Natural Sirtuin1 Activators and Atherosclerosis: an Overview

Purpose of Review The purpose of this review is to summarize the most recent findings investigating the impact of several natural sirtuin (SIRT) activators, particularly SIRT1, on atherosclerosis. Recent Findings Sirtuins that belong to a family of class III histone deacetylases are believed to be novel therapeutic targets to treat age-related and chronic diseases. SIRT expression is regulated by small molecules called SIRT-activating compounds that can be found in natural food products. SIRT1 may exert protective effects in atherosclerosis, which is said to be a major cause of cardiovascular diseases. Most of the evidence supporting the beneficial effects of these natural compounds comes from in vitro or animal-based studies, while there have been particularly few or inconsistent human-based studies evaluating their long-term impact in recent years. Summary SIRT1 activation has been demonstrated to mitigate or prevent atherosclerosis through various mechanisms. However, further research is required to determine the optimal SIRT activator dosage and to establish a stronger correlation between health effects and the administration of bioactive compounds. Additionally, conducting more human clinical trials is necessary to ensure the safety of these compounds for preventing atherosclerosis development.


Introduction
Noncommunicable diseases (NCDs) kill 41 million people each year, which is equivalent to 71% of all global deaths, as stated by the World Health Organization.Annually, more than 15 million people die from NCDs between the ages of 30 and 69; 85% of these "premature" deaths occur in low-and middle-income countries.Cardiovascular diseases (CVDs) account for the majority of NCD-related deaths, with 17.9 million people succumbing to them each year, followed by cancers (9.3 million), respiratory diseases (4.1 million), and diabetes (1.5 million).Atherosclerosis is the primary underlying cause of most cardiovascular diseases [1].
Atherosclerosis is the most common form of CVD, where the disease's main components are lipid accumulation and inflammation of the large arteries.These factors can eventually lead to clinical complications, such as myocardial infarctions (MIs) and strokes [2].The exact causes and risk factors of atherosclerosis are not fully understood.However, certain conditions, traits, or habits may increase the likelihood of developing atherosclerosis.High levels of total cholesterol (TC) and low-density lipoprotein (LDL) levels, along with low levels of high-density lipoprotein (HDL) in the blood, hypertension, exposure to tobacco smoke, diabetes mellitus, obesity, and a sedentary lifestyle are all risk factors.Therefore, atherosclerosis can be delayed or prevented by controlling these risk factors.
Members of the sirtuin (SIRT) family of proteins are class III histone deacetylases that are homologous to the yeast silent information regulator 2 (Sir2).Sirtuins mediate the deacetylation of histones and non-histone proteins in an NAD + -dependent manner.SIRT1 was the first SIRT to be discovered in mammals and is the most extensively studied SIRT protein, playing a role in promoting longevity [3].
Over the past few years, a healthy and balanced diet has been encouraged to prevent diseases in humans [4,5], atherosclerosis, and its development in particular [6][7][8].Food bioactive compounds are extra nutritional constituents that typically occur in small quantities in foods [9].Bioactive compounds in the diet can act as antioxidants and antiinflammatory agents, reducing the negative effects of oxidative stress and the incidence of chronic diseases, such as obesity, diabetes, and cardiovascular disorders [9][10][11].The beneficial effects of consuming foods rich in polyphenols have been widely discussed in relation to cardiovascular diseases, including atherosclerosis, high blood pressure, thrombotic diseases, stroke, or hyperlipidemia [12].
In the present review, we discuss novel insights into the effects of natural molecules considered as SIRT1-activating compounds and their impact on atherosclerosis in the last 5 years.

Resveratrol
Resveratrol (3,5,4′-trihydroxystilbene) is a polyphenolic chemical compound found in food products such as grapes, peanuts, and berries.It is biosynthesized in response to pathogens.Red wine is also a resveratrol-rich product, as the winemaking process involves crushing and mashing grapes, which leads to its release from the fruit [40].The concentration of resveratrol in red wines ranges from 0.1 to 14.3 mg/L.Its concentration in red grape juice, fresh grape skin, and grapes (dry sample) is 0.5 mg/100 ml, 5-10 mg/100 g, and 0.64 mg/100 g, respectively [41].Resveratrol exists in two isomeric structures: the cis and trans isoforms.The trans isoform can be converted to the cis isoform through heating [40].Oral intake of high doses of resveratrol (5 g) from resveratrol-containing foods or supplements has been demonstrated to be safe, with no serious adverse effects reported.The concentration of unmetabolized resveratrol found in plasma after oral administration of various resveratrol-rich sources in various studies did not exceed 5 µM and ranged from plasma resveratrol levels of 1.8 to 4.2 µM [42].Numerous studies have demonstrated its anti-aging and anti-inflammatory effects both in vivo (using yeasts, insects, mice, and other organisms) and in vitro (utilizing both animal and human cell lines) [43,44].
