrol supplementation (500 mg daily for 28 days) in healthy humans and found considerable improvements in cognitive performance, cerebral blood flow, subjective sleep, mood, health, and blood pressure. Berberine Alleviates Oxidative Stress in Islets of Diabetic Mice by Inhibiting miR-106b Expression and Up-Regulating SIRT1. BBR in combination with RSV displayed hypolipidemic effects likely mediated by SIRT1 expression regulation. (2012). Mutat. doi:10.1002/biof.1584, Li, Z., Jiang, T., Lu, Q., Xu, K., He, J., Xie, L., et al. Sirtuins at the crossroads of stemness, aging, and cancer. 11:1225. doi: 10.3389/fphar.2020.01225. Med. Toxicol. doi:10.1007/s11684-019-0724-6, Sun, T., Zhang, Y., Zhong, S., Gao, F., Chen, Y., Wang, B., et al. Toxicol. Oxidation can lead to harmful damage to DNA, and SIRT6 recruits. 9:19:19. doi:10.3389/fphar.2018.00019, Svajger, U., Jeras, M. (2012). Protective effect of curcumin on TNBS-induced intestinal inflammation is mediated through the JAK/STAT pathway. 120 (6), 97479757. Fisetin Confers Cardioprotection against Myocardial Ischemia Reperfusion Injury by Suppressing Mitochondrial Oxidative Stress and Mitochondrial Dysfunction and Inhibiting Glycogen Synthase Kinase 3beta Activity. 23 (12), 23692380. In addition, since mitochondrial dysfunction leads to the activation of apoptosis, SIRT1 can directly regulate the apoptotic process by modulating acetylation of PGC-1 (Zhang et al., 2019).
Application of berberine on treating type 2 diabetes mellitus. Fisetin: a dietary antioxidant for health promotion. The growing body of evidence supporting the beneficial effects of Que has led to its clinical use, as demonstrated by the number of clinical trials (72 studies on ClinicalTrials.gov).
These promising results have paved the way towards the clinical use of BBR. Biol. Nutr. Berberine Ameliorates Doxorubicin-Induced Cardiotoxicity via a SIRT1/p66Shc-Mediated Pathway. 106 (3), 383389. (2019). showed that fisetin mediated protective effects via SIRT1 activation, enhancing NF-B deacetylation and promoting inhibition of pro-inflammatory gene expression (Singh et al., 2019). Cur inhibits phosphorylation of JAK/STAT by binding with its ,-unsaturated carbonyl portion to residue 259 of cysteine in STAT3 with subsequent activation. doi:10.1007/978-3-319-41334-1_2, Costa, L. G., Garrick, J. M., Roque, P. J., Pellacani, C. (2016). 17 (1), 111. doi:10.1186/s12933-018-0754-4, Wan, D., Zhou, Y., Wang, K., Hou, Y., Hou, R., Ye, X. Pathol. Ageing Dev. 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). Int. Were very proud of the breakthrough and looking forward to our members benefitting from it for many years to come, says Graves. Resveratrol Reduces Oxidative Stress and Apoptosis in Podocytes via Sir2-Related Enzymes, Sirtuins1 (SIRT1)/Peroxisome Proliferator-Activated Receptor gamma Co-Activator 1alpha (PGC-1alpha) Axis. Quercetin, Inflammation and Immunity. Med. Physiol. Vasc. Oxid. (2013). Evaluation of Quercetin as a Countermeasure to Exercise-Induced Physiological Stress, in Antioxidants in Sport Nutrition. RSV-induced MnSOD also reduces oxidative stress (Li et al., 2020a). As an antioxidant, Cur is able to eliminate ROS and RNS by increasing the expression of antioxidant proteins via induction of upstream coding genes such as nuclear factor erythroid 2-related factor 2 (Nrf2), kelch-like ECH-associated protein 1 (Keap1), and antioxidant response element (ARE) (Abdelsamia et al., 2019). Pharm. A phase I study was published for the first time in 2001. 72 (3), 371380. 120 (3), 461472. Heart injury and mitochondrial oxidative damage are characterized by ROS overproduction and a reduction in succinate dehydrogenase or COX activity, leading to mitochondrial respiratory chain deficiency (Yang et al., 2013). (2019). Clin. Curcumin (Cur) or 1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione (diferuloylmethane) is a natural bioactive polyphenol compound mediating a wide spectrum of biological functions. (2016). 39 (5), 13791384. Nevertheless, the mechanisms of action are not yet well defined. Biochem. 2016:2986796. doi:10.1155/2016/2986796, Cui, Y., Han, Y., Yang, X., Sun, Y., Zhao, Y. In recent years, scientific interest focusing on the identification of SIRT1 modulators has led to the discovery of novel small molecules targeting SIRT1 activity. We will also discuss the potential therapeutic effects of these natural compounds in the prevention and treatment of human disorders, with particular emphasis on their metabolic impact. (2002). Modulation of Keap1/Nrf2/ARE Signaling Pathway by Curcuma- and Garlic-Derived Hybrids. Med. doi:10.2174/1871530319666190101120119. doi:10.1016/s0167-4889(02)00328-2, Oboh, G., Ademosun, A. O., Ogunsuyi, O. J. Int. Biochem. A list of completed and terminated clinical trials investigating the effects of Cur in metabolic and inflammatory diseases is reported in Table 5. 13, 97107. Cell Longev. 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. RSV was shown to activate SIRT1 and improve endothelial function in obese mice via upregulation of PPAR expression/activity in PPAR mutant mice (Cheang et al., 2019).
