ACTA SCIENTIFIC NUTRITIONAL HEALTH Volume 3 Issue 6 June 2019 Review Article

Allicin as Antioxidant: Possible Mechanisms for the Control of Diabetes-Induced Atherosclerosis

Lina N Tamimi1* and Hayder A.AL-Domi2 1Department of medicinal chemistry and pharmacology, Faculty of pharmacy, University of Petra, Amman, Jordan 2Professor of Dietetics, Department of Nutrition and Food Technology, Faculty of Agriculture, The University of Jordan, Amman, Jordan *Corresponding Author: Lina N Tamimi, Department of medicinal chemistry and pharmacology, Faculty of pharmacy, University of Petra, Amman, Jordan. Received: April 02, 2019; Published: May 09, 2019

Abstract

mitochondrial reactive oxygen species production (ROS), intracellular advanced glycation end-products formation and activation Diabetic atherosclerosis is strongly developed by oxidative stress and inflammation. Intracellular hyperglycemia promotes

density lipoprotein, and insulin resistance. In addition, they inhibit the activation of AMP-protein kinase and adiponectin, decrease of protein kinase C. ROS directly increase the expression of inflammatory and adhesion factors, the formation of oxidized-low endothelial nitric oxide synthase activity, which accumulatively accelerate and progress atherosclerosis. Allicin is one of the main active components in and exerts several therapeutic and antioxidant activity effects via attenuating superoxide production

considered as a natural component that may have a valuable preventive role in diabetes -induced atherosclerosis. and limiting inflammation and fibrogenesis. According to the role of oxidative stress within the diabetic complications, Allicin is Keywords: Diabetes; Reactive Oxygen Species; Allicin; Atherosclerosis

Abbreviations disease is accelerated associated with worse outcomes as diabetes - DM: Diabetes Mellitus; ROS: Reactive Oxygen Species; AMP-Protein matory cells, and plaque necrosis [2]. Kinase: Adenosine Monophosphate-Activated Protein Kinase; CVD: mellitus increases the risk of atherosclerosis, infiltration of inflam Cardiovascular Disease; GDM: Gestational Diabetes Mellitus; ECM: There are several factors that play great role in pathogenesis - of diabetes such as oxidative stress and hyperlipidemia leading to Extracellular Matrix; NFκB: Nuclear Factor Kappa-Light-Chain-En high risk of complications [3]. Introductionhancer of Activated B Cells; RAS: Renin–Angiotensin-System. Classification of diabetes - - Diabetes mellitus (DM) is defined as a chronic endocrine het cemia, this is due to either insulin secretion impairment, defective Diabetes• Type can 1 be diabetes: classified into the following general categories: erogeneous metabolic disorder, DM is characterized by hypergly [1]. Due to autoimmune β-cell destruction, • usuallyType 2 leadingdiabetes: to absolute insulin deficiency. insulin efficiency or both The chronic hyperglycemia of diabetes is associated with long- secretion frequently on the background of insulin resistance. Due to a progressive loss of β-cell insulin term microvascular and macrovascular complications combined • Gestational diabetes mellitus (GDM): Diabetes diagnosed with a high risk of cardiovascular disease (CVD). Patients with in the second or third trimester of pregnancy that was not diabetes mellitus (DM) have an over tenfold risk for cardiovascu- clearly overt diabetes prior to gestation. lar disease during their lifetime, the progression of cardiovascular

Citation: Lina N Tamimi and Hayder A.AL-Domi. “Allicin as Antioxidant: Possible Mechanisms for the Control of Diabetes-Induced Atherosclerosis". Acta Scientific Nutritional Health 3.6 (2019): 22-28. Allicin as Antioxidant: Possible Mechanisms for the Control of Diabetes-Induced Atherosclerosis

23 • been noted to contribute in oxidative stress promotion through monogenic diabetes syndromes such as neonatal diabetes free radical generation and suppression of the antioxidant defense Specific types of diabetes due to other causes, e.g., and maturity-onset diabetes of the young, diseases of the suppression in various tissues, which further exacerbate oxidative systems, via antioxidant enzymes and non-enzymatic antioxidants and drug- or chemical-induced diabetes such as with stress. This explains why diabetic persons tend to have more exocrine pancreas such as cystic fibrosis and pancreatitis, glucocorticoid use, in the treatment of HIV/AIDS, or after oxidative cell and organism environments than healthy individuals, organ transplantation (Table 1), [4]. oxidative stress plays important role in the development of vascular complications in diabetes particularly type 2 diabetes [6]. DM type DM type description According to epidemiological studies, diabetic mortalities can A result of pancreatic beta cell destruction combined with insulin be explained by progression of severed vascular diseases other Type 1 diabetes than hyperglycemia. Recently, evidences have supported the role of to an autoimmune process and beta cell oxidative stress in type 1 and type 2 diabetes pathogenesis, in dia- deficiency. This form includes cases due destruction with unknown epidemics. betes, free radicals are formed by: rapid lipid peroxidation, Predominant insulin resistance with Type 2 diabetes oxidation and non-enzymatic glycation of proteins that leads to Gestational insulin deficiency and secretory defects. in insulin resistance [7]. In addition, apolipoprotein component of diabetes mellitus recognition during pregnancy. damage of enzymes, cellular metabolic pathways and also increase Glucose intolerance with onset or first to hydroxyl radical that controls and accelerate oxidative damage forms of diabetes or diabetes associated LDL spontaneously forms insoluble oxidized aggregates of fat due as one of diabetic complication. Uncommonwith other conditions, diseases genetically or drug use. defined