Resveratrol treatment has been shown to reduce atherosclerosis in numerous in vivo studies using various animal models.Dietary enrichment with resveratrol resulted in a reduction in the size of atherosclerotic lesions [31,45,46].A study demonstrated its protective effect on vascular structure by showing that resveratrol prevented TNF-α-induced damage to elastin fibers in aortic cross sections of C57BL/6 mice [42].Many experimental studies using atherosclerosis mouse models have shown that resveratrol lowers TC, TG, LDL-C, and very-low-density lipoprotein (VLDL)-C levels while increasing HDL-C [31,45].In contrast, a randomized clinical trial involving human subjects with dyslipidemia provided a counterexample to the aforementioned reports.During an 8-week supplementation period with resveratrol (at doses of 100 mg/day, 300 mg/day, or 600 mg/day), there were no significant changes observed in the lipid profile when compared to the placebo, regardless of the dosage used.The researchers noted no significant differences in triglycerides, TC, HDL and LDL cholesterol, apoA1, apoB, or apoA1/apoB between baseline and follow-up in the four groups [47].The anti-atherogenic effect of resveratrol was demonstrated in ApoE −/− mice, where a reduction in macrophage infiltration was observed in animals treated with resveratrol [31].Resveratrol was found to reduce the expression and serum levels of various chemokines and adhesion molecules, such as CCL2, CXCL1/KC, MCP-1, ICAM-1, and VCAM-1, in both mice and human endothelial cells, as well as in THP-1 human monocytes.This effect has been demonstrated to influence the recruitment and adhesion of circulating blood monocytes [42,46].Atherosclerosis is regarded as an inflammatory disease, making compounds with anti-inflammatory properties, such as resveratrol, of paramount importance in the prevention of vascular atherosclerosis and the subsequent cardiovascular diseases that may arise [48].The in vivo part of the experimental study, a type of study, first demonstrated that resveratrol attenuated vascular endothelial inflammation by reducing VCAM-1 and F4/80 expression in aortic cross sections of C57BL/6 mice after TNF-α stimulation.This effect was achieved through the inhibition of NF-κB factor activation [42].A study using ApoE −/− mice and umbilical vein endothelial cells (UVECs) isolated from ApoE −/− mice demonstrated several positive effects of resveratrol.These effects included reduced atherosclerotic plaques; lower levels of TC, TG, LDL-C, and HDL-C; as well as decreased levels of TNF-α, C-reactive protein, matrix metallopeptidase 9 (MMP-9), and CD40L expression in arterial lesion tissue.The study suggested that resveratrol's anti-atherosclerotic properties were attributed to the modulation of the PI3K/AKT/mTOR pathway [45].   1 3 CD4 + T cells, which are present in atherosclerotic lesions, play crucial roles in all stages of atherogenesis and have a significant impact on the regulation of the inflammatory process.A study demonstrated that the administration of resveratrol not only reduced atherosclerosis in vivo but also inhibited CD4 + T cell activation.Additionally, it reduced the expression of DNA-methyltransferase 1 (Dnmt1) and DNA-methyltransferase 3 beta (Dnmt3b) in CD4 + T cells [31].In both animal-and human-based studies, resveratrol has demonstrated its ability to inhibit vascular smooth muscle cell (VSMC) proliferation induced by various mitogens.The specific molecular mechanisms involved depend on the type of mitogenic stimuli and may include the inhibition of the PI3K/Akt/mTOR pathway or cell cycle arrest [49].
