Effects of sesame (Sesamum indicum L.) and bioactive compounds (sesamin and sesamolin) on inflammation and atherosclerosis: A review

Abstract Inflammation, oxidative stress, obesity, infection, hyperlipidemia, hypertension, and diabetes are the main causes of atherosclerosis, which in the long term lead to hardening of the arteries. In the current study, we reviewed recent findings of the mechanism of sesame and its active compounds of sesamin and sesamolin regulates on atherosclerosis. Sesame can decrease the lipid peroxidation and affect the enzymes, which control the balance of oxidative status in the body. Besides modulating the inflammatory cytokines, sesame regulates the main mediators of the signaling pathways in the process of inflammation, such as prostaglandin E2 (PGE2), nuclear factor kappa light‐chain enhancer of activated B cells (NF‐kB) and peroxisome proliferator‐activated receptor gamma (PPAR‐γ). Sesame decreases the growth of different pathogens. It fights against obesity and helps to reduce weight, body mass index (BMI), waist circumference, and lipid count of serum and liver. In addition to lowering fasting blood sugar (FBS), it decreases the hemoglobin A1c (HbA1c) and glucose levels and improves insulin function. With high content of linoleic acid, α‐linolenic acid, and total polyunsaturated fatty acid (PUFA), sesame efficiently controls the blood plasma lipids and changes the lipid profile. In the case of hypertension, it maintains the health of endothelium through multiple mechanisms and conserves the response of the arteries to vasodilation. PUFA in sesame suppresses blood clotting and fibrinogen activity. All the mentioned properties combat atherosclerosis and hardening of blood vessels, which are detailed in the present review for sesame.


| INTRODUC TI ON
The use of natural diet and herbs has become very popular in recent decades due to tendency for the consumption of toxin-free food with minimal adverse effect (Kelly et al., 2005). Sesame seeds have the highest oil content among other seeds and are a common ingredient in various foods due to their unique flavor and aroma.
Sesame has long been used as a popular edible grain in the food industry of Asian countries in various forms such as edible oil, cake batter, flour, and snacks with nuts (Fukuda et al., 1986a(Fukuda et al., , 1986bBudowski & Markley, 1951;Hemalatha, 2004). The structural difference between sesamin and sesamolin is due to the replacement of oxygen between the furofuran and piperonyl groups (Jeng & Hou, 2005). The amount of sesamin and sesamolin in sesame seeds is 200-500 mg/100 g and 200-300 mg/100 g, respectively (Kamal-Eldin & Appelqvist, 1994). Also, the level of sesamin and sesamolin in sesame oils from roasted sesame seeds is 5-500 mg/kg and 5-500 mg/kg respectively . Lignans play an important role in protecting the sesame plant against pests in the form of powerful antioxidants and insecticides (Jeng & Hou, 2005). Sesamine and sesamolin have higher antioxidant effects due to the fact that they have four groups of OH compared with sesamol which has two groups of OH (Jeng & Hou, 2005). Sesamin is the most abundant lignan in roasted sesame seeds and sesame oils from roasted sesame seeds have the beneficial effects including antiinflammatory and antiallergic effects (Kamal-Eldin & Appelqvist, 1994;Liu et al., 2019).
It has also been shown to protect nerve cells from oxidative stress.
In addition, it leads to the detoxification of chemicals and reduces the incidence of cancerous tumors caused by chemicals in the liver cell (Majdalawieh et al., 2021). It has also been shown that sesamin and sesamolin have antihypertensive effects (Nakano et al., 2007), increase the antioxidant activity of vitamin E in the lipid peroxidation system (Hemalatha & Rao, 2004), lower cholesterol (Visavadiya & Narasimhacharya, 2008), raise the oxidizing enzymes of fatty acids in the liver (Ashakumary et al., 1999), and protect neurons against hypoxia and brain damage (Cheng et al., 2006;Lee et al., 2005).

| Biosynthesis of lignans in sesame
In the biosynthesis pathway of sesamine, E-Coniferyl alcohol is produced from the amino acid phenylalanine. It then leads to the production of pinoresinol in sesame seeds. Pinoresinol is converted to piperitol and sesamin in mature seeds by the CYP81Q1 gene. In younger seeds, pinoresinol is converted to sesamolin (Jiao et al., 1998;Ono et al., 2006).

