Black Garlic and Its Therapeutic Benefits

*Gia-Buu Tran, Tan-Viet Pham and Ngoc-Nam Trinh*

### **Abstract**

Black garlic is a functional food produced from fresh garlic (*Allium sativum* L.) via fermentation with the whole bulbs or peeled cloves in a chamber in which temperature (60–90°C) and humidity (70–90%) are regulated for a period of time. Black garlic possesses an abundant amount of antioxidant compounds such as polyphenols, flavonoids, tetrahydro-β-carboline derivatives, and organosulfur compounds, including S-allyl-cysteine and S-allyl-mercaptocysteine, as compared with fresh garlic. Note that fermentation not only alters the nutrition components and sensory attributes but also enhances the bioactivity of black garlic. A growing body of evidences demonstrating therapeutic effects of black garlic, including anticancer, anti-obesity, immunomodulatory, hypolipidemic, antioxidant, hepatoprotective, and neuroprotective effects, have been reported in the last few decades. This book chapter provides a literature review of therapeutic effects of black garlic from fundamental to clinical studies that can be used by food and nutrition experts, researchers, and scientists to improve people's health and wellness.

**Keywords:** functional food, therapeutic benefits, black garlic, nutrition, bioactivity

#### **1. Introduction**

Garlic (*Allium sativum* L.), a member of Alliaceae family, is a popular ingredient used for culinary art and traditional and modern medicine. It possesses not only a strong flavor and distinctive taste but also a variety of bioactive organosulfur compounds, comprising of allicin, allixin, diallyl disulfide, diallyl trisulfide, S-allylcysteine, S-allyl-mercaptocysteine, allixin, 1-propenyl allyl thiosulfonate, (E,Z)- 4,5,9-trithiadodeca-1,6,11-triene 9-oxide, allyl methyl thiosulfonate, etc. Therefore, garlic has been documented in several literatures as a prominent remedy by reason of its several health benefits such as anticancer, antioxidant, antibiotic, antihyperlipidemic, antidiabetic, anticoagulant, antimicrobial, anti-constipation, antiparasitic, diuretic, and hepatoprotective effects [1–3]. In Vietnamese traditional medicinal system, garlic is prescribed to treat amebic and bacillary dysenteries, wound infection, chronic bronchitis, hypertension, whooping cough, and threadworm infection [4]. Furthermore, bioactivity and garlic components are also quite disparate among different cultivars [5, 6]. Garlic could be used directly or as food processing or brewery products including black garlic, smoked garlic, garlic oil, garlic oil macerate, extract, powder, supplement pill, garlic juice, alcoholic tincture, etc. [7].

Among the garlic processing products, black garlic is emerging as one of the most well-known functional foods in the market. As compared with the raw garlic, black garlic has a typical black color, sweet taste, and chewy texture without the

offensive odor. Moreover, several bioactivities of black garlic including anticancer, anti-obesity, immunomodulatory, hypolipidemic, antioxidant, hepatoprotective, and neuroprotective effects have been documented in literature [8]. However, a systematic review of black garlic and its therapeutic effects from fundamental to clinical studies is still lacking. This chapter of the book provides food and nutrition experts, researchers, and scientists an overview of application of black garlic in functional food for a variety of specific diseases with clinical evidences to improve people's health and wellness.

