Potential Health Benefit of Garlic Based on Human Intervention Studies: A Brief Overview

Garlic is a polyphenolic and organosulfur enriched nutraceutical spice consumed since ancient times. Garlic and its secondary metabolites have shown excellent health-promoting and disease-preventing effects on many human common diseases, such as cancer, cardiovascular and metabolic disorders, blood pressure, and diabetes, through its antioxidant, anti-inflammatory, and lipid-lowering properties, as demonstrated in several in vitro, in vivo, and clinical studies. The present review aims to provide a comprehensive overview on the consumption of garlic, garlic preparation, garlic extract, and garlic extract-derived bioactive constituents on oxidative stress, inflammation, cancer, cardiovascular and metabolic disorders, skin, bone, and other common diseases. Among the 83 human interventional trials considered, the consumption of garlic has been reported to modulate multiple biomarkers of different diseases; in addition, its combination with drugs or other food matrices has been shown to be safe and to prolong their therapeutic effects. The rapid metabolism and poor bioavailability that have limited the therapeutic use of garlic in the last years are also discussed.


Metabolism and Bioavailability
Based on several in vitro studies for cancer treatment, a large number of in vivo and clinical studies have been conducted on raw garlic and/or its formulation, although results are conflicting. Indeed, the main sulfur-containing groups exhibit different bioavailability between raw garlic and specific garlic supplement formulations. For example, the bioavailability of allicin from nine garlicbased food and 13 garlic supplements was tested on 13 subjects measuring the concentration curve of breath allyl methyl sulfide, the most important garlic metabolite, highlighting a higher bioavailability of allicin from garlic supplements than that of crushed raw garlic [24]. In crushed raw garlic cloves, allicin is liable for most of the pharmacological activity and it is metabolized immediately under enzyme-inhibiting gastrointestinal conditions (half-life <1 min) to allylmercaptan. After consuming a large amount (25 g) of crushed raw garlic, allicin and its metabolites are available in the blood, urine, and stool [25] (Figure 1). Similarly, after intravenous injection, allicin rapidly disappears from circulation and is transformed into secondary metabolites, including Eajoene, 2-ethenyl-4H-1, 3-dithiin, and DADS [26]. On the other hand, allicin bioavailability of enteric tablets varies from 36% to 104% at ≥0.5 h after garlic product consumption, which was decreased from 22% to 57% in breath, when eating with a high protein meal. Independent of meal type, garlic capsules gave 26-109% lower bioavailability, while non-enteric tablets showed 80-111% higher bioavailability [24].
Additionally, protein derivative cystine interacts with allicin quantitatively at body temperature to form two equivalents of SAMC. This probably happens when cysteine is released from digested meal protein and comes in contact with allicin released from garlic products in the gastrointestinal tract. In addition to this, after an oral administration of 200 mg/kg of DADS in rats, the main metabolites, such as allyl methyl sulfoxide and allyl methyl sulfone, were found in plasma, stomach, liver, and urine [27]. The absorption of garlic occurs in the GI tract where allicin is released from alliin and contacts with cystine that is released from protein diet, forming Sallylmercaptocysteine (SAMC). After metabolism, the secondary metabolites of allicin including Eajoene, 2-ethenyl-4H-1, 3-dithiin, and diallyl disulfide (DADS) are available in blood, urine, and faces.
Aged garlic extract (AGE) contains primarily water-soluble organosulfur compounds, for example, S-allyl cysteine (SAC) and SAMC that have different pharmacokinetic behaviors than oilsoluble organosulfur compounds [28]. After garlic oral administration, SAC is absorbed immediately from the gastrointestinal tract (GI) tract, its half-life is more than 10 h and the renal clearance is more than 30 h in humans. The result after the evaluation of the safety and efficacy of SAC illustrated that it seems to play a key role in the biological effects of garlic [29].
Finally, extraction may improve the bioavailability of the whole garlic as well as of different crude ingredients and reduce toxicities. For example, in AGE, during the extraction process, the odorous, harsh, and irritating compounds of garlic are naturally transformed into stable and safe sulfur compounds; moreover, different toxicological studies have confirmed the safety of aged garlic [30].