In a randomized controlled trial involving adults with type 2 diabetes, researchers noted that resveratrol exhibited antioxidant properties and influenced markers of oxidative stress by activating SIRT1.They observed a significant reduction in markers of oxidative stress, and a more efficient antioxidant effect was evident in patients who received a resveratrol supplement at a dose of 1000 mg/day compared to those receiving 500 mg/day, which was associated with increased levels of SIRT1 [38].In a recent study discussing the oxidative stress effects of resveratrol, it was demonstrated that the depletion of SIRT1 abolished the beneficial effects of resveratrol and pterostilbene (PTS), a natural methylated analog of resveratrol.This was observed in the context of protection against mitochondrial reactive oxygen species overproduction, mitochondrial dysfunction, and apoptosis in an H 2 O 2 -exposed intestinal porcine enterocyte cell line.These findings suggest that SIRT1 is essential for resveratrol and pterostilbene to protect against oxidative stress-induced intestinal injury [50].In another recent study, it was demonstrated that resveratrol activated SIRT1 to enhance endothelial function in obese mice.This effect was achieved through the upregulation of peroxisome proliferator-activated receptor delta (PPARδ) expression in wild-type Ppard-wt mice on a high-fat diet [51].PPARδ plays a significant role in lipid absorption, muscle endurance, insulin sensitivity, and the suppression of atherogenic inflammation [52].Additionally, it was demonstrated that the SIRT1-mediated activation of PPARδ contributes to the beneficial effects of SIRT1 [51].A study revealed that resveratrol suppresses insulin-induced VSMC proliferation and migration, potentially through the activation of SIRT1 and the downregulation of the PI3K/ AKT pathway.This is supported by the fact that EX527, a specific inhibitor of SIRT1, nullified the role of resveratrol in inhibiting insulin-induced proliferation and migration while upregulating the phosphorylation of PI3K and Akt in VSMCs [53].SIRT1 has been reported to prevent premature senescence of endothelial cells, thereby protecting them from dysfunction [54,55].In one study, the effect of resveratrol and its dimers, ε-viniferin and δ-viniferin, on NO production and wound repair in vascular endothelial cells was examined.All three compounds increased the wound repair of vascular endothelial cells (ECs) by promoting NO production and enhancing the expression of SIRT1 and heme oxygenase 1 (HO-1).These findings suggest a potential prevention of atherosclerosis development [56].

Quercetin
Quercetin (3,3′,4′,5,7-pentahydroxyflavone) is the most common and widely distributed flavanol compound in our diet.It is commonly found in many fruits and vegetables, including apples, berries, red onions, grapes, cherries, broccoli, bell peppers, coriander, citrus fruits, and tea leaves (Camellia sinensis) [57,58].The estimated flavonoid intake ranges from 50 to 800 mg/day, with quercetin accounting for approximately 75% of that intake.This largely depends on the consumption of fruits and vegetables, as well as the intake of tea [59].The bioavailability of quercetin is very low, primarily due to its extensive metabolism [60].Another reason for its poor absorption is due to intestinal excretion [57].Quercetin has antiradical activity due to the presence of reactive hydroxyl groups in its structure [61].It reduces the formation of ROS by inhibiting NADPH oxidases and xanthine oxidases, decreases the activity of cyclooxygenases (COX) and lipoxygenases (LOX), and regulates the activity of intracellular signaling cascades involved in inflammatory reactions [62].Quercetin metabolites are believed to be accumulated in tissues shortly after quercetin-rich vegetables are consumed [63].It was indicated that these metabolites, originating from enterocytes and the liver, serve as antioxidants by impeding oxidation of low-density lipoprotein cholesterol [63].