### **2. Black garlic and its production**

The people from Asian countries such as Thailand, South Korea, and Japan have produced and used black garlic as a traditional food for centuries, but it has been introduced into global market in recent decades. In brief, black garlic is produced by fermentation of whole bulb of fresh garlic at high humidity and temperature which in turn results in garlic to turn black via a set of nonenzymatic browning reactions, including Maillard reaction, oxidation of phenols, and caramelizing. When garlic undergoes fermentation, not only physiochemical characteristics of garlic are altered, but also the concentration of bioactive compounds is also improved [8]. Choi and collaborators [9] showed that the moisture of garlic and pH decreased along with the fermentation process, whereas the reducing sugar and total acidity were accumulated. On the other hand, color spectra and composition of amino acids of black garlic also were altered as compared with fresh garlic [9]. As the consequence, black garlic has elastic and chewy texture, as well as sweet taste without offensive flavor of garlic (**Figure 1**). Furthermore, black garlic possesses an abundant amount of antioxidant compounds such as polyphenols, flavonoids, tetrahydro-β-carboline derivatives, and organosulfur compounds, including S-allyl-cysteine and S-allyl-mercaptocysteine, as compared with fresh garlic. Kim and collaborators suggested that the total polyphenol and flavonoid of black garlic increase 9.3- and 1.5-folds, respectively, after a program heat schedule as compared with fresh garlic [10]. The concentration of S-allyl-cysteine, one of the most important organosulfur bioactive compounds of garlic, also increases in black garlic from 4.3- to 6.3-folds depending of heating treatment [11].

Due to its palatability and abundant amount of bioactive compounds, black garlic has become one of the most well-known and prominent products in nutraceuticals and functional food market with a remarkable growth of consumption demand and profitability during recent years. Furthermore, black garlic has attracted not only

#### **Figure 1.**

*Fresh peeled garlic (A) and black garlic produced from peeled multi-clove garlic by fermentation in high humidity (90%) and temperature (75°C) after 15 days (B).*

**85**

*Black Garlic and Its Therapeutic Benefits DOI: http://dx.doi.org/10.5772/intechopen.85042*

**Figure 2.**

*clove garlic (B).*

consumer attention but also the researcher and manufacturers in the improvement of its production procedure as well as the innovation of new processing products of black garlic. Manufacturing processes of black garlic are diversely programmed depending on temperature, relative humidity, time, and materials. In previous study, Zhang and collaborators produced black garlic from a variety of thermal treatment from 60 to 90°C, and they concluded that higher temperature could shorten the maturity time and the sensory score of black garlic fermented at 70°C was the highest score as compared to other temperatures [12]. Moreover, Kang also investigated the production and physiochemical characteristics of black garlic fermented in programmed stepwise heating process at 60–90°C with 50–100% relative humidity [13]. The effect of time period on the production and antioxidant capacity of black garlic also has been proved in Choi's report [8]. On the other hand, the researchers have investigated the production of black garlic from a variety of materials from multi-clove garlic to single clove of garlic as well as from the unpeeled cloves of garlic to peeled cloves of garlic (**Figures 1** and **2**) [14, 15]. Recently, some black garlic processing products such as black garlic molasses, purée, paste, extract, and supple-

*Single-clove garlic, atypical product of garlic bulb-forming process (A) and black garlic produced from single-*

ment pills have been introduced in Vietnamese and global market.

Cancer, which has been regarded as one of leading cause of death in worldwide, is a type of disease related with uncontrolled or abnormal growth of cells or tissues in our bodies. With the growing number of the evidences reported for anticancer effect of black garlic in recent decades, some researchers suggested that black garlic could be used as a dietary product for preventing and treating cancers from gastric cancer to leukemia. The mechanism of anticancer effects of black garlic in different types of cancer diseases is various comprising of the induction of apoptosis, stopping the cell cycle, and inhibition of tumor growth and invasion. In 2011, Wang and collaborators suggested that aqueous extract of black garlic could inhibit proliferation and triggered the apoptosis of SGC-7901 cells, a human gastric cancer cell line, with dose-dependent manner. The authors also observed the inhibitory effect of black garlic on the growth of tumor in tumor-bearing mice [16]. Moreover, black garlic has the anti-invasive effect and prevents tumor metastasis in human gastric carcinoma AGS cells through the increase of tightness of tight junction as well as the

**3. Therapeutic effects of black garlic**

**3.1 Anticancer effect of black garlic**

**Figure 2.**

*Medicinal Plants - Use in Prevention and Treatment of Diseases*

4.3- to 6.3-folds depending of heating treatment [11].