| PHARM ACO K IN E TI C S OF S E SAME
Lot of work has been done to clarify the complex aspects of absorption, distribution, metabolism, and secretion of sesame seed lignans.
Once ingested, some lignans are absorbed from the small intestine.
In the liver, lignans undergo oxidative biotransformation and demethylation and finally make hydroxylated catechol metabolites.
It seems that the main catecholic metabolite of sesame lignan is a compound named heavy (IR,2S,5R,6S)-6-(13,4-dihydroxypheny1)-2-(3,4-methyl lenedioxypheny 1)-3,7-dioxabi-clo be 3,7-[3,3, O] octane. This compound may be responsible for some of the biological actions of sesame, especially in protecting the liver. Some of them are converted into mammalian lignan, enterolactone (ENL), and to a lesser degree into enterodiol (END), by the intestinal microflora in the proximal part or the upper part of the large intestine. Although ENL and END are animal lignans, and only exist in mammals, they are formed through plant lignans by the enzymatic removal of methyl and hydroxyl groups. ENL and END are absorbed through the hepatic-intestinal cycle. Also, it is possible that catechol metabolites are secreted into the bile and then metabolized to ENL and END by the intestinal flora of the large intestine. Catechol metabolites eventually form glucuronides and sulfates are secreted into the urine. In addition, there is evidence that part of the metabolism of sesame lignans occurs in the enterocytes of the small intestine before reaching the liver (Scott et al., 1999).

| ATHEROSCLEROS IS
Atherosclerosis is a chronic inflammatory disease resulting from the accumulation of lipids and inflammatory cells in the intima layer of the entire vascular system from the aorta to the coronary arteries and its characteristic is the intimal plaques. The formation of this plaque begins with the deposition of small cholesterol crystals in the intima and the smooth muscle beneath it. Then, the plaques grow and develop the fibrous tissue and surround the smooth muscle, which results in reduction in blood flow (Rafieian-Kopaei et al., 2014). The production of connective tissue by fibroblasts and calcium deposition in the lesion leads to sclerosis or hardening of the arteries and eventually causes a sudden blockage of blood flow. The rise in lipid and blood sugar is related to the rise in oxidative damage, which affects the antioxidant status and lipoprotein levels (Rafieian-Kopaei et al., 2014). In addition, obesity, high blood pressure, inflammation, and infectious agents are other causes of atherosclerosis. Studies have shown that plants and phytochemicals with lipid-lowering effect can prevent atherosclerosis and endothelial damage (Deng et al., 2021;Hou et al., 2020;Loy & Rivlin, 2000;Rahman, 2001).

| Sesame and oxidative stress
Various evidences suggest that increased oxidative stress due to the overproduction of free radicals or incompetence of the antioxidant system may develop the atherosclerosis. High concentrations of activated oxygen species can cause membrane peroxidation, protein alteration, DNA failure, activation of neutrophils, disruption of signal transmission pathways, and the regulation of vascular wall cells and heart cells (Kattoor et al., 2017). Low-density lipoprotein (LDL) cholesterol is not naturally atherogenic but when converted to oxidize LDL form, has the nature of its atherogenicity (Linton et al., 2019).
The most important sources that cause oxidative stress in the vessel wall and stimulate the above phenomenon are as follows: activation of nicotine amide adenine dinucleotide phosphate (NADPH), nitric oxide synthase (NOS), myeloperoxidase (MPO), xanthine oxidase, lipoxygenase, and cyclooxygenase (COX; Rabêlo et al., 2010).
In addition, increased levels of the antioxidant enzymes glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT) are seen; moreover, a decrease in E, A, C vitamins and reduced antioxidant capacity are observed in atherosclerotic patients (Lubrano & Balzan, 2015). MPO is one of the oxidizing enzymes that stimulate the monocytes and neutrophils, and it causes inflammation in the walls of blood vessels to form atherosclerotic plaques and consequently cessation of blood flow to the organs. Another symptom of the disease is a disruption in the production of nitric oxide (NO), as a vasodilator, and the production of reactive oxygen species (ROS), including hydroxyl radicals on the surface of the arteries, which damage the vascular endothelium (Cai & Harrison, 2000;Faruqi, 2013;Ndrepepa et al., 2005;Sukhovershin et al., 2015). The use of antioxidants can be somewhat effective in counteracting oxidative stress. Many studies have shown that boosting the antioxidant system by the consumption of plant sources rich in antioxidants and phenolic compounds can be effective in reducing oxidative stress (Lobo et al., 2010; Table 2).

| Clinical studies
In 18 women and 32 men with hypertension and diabetes, who received diuretics or beta-blockers, the consumption of sesame oil (edible oil) for 45 days reduced blood pressure, peroxidation, plasma glucose level, glycosylated hemoglobin (HbA1c), total cholesterol (TC), LDL, TG, and the amount of TBARS. However, it raised the activity of enzymatic (CAT, SOD, GPx) and non-enzymatic antioxidants (vitamin C; Sankar et al., 2006).