Berberine and Its Role in Chronic Disease. Pharmacother. However, as for RSV and nutraceuticals in general, the results of molecular studies on Que obtained from in vitro investigations and animal models are often inconsistent with data from clinical trials. It is known that in vitro, even at 7.5 M concentration, Cur is able to phosphorylate STAT3 and attenuate inflammatory response (Serafini et al., 2019). BioMed. 12 (2), 159162. 2 (3), 218229. Fisetin treatment in NAFLD mice reduced epididymal adipose tissue, hepatocyte steatosis, and fatty acid synthesis. In inflammation, Que inhibits the enzymes COX and lipoxygenase (Lee and Min, 2013; Savikin et al., 2017). In addition, Que reduces T cell proliferation by blocking IL-12-induced tyrosine phosphorylation of JAK2, TYK2, STAT3, and STAT4 (Muthian and Bright, 2004; Nabavi et al., 2012). It is not intended to be a substitute for professional medical advice, diagnosis or treatment. doi:10.1097/NT.0000000000000228, Ruan, H., Zhan, Y. Y., Hou, J., Xu, B., Chen, B., Tian, Y., et al. Que may reduce oxLDL-induced oxidative damage by upregulating SIRT1 and AMPK (Hung et al., 2015), therefore potentially preventing oxLDL-impaired SIRT1 inhibition linked to endothelial dysfunction. (2005). (2018). Figure 2 Nutraceutical action on SIRT1 expression. 
Berberine attenuated the cytotoxicity induced by t-BHP via inhibiting oxidative stress and mitochondria dysfunction in PC-12 cells. Biol. (2014). doi:10.1016/j.redox.2017.11.017, Lee, S. H., Min, K. J. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. doi:10.1007/978-3-319-41342-6_17, OCallaghan, C., Vassilopoulos, A. Despite the generally encouraging data from in vitro and in vivo studies, supporting molecular evidence providing clues to these unanswered questions is still lacking. In the latter study, Que supplementation was safely tolerated by patients with mild-to-severe chronic obstructive pulmonary disease, opening the way towards the potential use of Que as a therapeutic agent for this condition. Que can also act as both an antioxidant and pro-oxidant agent. Front. J. Nutr. Savikin, K. P., Krstic-Milosevic, D. B., Menkovic, N. R., Beara, I. N., Mrkonjic, Z. O., Pijevijakusic, D. S. (2017). Because of the pleiotropic actions of RSV, clinical trials are currently testing its therapeutic potential in a wide range of human diseases. (2010). 
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. Treatment with higher bioavailable preparations of Cur derivatives may result in increased SIRT1-activating action, further substantiating the link between SIRT1, Cur, and therapeutic effects. Endale, M., Park, S. C., Kim, S., Kim, S. H., Yang, Y., Cho, J. Y., et al. The editor and reviewer's affiliations are the latest provided on their Loop research profiles and may not reflect their situation at the time of review.
(2016). Pharmacol. In different organisms (S. cerevisiae, C. elegans, and D. melanogaster) expressing SIRT1 (or its homologous genes), RSV treatment is able to extend life span. J. Neurochem. SOCS is an antagonist of JAK/STAT signaling and is involved in the regulation of inflammatory proteins and cytokines. (2018). doi:10.1039/c4fo00948g, Cicero, A. F., Baggioni, A. Further investigations will be required to provide a more detailed understanding. (2009). 81 (1 Suppl), 268S276S. Discovery of curcumin, a component of golden spice, and its miraculous biological activities. SIRT1-mediated FoxOs pathways protect against apoptosis by promoting autophagy in osteoblast-like MC3T3-E1 cells exposed to sodium fluoride. (2019).