*humidity (90%) and temperature (75°C) after 15 days (B).*

people's health and wellness.

**2. Black garlic and its production**

offensive odor. Moreover, several bioactivities of black garlic including anticancer, anti-obesity, immunomodulatory, hypolipidemic, antioxidant, hepatoprotective, and neuroprotective effects have been documented in literature [8]. However, a systematic review of black garlic and its therapeutic effects from fundamental to clinical studies is still lacking. This chapter of the book provides food and nutrition experts, researchers, and scientists an overview of application of black garlic in functional food for a variety of specific diseases with clinical evidences to improve

The people from Asian countries such as Thailand, South Korea, and Japan have produced and used black garlic as a traditional food for centuries, but it has been introduced into global market in recent decades. In brief, black garlic is produced by fermentation of whole bulb of fresh garlic at high humidity and temperature which in turn results in garlic to turn black via a set of nonenzymatic browning reactions, including Maillard reaction, oxidation of phenols, and caramelizing. When garlic undergoes fermentation, not only physiochemical characteristics of garlic are altered, but also the concentration of bioactive compounds is also improved [8]. Choi and collaborators [9] showed that the moisture of garlic and pH decreased along with the fermentation process, whereas the reducing sugar and total acidity were accumulated. On the other hand, color spectra and composition of amino acids of black garlic also were altered as compared with fresh garlic [9]. As the consequence, black garlic has elastic and chewy texture, as well as sweet taste without offensive flavor of garlic (**Figure 1**). Furthermore, black garlic possesses an abundant amount of antioxidant compounds such as polyphenols, flavonoids, tetrahydro-β-carboline derivatives, and organosulfur compounds, including S-allyl-cysteine and S-allyl-mercaptocysteine, as compared with fresh garlic. Kim and collaborators suggested that the total polyphenol and flavonoid of black garlic increase 9.3- and 1.5-folds, respectively, after a program heat schedule as compared with fresh garlic [10]. The concentration of S-allyl-cysteine, one of the most important organosulfur bioactive compounds of garlic, also increases in black garlic from

Due to its palatability and abundant amount of bioactive compounds, black garlic has become one of the most well-known and prominent products in nutraceuticals and functional food market with a remarkable growth of consumption demand and profitability during recent years. Furthermore, black garlic has attracted not only

*Fresh peeled garlic (A) and black garlic produced from peeled multi-clove garlic by fermentation in high* 

**84**

**Figure 1.**

*Single-clove garlic, atypical product of garlic bulb-forming process (A) and black garlic produced from singleclove garlic (B).*

consumer attention but also the researcher and manufacturers in the improvement of its production procedure as well as the innovation of new processing products of black garlic. Manufacturing processes of black garlic are diversely programmed depending on temperature, relative humidity, time, and materials. In previous study, Zhang and collaborators produced black garlic from a variety of thermal treatment from 60 to 90°C, and they concluded that higher temperature could shorten the maturity time and the sensory score of black garlic fermented at 70°C was the highest score as compared to other temperatures [12]. Moreover, Kang also investigated the production and physiochemical characteristics of black garlic fermented in programmed stepwise heating process at 60–90°C with 50–100% relative humidity [13]. The effect of time period on the production and antioxidant capacity of black garlic also has been proved in Choi's report [8]. On the other hand, the researchers have investigated the production of black garlic from a variety of materials from multi-clove garlic to single clove of garlic as well as from the unpeeled cloves of garlic to peeled cloves of garlic (**Figures 1** and **2**) [14, 15]. Recently, some black garlic processing products such as black garlic molasses, purée, paste, extract, and supplement pills have been introduced in Vietnamese and global market.

