Anti-inflammatory and Antioxidant Effects of Sesame Oil on Atherosclerosis: A Descriptive Literature Review

Sesame oil (SO) is a supplement that has been known to have anti-inflammatory and antioxidant properties, which makes it effective for reducing atherosclerosis and the risk of cardiovascular disease. Due to the side effects of statins, the current recommended treatment for atherosclerosis and cardiovascular diseases, the idea of using dietary and nutritional supplementation has been explored. The benefits of a dietary health regime have piqued curiosity because many different cultures have reaped health benefits through the ingredients in their cooking with negligible side effects. The purpose of this literary review is to provide a broad overview of the potential benefits and risks of SO on the development of atherosclerosis and its direction toward human clinical use. Current in vivo and in vitro research has shed light on the effects of SO and its research has shown that SO can decrease low-density lipoprotein (LDL) levels while maintaining high-density lipoprotein (HDL) levels. Current limitations in recent studies include no standardized doses of SO given to subjects and unknown specific mechanisms of the different components of SO. Future studies should explore possible synergistic and adverse effects of SO when combined with current recommended pharmaceutical therapies and other adjunct treatments.


Introduction And Background
Atherosclerosis, the formation of plaques in arteries, has been the topic of extensive research due to its critical role in increasing the risk of cardiovascular diseases such as coronary heart disease (CHD) [1][2]. CHD is one of the leading causes of mortality and morbidity in Americans and causes approximately 610,000 deaths in the United States annually. Due to the high prevalence rate of one in four deaths due to CHD [1], many research studies have explored the mechanism of atherosclerotic plaque formation. Studies have come up with two prominent hallmarks of pathogenesis: the accumulation of cholesterol in the endothelial lining of arteries carried by low-density lipoproteins (LDLs) and chronic inflammation due to a high ratio of prooxidants to antioxidants [2][3]. Studies have implied that these hallmarks of atherosclerosis are not independent but are part of the same process where the abnormal deposition of LDL-cholesterol (LDL-C) leads to an inflammatory response resulting in fatty plaques and vascular occlusion [4][5].
Previous literature has established that high serum cholesterol, more specifically elevated LDL levels, is a measure of atherosclerotic risk and, therefore, the reduction of plasma LDL levels should reduce the amount of atherosclerosis and its consequent risk of CHD [4]. LDL and high-density lipoprotein (HDL) are carriers of cholesterol. LDL carries cholesterol to tissues in contrast to HDL, which carries cholesterol to the liver for disposal [6]. An increase of LDL in blood plasma can cause an imbalance in lipoproteins that can lead to build-up of cholesterol, especially in the tunica intima of the large and medium-sized arteries [7]. Cells of the vascular wall secrete oxidative products and can initiate lipid oxidation of the LDL. While the oxidized LDL levels increase and accumulate in the artery, damaged endothelial cells release inflammatory signals to initiate an immune response to fight the cholesterol aggregation [2,8]. This induces oxidative stress, an imbalance between pro-oxidants and antioxidants, and can cause oxidative damage to surrounding endothelial cells [3,9]. Macrophages sense the signals and infiltrate the tunica intima to phagocytose the oxidized LDL aggregation [10][11][12]. With a chronic inflammatory response and the accumulation of oxidized LDL, a fatty streak in the arterial tunica intima forms [13]. Over time, the fatty streak grows, thickens the arterial walls, and contributes to chronic inflammation [14]. This leads to the development of a stable plaque, which can be at risk for eruption when it becomes unstable [15].
The guidelines for cholesterol management through the American College of Cardiology/American Heart Association recommend using statin therapy as the primary prevention treatment for managing cholesterol levels [16]. Statins are hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, which inhibit the HMG-CoA reductase, an essential rate limiting enzyme in the cholesterol synthesis pathway [17]. Previous literature has shown that statins are a powerful treatment option, which at a dose of 80 mg/day can reduce LDL-C by about 47% [18]. The use of statins became more frequent when the Scandinavian Simvastatin Survival Study showed that long-term treatment with simvastatin was safe and improved survival rates in CHD patients [17].
