Author: Gianpiero Pescarmona
These compounds are ......
Umberto Maccio 19 12 2012
In in vitro studies, garlic has been found to have antibacterial, antiviral, and antifungal activity. However, these actions are less clear in vivo. Garlic is also claimed to help prevent heart disease (including atherosclerosis, high cholesterol, and high blood pressure) and cancer. Animal studies, and some early research studies in humans, have suggested possible cardiovascular benefits of garlic. A Czech study found garlic supplementation reduced accumulation of cholesterol on the vascular walls of animals. Another study had similar results, with garlic supplementation significantly reducing aortic plaque deposits of cholesterol-fed rabbits. Another study showed supplementation with garlic extract inhibited vascular calcification in human patients with high blood cholesterol. The known vasodilative effect of garlic is possibly caused by catabolism of garlic-derived polysulfides to hydrogen sulfide in red blood cells (RBCs), a reaction that is dependent on reduced thiols in or on the RBC membrane. In fact, from garlic is obtained an organosulfur compound, allicin, which is not present in garlic, unless tissue damage occurs, and is formed by the enzyme allinase on alliin.
From allicin derives hydrogen sulphide, which is also produced in small amounts by some cells of the mammalian body and has a number of biological signaling functions.
In humans, the gas is produced from cysteine by the enzymes cystathionine beta-synthase and cystathionine gamma-lyase. It acts as a relaxant of smooth muscle and as a vasodilator. Eventually the gas is converted to sulfite in the mitochondria by thiosulfate reductase, and the sulfite is further oxidized to thiosulfate and sulfate by sulfite oxidase. The sulfates are excreted in the urine.
Due to its effects similar to nitric oxide (without its potential to form peroxides by interacting with superoxide), hydrogen sulfide is now recognized as potentially protecting against cardiovascular disease.
Thus, the cardioprotective role effect of garlic is caused by catabolism of the polysulfide group in allicin to H2S, a reaction that could depend on reduction mediated by glutathione.
Though both nitric oxide (NO) and hydrogen sulfide have been shown to relax blood vessels, their mechanisms of action are different: while NO activates the enzyme guanylyl cyclase, H2S activates ATP-sensitive potassium channels in smooth muscle cells. Researchers are not clear how the vessel-relaxing responsibilities are shared between nitric oxide and hydrogen sulfide. However there exists some evidence to suggest that nitric oxide does most of the vessel-relaxing work in large vessels and hydrogen sulfide is responsible for similar action in smaller blood vessels.
Recent findings suggest strong cellular crosstalk of NO and H2S, demonstrating that the vasodilatatory effects of these two gases are mutually dependent. Additionally, H2S reacts with intracellular S-nitrosothiols to form the smallest S-nitrosothiol, thionitrous acid (HSNO), and a role of hydrogen sulfide in controlling the intracellular S-nitrosothiol pool has been suggested. S-Nitrosothiols have received much attention in biochemistry because they serve as donors of the nitrosonium ion NO+, and nitric oxide and some organic nitroso derivatives serve as signaling molecules in living systems, especially related to vasodilation. Red blood cells, for instance, release S-nitrosothiols into the bloodstream under low-oxygen conditions, causing the blood vessels to dilate.
The addition of a nitroso group to a sulfur atom of an amino acid residue of some protein is known as S-nitrosation or S-nitrosylation. This is a reversible process and a major form of posttranslational modification of proteins.
S-Nitrosated proteins (SNOs) serve to transmit nitric oxide (NO) bioactivity and to regulate protein function through mechanisms analogous to phosphorylation: NO donors target specific amino acids motifs; post-translational modification leads to changes in protein activity, protein interactions, or subcellular location of target proteins; all major classes of proteins can undergo S-nitrosylation; and enzymes play a primary role in regulation of S-nitrosylation.
Like nitric oxide, hydrogen sulfide is involved in the relaxation of smooth muscle that causes erection of the penis, presenting possible new therapy opportunities for erectile dysfunction.
Moreover, allcin, how in vitro studies show, inhibits HMG-CoA reductase, which is involved in cholesterol synthesis, and this could partially explain the reduction of blood cholesterol levels.
Garlic is known for causing halitosis, as well as causing sweat to have a pungent 'garlicky' smell, which is caused by allyl methyl sulfide (AMS). AMS is a volatile liquid which is absorbed into the blood during the metabolism of garlic-derived sulfur compounds; from the blood it travels to the lungs (and from there to the mouth, causing bad breath) and skin, where it is exuded through skin pores.
