Sesame Seed ( Sesamum indicum L.) Extracts and Their Anti

Chapter 19

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Sesame Seed (Sesamum indicum L.) Extracts and Their Anti-Inflammatory Effect Dur-Zong Hsu, Pei-Yi Chu, and Ming-Yie Liu* Department of Environmental and Occupational Health, National Cheng Kung University, 138 ShengLi Road, Tainan, Taiwan *E-mail: [email protected]

Steroids and non-steroidal anti-inflammatory drugs (NSAIDs) are the main choices for controlling inflammation. However, their adverse effects limit their clinical use. Sesame (Sesamum indicum L.) is one of the oldest cultivated plants in the world. Its extracts, such as sesame oil, have been widely used since ancient times. Recently, sesame oil and its lignan sesamol have been proved to be potent anti-inflammatory agents. They have an excellent protective effect against endotoxin-associated inflammatory damage because they inhibit the release of inflammatory mediators. Sesamol also inhibits endotoxins from binding to its receptor; this reduces inflammatory transcription factor NF-κB activation. In summary, sesame oil or sesamol may be beneficial for reducing the inflammatory response in inflammation-associated diseases.

Introduction Sesame seed is one of the most-used ingredients in Asian dishes in China, India, Japan, and Taiwan. Its oil is high in polyunsaturated fats and in the unique antioxidants sesamol and sesamin. Sesame seed oil and other extracts are believed to have antibacterial and anti-inflammatory properties (1). Therefore, it is often recommended in alternative medicine. Despite a growing number of recent studies showing sesame seed oil’s anti-inflammatory property, the U.S. Food and Drug Administration has not approved it as a drug for controlling inflammation.

© 2012 American Chemical Society In Emerging Trends in Dietary Components for Preventing and Combating Disease; Patil, B., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.


Botanical Descriptions Sesame (Sesamum indicum) is an annual bushy plant. The prime season for sesame seeds is between September and April. Sesame can grow as high as seven feet tall, though most plants range between two and four feet. The leaves are oval, deeply-ribbed, light green, and 7.5 to 12.5 cm long. The gamopetalous flowers, which look somewhat like foxglove, are white to purple, tubular, 3 to 5 cm long, have a four-lobed mouth, and produce pods inside measuring 2.5-8.0 cm long by 0.5-2.0 cm in diameter (2). When ripe, the pods burst and release small, flat, oval seeds about 1 mm thickness. The seeds are high in oil and, come in a variety of colors depending on the plant variety: shades of brown, red, black, yellow, and, most commonly, a pale grayish ivory (3).

Cultivation and Use Sesame is an ancient oilseed. There is botanical and textual evidence for sesame cultivation in the ancient world. Excavations at the Indus Civilization site in Harappa (contemporary West Punjab, Pakistan) have yielded charred sesame from a stratum attributed to 3050-3500 B.C. Sesame was grown during the ancient Harappan, Mesopotamian, and Anatolian eras for its edible seed and its oil (4). Ancient peoples used sesame seed oil as a food, salve, medication—especially in Chinese and Indian herbal medicine—and source of light (3). As early as the 8th century B.C., the Chinese used sesame seeds to treat insect bites and toothache. Indians believed that sesame seed oil gave the body energy (4). Nowadays, sesame is grown in many areas of the world. India ranks first in area (46.5%) under sesame cultivation; it produces about 27.9% of the world’s sesame (5), but the crop is also grown in China, Burma, Sudan, Ethiopia, and other places. U.S. commercial production reportedly began in the 1950s, primarily in Texas and the southwestern states; however, the U.S. imports more sesame than it grows. Sesame seed oil is nutritious and has great moisturizing, soothing, and emollient qualities. Therefore, sesame seed oil is currently used in salad and as a cooking oil, an ingredient in cosmetics, and in the manufacture of soaps, pharmaceuticals, and lubricants (3).