| In vivo studies
Treatment of male Wistar rats with sesame oil (8 mL/kg, subcutaneously) was reported to reduce the amount of lipid peroxidation, hydroxyl radicals, and the amount of nitrate induced by lipopolysaccharides (LPS) while raising the activity of antioxidant enzymes, such as SOD and CAT (Hsu & Liu,2004). A similar protective effect was seen in rats when the lipid peroxidation induced by cecal ligation and puncture and treated with sesame oil (4 mL/kg, orally) . Also, oral treatment of rats with sesame oil (0.5 mL/ kg) inhibited the expression of renal lipid peroxidation and MPO and reduced ROS induced by gentamicin-plus-iodinated contrast (Hsu et al., 2011). Interestingly, subcutaneous injection of sesame oil (8 mL/kg) raised the activity of enzymatic antioxidants in rats with kidney damage induced by lipopolysaccharide (Hsu et al., 2005).
In addition, it has been shown that the consumption of sesame oil (200 mL) increases the activity of enzymatic and non-enzymatic antioxidants in rats with ischemia induced by occlusion of the right common carotid artery and the right cerebral artery in the midbrain (Ahmad et al., 2006). Also, oral administration of sesame oil (5 and 10 mL/kg) reduced oxidative myocardial damage caused by isoproterenol in rats (Saleem et al., 2014). Similarly, oral administration of sesame oil (5 and 10 mL/kg) raised the cardiac endogenous antioxidants and reduced oxidative stress induced by doxorubicin in rats (Saleem et al., 2013). Furthermore, feeding rats with 2% w/w oil in their diet (contained 6% w/w sesame oil) reduced TBARS, lipid hydroperoxides, and blood glucose, and increased GSH and hexokinase activity in the liver and kidney; it also combats oxidative stress induced by streptozotocin (STZ) (Ramesh et al., 2005). In rats suffering from iron damage, sesame oil (0.4 g/kg) decreased the levels of serum glutamate and TBARS in the liver (Hemalatha & Raghunath, 2004).
Sesame oil (10% w/w)-containing food supplements reduced lipid peroxidation and raised the amount of GSH against ROS induced by fenvalerate in the liver, brain, thymus, and spleen (Prasanthi & Rajini, 2005).
The use of sesame oil (8 mL/kg) has been shown to decrease the amount of superoxide anion, hydroxyl radical, and lipid peroxidation against ROS induced by acetaminophen in rat liver (Chandrasekaran et al., 2008). Additionally, oral administration of sesame oil (5 mL/kg) increased the level of GSH and reduced the amount of TBARS; also it has a protective effect against oxidative stress induced by cypermethrin in the liver and kidney of rats (Abdou et al., 2012). It has been shown that oral administration of sesame oil (1.5-3 mL) to rats has a protective effect against ROS induced by chronic electromagnetic radiation (EMR) and decreased the cholesterol level in the blood (Marzook et al., 2014). Furthermore, the rise in the expression of tissue inhibitors of matrix metalloproteinase 1 (TIMP-1) and reduction in the expression of matrix metallopeptidase 9 (MMP-9) and also the protection against ROS induced by monocrotaline have been shown in rat's colon by 1, 2, or 4 mL/kg dose of sesame oil (Periasamy et al., 2013). In another study, treatment of sesame oil (1 mL/kg, gavage) had protective effects on ROS damage in rats exposed to cyclosporine-A by increasing the level of antioxidative enzymes, such as GSH, SOD, and CAT in blood, liver, and kidney (Gülcan et al., 2015).
It has been reported that treatment of rats with sesame oil (0.5 or 1 mL/kg, gavage) reduced the activity of superoxide anion, hydroxyl radical, and lipid peroxidation in the kidney .

References
Oil (edible oil) Antioxidative Human 35 g Reduction in blood pressure, peroxidation, increase in the activity of enzymatic (CAT, SOD, GPx) and nonenzymatic antioxidants (vitamin C) Sankar et al. (2006) Oil Antioxidative Rat 4 and 8 mL/kg Reduction in lipid peroxidation, hydroxyl radicals, and the amount of nitrate, increase in antioxidant enzymes Hsu and Liu (2004), Hsu et al. (2008) Oil Antioxidative Rat 0.5 mL/kg Inhibits the expression of renal lipid peroxidation and MPO and reduces ROS Hsu et al. (2011) Oil Antioxidative Rat 8 mL/kg Increase in enzymatic antioxidants Hsu et al. (2005) Oil Antioxidative Rat
According to the above studies, it can be concluded that sesame

| Sesame and inflammation
The possible connection of endothelial cells with white blood cells, including monocytes and T lymphocytes, happens during vascular F I G U R E 1 Mechanism of effects of sesame and bioactive compounds (sesamin and sesamolin).
inflammation through a molecule attached to the vascular smooth muscle (VASM-1). White blood cells migrate to the intima of the artery with the help of metalloproteinase and digestion of extracellular matrix that stimulates the production of cytokines. Monocyte and T lymphocytes start to swallow the oxidized lipoproteins, including LDL, and produce foam-like cells, and their accumulation is associated with the progression of the lesion. Atherosclerotic plaque cells (monocytes, smooth muscle cells, and T cells) secrete IL-6, complement factor, cytokines, C-reactive protein (CRP), and NO (Hansson et al., 2006;Libby et al., 1995;Speidl et al., 2005). Macrophages exacerbate the aggregation of plaque by producing interleukin 1 (IL-1) and tumor necrosis factor-alpha (TNFα). Activated lymphocytes stimulate the proliferation of smooth vascular muscle cells and the production of a dense extracellular substrate, by releasing polypeptide growth factors, which is seen in advanced atherosclerotic lesions (Hansson et al., 2006;Petyaev et al., 2018;Tong et al., 2020; Table 2).