Clinical Trials on Garlic
Recently, garlic consumption has gained particular attention due to its therapeutics properties against cancer, cardiac disease, blood pressure, diabetes, bone and skin diseases, and other pathologies, thanks to its antioxidant, anti-inflammatory, and lipid-lowering effects. All clinical studies are summarized in Tables 1-4

Antioxidant Capacity
Garlic has strong antioxidant properties due to its nutritional and phenolic compounds [31]. For example, the antioxidant properties of aged garlic extract (AGE) decrease reactive oxygen species, which are produced through increased metabolism or chronic inflammation, thus preventing the endothelial dysfunction, an early marker of atherosclerosis [32]. In a randomized double-blind placebo-controlled nutritional intervention, garlic extract (GE) intake at 400 mg/day for three months enhanced antioxidant status, reducing in turn the cardiovascular risk in obese patients through modulating endothelial biomarkers, such as C-reactive protein (hs-CRP), low-density lipoprotein cholesterol (LDL), high-density lipoprotein (HDL) levels, triglycerides (TGs), and plasminogen activator inhibitor-1 (PAI-1) [33]. Moreover, in diabetic patients after 30 days of supplementation with 3.6 g garlic clove per day, enhanced antioxidant activities, such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities, significantly increased in circulating human erythrocytes compared with control [34]. Recent meta-analysis of clinical trials demonstrated that garlic supplementation modulates oxidative stress markers, including total antioxidant capacity (TAC) and malondialdehyde (MDA) [35]; for example, the garlic tablet (Garlet) exerted a significant role on oxidative stress via decreasing MDA levels and improving TAC concentration in postmenopausal osteoporotic women at a dose of 1200 μg allicin daily for one month compared with placebo [36]. Furthermore, garlic administration synergistically improved (resistance and endurance) the training effect against oxidative stress by modulating oxidative stress markers, such as TAC and MDA, after eight weeks of treatment at a dose of 250 mg garlic capsule per day for eight weeks [37]. However, another double-blind crossover pilot study conducted on type 2 diabetic patients revealed that AGE has no significant effect at 1200 mg per day on the oxidative stress in endothelial tissue after four weeks treatment [38]. Similar results were found in a randomized crossover study, where in men with coronary artery disease, the administration of AGE supplementation at 2.4 g per day for two weeks did not change markers of oxidant stress and systemic inflammation significantly during the study, even if an improvement of the flow mediated endothelium-dependent dilation from baseline and of endothelial function were found [39].
Finally, a few crossover studies showed that the consumption of a high antioxidant spices diet, including garlic, improved antioxidant status in cancer patients and postprandial lipemia in healthy overweight adults compared to low spices meal [40,41]. In addition, consumption of 400 mg garlic and 1 mg allicin per day decreased oxidative stress after nine weeks in pregnant women at risk for pre-eclampsia but had no significant effect on TAC and pregnancy issues [42].

Anti-Inflammatory Properties
Various chronic diseases, such as cancer and cardiovascular diseases, are related with inflammatory processes; in these conditions, different types of therapeutic and natural tools have been used to prevent them [43]. In this context, garlic has shown to exert potent anti-inflammatory effects by decreasing the inflammatory biomarkers in end-stage renal disease and adult patients. A double-blind randomized clinical trial showed a significant reduction of inflammatory cytokines, such as interleukin 6 (IL-6), C-reactive protein (CRP), and erythrocyte sedimentation rate when standardized GE was administered at 400 mg twice a day for eight weeks in peritoneal dialysis patients [44,45]. In addition, a meta-analysis revealed that garlic supplementation, including AGE, garlic powder and garlic capsule, reduced serum concentrations of tumor necrosis factor alpha (TNFα), and CRP, but did not affect serum adiponectin and leptin in healthy adults [46].
Immune cells are responsible for the anti-inflammation effect; aged garlic contains various compounds that can improve immune systems by modulating cytokine production. For example, the consumption of aged garlic supplementation at a dose of 2.56 g per day for 90 days increased the activity of immune cells, such as γδ-T and natural killer (NK) cells and decreased inflammation by reducing TNF-α and IL-6 in obese adults [47]. Interestingly, the same dose of GE boosted immune cell function, decreasing the severity of cough and flu [48] and increasing urinary cytokine IL-12 excretion, even if no significant effect on IL-8 and TNF-α were found [16]. In addition, a negative correlation has been found between organosulfur compounds of AGE and obesity-induced inflammation in a randomized, double-blind, placebo-controlled clinical trial. After taking AGE supplement at a dose of 3.6 g per day for six weeks, SAC reduced obesity-induced inflammation by releasing hydrogen sulfide (H2S) via increasing its endogenous products [49]. Moreover, garlic supplementation increased microbial richness and diversity and improved inflammation condition, in patients with uncontrolled hypertension [50], while no significant effects have been found after garlic consumption at 2.1 g per day for 12 weeks, on inflammation in overweight subjects [51] and type 2 diabetes patients with high cardiovascular risk [38].