## **3. Therapeutic effects of black garlic**

### **3.1 Anticancer effect of black garlic**

Cancer, which has been regarded as one of leading cause of death in worldwide, is a type of disease related with uncontrolled or abnormal growth of cells or tissues in our bodies. With the growing number of the evidences reported for anticancer effect of black garlic in recent decades, some researchers suggested that black garlic could be used as a dietary product for preventing and treating cancers from gastric cancer to leukemia. The mechanism of anticancer effects of black garlic in different types of cancer diseases is various comprising of the induction of apoptosis, stopping the cell cycle, and inhibition of tumor growth and invasion. In 2011, Wang and collaborators suggested that aqueous extract of black garlic could inhibit proliferation and triggered the apoptosis of SGC-7901 cells, a human gastric cancer cell line, with dose-dependent manner. The authors also observed the inhibitory effect of black garlic on the growth of tumor in tumor-bearing mice [16]. Moreover, black garlic has the anti-invasive effect and prevents tumor metastasis in human gastric carcinoma AGS cells through the increase of tightness of tight junction as well as the downregulation of matrix metalloproteinases (MMP)-2 and metalloproteinases-9, which play a role as mediators of metastasis and invasiveness [17]. The anticancer effect of black garlic on colon cancer cell line also has been demonstrated. Moreover, treatment with alcoholic extract of black garlic could upregulate PTEN and downregulate Akt/pAkt expression, the members of phosphatidylinositol 3-kinase protein kinase B (PI3K/Akt) signal transduction pathway, leading to the modulation of p70S6K1 protein, induction of apoptosis, and arresting of the cell cycle of HT29 human colon cancer cell line [18]. Park and collaborators have reported that hexane extract of black garlic could reduce the cell viability of U937 cells, human histiocytic lymphoma. It has been found that hexane extract of black garlic exhibited induction of both intrinsic and extrinsic pathways through the alteration of the expression of apoptosis-relating proteins. They found that black garlic upregulates death receptor (DR)-4 and Fas ligand, increases Bax/Bcl-2 ratio, as well as induces the truncation of Bid protein, which involves not only endogenous mitochondrial pathway but also death receptor-mediated apoptotic pathway [19]. Some authors also proved that black garlic could inhibit cell growth and enhance sensitization of Lewis cells, lung cancer cell line, against ionizing radiation [20].

### **3.2 Benefit effect on dyslipidemia and anti-obesity**

Obesity is a threatening problem to public health in Western and developed countries which causes several metabolic syndromes and chronic diseases. Obesity can be prevented by a combination of physical activity and healthy diet balance between energy intake and expenditure. Note that several functional foods such as γ-oryzanol, butyric acid, legumes, bromelain, peas, lentil, fabas beans, conjugated linoleic acid, diacylglycerols, purified black raspberries, apples, bilberries, sea buckthorn, etc. have been indicated as preventing and/or treating obesity agents via several mechanisms including the induction of satiation, decreasing of appetite, regulation of lipid metabolism, and thermogenesis [21]. Among them, black garlic is known as a prominent lipid and weight-lowering ingredient. In 2015, Ha and collaborators showed that the diet supplemented with 1.5% black garlic extract could only reduce weight but also decrease kidney and epididymal fat in high-fat model [22]. Moreover, black garlic extract attenuates dyslipidemia induced by high-fat diet. In Ha's work, the authors observed the lowering effect of black garlic on the plasma level of total lipid, total cholesterol, and triglyceride. On the contrast, highdensity lipoprotein cholesterol (HDL) of black garlic group was higher than highfat diet group. Of note, treatment with black garlic reduces both glucose and insulin in plasma levels in high-fat diet. One of the explanations for the anti-obesity effect of black garlic is that black garlic could ameliorate diet-induced obesity through downregulation of transcription factors and enzymes related with fat and cholesterol syntheses such as sterol regulatory element-binding protein-1c (SREBP-1c), acetyl-coA carboxylase (ACC), fatty acid synthase (FAS), glucose-6-phosphate dehydrogenase (G6PDH), hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, and acyl-CoA cholesterol acyltransferase (ACAT) or fatty acid oxidation rate via increase of the expression of carnitine palmitoyltransferase-1 (CPT-1), a key enzyme related with lipolysis and fatty acid breakdown [22]. Furthermore, Chen and collaborators also recommended that the anti-obesity effect of methanol extract of black garlic could be related with regulation of lipogenesis, adipokine biosynthesis, fatty acid oxidation, fatty acid and glucose transport, and lipolysis in both the adipose tissue and liver [23]. Furthermore, Seo and collaborators found that black garlic extract could augment the anti-obesity and cholesterol-lowering effect of exercise in animal models [24]. Combination of black garlic and exercise showed a greater effect on decreasing visceral fat, epididymal fat, and liver weight