| Clinical studies
It has been shown that the consumption of sesame seed (40 g) for 2 months reduces MDA, high-sensitivity C-reactive protein (hs-CRP), and IL-6 in 50 people with knee osteoarthritis (Haghighian et al., 2014). In addition, it has been reported that the treatment of 104

| In vivo studies
Oral administration of rats suffering from rheumatoid arthritis, with sesame oil (1 mL/kg) and methotrexate (MTX) (1 and 2 mg/kg) reduced IL-6, and TNFα also increased the amount of IL-10 (Ali et al., 2017). In another study, in rats suffering from rheumatoid damage induced with injection of complete Freund's adjuvant in the left foot, oral administration of dronabinol (Δ9-THC)/sesame oil, 2.5 mg/ kg for 21 days decreased the deposition of erythrocytes and inflammatory cytokines, including TNFα, IL-6, and IL-10. Moreover, it dramatically reduced oxidative stress by increasing the activity of antioxidant enzymes, such as CAT, SOD, and GSH (Ismail et al., 2018).

| Sesame and obesity
Obesity increases the risk factors for heart disease including high blood pressure, cholesterol abnormalities, and type 2 diabetes.
Additionally, being overweight increases the risk of metabolic syndrome (a group of risk factors for heart disease including high blood pressure, low HDL cholesterol, high TG, high blood glucose, and high waist size). In addition, high blood pressure from obesity accelerated the plaque formation in the blood vessels, making them prone to rupture. In addition, latent inflammation caused by obesity in the body increases the risk of atherosclerosis and plaque hardening on the walls of arteries. Obesity also causes the release of inflammatory factors in the blood that may rupture the vascular plaque and causes heart attack. In addition, abnormalities in the metabolism of lipid, vascular endothelial function, and adipocytokines balancing also insulin resistance, have been linked to the prevalence of obesity and atherosclerosis (Lovren et al., 2015) Table 2.

| Clinical studies
It has been shown that the consumption of sesame seed powder (50 g) for 6 weeks reduced weight loss, BMI, and waist circumference in 46 women with metabolic syndrome (Shishehbor et al., 2015).
Based on the above studies, consumption of sesame seeds and their products seems to play a significant role in weight control.
In addition, sesame lignans may cause weight loss due to the fatburning effect of the oil, and increase in the expression of uncoupling proteins in the inner mitochondrial membrane. These proteins provide the energy needed for oxidative phosphorylation. Also, lignans in sesame increase the expression of the enzymes involved in β-oxidation of lipids and increase the cellular capacity for fat burning (Kushiro et al., , 2002; Figure 1).

| Sesame and diabetes
People with diabetes are two to six times more likely to develop atherosclerosis than non-diabetics. The process of accelerating atherosclerosis in person with diabetes can be attributed to the decrease in the production of NO. NO, which is normally secreted from vascular endothelial cells, causes vasodilation and proper blood flow inside the arteries. On the other hand, NO protects the reaction of platelets and leukocytes with the walls of blood vessels and is followed by intravascular damage. In diabetic patients, the level of NO is decreased, as a result, disruption in the vasodilation process increases the platelet aggregation (Hamed et al., 2011). Moreover, in diabetic patients, the entire coagulation cascade is impaired. Disruption in the functions of insulin as a natural platelet antagonist and inflammatory responses due to fluctuations in blood sugar level in diabetic patients accelerate the platelet adhesion to the blood vessels (Barlovic et al., 2011;Duarte et al., 2019;Ko et al., 2018Ko et al., , 2019. Inflammatory responses characterized by elevated CRP cause vascular disease in patients . Furthermore, endothelin-1 (responsible for the dysfunction of endothelium and secreted from endothelial cells, vascular wall smooth muscle (Kalani, 2008) and inflammatory cells) is secreted more in diabetic patients than in healthy individuals (Gogg et al., 2009; Table 2).

| Clinical studies
In 48 patients with type 2 diabetes, the consumption of sesamin (200 mg) for 8 weeks reduced the amount of FBS, HbA1c, TNFα, waist circumference, hip circumference, body adiposity index (BAI), IL-6, and elevates the amount of adiponectin (Mohammad Shahi et al., 2017). Moreover, it has been shown that treatment with sesame oil blend (35-40 mL) and glibenclamide (5 mg) for 8 weeks reduces the amount of FBS, HbA1c, TC, TG, LDL, and increases HDL in 300 patients with type 2 diabetes Devarajan, Chatterjee, Urata, et al., 2016). Besides, the consumption of sesame oil (35 g) and glibenclamide (5 mg) for 60 days improved antidiabetic effects by reduction in the level of glucose, HbA1c, TC, LDL, and TG and elevation of the level of HDL in 33 patients with type 2 diabetes (Sankar et al., 2011). In another study, in 46 patients suffering from type 2 diabetes, the consumption of sesame oil (900 mL) decreased glucose, HbA1c and increases insulin, the expression of SOD, CAT, and GPx (Aslam et al., 2019).
Furthermore, the consumption of sesame seed-based breakfast