Quercetin acts as an anti-inflammatory [60,[64][65][66] and anti-atherogenic [67][68][69] agent.Recent animal and in vitro studies have shown that quercetin reduces the size of atherosclerotic lesions [21,22,68,70].It has been suggested that excessive accumulation of oxidized LDL (ox-LDL) leads to an excessive inflammation in macrophages and a worsening condition of atherosclerosis by activating the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome.It has also been noted that quercetin suppresses the galectin-3 NLR family pyrin domain containing 3 (Gal-3-NLRP3) proinflammatory signaling pathways in macrophages, subsequently alleviating atherosclerotic lesions [67].Quercetin reduced the levels of IL-1β, TNF-α, IL-10, and IκBα gene expression, indicating a decrease in the transcriptional activity of NF-κB in individuals with coronary artery disease [62].The reverse cholesterol transport (RCT) of macrophages in atherosclerotic plaques is a critical mechanism in the context of antiatherosclerosis [71].LXRα, SR-BI, and ABCA1 play a vital role in promoting macrophage RCT and in maintaining intracellular cholesterol homeostasis [58], and quercetin increased the expressions of PPARγ, LXRα, and ABCA1 genes in RAW264.7 macrophages exposed to ox-LDL [72].Quercetin also attenuated the expression of PPARγ, LXRα, and ABCA1 in the aortas and livers of ApoE −/− mice fed a high-fat diet [73].Quercetin can alleviate vascular endothelial injury through multiple mechanisms.It can reverse endothelial damage caused by excessive NO by inhibiting nitrosative stress and protecting ECs.Additionally, it inhibits the promoting effect of ATP on NO production in vascular ECs and reduces intracellular calcium concentration and eNOS activity, ultimately reducing vascular endothelial injury and stabilizing intravascular homeostasis [58].In a new animal study utilizing aneurysm and dissection mouse models, quercetin was found to suppress the expression of VCAM-1 and pro-matrix metalloproteinase-9 activity in the aorta of mice, along with reducing macrophage infiltration into the aortic wall.Quercetin also significantly inhibited the enlargement of the abdominal aortic diameter, reduced the incidence of aortic aneurysms, and prevented death from rupture in mice.Moreover, quercetin suppressed the expression of VCAM-1 in response to TNF-α stimulation in human umbilical vein endothelial cells.These findings suggest that quercetin effectively prevents the onset of atherosclerosisrelated acute aortic syndromes through its anti-inflammatory properties [74].
Numerous in vivo and in vitro studies have demonstrated that quercetin increases the expression of SIRT1 [75][76][77][78][79].A study showed that quercetin inhibited endoplasmic reticulum stress through activating the SIRT1/AMPK signaling pathway [80].In another study, the administration of 20 mg/ kg/day of quercetin for 8 weeks effectively reduced lipid deposition in arterial lumina and atherosclerotic lesions, concurrently decreasing the levels of serum ICAM-1, IL-6, and VCAM-1 in the aorta.Moreover, it increased the density of SIRT1 in the aorta of ApoE −/− mice.In in vitro studies, quercetin reduced the expression of senescence-associated β-galactosidase and improved the cell morphology of human aortic endothelial cells (HAECs).Furthermore, quercetin reduced cellular apoptosis, increased mitochondrial membrane potential (ΔΨm) in a dose-dependent manner, and decreased ROS generation [22].In diabetic rats fed high-fat diet, treatment with quercetin was reported to improve the lipid profile, reduce atherosclerotic lesions, lower the atherogenic index, decrease malondialdehyde (MDA) levels, and increase the activity of enzymatic antioxidants in the carotid artery.Additionally, quercetin suppressed the inflammatory response by reducing NF-κB and IL-1β levels, while increasing IL-10 levels through the AMPK/SIRT1/NF-κB signaling pathway [21].In a recent study, quercetin was shown to regulate mitophagy and endoplasmic reticulum stress through the SIRT1/TMBIM6 pathway, inhibiting oxidative stress damage in human cardiomyocytes.The study also revealed that the number of cell apoptosis in the quercetin-treated group was significantly reduced, with increased expression of SIRT1, PGC-1α, and Bcl-2 proteins [81].

Berberine
Berberine (BBR) is an isoquinoline quaternary alkaloid (or a 5,6-dihydrodibenzo(a,g)quinolizinium derivative) widely used in traditional Chinese herbal medicine isolated from several plants such Berberis vulgaris (barberry), Hydrastis canadensis (goldenseal), Coptis chinensis (Chinese goldthread), Cortex phellodendri (Huangbai), and Rhizoma coptidis (Huanglian) [82].Berberine is a yellow powder, odorless with characteristic alkaloid bitterness.It is sparingly soluble in water and slightly soluble in ethanol or methanol; however, the salt form is relatively water-soluble.Berberine can be easily obtained from medicinal plants or through total synthesis.Chlorides or sulfates of berberine are commonly used for clinical purposes [83].Over the past few decades, berberine has gained significance in traditional Chinese medicine due to its wide range of applications.However, despite its strong pharmacological effects, its oral bioavailability is exceptionally low [84].