While statin use has continued to grow in popularity, an issue with the statin treatment is the intolerance of the side effects associated with taking the drug [19]. Statin therapy is not for every patient; patients with higher levels of LDL-C are more likely to benefit from statin use than patients with lower levels of LDL-C [20]. About 10% of patients complain about the side effects, such as myalgia, and this decreases their patient compliance [16]. Due to the side effects of statins and other pharmaceutical drugs, the idea of using dietary and nutritional supplementation has gained traction in the scientific community [16]. The benefits of a dietary health regime have piqued curiosity because many different cultures have reaped health benefits through the ingredients in their cooking. For example, the use of sesame oil (SO) in Asian cultures has inspired studies on the dietary benefits of consuming SO. One study found that traditional Korean cooking called bugak prepared with pan-fried unroasted SO has been shown to decrease LDL, triglyceride (TG), and total cholesterol (TC) levels [21]. Experimental studies on rats fed a sesame seed extract exhibited a significant decrease in plasma cholesterol, triglycerides, very low-density lipoprotein (VLDL) cholesterol, and LDL. One study tested the effect of sesamin, a lignan in SO, in humans and found a significant reduction in LDL-C [22]. This study also referenced other literature, stating that sesamin may potentially reduce HMG-CoA reductase activity by altering the amount of cholesterol ester and free cholesterol by decreasing acyl-CoA cholesterol acyltransferase (ACAT) activity [22]. By reducing HMG-CoA reductase activity, sesamin could potentially reduce LDL levels in a similar manner as statin drugs without the myopathy side effects.
While these studies were conducted many years ago, more recent studies into the properties of sesamin have concluded that sesamin and other constituents of SO have antihyperlipidemic effects and can improve many of the biochemical measurements found in a lipid panel. An experiment conducted on rats studied how sesamin influenced lipid metabolism because of the relationship between increased secretions of LDL in rat liver, following a decrease in fatty acid oxidation. This study concluded that sesamin appears to be a potent inducer of hepatic fatty acid oxidation and is an inhibitor of hepatic lipogenic enzyme gene expression by down regulating sterol regulatory element bind protein-1 (SREBP-1), which is a transcriptional factor that regulates gene expression for both fatty acid and cholesterol synthesis [23]. A more recent study extracted SO from Sesamum indicum L. and examined the effects on rabbits fed on a high fat diet (HFD). The study found that the rabbits supplemented with SO had a lower circulating level of LDL [24]. Sesamol is another lignan of SO that has also shown anti-inflammatory and antioxidant properties in studies [25].
All of these previous studies strongly indicate that SO supplementation has anti-atherogenic effects [26]. Despite indications of cholesterol-lowering effects through different constituents of sesame seeds and oil in many animal studies, the potential hypocholesterolemia properties of raw SO have not been tested much, to the best of our knowledge, in human studies.
The purpose of this literary review is to provide a broad overview of the effects of SO on atherosclerosis and its direction toward human clinical use. This review will examine the recent experimental studies that have been specifically conducted on SO and its effects on cholesterol levels and inflammation in animal atherosclerotic models and in vitro interactions between leukocytes involved in atherosclerosis and arterial tissues. The basis for this review is to select scientific research that tests SO or its lignans as a dependent variable in experiments about atherosclerosis and its hallmarks, inflammation or cholesterol. The time frame for research reviewed is from January 2010 to January 2016 in order to distinguish the most recent studies about SO.

Materials and methods
To begin the review article search, search words [SO] and [cholesterol or inflammation or atherosclerosis] were used to begin the search for papers that studied the effects of SO on levels of cholesterol or inflammation or atherosclerosis. The following criteria were used to further narrow down papers published:

Results
After the initial search of [SO] and [cholesterol, inflammation, or atherosclerosis] in the PubMed database, a total of 134 papers that included the key terms were found. After narrowing down the results with a time frame from January 2010 to January 2016, the number of studies dwindled down to 43. Afterward, each abstract of the 43 search results were individually scanned with the criteria stated in the methods. The final search yielded 14 studies that experimented on the effects of SO on atherosclerotic risk factors, such as cholesterol levels and inflammation, and key players that initiate or lead to the progression of atherosclerosis. Below is a table of summary of each of the chosen studies (   Out of the 14 studies in Table 1, studies 4 and 14 were the only two studies using human subjects. Study 4 studied SO and its effects on endothelial function in hypertensive men. The results were that postprandial and long-term effects of SO increased flow-mediated dilation (FMD) from baseline comparison. The measured levels of intracellular adhesion molecules (ICAM) decreased significantly at 60 days in the longterm study but did not decrease significantly in the short-term postprandial study. The results of this study showed that SO has both local and short acting benefits such as vasodilation and also longer acting properties involved with the downregulation of the integrin ligand of the ICAM. Since the ICAM did not decrease significantly for the postprandial two-hour period, but did for the long-term period, this may suggest that the downregulation of the ICAM protein is due to the SO changing the gene expression of the ICAM gene. Study 14 was the second study out of the 14 studies that had human participants. The study was comparing nifedipine against nifedipine and an oil mix of SO and sunflower oil. Nifedipine and oil-mix patients showed a significant decrease in blood pressure, lipid peroxidative markers, lipid profile (excludes HDL levels), sodium, and chloride in comparison to nifedipine-only patients. Nifedipine and oil-mix patients showed a significant increase in enzymatic antioxidants, non-enzymatic antioxidants, HDL, and potassium levels in comparison to nifedipine-only patients.