Lipid Lowering Effect
Garlic has shown promising lipid-lowering effects on hyperlipidemic patients through the reduction of serum cholesterol concentration [52]. In diabetic patients the combination of garlic with olive oil effectively regulated serum cholesterol and triglycerides levels, as well as dyslipidemia [53]. Silagy and Neil (1994) suggested that garlic in non-powder and powder forms undoubtedly reduced serum lipids levels over a one to three month period. After four months, the consumption of GE raised HDL and lowered LDL and cholesterol levels in 23 hyperlipidemic patients [54]. Several studies showed that the administration of aged black garlic or garlic tablet at a dose 300 mg or 6 g two times per day for 4 or 12 weeks reduced the levels of total cholesterol (TC), triglycerides, and LDL while it elevated that of HDL in patients with mild hypercholesterolemia and dyslipidemia or type 2 diabetics [55][56][57]. Moreover, aged garlic reduced TC and TG at a dose of 2.4 g per day for two weeks in patients with coronary artery disease [39]. In another randomized, double-blind, placebocontrolled trial, 10.8 mg per day of garlic powder tablet for 12 weeks reduced the triacylglycerol concentration in healthy volunteers [58]. Furthermore, enteric-coated garlic powder tablet containing 400 mg garlic and 1 mg allicin two times daily reduced cholesterol and LDL levels, showing protective effects in a single-blind study with 150 hypercholesterolemia patients [59].