It also includes latent autoimmune In diabetes mellitus, mitochondria are considered as main diabetes in adults (LADA); the term used to source of oxidative stress, during oxidative metabolism in mito- types describe the small number of people with Other specific apparent type 2 diabetes who appear to and the remaining oxygen is transformed to oxygen free radicals have immune-mediated loss of pancreatic chondria, a component of the utilized oxygen is reduced to water, beta cells. which is an important ROS that is converted to ONOO, OH and H2O2 [8]. Table 1 During the production of ATP by oxidative phosphorylation in Oxidative stress in diabetes: DM Milletus classification 2 is re- Similar to numerous other health conditions, oxidative stress duced to superoxide O2 - has been widely linked with the incidence of diabetes mellitus. the mitochondrial electron transport chain, 1–5% of the O – radicals, which can be converted by an Several studies have approved that oxidative stress is a key element or react with NO to form peroxynitrite. Excess ROS production or in diabetes development and its complications progression. In line tioxidant enzymes to , hydroxyl free radicals, with this view, oxidative stress was proposed as a major participant stress, which occurs in various pathologies [9]. in the pathophysiology of diabetes and its complications. Oxidative insufficient antioxidant activity lead to mitochondrial oxidative stress occurs when there is an abnormal distortion in the redox Diabetes-induced excessive ROS production and balance of the cell, resulting in vital biomolecules and structures atherosclerosis incidence damage such as DNA, proteins and lipids, as it compromises in The development of diabetes-related atherosclerosis follows the both; insulin secretion and insulin action . same histologic course as atherosclerosis in nondiabetic patients, atherosclerosis is accelerated in both type 1 and type 2 diabetes. Reactive oxygen species (ROS) do not[5] only promote the onset The hallmark of diabetes is the presence of hyperglycemia. This of diabetes but also exacerbates its associated complications. includes endothelial injury, smooth muscle cell proliferation, Experimental evidence implicates the role of in impaired beta- cell function caused by autoimmune reactions, cytokines and foam cell development and infiltration, platelet activation, and increased inflammation. Increased endothelial permeability leads inflammatory proteins in type 1 diabetes. Also, hyperglycemia has Citation: Lina N Tamimi and Hayder A.AL-Domi. “Allicin as Antioxidant: Possible Mechanisms for the Control of Diabetes-Induced Atherosclerosis". Acta

Scientific Nutritional Health 3.6 (2019): 22-28. Allicin as Antioxidant: Possible Mechanisms for the Control of Diabetes-Induced Atherosclerosis

24 to intensive low-density lipoproteins (LDL) retention that interact Diabetes mellitus and atherosclerosis share the same oxidative with the underlying extracellular matrix (ECM) which retains the stress and mitochondrial pathologies, hyperglycemia increases LDL in the vessel wall where oxidation by reactive oxygen species ROS production by driving mitochondria toward increased oxygen use and increased redox potential. the overlying endothelial cells to upregulate cellular adhesion (ROS) is spontaneously occurring. The oxidized LDL stimulates molecules, chemotactic proteins, growth factors, and inhibit nitric In addition, hyperglycemia increases the mutation rate of nu- oxide (NO) production. These processes activate monocytes and clear DNA because exposure to oxygen radicals is increased. The mechanism of ROS induced breaks in nuclear DNA strands may

include an increase in superoxide-related release of Fe2+ from fer- macrophages to interact with highly oxidized LDL aggregations to which stimulates proliferation of vascular smooth muscle cells ritin and iron- cluster containing proteins and increase of form foam cells leading to pro-inflammatory cytokine production hydroxyl radicals that lead to bond cleavage [13], as a result, an increase in progression of atherosclerosis. (figure 1). Intimal smooth muscle cells subsequently produce rupture, and thrombosis formation leading to an acute vascular fibrous cap while the resulting complex plaque is vulnerable to Some evidence suggests that mitochondrial dysfunction pre- occlusion [10]. exists diabetes mellitus, as increased ROS damages pancreatic

mitochondrial ROS is also associated with increased oxidation of β-cells and decreases peripheral tissue insulin sensitivity. Elevated LDL, vascular smooth muscle cell apoptosis, and endothelial cell dysfunction, all of which promote atherosclerosis [14].