People taking insulin should not consume medicinal amounts of garlic without consulting a physician. The effect on blood sugar levels, is due to the hydrogen sulfide, which acts on K-ATP channels: in beta-cells of pancreas, these are closed by ATP, which is produced by glycolysis and respiratory cycle when glucose comes into the cell using GLUT-2. Thus, beta-cell are depolarized, and this results in an income of calcium, and hence the secretion of insulin; H2S activates these channels, and so beta-cells are hyperpolarized, and so there is a reduction in secretion of insulin, and consequently hyperglycemia. This is the reason why people taking insulin should not consume medicinal amounts of garlic without consulting a physician.
Garlic was used as an antiseptic to prevent gangrene during World War I and World War II. More recently, it has been found from a clinical trial that a mouthwash containing 2.5% fresh garlic shows good antimicrobial activity, although the majority of the participants reported an unpleasant taste and halitosis.
Garlic cloves are used as a remedy for infections (especially chest problems), digestive disorders, and fungal infections such as thrush. Garlic can be used as a disinfectant because of its bacteriostatic and bacteriocidal properties.
All these antiseptic proprieties are due to allistatin, an antibiotic that is found naturally in plants belonging to the Allium group (garlic, onion, etc), whose mechanism is based on the inhibition of microorganisms’ enzymes containing thiols.
Garlic has been found to enhance thiamin absorption, and therefore reduces the likelihood for developing the thiamin deficiency beriberi.
In 1924, it was found to be an effective way to prevent scurvy, because of its high vitamin C content.
Complementary and alternative medicines are gaining popularity among general population because of their safety profile and easy administration. Garlic, in particular, is considered to be one of the best disease-preventive foods because of its potent and widespread effects.
Various clinical trials and meta-analyses conducted have shown positive impact of garlic in cardiovascular-disease prevention especially its effects on lipid levels, hypertension control and platelet, however, some contradictory results are also present.
Garlic can be used as an adjuvant with lipid-lowering drugs for control of lipids, however, its role as a main therapeutic agent cannot be recommended and it is suggested that more meta-analyses using standardized preparations with a close watch on methodological shortfalls should be conducted to prove its role.
The epidemic of cardiovascular disease is growing at an alarming pace throughout the world Novel therapeutic concepts: the epidemic of cardiovascular disease in the developing world: global implications, 2010 .
It is recognized as one of the leading causes of mortality worldwide causing more than 80% of deaths Cardiovascular diseases (CVDs) key facts, 2013 .
Cardiovascular disease refers to spectrum of illnesses that includes heart disease, vascular diseases of the brain, kidney, and peripheral arterial disease World Health Organization, “Cardiovascular diseases”, 2013 .
Atherosclerosis and hypertension are measured as the major risk factor along with smoking, obesity, and sedentary life styles leading to increasing trend of this major threat World Health Organization, “Cardiovascular diseases fact sheet”, 2012 .
It is anticipated that by 2020 cardiovascular diseases are predicted to be the major cause of morbidity and mortality in most developing nations around the globe Cardiovascular disease in the developing world prevalence’s, patterns, and the potential of early disease detection,Journal of the American College of Cardiology, vol. 60, no. 14, pp. 1207–1216, 2012 .
Today, in this era of rapid advancement in medical technology, herbal or botanical preparations, commonly referred to as complementary and alternate medicine (CAM), approaches have gained lots of popularity in terms of health care maintenance, and a large number of population in the world prefer to use (CAM) as a source of curative and preventive remedy for various illnesses.
But what is CAM?
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CAM is defined as a group of diverse medical and health systems practices and products that are not generally considered as part of conventional medicine “Complementary medicine: common misconceptions,” Journal of the Royal Society of Medicine, vol. 88, no. 5, pp. 244–247, 1995 .
According to 2007 National Health Interview Survey (NHIS) report, approximately 38% of US adults and 12% of children are using CAM in the past 12 months.
Most common types of CAM therapies used were natural products, such as fish oil/omega 3, glucosamine, Echinacea, and flaxseed (17.7%), deep breathing (12.7%), meditation (9.4%), chiropractic and osteopathic (8.6%), and massage (8.3%), followed by yoga, diet-based therapies, progressive relaxation, guided imagery, and homeopathic treatment.
Among all these remedies, plants-based functional foods have gained lots of recognition throughout the world and it is believed that these natural substances have the potential to reduce the detrimental effect of a number of cardiovascular diseases and associated risk factors Hospital-based study on the use of herbal medicine in patients with coronary artery disease in Jordan, Journal of the Pakistan Medical Association, vol. 61, no. 7, pp. 683–687, 2011 .
Garlic has been used as a therapeutic agent for many illnesses over centuries as evident from various studies; however, its role in cardiovascular disease prevention is still questionable.
Garlic (Allium Sativum):
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has played an important dietary as well as medicinal role in human history. The role of garlic as a potential herb has been acknowledged for over 5000 years. Garlic and its various preparations are being readily consumed as a food and spice by various cultures for centuries. It was also documented as a choice of medical therapy to combat many diseases among Egyptians.