Cancer
Cancer is one of the main causes of deaths worldwide. Based on National Cancer Database and the Surveillance, Epidemiology, and End Results, about 16.9 million people were identified with cancer in 2019 and this number will probably rise to more than 22.1 million in 2030 [60]. The Food and Drug Administration's evidence-based review system for the scientific evaluation of health showed no reliable evidence for the relation between garlic and a reduced risk of gastric, breast, and lung cancer [61]. However, credible evidence for an association between garlic intake and colon, prostate, esophageal, larynx, oral, ovary, and renal cell cancers has been reported, even if all studies were observational and the number of such trials that are scientifically considered valid in this analysis is remarkably few and the number of subjects involved generally small. As a result, relations between garlic and reduction of risk of cancers are still uncertain [62,63]. Interestingly, garlic can provide symptomatic relief of various cancer conditions, including breast, colorectal, colon, gastric, lung, and pancreatic cancers. It may be a therapeutic potential for specific cancer treatment that has been reported in human-based clinical studies, presented and discussed in Table 2. In this context, personalized diets with supplemented functional elements, including functional phytochemicals, such as allyl sulfur compounds or allicin, have provided high amounts of antioxidants to patients in chemotherapy and in remission [40]. A randomized controlled trial showed that dietary intervention for six months among breast cancer survivors increased adherence to a Mediterranean style diet and consequently raised the consumption of anti-inflammatory spices, such as garlic [63]. Another randomized double-blind factorial trial on garlic highlighted a decreased appearance of precancerous gastric lesions or gastric cancer [64], while consumption of 200 mg of synthetic allitridum (diallyl trisulfide) with 100 mg of selenium reduced gastric cancer risk [65]; similar results were found with 7.3 years consuming garlic supplementation at a dose of 200 mg caps or steam-distilled garlic oil 1 mg two times per day that reduced advanced gastric lesions [64]. In addition, long-term consumption of garlic, garlic supplements or garlic with vitamins reduced gastric cancer [66], precancerous gastric lesions [67], and mortality rate [68]. Garlic supplementation at a dose of two capsules two times a day for 7.3 years increased serum folate and improved moderate folate deficiency in patients with gastric lesions in rural Chinese populations [69]. In addition, the intake of garlic supplements <0.60 to >3.65 kg per year for two years was significantly associated with decreased risk of colorectal adenoma, which is a precursor of colorectal cancer (CRC) [70,71]. Epidemiological studies of randomized controlled trials explained that the administration of GE decreased colon adenomas and CRC in patients with CRC [72] via increased NK cell activity [73]. Correspondingly, AGE at a dose of four caps per day for six months prevented the reduction of NK cell number in patients with liver and pancreatic cancer [73].
Few epidemiological studies conducted in the Chinese population found a significant inverse relation between consumption of raw garlic or garlic components 8.4 g or 33.4 g per week for seven years and lung cancer [74]. Finally, GE showed preventive effect on febrile neuropathy after receiving chemotherapy in patients with hematological malignancies, potentially reducing the risk of chemotherapy related febrile neutropenia after receiving GE at 900 mg per day for three weeks compared with placebo [75].
Numerous mechanisms have been recommended to explain the chemo-preventive effects of garlic, including the inhibition of DNA adduct formation, the inhibition of mutagenesis by blocking metabolism, through its free-radical scavenging, or by decreasing cell proliferation and tumor growth [74]. In this context, Charron et al. [76] performed a clinical trial on gene expression related to immunity, apoptosis, and xenobiotic metabolism in humans, after consumption of 5 g raw, crushed garlic daily for 10 days. A single meal containing raw crushed garlic activated the expression of seven genes, such as activating protein with immunoreceptor tyrosine-based activation motif 1, aryl hydrocarbon receptor nuclear translocator, aryl hydrocarbon receptor, hypoxia-inducible factor 1α, c-Jun, nuclear factor of activated T cells, oncostatin M and V-rel avian reticuloendotheliosis viral oncogene homolog in blood of healthy volunteers, thus inhibiting tumorigenesis.

Cardiovascular Diseases
Currently, cardiovascular disease (CVD) represents the major cause of morbidity and death worldwide, with 17.3 million deaths per year, a number that is anticipated to rise to over 23.6 million by 2030 [77]. Many risk factors affect the development of CVD, including type 2 diabetes mellitus, obesity, resistance to insulin, high blood pressure, metabolic syndrome and high serum triglycerides levels and plasma lipid profile [78]. Based on current research, garlic can significantly reduce the risk of atherosclerosis, hypertension, diabetes, hyperlipidemia, myocardial infarction, and ischemic stroke [79], thanks to the synergistic effects of its nutritional and phytochemical components. For example, atherosclerosis and vascular inflammation are usually accompanied with oxidative stress, endothelial dysfunction, and inflammatory cytokines [80,81]. From a dietary approach, garlic has the potential role in the prevention and treatment of atherosclerosis and myocardial infarction [82,83], as demonstrated by a randomized trial performed with AGE on adipose tissue surrogates for coronary atherosclerosis progression, that reported a decrease of the coronary atherosclerosis growth at dose of 250 mg AGE daily for 12 months by reducing epicardial adipose tissue, pericardial adipose tissue, periaortic adipose tissue, and subcutaneous adipose tissue [84]. In addition, AGE prevented atherosclerosis process by developing microcirculation in patients at a dose of 2400 mg AGE per day [85]. Moreover, isoflavonoid-rich garlic herbal preparation blocked atherosclerosis progression 1.5fold in postmenopausal women at a dose of 500 mg for 12 months after administration [86]. Another randomized double-blind study demonstrated that 2400 mg AGE per day for 52 weeks decreased low attenuation plaque in coronary arteries of patients with metabolic syndrome [87], but no significant effect on lipoprotein levels was highlighted [88]. On the other hand, AGE at 6 g daily for 12 weeks reduced the levels of lipoprotein B and raised HDL levels, showing cardioprotective effect in patients with mild hypercholesterolemia [55]. In addition, GE administrated at 400 mg per day for three months modified the markers of endothelial function such as hs-CRP, PAI-1, cholesterol (total, LDL, HDL) and triglycerides as well as suppressed chronic inflammation in obese individuals [33], probably also modulating by ATP-binding cassette (ABC) A1 or ABCG1 expressions in peripheral blood mononuclear cells (PBMCs) [89]. Another meta-analysis suggested that garlic has a cardioprotective effect by decreasing serum TC and TG levels in patients with mild hypercholesterolemia [90].
Finally, even if several experimental studies demonstrated that garlic exerts antiplatelet properties, a randomized clinical trial suggested that garlic oil and tablet have little or no effect on the aggregation of platelets and showed mild adverse effects by increasing bleeding in some tested volunteers, even if the tablet dose might be equivalent to the dose of cardio-protective agent aspirin [91,92]. Thus, substantial attention is being given to the assurance of using GE along with oral anticoagulation therapy. A double-blind, randomized, placebo-controlled pilot study showed that 5 mL of AGE two times per day may be safe for patients with hemorrhages when combined with warfarin therapy [93].