Oxidative stress and antioxidants Even oxygen is considered as the major factor that has made

of cells when it generates reactive species that causes necrosis and the life finite, in some circumstances, this oxygen may be a killer ultimately the cell death . As previously mentioned, that oxida-

Figure 1: The stages of development of an [15] atherosclerotic plaque. oxidants in favor of the later due to multiple factors, it is excess for- tive stress can be defined as an imbalance of antioxidants and pro-

and causes severe loss of cellular function and structure which en- High glucose conditions may enhance monocyte/macrophage mation or insufficient removal of (ROS) which damages molecules hances the pathogenesis of many diseases [16]. of protein kinase C, and increased release of superoxide, which activation, this process involves activation of NFκB and induction There are several species of endogenous or exogenous mole- could play a role in glucose-mediated oxidative stress [11,37]. cules that play a role in antioxidant defense and may be considered Atherosclerotic plaques in the presence of diabetes generally as biomarkers of oxidative stress, antioxidants may protect cells [17]. has increased calcification, necrotic cores, macrophage and T-cell fromAlthough the damage oxidation by interacting reactions with are and crucial stabilize for life, free they radicals can also These features can contribute to severe atherosclerosis and a high- infiltration with healed plaque ruptures and vascular remodeling. be damaging; hence, plants and animals maintain complex sys- er incidence of acute adverse clinical complications [11]. tems of multiple types of antioxidants, such as glutathione, vitamin ROS can be generated in the vascular wall by NADPH oxidase, dismutase and various peroxidases. Low levels of antioxidants, or xanthine oxidase, the mitochondrial electron transport chain, and C and vitamin E as well as enzymes such as catalase, superoxide - sulin generation by inhibiting insulin gene transcription factors may damage or kill cells. As oxidative stress might be an important uncoupled eNOS. Increased ROS in pancreatic β-cells suppress in inhibition of the antioxidant enzymes, causes oxidative stress and [12]. part of many human diseases, the use of antioxidants in pharma-

Citation: Lina N Tamimi and Hayder A.AL-Domi. “Allicin as Antioxidant: Possible Mechanisms for the Control of Diabetes-Induced Atherosclerosis". Acta

Scientific Nutritional Health 3.6 (2019): 22-28. Allicin as Antioxidant: Possible Mechanisms for the Control of Diabetes-Induced Atherosclerosis

cology is intensively studied, particularly as treatments for stroke Garlic allicin 25 and neurodegenerative diseases. In addition, antioxidants are also The earliest recorded use of garlic as a medicine is probably the widely used as ingredients in dietary supplements in the hope of therapeutic formulas written in the Codex Ebers, an Egyptian medi- maintaining health and preventing diseases such as cancer and - coronary heart disease [18]. cine against tumors, worms and heart problems. cal papyrus dating to approximately 1550bc, as an effective medi Classification of antioxidants In India, garlic has long been used as a treatment for otitis as Antioxidants are grouped into two namely: (1) Natural antioxi- well as an antiseptic lotion for washing wounds and ulcers, while in dants. (2) Synthetic antioxidants. France, an antibiotic concoction called ‘vinaigre des quatre voleurs’ is available, and it consists of macerated garlic in wine . Natural antioxidants [23-25] They are the chain breaking antioxidants which react with In more recent times, garlic is considered as antibacterial and lipid radicals and convert them into more stable products. antifungal, garlic was used in Africa for the treatment of amoebic Antioxidants of this group are mainly phenolic in structures and dysentery and as an antiseptic in the prevention of gangrene [27]. include the following: (a) antioxidants minerals; these are cofactor