Similarly, it is also considered as an imperative part of Indian traditional medicine, that is, Ayurveda, Tibbi and Unani, and so forth.
In addition, it is also claimed to possess beneficial effects for the prevention of various aspects of cardiovascular disease including hypertension and dyslipidemia.
Garlic is available in many forms among these: raw garlic, aqueous extract preparation is used more frequently.
Allicin is the principal bioactive compound present in garlic and primarily contains sulphur as a main constituent which on break down gives garlic its characteristic odor. It is produced as a result of activation of alliinase enzyme after crushing or chopping of raw garlic.
The enzyme Allinase is inactivated by heat leaving behind alliin as the main constituent present in the water extract of heat-treated garlic.
The composition of garlic powder which is produced after dehydration and crushing is the same as raw garlic and alliinase activity is preserved; however, caution needs to be taken regarding temperature regulation as Allinase is inactivated if temperature exceeds beyond 60°C.
OTHER PREPARATION OF GARLIC:
Aged garlic extract (AGE): this form is produced by storage of sliced raw garlic in 15–20% ethanol for 20 months. This process of storage leads to alteration in composition of the garlic extract, the odorous, harsh, and irritating compounds in garlic are converted naturally into stable and safe sulfur compounds with substantial loss of allicin activity and increased activity of new compounds, like S-allylcysteine (SAC), S-allylmercaptocysteine.
Garlic oil: is produced as a result of distillation process of raw garlic. Garlic essential oil is obtained by steam distillation of garlic. The essential oil content of garlic cloves is 0.2–0.5% and consists of a variety of sulfides, such as diallyl disulphide (DADS) and diallyl trisulfide (DATS). All the water soluble contents including allicin are completely eliminated from the oil. Oil macerates were originally developed for use as condiments. Oil macerate products are made of encapsulated mixtures of whole garlic cloves ground into vegetable oil. This preparation contains allicin-decomposed compounds such as dithiins, ajoene and sulfides, residual amounts of alliin, and other constituents in garlic.
Garlic powder: is primarily used as a flavoring agent for condiments and processed foods. Garlic cloves are sliced or crushed, dried, and ground into powder. The composition of garlic powder is the same as that of raw garlic; however, the proportions and amounts of various constituents differ significantly; that is, average content of alliin present in garlic is 0.8% however, raw garlic contains around 3.7 mg/gm of alliin.
Dyslipidemia is documented as a major risk factor responsible for the development of atherosclerosis and cardiovascular disease Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study, The Lancet, vol. 364, no. 9438, pp. 937–952, 2004 .
Lipid abnormalities include: high LDL-C (low-density lipoprotein cholesterol), high triglycerides and low HDL-C (high-density lipoproteins cholesterol) levels.
Cholesterol present in β-lipoprotein (LDL) and pre-B-lipoprotein gets deposited into the blood vessels, while α-lipoprotein (HDL) helps to reduce serum cholesterol. Considerable evidence from the literature supports the invaluable role of garlic in the treatment of hypercholesterolemia through inhibition of cholestrol biosynthesis in the liver and also by inhibition of oxidation of low-density lipoproteins New pharmacological activities of garlic and its constituents, Folia Pharmacologica Japonica, vol. 110, supplement 1, pp. 93P–97P, 1997 .
Dietary approach is the initial step in the management of dyslipidemia, and many people with dyslipidemia are using garlic as an alternative medicine to normalize their raised lipid levels.
A number of randomized, controlled trials were carried out to see the effect of different preparation of garlic on lipid levels. Clinical trials using different types of garlic preparations in hypercholesterolemia patients have demonstrated debatable results, and it was assumed that these discrepancies may have resulted due to the differences of the composition of garlic preparations and the response they may induce.
Despite the existence of various clinical trials, the role of garlic in treating dyslipidemia is still debatable.
A recent meta-analyses conducted by Zeng et al. in 2012 clearly illustrated that garlic therapy is more effective if used for a long term with higher baseline total cholestrol levels; they also concluded that garlic powder and aged garlic extract were more effective in reducing serum TC levels, while garlic oil was more effective in lowering serum TG levels "A meta-analysis of randomized, double-blind, placebo-controlled trials for the effects of garlic on serum lipid profiles,” Journal of the Science of Food and Agriculture, vol. 92, no. 9, pp. 1892–1902, 2012"
Clinical investigations exploring the effects of garlic and its various preparations in hypercholesterolemia have demonstrated somewhat contradictory results. The diverse composition and amount of active sulfur compounds of different garlic preparations used in various trials might be responsible for the above mentioned inconsistent findings. Other factors like subject recruitment, duration of study, dietary control, lifestyle, and methods of lipid analyses may also have an influence. These findings emphasize the need for standardization of garlic preparations in order to reach to a valid conclusion.