Metabolic Syndrome
Metabolic syndrome is a cluster of metabolic diseases, including abdominal obesity, hypertension, atherogenic dyslipidemia, prothrombotic, and proinflammatory conditions and the risk of this disease increases approximately five-fold and two-fold in patients affected by type 2 diabetes mellitus and cardiovascular disease, respectively [94,95].
In this context, the consumption of raw crushed garlic at 100 mg two times per day for four weeks significantly decreased several risk factors of metabolic syndrome, including blood pressure, triglyceride levels, fasting blood glucose, as well as improved serum high-density lipoprotein cholesterol [95]. Moreover, a double-blinded placebo-controlled study revealed that the treatment with garlic tablet Allicor at a dose of 300 mg two times a day for four weeks along or combined with sulfonylureas drugs led to excellent metabolic control by lowering fasting blood glucose, serum fructosamine, and serum triglyceride levels in patients affected by type 2 diabetes mellitus, also decreasing cardiovascular risk [56]. In addition, administration of garlic clove for 30 days in type 2 diabetic patients reduced blood glucose and lipids metabolism and reduced the serum lipid such as cholesterol, TG, and LDL but improved HDL fraction [34]. Similarly, administration of 100 mg daily garlic for five months and 300 mg garlic twice daily for 24 weeks in diabetic patients decreased blood glucose, cholesterol, and TG and increased HDL levels [96]. Another study revealed that AGE reduced the risk factors of metabolic syndrome at a dose of 1.2 g per day for 24 weeks through increased plasma adiponectin levels in patients, without any side effects [97]. Accordingly, AGE reduced low attenuation plaque in coronary arteries of patients with metabolic syndrome after consumption of 2400 mg AGE per day [87], highlighting its antidiabetic, anti-lipidic, and antioxidant properties [96].

Blood Pressure
When blood force gives pressure against blood vessels or arteries walls hypertension is developed [98]. Recently, garlic showed a satisfactory effect as a hypertensive remedy by regulating high cholesterol levels and stimulating the immune system [99]. A dose-response trial reported that AGE had an antihypertensive effect by lowering systolic blood pressure in the case of uncontrolled hypertension without any remarkable side effects [100]. Moreover, in moderately hypercholesterolemic subjects the administration of AGE extracts or dried garlic powder at 7.2 g per day for four weeks decreased systolic blood pressure (SBP) and diastolic blood pressure (DBP) moderately (5.5%) through decreasing serum TC, and LDL, even if no prominent change in HDL was found compared with placebo [101,102]. A similar result was observed with raw crushed garlic at 100 mg/kg two times per day, that reduced SBP and DBP via downregulation of TG level and upregulation of serum HDL cholesterol after four weeks consumption in patients with metabolic syndrome [96]. Furthermore, administration of garlic homogenate-based supplementary diet at 300 mg per day for 12 weeks significantly reduced SBP and DBP in mild hypertension patients but not in prehypertension patients, without any clinical side effects [103].
In addition, the combined intake of garlic and coriander exerted a significant effect on lipid profile, where garlic, coriander or their mixture intake at a dose of 2 g/day highly modulated body mass index, TC, LDL, and HDL and decreased blood pressure in hypertensive patients [104]. In contrast, Simons et al. found no significant outcomes of garlic supplementation on lipid and lipoprotein levels in patients with mild hypercholesterolemia [105].