| In vivo studies
Oral treatment with sesame oil (0.5 g/kg) and sesame butter (1.25 g/ kg) for 6 weeks decreased the level of glucose and elevated the level of HD against diabetic induced by STZ in rat (Haidari et al., 2016).
Similarly, diet supplementation with Nigella sativa (5% + 10% w/w) and sesame seeds (5% + 10% w/w) reduced lymphocytes count and generation of TNFα, IL4, IL8, the level of FBG, TC, TG, blood urea nitrogen, and creatinine; however, it increased the expression of SOD, GPx, and CAT in alloxan-induced diabetic rats (Ibrahiem, 2016). In addition, the consumption of sesame lignans and tocopherols (0.25% w/w sesame lignin+0.25% w/w α tocopherol) decreased lipid profile and production of ROS in diabetic (DM) rat (Dhar et al., 2007). In rats suffering from cardiac dysfunction caused by type 1 diabetes with STZ, oral treatment with sesamin (100 and 200 mg/kg) reduced blood pressure and heartbeat (Thuy et al., 2017). Furthermore, consumption of sesame oil (6% w/w) reduced the amount of blood glucose, HbA1c, TBARS, lipid hydro peroxides, the expression of glucose-6-phosphatase, and fructose-1, 6-bisphosphatase. However, it increased the level of hemoglobin, vitamin E, GSH, and expression of hexokinase against diabetes induced by STZ in rat (Ramesh et al., 2005). Sesamin (10-20 mg/kg, gavage) attenuated the contractile response to phenylephrine and elevated the relaxation response to acetylcholine in endotheliumintact aortic rings model of vascular dysfunction through a rise in NOS in STZ-induced diabetic rat (Baluchnejadmojarad et al., 2013).
Also, feeding mice with sesamin (0.2% w/w) for 8 weeks inhibited the elevation in the amount of blood insulin, lipid, superoxide anion, and the expression of NAD (P) H oxidase induced by high-fat diet.
In addition, it increased the capacity of exercise and the expression of citrate synthase in the skeletal muscle of diabetic mice (Takada et al., 2015). Additionally, treatment with sesamin (100 or 50 mg/ kg) for 2 weeks reduced the amount of FBG, glycosylated protein in serum, insulin in serum, TG, cholesterol, FFA, MDA, and increased the ability of insulin to bind to its receptors on the liver membrane and the amount of glycogen in the liver. Moreover, it improved the histopathological changes of pancreas and the expression of GSH, SOD, GPx against hyperglycemia, hyperlipidemia, and insulin resistance in KK-Ay mice with type 2 diabetes (Hong et al., 2013).

| In vitro studies
Pretreatment with sesamin (200 and 400 μg/mL for 24 h) reduced the level of MDA, generation of NO and the expression of NOS and iNOS against the damage induced by STZ in NIT-1 pancreatic β-cells (Lei et al., 2012).
According to the studies conducted above, it seems that sesame seeds have antidiabetic effects by reducing the FBS, glucose, AIP, glycosylated protein, and insulin and increasing the amount of glycogen in the liver. Also, as mentioned, consumption of sesame seeds reduces inflammatory factors such as hs-CRP, TNFα, IL4, and IL8 in diabetic patients. Therefore, it can be concluded that sesame seeds have shown favorable effects through the reduction in special parameters, especially the reduction in inflammatory factors, which are the causes of dysfunction in the endothelium of the blood vessels of diabetics and may predispose to atherosclerosis (Figure 1).

| Sesame and lipid profile
Hyperlipidemia is one of the known risk factors of the coronary artery disease and atherosclerosis (Smith Jr et al., 2004). High LDL is directly correlated to coronary artery disease, HDL is one of the strongest protective factors against atherosclerosis (Rudel & Kesäniemi, 2000) and a slight increase in TG prompts the risk of coronary heart disease and formation of new lesions (Assmann & Schulte, 1992;Bjørndal et al., 2020;Hokanson & Austin, 1996; Table 2).

| Clinical studies
It has been reported that treatment with sesamin (3.6 mg) + vitamin E (180 mg) capsules for 4 and 8 weeks reduces the level of cholesterol in serum (LDL) and inhibits HMG-CoA reductase (HMGR) in 20 males with hypercholesterolemia (Hirata et al., 1996). In 38 patients suffering from hyperlipidemia, treatment with white sesame seed (40 g) for 60 days reduced the level of TC, LDL, TBARS, and increased the gene expression of GPX and SAD (Alipoor et al., 2012).
Moreover, consumption of sesame oil (60 g) for 1 month reduced the level of LDL, TG, and increased the level of HDL. Also, it reduced body weight and waist circumference in 48 patients with hypercholesterolemia (Namayandeh et al., 2013).