In recent years, numerous in vivo and in vitro studies have demonstrated that berberine effectively reduces plasma levels of TC, TG, LDL-C, and non-HDL-C while elevating HDL-C.It also mitigates lipid and cholesterol accumulation in macrophages [85].Furthermore, many studies have observed a reduction in atherosclerosis lesions, accompanied by decreased TNF-α, IL-1β, and IL-6 levels, along with increased IL-10 and adiponectin levels [86][87][88][89].Recently, the effects of berberine on trimethylamine N-oxide (TMAO) production in the gut microbiota and its impact on plaque development in atherosclerosis were investigated.This research encompassed studies involving animal intestinal bacterial cultures, HFD-fed hamsters, and atherosclerotic patients [90].Twenty-one patients with atherosclerosis showed an average decrease in plaque score by 3.2% after taking 0.5 g of oral berberine for 4 months.Furthermore, trimethylamine (TMA) and TMAO levels in patients decreased by 38% and 29% in feces and by 37% and 35% in plasma after 4 months of berberine treatment [90].Another study demonstrated that in C57BL/6 J and ApoE KO mice on a choline-supplemented chow diet, berberine attenuated TMA/ TMAO production.This treatment also reduced atherosclerotic lesion areas in ApoE KO mice.Furthermore, berberine exhibited a significant inhibitory effect on TMA formation in the gut microbiota isolated from human fecal samples [91].The berberine-induced inhibition of TMA/TMAO production was observed in both in vivo and in vitro human-based studies.This has offered novel insights into the mechanisms responsible for the anti-atherosclerosis effects of berberine [90,91].In another study, berberine was found to reduce serum lipid levels, counteract hepatic lipid accumulation, improve intima-media thickening, reduce aortic ROS generation, and decrease serum levels of MDA, ox-LDL, and IL-6 in ApoE −/− mice fed a western-type diet for 12 weeks.Additionally, berberine ameliorated endothelial dysfunction and provided protection against atherosclerosis through its involvement in pathways associated with mitochondrial dysfunction, fatty acid β-oxidation, and FXR/RXR activation [92].
Recent studies, both in vivo and in vitro, have focused on the activities of berberine and SIRT1 [24,[93][94][95] and their underlying anti-atherogenic mechanisms.Berberine promoted autophagy of peritoneal macrophages by activating SIRT1 via the NAD + synthesis pathway, thus promoting transcription factor EB (TFEB) nuclear translocation and deacetylation [94].Berberine, through the activation of SIRT1 via the NAD + synthesis pathway, promotes the autophagy of peritoneal macrophages.This, in turn, facilitates TFEB nuclear translocation and deacetylation, contributing to its underlying anti-atherogenic mechanisms [23].Klotho (KL) is an anti-aging protein known to promote health and extend the lifespan of individuals.Deficiency of KL has been correlated with cardiovascular disease, and low expression of KL is considered an early predictor of atherosclerosis [96].Berberine increased KL expression and significantly reversed the downregulation of SIRT1 in the aging heart.This effect markedly suppressed the development of doxorubicin (DOX)-induced cardiac senescence and protected the aging heart of male Sprague Dawley rats [23].Furthermore, in H9c2 cells, berberine and KL were found to increase the expression of SIRT1 [23].Berberine also demonstrated its ability to protect against DOX-induced cardiotoxicity and oxidative stress through the downregulation of SIRT1-mediated p66Shc signaling.This protection was associated with the modulation of ROS both in vivo and in vitro [24].
Fisetin administered as an aqueous solution at a dose of 12.5 mg/kg was shown to reduce atherosclerosis in ApoE −/− mice after 12 weeks.In the aortic sinus, atherosclerotic changes and lipid accumulation were significantly reduced compared to the control group when fisetin was administered.Fisetin also demonstrated the ability to reduce the expression of PCSK9 and LOX-1, as well as aging markers including p21 (cyclin-dependent kinase inhibitor 1A), p53 (tumor suppressor protein p53), and p16 (multiple tumor suppressor-1).These transcription factors are associated with apoptosis, cell cycle regulation, and senescence in ApoE −/− mice [25,109].Fisetin exhibits anti-inflammatory properties.In a study using macrophages where inflammatory responses were induced with lipopolysaccharide (LPS), fisetin reduced the expression of pro-inflammatory MCP-1, IL-1β, and iNOS.Additionally, fisetin prevented foam cell formation by impacting macrophage recruitment and infiltration through the reduction in the expression or activity of uPA, uPAR, MMP-2, and MMP-9, which are factors associated with macrophage recruitment and infiltration [32].