Hypertension is an important risk factor for leading to cardiovascular disease. Currently, it affects 1 billion people worldwide, and this number is expected to rise to 1.6 billion by 2025 Global burden of hypertension: analysis of worldwide data, The Lancet, vol. 365, no. 9455, pp. 217–223, 2005 .
Garlic regular consumption has shown some association with blood pressure control. Blood pressure reducing properties of garlic are related with the hydrogen sulphide production and allicin content liberated from alliin and the enzyme alliinase which is assumed to possess angiotensin II inhibiting and vasodilating effects.
Garlic is used as a treatment remedy by many people worldwide to control blood pressure. According to one survey, approximately 29% of people are using garlic for their blood pressure control.
To ascertain the effectiveness of garlic in blood pressure reduction, very few studies are available which have shown small positive effects, insufficient to draw any conclusions. Therefore, use of garlic cannot be recommended as antihypertensive advice for hypertensive patients in daily practice.
Garlic has a beneficial effect on platelet adhesion or aggregation, a potential risk factor for cardiovascular disease.
The self-condensation products of allicin and ajeones are said to have antithrombotic action, in addition to its potential effect in the inhibition of platelet aggregation Inhibition of baboon platelet aggregation in vitro and in vivo by the garlic derivative, ajoene, Xenotransplantation, vol. 10, no. 4, pp. 374–379, 2003.
Dissolution of clots and thrombi through fibrinolysis is also improved by garlic.
A number of trials have been conducted to find out the usefulness of garlic or its preparation against platelets.
A trial by Rahman and Billington reported that garlic causes inhibition of platelet aggregation by various mechanisms including inhibition of cyclooxygenase activity leading to thromboxane A2 formation, by suppressing mobilization of calcium into the platelets, and by increasing levels of messengers (cAMP and cGMP) with in the platelets.
It also exhibits strong antioxidant property by increasing production of platelet-derived NO. Simultaneously, it also reduces the ability of platelets to bind to fibrinogen, thus overall resulting in inhibition of platelet aggregations and enhance fibrinolytic activity.
This fact was further confirmed by a trial by Allison et al. which showed that AGE extract modified raw preparation of garlic-inhibited platelet aggregation by suppressing the influx of calcium ions through their chelation within platelet cytosol or by altering other intracellular second messengers within the platelets.
It is concluded that garlic inhibits platelet aggregation by multiple mechanisms and may have a role in preventing cardiovascular disease. However, data is scarce, and further studies are required to prove this fact.
Few studies suggest that Garlic has some effects on endothelium and vascular dilatation through inhibition of oxidation process.
SIDE EFFECTS OF GARLIC:
A couple of case reports have published the adverse effects of garlic ingestion, where one claimed allergic dermatitis observed in a patient taking raw garlic Anaphylaxis induced by ingestion of raw garlic, Foodborne Pathogens and Disease, vol. 9, no. 8, pp. 773–775, 2012 .
In conclusion, the beneficial effect of garlic preparations on lipids and blood pressure extends also to platelet function, thus providing a wider potential protection of the cardiovascular system through its major effects on cholestrol reduction. However, its efficacy in blood pressure reduction is mild with some beneficial effects on platelet aggregation. So it is important to using standardized preparations to study more the potential beneficial effect of garlic. Garlic can be used as an adjuvant with lipid-lowering drugs for control of lipids, however, its role as a main therapeutic agent cannot be recommended and it is suggested that more meta-analyses using standardized preparations with a close watch on methodological shortfalls should be conducted to prove its role.
-B.G. Katzung, S.B. Masters, A.J. Trevor, Basic & Clinical Pharmacology, 11 ed.
-"Garlic: A natural antibiotic". ACM Modern Drug Discovery April 2002
-Kimura, Hideo (2002). "Hydrogen sulfide as a neuromodulator". Molecular Neurobiology 26
-Benavides, Gloria A; Giuseppe L Squadrito, Robert W Mills, Hetal D Patel, T Scott Isbell, Rakesh P Patel, Victor M Darley-Usmar, Jeannette E Doeller, David W Kraus (2007-11-13). "Hydrogen sulfide mediates the vasoactivity of garlic". Proceedings of the National Academy of Sciences of the United States of America 104
-Filipovic, M. R.; Miljkovic, J. L.; Nauser, T.; Royzen, M.; Klos, K.; Shubina, T.; Koppenol, W. H.; Lippard, S. J. et al. (2012). "Chemical Characterization of the SmallestS-Nitrosothiol, HSNO; Cellular Cross-talk of H2S andS-Nitrosothiols". Journal of the American Chemical Society 134