| In vivo studies
It has been shown that feeding rats with sesamin (0.2% and 0.4% w/w) for 15 days inhibits the expression of SREBP-1 and reduces the gene expression of ACC, fatty acid synthase, ATP-citrate lyase (ACLY), and glucose-6-phosphate dehydrogenase (G6PD) involved in the lipogenesis . Also, feeding male rats with sesame seed powder which is rich in sesamin and sesamolin (200 g/kg) increased the amount of fatty acid oxidation of hepatic mitochondria. In addition, it reduced the activity of enzymes involved in the synthesis of fatty acids and TG (Sirato-Yasumoto et al., 2001). Similarly, elevation in the enzymes involved in the oxidation of fatty acid in rat liver seen when sesamin (0.2% w/w) plus fish oil (8% w/w; Ide et al., 2004) or sesamin (0.2% w/w) alone was fed for 15 days in rats (Kushiro et al., 2002). It has been reported that the consumption of sesame oil (5% or 10% w/w) reduced lipid profiles in serum and liver including: TG, cholesterol, LDL, VLDL, and decreased the expression of liver enzymes including: AST, ALT, GGT, ALP. Also, it is increased in HDL, adiponectin, and thyroid hormones against the hyperlipidemia induced by triton WR1339 in rat (Taha et al., 2014). Moreover, feeding with sesamin (2% w/w) for 15 days elevated the gene expression of enzymes involved in metabolism of glucose, cholesterogenesis, and lipogenesis in the liver. In addition, it stimulated the oxidation of fatty acid in the liver of rat (Ide et al., 2009). Moreover, sesame seed powder (200 g/kg) decreased the gene expression of lipogenic enzymes and the level of TG and MDA in rat (Ide et al., 2015). In addition, supplementing with sesamin (0.5% w/w) for 4 weeks decreased cholesterol absorption through the lymph and increased its extraction in the feces of rat (Hirose et al., 1991).
Besides, feeding with sesamin (5% w/w) for 4 weeks prevented the Δdesaturation of n-6 fatty acids in rat hepatocytes (Fujiyama-Fujiwara et al., 1995). Similarly, it has been shown that treatment with sesamin (155 μM) for 4 week inhibits Δ5 desaturase and the biosynthesis PUFA in rat liver microsomes . Consumption of sesamin (0.5% w/w) for 15 days elevated the genes expression of enzymes involved in the β-oxidation of unsaturated fatty acids and mitochondrial and peroxisomal oxidation of fatty acid also reduced the expression of lipogenic enzyme in rat liver (Ashakumary et al., 1999). Feeding with sesamin (0.5% w/w) for 4 weeks decreased the level concentration of linoleic acid, α-linolenic acid, and total PUFA and elevated the level of dihomoγ-linolenic acid, and the gene expression of enzyme involved in the β-oxidation of PPUFA in high-fat diet rats (Mizukuchi et al., 2003).
In addition, sesamin (2 g/kg for 15 days) elevated the gene expression of enzymes involved in the β-oxidation and reduced lipogenesis in rat . Feeding with sesamin (0.5% w/w) increased the amount of DGLA and prevented the Δ-desaturation of n-6 fatty acids in rat liver microsomes .
Furthermore, sesamin (0.2% w/w) for 16 days stimulated the production of ketone body and reduced TG, lipid secretion. Also, feeding sesamin lowered the ratio of β-hydroxyl butyrate to acetoacetate in rat liver (Fukuda et al., 1998). Moreover, feeding with sesamin (0.2% w/w) and α-tocopherol (1% w/w) for 10 days fought against high-cholesterol diet in rats (Rogi et al., 2011). In one study, supplementing with sesame oil (10% w/w) or N-acetylcysteine (NAC) (230 mg/kg) reduced the level of lipid profile, lipid peroxidation, ALP, and hypothalamic glucocorticoid receptors (GR) and prevented the hepatic damage in mice fed with high-cholesterol-enriched diet (Korou et al., 2014). It has been shown that bugak (pan-fried unroasted sesame oil) (20 g/100 g of feeding diet) reduces TG, TC, and LDL, and inhibits the expression of HMGCR and hepatic FAS in LDLR −/− mice (Kim et al., 2014  . Also, sesame lignans (50 mg/ kg, orally) reduced the expression of platelet-activating factor acetylhydrolase and prolonged the LDL oxidation delay time in rabbits fed with fat/cholesterol-enriched diet (Nakamura et al., 2020).