**87**

*Black Garlic and Its Therapeutic Benefits DOI: http://dx.doi.org/10.5772/intechopen.85042*

as compared to exercise-alone group and exhibited lowering triglyceride effects in

(6 g/day) for a long term (12 weeks) also has the cardioprotective effect in patients from a double-blind, randomized placebo-controlled trial by diminishment of atherosclerosis markers and improvement of dyslipidemia. In Jung study, black garlic supplement group exhibited a significant increase of high-density lipoprotein cholesterol levels and low-density lipoprotein cholesterol/apolipoprotein B along with a decline of apolipoprotein B as compared to placebo group [25]. Recently, some researchers have developed fermented products from garlic extract that also manifested an anti-obesity effect similar with black garlic extract. Jung and collaborators demonstrated that fermented black garlic extract, a product created by fermented *Saccharomyces cerevisiae* (KTCT7910) in medium supplemented with 5%, also exhibited the hypolipidemic and anti-obesity effects but not hypoglycemic effect [26]. In 2016, Lee and collaborators fermented black garlic extract with *Lactobacillus plantarum* BL2 to produce functional food that could reduce body weight and epididymal, retroperitoneal, and mesenteric adipose tissue mass as well as plasma level of triglyceride and total cholesterol in diet-induced obese mice. The fermented product inhibited adipose tissue hypertrophy via the downregulation of a set of proteins related with adipogenesis and lipogenesis including peroxisome proliferator-activated receptor γ (PPARγ), CCAAT-enhancer-binding protein α

high-fat diet-induced rats. On the other hand, consumption of black garlic

(C/EBPα), stearoyl-CoA desaturase (SCD-1), SREBP-1c, and FAS [27].

Black garlic contains abundant antioxidant compounds including polyphenols,

alkaloids, flavonoids, S-allyl-cysteine, and antioxidant intermediate products derived from Maillard reaction [8, 9]. Several studies suggest that black garlic not only scavenges the free radicals in vitro but also activates the antioxidant enzymes in vivo. Wang and Sun reported that black garlic ethanol extract has an identical DPPH radical inhibitory effect with vitamin C in concentrations 200 and 250 μg/ ml and comparable OH radical scavenging effect with vitamin C in concentrations 400 and 500 μg/ml. Black garlic extract could reduce malondialdehyde (MDA) concentration in serum, an end product of lipid peroxidation, and enhance serum superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities in oxidative damage murine model induced by benzene bromide [28]. These results were similar with Lee and collaborators work. A diet supplemented with 5% black garlic aqueous extract could decrease oxidative stress and diabetes complications. Black garlic exerts a strong antioxidant capacity through the strong scavenging 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) or ABTS radical activity, which is four times higher than those of raw garlic, and suppression of oxidative stress marker, such as thiobarbituric acid reactive substances (TBARS) content in the liver, and activation of antioxidant defense system, including SOD, GSH-Px, and catalase (CAT) in db/db mice, a genetically modified model for diabetes mellitus [29]. Additionally, Ha and collaborators suggested that black garlic could specifically upregulate the mRNA expression of nuclear factor erythroid 2-like factor (Nrf2)-related antioxidant proteins, such as heme oxygenase-1 (HO-1), glutathione S-transferase alpha 2 (GSTA2), and NAD(P)H quinone oxidoreductase-1 (NQO1) to prevent accumulation of reactive oxidative species in the liver [30]. According to a Hungarian research, black garlic also improves superior postischemic cardiac function, infarct size reduction, and HO1 and inducible NOS (iNOS) levels after ischemia/reperfusion, which in turn exerts a cardioprotective effect [31]. Moreover, antioxidant effect of black garlic has also been proved in clinical study. In previous study, Wang and collaborators performed a double-blind,