The alteration of gene expression is supported by studies 1, 2, 3, 7, 9, and 13, which all show that SO's mechanism of action includes the change in gene expression to inflammatory or lipid metabolism proteins. Study 1 found that mice livers showed increased expression of genes related to the reverse cholesterol transport (RCT) and lipid metabolism in SO-fed mice. Gene expression in mice aortas showed that SO-fed mice had increased mRNA levels of genes related to RCT but reduced levels of monocyte markers, ABCG, and scavenger receptors. Cytokines array showed that SO increased expression of genes pertaining to RCT and cholesterol metabolism. This indicates that SO is associated with increasing or decreasing of certain proteins. This study fed the mice the SO diet for 15 weeks, which is congruent with the idea of long-term gene expression changes. Study 1 is not the only study though that showed that SO could have short-term benefits also. Study 2 showed in mice not only that the expression of inflammatory mediators could be significantly reduced but also that the sesame oil aqueous extract (SOAE) could inhibit the oxidation of lipoproteins through lipopolysaccharides (LPS)-induced tumor necrosis factor (TNF)-α and interleukin (IL)-6. Study 3 examined SO and its ability to augment macrophage cholesterol efflux through a mitogenactivated protein kinase (MAPK) signaling pathway.
Study 5 examined α-lipoic acid and SO's antioxidant protective property from diazinon (DZN) toxicity. The rats were sacrificed after four weeks, which showed that the combination of α-lipoic acid and SO was able to ameliorate the DZN intoxication. Study 6 showed that SO significantly decreased lipid peroxidation but did not significantly increase nitric oxide compared to n-acetyl cysteine. Also, the results found that 10% SO in the HFD for eight weeks in the mice did not decrease the lipid levels significantly compared to the control. The decrease in lipid peroxidation is consistent with the other studies that found that SO could affect lipid metabolism. Study 6 does not seem to be consistent with study 4, which showed both short-and long-term FMD. FMD is due to the sheer stress stimulus that produces a nitric oxide-dependent response. FMD is a direct marker of nitric oxide (NO) bioavailability and study 6 showed that only NAC restored NO bioavailability and not sesame oil supplementation. Study 4 was conducted on hypertensive males, and study 6 was conducted on mice. Study 7 showed that sesamol could decrease lipids and increase hepatic protein expression, while study 8 found that SO and not sesame seed could ameliorate high lipid levels and hepatic enzymes in rabbits fed a HFD. Studies 9 to 12 supported increased hepatic enzymes to decrease lipid levels. Study 13 was consistent with study 6 and found that sesamol inhibited production of NO and other proinflammatory markers.

Review
In the studies that analyzed the effect of SO and its lignans on a lipid profile, SO has been shown to decrease TC, LDL, and VLDL plasma levels in hypercholesterolemic rodent and rabbit models. However, one reviewed study had stated that SO has no significant effects on lipid levels compared to the control [32]. Study 6 stated that SO treatment was not significantly different from the control treatment, which supported that the beneficial effects resulting from treatment with N-acetylcysteine (NAC) and SO together was only due to NAC; there was not enough SO to counteract the high cholesterol diet, which implies that SO treatment may be dose dependent. Other studies also agree that their research results that indicate the benefits of SO were truly significant at a certain dose [33][34][35]. Plant studies showed that plant stanols decreased LDL levels in a dose-dependent manner up to ~17% in a linear fashion when given up to 9 grams/milliliter [40]. The diet fed to the subjects in study 6 was composed of 10% SO compared to other studies that administered SO amounts depending on the weight of the subject. Depending on the weight of the subjects, 10% of SO in the diet may not have been enough to show SO's anti-lipidemic effects [41]. Since caloric intake is higher than recommended in many populations, research has pointed out that consumption of supplemental oil should be associated with reduced intake of saturated fat [42]. This implies that SO could also be present in high amounts but not enough to induce its effects relative to the subject ingesting it.
In order to research additive effects of SO, some research explored the effects of mixed oils containing SO. Many vegetable oils, like sunflower or olive oils, also show hypocholesterolemic effects when ingested [43].