| In vitro studies
It has been shown that pretreatment with sesame oil (1-10 μg/mL) increases the gene expression of PPARc1, liver X receptor alpha (LXRα), and MAPK. Also, it increases the cholesterol efflux in primary macrophages isolated from C57/BL6 mice (Majdalawieh & Ro, 2015).
The use of sesame oil in Asian cultures has inspired many studies on its beneficial effects on lipid profile. For example, in China, 28 kg of edible oil, especially sesame oil, is used annually. Sesamin appears to induce lipid oxidation in the liver by activating PPAR.
Also, it reduces the gene expression of hepatic lipogenic enzyme with down-regulation of SREBP-1 transcription factor (Ide et al., 2003;Majdalawieh et al., 2020). In addition, it prevented the Δdesaturation of n-6 fatty acids, inhibited the expression of HMGCR and hepatic FAS, and reduced the amount of plasma cholesterol, TG, and LDL. The proposed mechanism is an increase in the biliary excretion of cholesterol in the liver via increasing in gene expression of ATP-binding cassette subfamily G members 5 (ABCG5), ATP-binding cassette subfamily G members 8 (ABCG8) and a reduction in the secretion of apolipoprotein B (ApoB) via decreasing in the gene expression of apolipoprotein A4 (ApoA4) (Rogi et al., 2011). Therefore, it seems that sesame seeds combated atherosclerosis induced by the consumption of high-fat diet through the mentioned possible mechanisms ( Figure 1). Also, β-carbonyls such as Harman and nor-Harman have been detected in sesame oil (Liu et al., 2022). Perhaps, the existence of these active compounds is a source of the effects of sesame oil in dealing with dyslipidemia. Of course, investigating this issue requires more research.

| Sesame and hypertension
Hypertensive vascular disease affects large and small arteries and arterioles and is characterized by the thickening of the fibromuscular layer of the intima and media and finally narrowing of arteries and arterioles. The physical pressure of hypertension on the arterial wall also leads to the exacerbation and acceleration of atherosclerosis, especially in coronary arteries. In addition, high blood pressure appears to increase the susceptibility of small and large arteries to atherosclerosis. Therefore, a patient with high blood pressure is a candidate for high blood pressure and atherosclerotic diseases, which leads to blockage of large and small arteries, resulting in myocardial infarction (Hollander, 1976) (Table 2).

| Clinical studies
It has been reported that in 25 patients suffering from metabolic syndrome, co-consumption of sesame oil (30 mL) and vitamin E (400 mg) reduces the level of TG, FBG, homeostatic model assessment (HOMA-IR), MDA, hs-CRP, TC, and LDL. Furthermore, it improved systolic and diastolic blood pressure (Farajbakhsh et al., 2019). It has been shown that in 13 hypertensive patients, administration of capsules with sesamin (60 mg) reduces the level of systolic and diastolic blood pressure (Miyawaki et al., 2009

| In vivo studies
It has been shown that feeding with sesamin (0.15% w/w) for 4 weeks prevents the cholesterol accumulation in the liver and fought against hypercholesterolemia induced by high-fat and cholesterol diet in hypercholesterolemic, stroke-prone/spontaneously hypertensive rats (Ogawa et al., 1995). Similarly, co-consumption of sesamin (1000 mg) and vitamin E (1000 mg) for 5 weeks reduced the systolic blood pressure, and the level of 8-hydroxy-2′-deoxyguanosine (8-OHdG) also attenuated thrombotic tendency of cerebral arterioles induced by a helium-neon laser in stroke-prone spontaneously hypertensive rat (Noguchi et al., 2001). Feeding with sesamin (1% w/w) decreased the systolic blood pressure, the weight of the left ventricle, and vascular hypertrophy in DOCA/salt-treated twokidney, one clip hypertensive rats Matsumura et al., 1995Matsumura et al., , 1998Matsumura et al., , 2000Nakano et al., 2004). Moreover, consumption of sesamin (0.1% w/w) for 5 weeks suppressed the increase in the production of vascular superoxide and reduced the systolic blood pressure against hypertension induced by DOCA/salt in rat (Nakano et al., 2002). In addition, oral treatment with sesame oil (0.5 or 1 mL/kg) decreased the systolic and diastolic blood pressure, abnormalities in electrocardiography (ECG), and elevated the level of K + and Mg 2+ . Also, it limited the excretion of K + from urine against hypertension induced by DOCA/salt in rat . As well, oral treatment with sesamin (>94% purity) elevated the biosynthesis of NO via increasing in the level of phosphorylated eNOS and inhibition of eNOS uncoupling. In addition, it reduced nitrotyrosine, dihydrofolate reductase (DHFR), oxidative inactivation of NO, and the generation of superoxide anion in the aortas of spontaneously hypertensive rats . Oral administration of sesame protein hydrolysate powder (1 and 10 mg/kg) decreased the level of systolic blood pressure and suppressed the activity of angiotensin I converting enzyme in spontaneously hypertensive rat Nakano, Ogura, et al., 2006). Oral treatment with sesamin (40, 80, and 160 mg/kg) improved the relaxation response of endothelium aorta to acetylcholine, nitroprusside, and increased protein expression of eNOS and the amount of MDA. Also, it reduced protein expression of NADPH oxidase subunits p47 phagocyte oxidase (p47phox) and p22 phagocyte oxidase (p22phox) and fought against the arterial dysfunction in spontaneously hypertensive rats . Intragastric injection of sesamin (80 and 160 mg/kg) for 12 weeks reduced the amount of transforming growth factor-β1 (TGF-β1), phosphorylated Smad2, protein expression of NADPH oxidase subunits p47phox, and the expression of type I and type III collagen protein. Additionally, it increased the total antioxidant capacity and SOD and fought against myocardial fibrosis in spontaneously hypertension rats (Zhao et al., 2015).
As well, oral treatment with sesamin (>94% purity) decreased the blood pressure, the amount of MDA, and the expression of NADPH oxidase subunits p47phox while improving the relaxation response of endothelium aorta to acetylcholine. Also, it increased the biological activity of NO against hypertension and endothelial dysfunction against renovascular hypertension models induced by two-kidney one clip renal in rats fed with a high-fat, high-sucrose diet (2K1C rats on HFS diet) (Kong et al., 2009). Treatment with four demethylated sesamin metabolites (50 μM, orally) elevated the vasodilation response of endothelium in the aorta of rats with hypertension Nakano, Ogura, et al., 2006). It has been shown that oral treatment with sesamin (100 mg/kg) for 3 weeks reduced the hypertrophy of the heart and suppressed fibrosis and inflammation via decreasing the amount of ROS, phosphorylated ERK1/2, and phosphorylated Smad2. The possible mechanism of the protective effect of sesamin to reduce cardiac remodeling induced by transverse aortic constriction in mice appears to be through elevation in phosphorylation of sirtuin 3 (Sirt3) (Fan et al., 2017).