**3.3 Black garlic and its antioxidant properties**

#### *Black Garlic and Its Therapeutic Benefits DOI: http://dx.doi.org/10.5772/intechopen.85042*

*Medicinal Plants - Use in Prevention and Treatment of Diseases*

cancer cell line, against ionizing radiation [20].

**3.2 Benefit effect on dyslipidemia and anti-obesity**

downregulation of matrix metalloproteinases (MMP)-2 and metalloproteinases-9, which play a role as mediators of metastasis and invasiveness [17]. The anticancer effect of black garlic on colon cancer cell line also has been demonstrated. Moreover,

Obesity is a threatening problem to public health in Western and developed countries which causes several metabolic syndromes and chronic diseases. Obesity can be prevented by a combination of physical activity and healthy diet balance between energy intake and expenditure. Note that several functional foods such as γ-oryzanol, butyric acid, legumes, bromelain, peas, lentil, fabas beans, conjugated linoleic acid, diacylglycerols, purified black raspberries, apples, bilberries, sea buckthorn, etc. have been indicated as preventing and/or treating obesity agents via several mechanisms including the induction of satiation, decreasing of appetite, regulation of lipid metabolism, and thermogenesis [21]. Among them, black garlic is known as a prominent lipid and weight-lowering ingredient. In 2015, Ha and collaborators showed that the diet supplemented with 1.5% black garlic extract could only reduce weight but also decrease kidney and epididymal fat in high-fat model [22]. Moreover, black garlic extract attenuates dyslipidemia induced by high-fat diet. In Ha's work, the authors observed the lowering effect of black garlic on the plasma level of total lipid, total cholesterol, and triglyceride. On the contrast, highdensity lipoprotein cholesterol (HDL) of black garlic group was higher than highfat diet group. Of note, treatment with black garlic reduces both glucose and insulin in plasma levels in high-fat diet. One of the explanations for the anti-obesity effect of black garlic is that black garlic could ameliorate diet-induced obesity through downregulation of transcription factors and enzymes related with fat and cholesterol syntheses such as sterol regulatory element-binding protein-1c (SREBP-1c), acetyl-coA carboxylase (ACC), fatty acid synthase (FAS), glucose-6-phosphate dehydrogenase (G6PDH), hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, and acyl-CoA cholesterol acyltransferase (ACAT) or fatty acid oxidation rate via increase of the expression of carnitine palmitoyltransferase-1 (CPT-1), a key enzyme related with lipolysis and fatty acid breakdown [22]. Furthermore, Chen and collaborators also recommended that the anti-obesity effect of methanol extract of black garlic could be related with regulation of lipogenesis, adipokine biosynthesis, fatty acid oxidation, fatty acid and glucose transport, and lipolysis in both the adipose tissue and liver [23]. Furthermore, Seo and collaborators found that black garlic extract could augment the anti-obesity and cholesterol-lowering effect of exercise in animal models [24]. Combination of black garlic and exercise showed a greater effect on decreasing visceral fat, epididymal fat, and liver weight