The relationship between fisetin and SIRT1 has been a topic of discussion for several years [110][111][112].In a recent study involving mice, fisetin was found to suppress the activation of Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and NF-κB and subsequently inactivate pro-inflammatory factors, including IL-6 and TNF-α, with an increased expression of AMPK/SIRT1.Additionally, the study demonstrated that lead (Pb) exposure inhibited the expression of p-AMPK and SIRT1 [26].Studies demonstrate a link between non-alcoholic fatty liver disease (NAFLD) and atherosclerosis disease [113,114].Fisetin regulated lipid metabolism in vitro in FL83B hepatocytes and in male C57BL/6 mice with induced non-alcoholic fatty liver disease.The reduction of serum free fatty acid concentration and decreased lipid accumulation were observed.The mechanism of action indicated a significant increase in the phosphorylation of AMPKα, as well as increased SIRT1 production in liver tissue [112].

Curcumin
Curcumin, with the chemical formula C 21 H 20 O 6 , is a natural yellow pigment that can be isolated from turmeric (Curcuma longa L.).It is also known as diferuloyl methane.The IUPAC (International Union of Pure and Applied Chemistry) name of curcumin is (1E,6E)-1,7-bis (4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione [115].Researchers became particularly interested in curcumin due to its discovery of anticancer properties by Singh and Aggarwal [116].Curcumin has demonstrated antioxidant, anti-inflammatory, antiapoptotic, antihypertensive, antidiabetes, anti-obesity, anti-carcinogenic, and anti-aging properties both in vivo and in vitro [117][118][119].Turmeric is a distinctive and essential spice for Indian cuisine.It is estimated that the usual intake of curcumin in India averages 100 mg/day, and studies show that even consumption of up to 8 g/day is safe [120].
Recent in vivo and in vitro studies provide support for the potential of curcumin to reduce atherosclerosis and the pathogenic factors involved in its development [117,118,[121][122][123].A study involving male New Zealand white rabbits demonstrated that the administration of curcumin-phosphatidylserine (100 mg/kg) solid dispersion significantly reduced the intima-media thickness ratio and the grading of atherosclerotic plaque.Rabbits exposed to the 100 mg/ kg dosage of curcumin-phosphatidylserine exhibited significantly fewer inflammatory cells in the atherosclerotic lesions compared to the control group [124].In ApoE −/− mice, curcumin reduced serum levels of LDL-C, TC, and TG and significantly decreased the formation of atherosclerotic plaque in the aorta.It also reduced lipid deposition in the liver and mitigated inflammatory damage in the heart, lung, and kidney [125].Curcumin has also been shown to play a role in lipid metabolism, inflammation, and autophagy [126][127][128][129][130][131][132][133].
ox-LDL is responsible for impairment of autophagy [134] and the adverse effects of ox-LDL on macrophages can be reversed by the properties of curcumin [122].Curcumin has demonstrated the ability to restore foam cell autophagy, thereby contributing to the inhibition of atherosclerosis.An in vitro study identified a novel axis, TFEB-P300-BRD4, that appears to be responsible for curcumin's capacity to inhibit inflammation, reduce lipid content, and regulate autophagy [122].The anti-inflammatory properties of curcumin have been confirmed on human ECs and monocytes.Curcumin reduced IL-1β in human umbilical vein endothelial cells (HUVECs) and reduced IL-6 and TNF-α in THP-1 cells, resulting in reduced inflammation [33].Curcumin attenuated VSMC migration by inhibiting NF-κB-mediated NLRP3 expression.It also inhibited NLRP3 expression and reduced IL-1β concentration in VSMCs [135].
The relationship between curcumin and SIRT1 has been a subject of discussion for years.In a study involving a highfat diet, curcumin inhibited age-related vascular changes by increasing SIRT1 expression and also led to decreased glucose and TC levels [27].A recent study demonstrated that curcumin treatment induced the activation of the SIRT1/ NRF2 pathway and inhibited TLR4 expression in newborn rats.This led to an improvement in the inflammatory condition of necrotizing enterocolitis, with reduced expression of inflammatory factors in the intestinal tissue of NEC newborn rats.Furthermore, curcumin inhibited the expression of inflammatory factors in intestinal epithelial cells induced by LPS/ATP and attenuated the LPS/ATP-induced focal death pathway in intestinal epithelial cells through the SIRT1 pathway [136].Another study demonstrated that tetrahydrocurcumin, a natural curcumin metabolite, increased the expression of SIRT1 and deacetylated SOD2, both in in vitro and in vivo settings.This effect protected cardiomyocytes against oxidative damage [137].