Diabetes
Diabetes is one of the major non-communicable life threatening chronic and pervasive conditions. It results from an absolute or relative deficiency or resistance to insulin [79], remaining a prominent chronic disease with the number of diabetics quadrupling in the last three decades in the world [106,107]. The International Diabetes Federation estimated that 415 million adults had diabetes in 2015, and it is projected to reach 642 million within 2040 [108]. Oxidative stress is responsible for promoting diabetes and preclinical studies showed that garlic active organosulfur compounds reduced hyperglycemia via improving the antioxidant status in circulation of diabetic rats [106]. In addition, the garlic component acts as hydrogen sulfide donors which also control type 2 diabetes [109]. Recently, few meta-analyses demonstrated that garlic may decrease lipid profile and glucose parameters such as fasting blood glucose concentrations [110,111] and hemoglobin A1c (HbA1C) in diabetics patients [112]. In addition, uptake of 300 mg garlic supplementation two times per day for 12 weeks significantly improved serum TG, TC, and LDL level and decreased the serum lipid level compared with placebo diabetic patients with uncontrolled dyslipidemia [113]. Moreover, the combination of antidiabetic drug metformin at 500 mg two times per day with garlic at 300 mg three times per day for 24 weeks had more potential in the management of patients with diabetes by reducing total cholesterol, LDL, and TG and improving hyperlipidemia [114]. On the other hand, a double-blind, placebo-controlled crossover pilot study showed that AGE had no significant effect on insulin resistance at 1200 mg per day for four weeks in adults with type 2 diabetes [37]. Finally, a double-blind clinical trial in diabetic patients revealed that herbal medicine containing garlic at a dose of 750 mg 3 times per day for 12 weeks had potential effects for diabetes management by reducing fasting glucose blood levels through the decrease of HbA1 [115].

Bone Disease
Osteoarthritis (OA) is an extensive degenerative disease of bone joints, which is related to chronic and disabling pain, where adipocytokines, resistin, and proinflammatory markers have a particular role in its pathogenesis [116]. Garlic supplement at 1000 mg per day has been shown to be effective on symptom relief in overweight or obese women with knee osteoarthritis, after 12 weeks of administration [117]. Moreover, the intake of garlic tablet at 500 mg two times daily for 12 weeks showed anti-inflammatory and analgesic effects by reducing serum resistin and TNF-α concentrations and pain severity in obese or overweight women with knee OA [116].
Another randomized clinical trial revealed that garlic tablet acts as an antioxidant in postmenopausal osteoporotic women. In this study, a significant decrease in advanced oxidation protein products and plasma protein carbonyl plasma levels and a concomitant increase in TAC as well as a reduction of oxidative stress and osteoporosis were found after garlic tablet consumption at a dose of 2 tablets (equivalent 2 g fresh garlic) per day for 12 months [118]. In addition, a correlation was found between pro-inflammatory cytokine activity and garlic tablet administration two times daily for eight months in postmenopausal bone loss, where garlic modulated cytokine production and reduced osteoporosis in postmenopausal osteoporotic women [36].