| In vitro studies
It has been shown that pretreatment with sesamin (1, 5, and 10 μmoL/L) increased the level of NO, protein, and mRNA expression of eNO and inhibited the level of ET-1, protein, and mRNA expression of endothelin-converting enzyme-1 (ECE-1). Also, it elevated the biological activity of NOS in HUVECs (Lee et al., 2004).
To conclude, sesame seeds probably show higher protective effects against high blood pressure compared with other oil seeds due to high content of PUFA, such as omega-3 fatty acids, antioxidant properties, and the lignans, such as sesamin (Vennila, 2017).
It increases the biosynthesis of NO, which is one of the factors of vasodilation. Also, it elevates the phosphorylation of Sirt3 that plays a key role in the reduction in cellular ROS levels, and finally inhibition of NF-κB, MEK-ERK1/2, and smad2 signaling pathways. Another possible mechanism is through lowering the protein expression of NADPH oxidase subunits p47phox and p22phox (Figure 1).

| Sesame and thrombosis
Various factors, such as free radicals, infection, or trauma inside the blood vessels may harm the walls and initiate the thrombosis cascade (Meade, 1995). The damaged part of the walls of blood vessels acts like a magnet for blood platelets (Kannel, 1997). Raised plasma fibrinogen levels, decreased fibrinolytic activity, and blood clotting time lead to the development of clot formation in atherosclerotic vessels (Smith et al., 1997) (Table 2).

| In vivo studies
It has been shown that oral or intra-arterial treatment with sesamin and sesamolin for 12 weeks has antithrombotic effect against thrombosis induced by He-Ne laser in mice carotid artery (Kinugasa et al., 2011). Also, feeding with sesame or sesame oil (1% w/w) reduced the level of blood clotting fibrinogen and blood clotting factor VII against hypercholesterolemia induced by high-cholesterol diet in rabbits (Asgary et al., 2013). Due to the high amount of PUFA, sesame oil has the potential to stimulate anticoagulant agents, and reducing blood clots (Jonnalagadda et al., 1996) (Figure 1).

| CON CLUS ION
In this review, we collected different in vivo, in vitro, and clinical studies to provide evidences about the role of sesame and bioactive compounds (sesamin and sesamolin) on inflammation and atherosclerosis. Oxidative stress, inflammation, hyperlipidemia, infection, blood pressure, thrombosis, obesity, and diabetes may accelerate atherosclerosis. The possible mechanism of sesame against atherosclerosis appears to be via: 1. Reduction in ROS and oxidative enzymes, such as MDA and TBARS, and increase in the expression of antioxidative enzymes including CAT, SOD, and GPx. project administration (equal); visualization (equal); writing -review and editing (equal). Seyed Ahmad Emami was responsible for investigation, methodology, literature searches.

ACK N OWLED G M ENTS
The authors are thankful to the Research Council of Mashhad University of Medical Sciences, Iran.

FU N D I N G I N FO R M ATI O N
The study was funded by Research Council of Mashhad University of Medical Sciences, Iran.

CO N FLI C T O F I NTE R E S T S TATE M E NT
The authors report no conflicts of interest in this work. The authors alone are responsible for the content and writing of this article.

DATA AVA I L A B I L I T Y S TAT E M E N T
Data wil be available upon request.