Catechins are known to influence vasodilation, a key factor in maintaining proper endothelial function and preventing atherosclerosis development.Studies conducted in HUVECs, bovine coronary artery endothelial cells (BCAECs), and male Wistar rats have demonstrated that catechins can enhance eNOS expression and NO production, offering protection against endothelial dysfunction and vasoconstriction [30,34].Catechins also exhibit antiatherosclerotic properties by influencing cellular aging and apoptosis [34,141].In the in vitro part of the study, epicatechin reduced β-galactosidase activity, a marker of cell aging [34].Researchers found that ( +)-catechin had broad atheroprotective effects, including reducing oxidative stress and inhibiting monocyte and smooth muscle cell migration.It also mitigated inflammation and normalized the lipid profile.In cell studies, it decreased ROS production in THP-1 cells, HUVECs, and HASMCs.In a 3-week study with C57BL/6 J mice on a high-fat diet, ( +)-catechin reduced triacylglycerols, IL-1β, and IL-2 in plasma.It also influenced liver gene expression, particularly genes related to cell proliferation, migration, and lipoprotein levels.The intake of catechins reduced atherosclerotic lesion size and increased plaque stability by 58.87% in LDLR −/− mice [142].ECG exhibits anti-atherosclerotic effects similar to ( +)-catechin.ECG reduces oxidative stress by lowering MDA levels and increasing SOD activity in both in vitro and in vivo studies.In ApoE −/− mice, ECG reduces lipid accumulation in the aorta and aortic roots, stabilizes atherosclerotic plaques, and decreases MMP-2 and ICAM-1 expression [143].In addition, ECG's mechanism of action involves inhibiting the proinflammatory NF-κB pathway, particularly the p65 subunit, resulting in the downregulation of inflammatory mediators.ECG also exerts anti-inflammatory and antioxidant effects by interacting with Nrf2 and increasing HO-1 expression [143].The induction of autophagy and cholesterol efflux by oligomeric proanthocyanidins and ECG through the class III PI3K/beclin1 pathway in foam cells represents a promising therapeutic strategy for combating atherosclerosis.Impaired autophagy is a significant contributor to atherosclerotic disease, and these compounds could potentially address this issue [144].
Many in vitro and in vivo studies have demonstrated that curcumin increased the expression of SIRT1 [95,145,146].A recent study showed that EGCG reduced serum TG, TC, LDL-C, and free fatty acid levels; reduced lipid droplets in hepatocytes; and increased serum HDL-C levels, T-AOC, and SOD activity in hyperlipidemic rats.Additionally, it was shown that EGCG activated SIRT1, activated FoxO1 protein, regulated SREBP-2 protein, and inhibited hepatic cholesterol synthesis with decreased SREBP-2 expression.Also, it was shown that EGCG reduced MDA and increased T-AOC and SOD in the liver, indicating that it improved the body's antioxidant capacity, reducing the generation of peroxides [147].

Conclusions
In vitro and in vivo studies, as well as clinical trials in humans, have shown that SIRT1 activation might reduce or prevent atherosclerosis through various mechanisms.SIRTactivating compounds derived from natural sources emphasize the importance of dietary interventions to prevent atherosclerosis.However, it remains unclear whether the effects of these compounds are mostly related to SIRT activation.It is important to determine the correct dose or concentration, as many of the effects are dose-dependent.Since most of the natural compounds described here exhibit pleiotropic effects, establishing a direct link between SIRT1 activation and the prevention or reduction of atherosclerosis is quite challenging.It is also evident that a more robust correlation between health effects and the administration of bioactive compounds needs to be established to understand their biological impact and their direct association with SIRT1 activation.
Additionally, the bioavailability and solubility of these natural compounds is very low.Treatment with higher concentrations of bioavailable, bioactive compounds may result in increased SIRT1-activating action, further substantiating the link between SIRT1, compounds, and their therapeutic effects.Despite the generally encouraging data from in vitro and in vivo studies, supporting molecular evidence that provides clues to these unanswered questions is still lacking.A better understanding of the molecular mechanisms of these natural molecules or their derivatives is needed for their preclinical and clinical usage.Berberine, fisetin, curcumin, catechins, and resveratrol have shown the ability to activate sirtuins, particularly SIRT1.Our review focused on recent studies investigating the atheroprotective effect and the underlying molecular mechanisms.The conclusion of many studies is that it is necessary to better understand the molecular and epigenetic mechanisms of these compounds to prevent or treat atherosclerosis in humans.