Skin Disease
Garlic has long been used in traditional and complementary medicine [119] and several clinical trials have demonstrated the efficacy of its administration or application in resolving symptoms associated with warts [120], denture stomatitis [121], venous ulcers [122], and skin wounds [85,123]. For example, in preclinical studies AGE showed wound healing potential in a dose-dependent manner after six days application [123,124]. Treatment of wart virus by improving immune system might be accomplished by intralesional immunotherapy [125,126] and it may damage all sores on the body [127]. A randomized control study showed that lipid portion of GE two times daily for four weeks had greater potential on patients with recalcitrant multiple common warts compared to any other treatment, through the modulation of TNF-α serum level as well as the promotion of immunotherapy [120]. Similarly, denture stomatitis expresses a common form of chronic oral candidiasis and a randomized clinical trial study demonstrated that GE at 40 mg/mL three times per day could be a potential substitution for denture stomatitis treatment compared with nystatin [121]. Finally, a prospective non-randomized pilot study was performed on venous ulcer patients with herbal ointment containing garlic, showing antierythematous, epithelizing, and anti-edematous properties and decreased the venous ulcer area after seven weeks of application [122].

Other Diseases
In recent years, antibiotic-resistance against microorganisms has become a serious issue, thus substantial attention is being given to the antimicrobial activities of spices, such as garlic, because of their inhibitory effects against pathogenic viruses [128], bacteria [129], yeast [130], and fungi [131]. The antimicrobial mechanism of garlic may include the inhibition of extracellular enzymes, the deprival of the substrates needed for microbial growth, the morphological change and the antiadherence of bacteria to epithelial cells [132]. For example, a randomized double-blind controlled clinical trial found an inversed relation between Streptococcus mutans, Lactobacilli species, and Candida albicans and garlic with lime containing mouth rinses in children with severe early childhood caries [133]. In addition, garlic tablet Garcin at a dose of 1500 mg per day for seven days has been shown to be effective for the treatment of Candida vaginitis instead of fluconazole in women with vaginitis [134]. In contrast, another randomized placebo controlled double-blind trial showed adverse effects of garlic in asymptomatic women with culture-positive on vaginal candida colony counts at dose of 350 mg garlic tablets two times per day [135]. Moreover, in the case of acute respiratory viral infection, garlic tablet Allicor at 600 mg per day for five months diminished acute respiratory diseases morbidity 2-4-fold at the first stage and 1.7-fold at the second stage compared to the controls, as a consequent inhibition of infection [136].
Garlic tablets at dose 400 mg daily are also a promising candidate for nosocomial infections in hospitalized patients in intensive care units and might be used for the prevention of septicemia and urinary tract infections after six days of treatment [137]. Furthermore, laboratory studies and clinical trials demonstrated that GE contains organosulfur compounds that exhibit antileishmanial and immunomodulatory activity [138]. For example, garlic topical gel showed anti-leishmanial activity in cutaneous leishmaniasis patients and recovered the lesions after applying topical gel for six and eight weeks [139]. In contrast, another pilot randomized controlled trial on garlic capsule showed no significant effect with minor adverse effects against Pseudomonas aeruginosa quorum sensing in cystic fibrosis patients after daily treatment for eight weeks [140].

Conclusions and Future Perspectives
This work highlights garlic as a promising candidate for preventing and treating different health conditions. This review has summarized the anticancer, cardioprotective, antihyperglycemic, antimicrobial, antihypertensive, and others effect of the administration of garlic and its preparation through their antioxidant, anti-inflammatory and lipid-lowering activities (Figure 2). Garlic has been shown to modulate several biomarkers in different diseases in a multiple ways, however, to understand the exact mechanisms, it is necessary to perform large, long-term, fully blinded and well-controlled studies to obtain more precise and consistent findings. Additionally, further studies are needed to determine pharmacokinetic and pharmacodynamic limits in humans, such as pharmacologically active concentrations of garlic-derived sulfur compounds in garlic preparation that may be achieved via oral intake or through pharmacological interventions. In addition, the rapid metabolism and poor bioavailability of garlic are responsible for limiting its therapeutic use. Special attention needs to be focused to improve the bioavailability of garlic for the development of novel dosage. Finally, limited clinical evidence exists for the effects of garlic on neurodegenerative disorders, including Alzheimerʹs disease, Parkinson's disease, Huntingtonʹs disease, and amyotrophic lateral sclerosis. This review could be helpful for future research priorities on garlic to be used in medicine, providing a wide range of health benefits.