Sesame Extracts for Preventing Inflammatory Diseases Inflammation Burns, chemical irritants, frostbite, toxins, infection by pathogens, some physical injuries, ischemia, oxidative stress, and immune reactions caused by hypersensitivity induce inflammatory responses. During these responses, inflammatory cells (macrophages and neutrophils) and additional effector molecules (cytokines and chemokines) are delivered to the stimulated sites to accelerate the elimination of harmful proinflammatory agents. In addition, the inflammatory response is associated with the preventing the spread of infection and promoting the repair of injured tissue (6). The release of inflammatory mediators, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and nitric oxide (NO), not only activates inflammatory cells, but also changes blood vessel permeability. 336 In Emerging Trends in Dietary Components for Preventing and Combating Disease; Patil, B., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.


Therefore, inflammatory responses are characterized by pain, redness, heat, and swelling at the inflammatory site (6). Although inflammation is the body’s defense response, inducing an inappropriate or excess inflammatory response leads to severe fever, agonizing pain, and even organ damage. Rheumatoid arthritis, shoulder tendinitis, gouty arthritis, hay fever, asthma, allergies, and autoimmune disorders are all associated with inflammation. In particular, sepsis, a systemic inflammatory response caused by bacterial endotoxins, is the primary cause of death in patients in intensive care units (7). Severe sepsis causes acute respiratory distress syndrome, multiple organ dysfunction, and death (8). Mortality is 26% in patients with systemic inflammation (9). However, effective therapeutic interventions for treating patients with sepsis are being developed. Currently Used Anti-Inflammatory Drugs To control inflammatory diseases, anti-inflammatory drugs, such as non-steroidal anti-inflammatory drugs (NSAIDs) (aspirin and diclofenac, for example), corticosteroids (such as prednisone), methotrexate, and leflunomide, have been used. However, they all have significant adverse side effects. NSAIDs are commonly used in clinical practice to manage pain, fever, and various inflammatory diseases in patients; however, NSAIDs have been identified as gastrotoxic (10, 11). Mild to severe gastric ulceration and bleeding occur not only in patients who undergo long-term NSAID treatment, but also in patients who intentionally or accidently overdose on NSAIDs (12, 13). Acute gastrointestinal symptoms can even be found within 2 hours after an NSAID overdose (13). Although short-term corticosteroid treatment rarely induces serious adverse side effects, long-term treatment may lower the body’s ability to fight off infections or may make infections harder to treat. Excessive exposure to corticosteroids may cause Cushing’s syndrome (14). Methotrexate is commonly a first-choice disease-modifying antirheumatic drug. However, methotrexate may cause blood dyscrasias (some fatal) and liver cirrhosis (15). The adverse effects of leflunomide, which is used to treat rheumatoid arthritis, include diarrhea, alopecia, increased liver enzyme expression, and hepatic failure (15). Anti-Inflammatory Effect of Sesame Seed Oil The primary constituents of sesame seed oil, which is derived from sesame seeds, include fatty acids and lignans. The fatty acids are palmitic acid (16:0; 7.0-12.0%), palmitoleic acid (16:1; less than 0.5%), stearic acid (18:0; 3.5-6.0%), oleic acid (18:1; 35-50%), linoleic acid (18:2; 35-50%), linolenic acid (18:3; less than 1%), and eicosenoic acid (20:1; less than 1%). The nonfat portion (1-2 wt%) contains lignans such as sesamin, sesamol, sesamolin, sesaminol, and episesamin. Sesame seed oil is unique because of its unusually high oxidative stability and anti-inflammatory property compared with other edible oils (16). Sesame seed oil’s strong antioxidant activity has been attributed mainly to γ-tocopherol and antioxidative sesame lignans such as sesamin, sesamolin, and sesamol (17) (Figure 1). 337 In Emerging Trends in Dietary Components for Preventing and Combating Disease; Patil, B., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.


Figure 1. The major chemical ingredients of sesame seed extract.