Research on the use of SO to treat atherosclerosis has yet to accumulate studies and research. So far, there are mixed reviews about SO, some studies stating that SO is not as effective as other edible oils. Study 6 studied the effects of SO in comparison to other oils in order to compare SO as a novel nutritional element to other vegetable oils that are part of our daily nutrition. Results in the study showed that SO was not as effective as the other oils [30]. This can be due to a few reasons, one being that the SO is not isolated and tested on its own. Blending different oils could result in a synergistic, antagonistic, or neutral effect. SO on its own can decrease cholesterol levels in the blood, but studies showed that SO blended with α-lipoic acids decreased cholesterol levels in the blood much more than α-lipoic acids or SO alone [31]. Another reason could be that there is no universal SO used throughout all the studies. There are many brands of SO, which are made with different techniques and compositions that may influence the effects of SO [44]. For example, SO is derived from heating sesame seeds to a certain temperature in order to create many of the lignans that are abundant in the oil but not the seeds [45]. This may increase or decrease the potency of SO compared to other vegetable oils and vice versa. In order to be able to properly compare the studies, one standardized concoction of SO should be created and consistently used throughout the studies.
Another way research explores the effects of SO is to test it in a mix with other components. For example, study 14 compared the effects of nifedipine to the effects of an oil mix of nifedipine with SO and sunflower oil on hypertensive patients, which resulted in a decrease in hypertensive factors. However, it is possible that the benefits could have been from the sunflower oil alone or that the SO had no benefit. It is also possible that the SO could have had adverse effects that negated some of the benefits of nifedipine or vice versa. The conclusion is that many of these studies are limited because they do not isolate the benefit of SO in humans alone and that different concentrations of SO are used in different studies and that a future study should examine the different concentrations of SO and its effects on humans with hyperlipidemia, hypertension, and diabetes mellitus. New studies can compare patients treated with differing mixes of medication, such as nifedipine, statins, metformin, with different concentrations of SO. Like statin therapy, many studies have promising results that show SO, when used as a dietary supplement, to lower LDL levels in the blood in coronary and aortic vasculature, as well as the liver and the brain [46][47]. The 14 studies did not examine the effects of SO on pancreatic beta cells, and future studies may want to see if SO has any potential effects since diabetes is also often associated with increased cardiovascular disease.
In most of the mentioned studies performed on animal models with SO, the benefits of SO and its components (e.g., sesaminol) can change the amount of gene transcription in different targets, such as endothelial cells, hepatocytes, and macrophages. Lignans such as sesamin and sesamol have gained popularity as they have been shown to have antioxidant and hypocholesterolemic effects [48][49]. However, many more studies need to be conducted on human participants since only two out of the 14 were on humans and one of the studies did not examine SO directly. In study 4, hypertensive men who took SO showed an increase in short-and long-term FMD and long-term ICAM. While these results look promising, there is a lot more that needs to be examined. In contrast, study 14 compared the benefits of SO and nifedipine with nifedipine alone. Neither of these studies compared the efficacy of SO to current pharmaceutical treatments in treating atherosclerosis. Previous studies have looked at the synergistic benefits as opposed to a direct comparison of SO with insulin-independent diabetic medications and antihypertensive medications [50]. These results show that in order to properly assess the effects of SO, there is a strong requirement for human trials with SO. Animal studies have shown that SO has decreased atherosclerotic factors without significant harm to the models, but it is unknown whether the same effects of SO would affect humans in the same way. In order to one day implicate SO and its effects on atherosclerotic patients, SO must past more clinical trials in order to gain traction as a possible treatment for atherosclerosis and other cardiovascular diseases. atherosclerosis, and delaying the onset of cardiovascular diseases. Since SO is very inexpensive and natural, progressing research on SO to someday implement SO as a good pharmaceutical treatment would be an investment, especially when SO has yet to show adverse effects. However, SO has not had many clinical trials, and the benefits relative to other oils and medications still need to be investigated. This literature review found that the benefits of SO vary between studies due to the methodology of SO product, dose dependence, and examination of different variables. Many of these studies are limited because they do not isolate the benefit of SO in humans alone and because there are different concentrations of SO used in each study. Future studies should examine the different concentrations of SO and its effects on humans with hyperlipidemia, hypertension, and diabetes mellitus in a dose-dependent manner relative to the patient's body habitus. Future studies can also look at synergism by comparing patients treated with differing combinations of medication, such as nifedipine, statins, metformin, with different concentrations of SO relative to the individual's saturated fat diet.