hypertensive patients as the major bioactive compound of garlic is many macromolecules such as carbohydrates, proteins and lipids, Garlic has shown its efficiency in reducing blood pressure in of antioxidants enzymes, their absence will affect metabolism of allicin which plays an important part in decreasing blood pressure. Garlic could effectively produce hypotensive effects, and reduce cir- minerals [19]. (b) Antioxidants vitamins: it is needed for most body selenium, copper, iron, zinc and manganese are examples of these metabolic functions, they include vitamin C, vitamin E, vitamin culatory levels of vasoconstrictor thromboxane-B2, prostanoid-E2 the nitric oxide (NO) system might be involved in the antihyperten- and ACE, suggesting that the renin–angiotensin-system (RAS) and B. (c) : these are phenolic compounds that are sive effects of garlic [28]. compounds that give colors to several plant parts. Catechins are neither vitamins nor minerals, these include: flavonoids; phenolic the most active antioxidants in green and black tea and sesame. total antioxidants and inhibit oxidative DNA damage in young es- In addition, supplement with garlic could significantly improve carotene, which is rich in carrot and converted to vitamin A when Carotenoids are fat soluble color in fruits and vegetables. Beta sential hypertensives. In cultured aortic smooth muscle cells, allyl the body lacks enough of the vitamin. Lycopene, high in tomatoes angiotensin-II-stimulated cell-cycle progression, migration and methyl sulfide and diallyl sulfide extracted from garlic inhibited spices-source include Diterpene, rosmariquinone, , nutmeg, and zeaxanthin is high in spinach and other dark greens. Herbs and - , , , garlic and derivatives [20,21]. cial effects of garlic against hypertension. To date, garlic treatment generation of reactive oxygen species (ROS), indicating the benefi Synthetic antioxidants gastrointestinal effects [29]. has not presented significant adverse reactions other than minor These are phenolic compounds that perform the function of capturing free radicals and stopping the chain reactions [22], the Allicin as antiatherosclerotic antioxidant compound includes: Garlic ( sativum) bulbs contain between 6 and 14 mg/g of chemical called ‘’ (S‐allylcysteine sulfoxide) [30], when • - • Butylated hydroxyl anisole. rate compartment unless the cell is damaged) is mixed with the crushed, an enzyme called (normally enclosed in a sepa • ButylatedPropyl gallate hydroxyrotoluene. (PG) and metal chelating agent. compound (Figure 2). • Tertiary butyl hydroquinone. alliin, resulting in the formation of allicin, the diallyl • Nordihydroguaretic acid. - - Allicin (diallylthiosulfinate), an active compound in garlic, rep tions formed upon crushing of [31]. resents approximately 70% of the overall thiosulfinate concentra

Citation: Lina N Tamimi and Hayder A.AL-Domi. “Allicin as Antioxidant: Possible Mechanisms for the Control of Diabetes-Induced Atherosclerosis". Acta

Scientific Nutritional Health 3.6 (2019): 22-28. Allicin as Antioxidant: Possible Mechanisms for the Control of Diabetes-Induced Atherosclerosis

26 Conclusion

As discussed in this review, oxidative stress is a key element in the incidence and complications of diabetes. Patients with diabetes mellitus (DM) have higher risk for cardiovascular disease during their lifetime, the development of diabetes-related atherosclero- sis follows the same histologic course as atherosclerosis in non- diabetic patients. Allicin is one of the main active components in garlic and exerts several therapeutic effects, such as promoting in- sulin sensitivity and attenuating superoxide production. Allicin has Figure 2: The molecular structures of alliin, allicin and the relevant allicin derivatives. given the role of antioxidative stress factor within the etiology and pathogenesis of diabetic complications.

Allicin possesses some remarkable antioxidant activity, its main breakdown products) back into allicin, the proprietary garlic Liver can metabolize (one of the allicin function is the reaction with thiol containing proteins, particularly derivative that has been successfully used as a systemic in vivo those which possess very reactive or unshielded SH-groups. antioxidant. Allitridi (allitridium), has been shown to be mainly However, it is a major concern that with the crucial role distillation of garlic cloves, and one of the main breakdown of oxidative stress in diabetes and diabetic complications, , a substance that can be obtained by the steam products of allicin [32]. consumption of antioxidants apparently does no not prevent diabetes mellitus. The reason for this is worthy of investigation. Two possible mechanisms of allicin action as antioxidant were suggested. One stressed the antioxidant activity of allicin while Bibliography the other suggested that the particular structure of allicin make 1. it a good candidate for interaction with SH-groups of proteins and diagnosis of diabetes mellitus”. Experimental and Clinical other biological active molecules [33]. Kerner W and Brückel J. “Definition, classification and Endocrinology and Diabetes 122.7 (2014): 384-386. Allicin is a lipid-soluble chain breaking natural antioxidant, able 2. Appleton SL., et al. “Diabetes and cardiovascular disease outcomes in the metabolically healthy obese phenotype: a levels in the brain, as it reduces lipid peroxidation. Allicin has the to cross the blood–brain barrier and accumulate at therapeutic cohort study”. Diabetes care 36.8 (2013): 2388-2394.

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37. (2017): 563. there a role for hyperglycemia?”. Journal of Lipid Research Chait A and Bornfeldt KE. “Diabetes and atherosclerosis: is 50 (2009): S335-S339. Volume 3 Issue 6 June 2019 © All rights are reserved by Lina N Tamimi and Hayder A.AL-Domi.

Citation: Lina N Tamimi and Hayder A.AL-Domi. “Allicin as Antioxidant: Possible Mechanisms for the Control of Diabetes-Induced Atherosclerosis". Acta

Scientific Nutritional Health 3.6 (2019): 22-28.