Lipopolysaccharide (LPS), the important component of the Gram-negative bacterial cell wall, is a potent stimulator of the inflammatory response. In animals and humans, LPS intoxication leads to a systemic inflammatory response and causes the dysfunction of various organs, including lungs, liver, and kidneys (18). Because LPS is considered the primary clinical cause of the systemic inflammatory response (19), it is usually used in animal models of sepsis and inflammation. LPSinduced proinflammatory cytokines, such as TNF-α, IL-1β, and NO, are involved in generating oxidative stress and organ damage in LPS intoxication (8). Sesame seed oil has an excellent anti-inflammatory effect in LPS-induced systemic inflammatory models and lead-plus-LPS-induced hepatic inflammation. Sesame seed oil reduces the release of the proinflammatory mediators NO, TNF-α, and IL-1β in serum in LPS-stimulated rats (20) and in the liver in rats treated with LPS-plus-lead (21). Both of these anti-inflammatory effects are associated with oxidative stress inhibition and organ protection in LPS-treated rats. Anti-Inflammatory Effect of Sesamol, a Lignan in Sesame Seed Sesamol (3, 4-Methylenedioxyphenol) (C7H6O3), one of the sesame seed oil lignans, has been generally regarded as the main antioxidative component in sesame seeds (22). During sesame seed oil manufacturing, sesamolin can be converted to other lignans, including sesamol, sesaminol, and sesamol dimers. Some details of the mechanism by which LPS activates phagocytes are now understood. After bacteria release LPS into the bloodstream, it first binds to LPS binding protein (LBP), an acute-phase reactant in the blood. LBP catalyses the transfer of LPS to CD14 (an LPS receptor), which increases the LPS-induced activation of monocytes, macrophages, and polymorphonuclear neutrophils 100-1000 times (23). LPS·CD14 complexes activate LPS signaling receptor MD2 and toll like receptor 4 (TLR4) (24). When activated, TLR4 recruits adapter molecules within the cytoplasm of cells to propagate a signal. The adapters 338 In Emerging Trends in Dietary Components for Preventing and Combating Disease; Patil, B., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.


activate the downstream protein kinases (IRAK1, IRAK4, TBK1, and IKKi) that amplify the signal, which results in the activation of MAPK and IKK. This activation leads, in turn, to the activation of the transcription factor nuclear factor-κB (NF-κB) and activator protein-1 (AP-1), both of which mediate the production of inflammatory cytokines (25). NF-κB is a fundamental transcription factor vital for the expression of proinflammatory genes (26). Non-activated NF-κB is retained in the cytoplasm by binding to an inhibitory protein, inhibitor κB (IκB)-α. During inflammation, LPS activates the NF-κB pathway and phosphorylates IκB, which leads to a disassociation of the IκB/NF-κB complex. Subsequently, free NF-κB enters the nucleus and binds to the DNA, thereby allowing rapid gene activation and the expression of TLR4-associated protein and proinflammatory mediators (27). Sesamol inhibits LPS receptor activation in macrophages. Sesamol causes macrophages to downregulate the LPS-induced proinflammatory mediators TNF-α, IL-1β, and NO (28), inhibits the LPS-receptor (TLR4) activating pathway in macrophages, and inhibits bound LPS and LBP (IC50 = 0.016 ± 0.003 nM). It is more effective than polymyxin B (IC50 = 126 ± 28 nM), a well-known and potent antibiotic that binds and neutralizes bacterial LPS. Sesamol inhibits LPS from binding to LBP even after LPS and LBP have been co-incubated (29). The IC50 of sesamol in the displacement effect is (1.3 ± 0.2 μM). In addition, sesamol inhibits NF-κB activation downstream of the TLR4-activating pathway. It also inhibits LPS-induced IκB phosphorylation and NF-κB translocation without affecting macrophage viability (28). It is likely that sesamol blocks LPS from binding to LPS binding protein and inhibits the inflammatory response.

Adverse Effects and Reactions In sesame’s long history as a crop, no harmful effects of sesame seed extracts in humans have been reported. However, some studies report that sesamol is carcinogenic in rodents.

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Sesame Seed ( Sesamum indicum L.) Extracts and Their Anti

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