treatment with alcoholic extract of black garlic could upregulate PTEN and downregulate Akt/pAkt expression, the members of phosphatidylinositol 3-kinase protein kinase B (PI3K/Akt) signal transduction pathway, leading to the modulation of p70S6K1 protein, induction of apoptosis, and arresting of the cell cycle of HT29 human colon cancer cell line [18]. Park and collaborators have reported that hexane extract of black garlic could reduce the cell viability of U937 cells, human histiocytic lymphoma. It has been found that hexane extract of black garlic exhibited induction of both intrinsic and extrinsic pathways through the alteration of the expression of apoptosis-relating proteins. They found that black garlic upregulates death receptor (DR)-4 and Fas ligand, increases Bax/Bcl-2 ratio, as well as induces the truncation of Bid protein, which involves not only endogenous mitochondrial pathway but also death receptor-mediated apoptotic pathway [19]. Some authors also proved that black garlic could inhibit cell growth and enhance sensitization of Lewis cells, lung

**86**

as compared to exercise-alone group and exhibited lowering triglyceride effects in high-fat diet-induced rats. On the other hand, consumption of black garlic (6 g/day) for a long term (12 weeks) also has the cardioprotective effect in patients from a double-blind, randomized placebo-controlled trial by diminishment of atherosclerosis markers and improvement of dyslipidemia. In Jung study, black garlic supplement group exhibited a significant increase of high-density lipoprotein cholesterol levels and low-density lipoprotein cholesterol/apolipoprotein B along with a decline of apolipoprotein B as compared to placebo group [25]. Recently, some researchers have developed fermented products from garlic extract that also manifested an anti-obesity effect similar with black garlic extract. Jung and collaborators demonstrated that fermented black garlic extract, a product created by fermented *Saccharomyces cerevisiae* (KTCT7910) in medium supplemented with 5%, also exhibited the hypolipidemic and anti-obesity effects but not hypoglycemic effect [26]. In 2016, Lee and collaborators fermented black garlic extract with *Lactobacillus plantarum* BL2 to produce functional food that could reduce body weight and epididymal, retroperitoneal, and mesenteric adipose tissue mass as well as plasma level of triglyceride and total cholesterol in diet-induced obese mice. The fermented product inhibited adipose tissue hypertrophy via the downregulation of a set of proteins related with adipogenesis and lipogenesis including peroxisome proliferator-activated receptor γ (PPARγ), CCAAT-enhancer-binding protein α (C/EBPα), stearoyl-CoA desaturase (SCD-1), SREBP-1c, and FAS [27].

#### **3.3 Black garlic and its antioxidant properties**

Black garlic contains abundant antioxidant compounds including polyphenols, alkaloids, flavonoids, S-allyl-cysteine, and antioxidant intermediate products derived from Maillard reaction [8, 9]. Several studies suggest that black garlic not only scavenges the free radicals in vitro but also activates the antioxidant enzymes in vivo. Wang and Sun reported that black garlic ethanol extract has an identical DPPH radical inhibitory effect with vitamin C in concentrations 200 and 250 μg/ ml and comparable OH radical scavenging effect with vitamin C in concentrations 400 and 500 μg/ml. Black garlic extract could reduce malondialdehyde (MDA) concentration in serum, an end product of lipid peroxidation, and enhance serum superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities in oxidative damage murine model induced by benzene bromide [28]. These results were similar with Lee and collaborators work. A diet supplemented with 5% black garlic aqueous extract could decrease oxidative stress and diabetes complications. Black garlic exerts a strong antioxidant capacity through the strong scavenging 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) or ABTS radical activity, which is four times higher than those of raw garlic, and suppression of oxidative stress marker, such as thiobarbituric acid reactive substances (TBARS) content in the liver, and activation of antioxidant defense system, including SOD, GSH-Px, and catalase (CAT) in db/db mice, a genetically modified model for diabetes mellitus [29]. Additionally, Ha and collaborators suggested that black garlic could specifically upregulate the mRNA expression of nuclear factor erythroid 2-like factor (Nrf2)-related antioxidant proteins, such as heme oxygenase-1 (HO-1), glutathione S-transferase alpha 2 (GSTA2), and NAD(P)H quinone oxidoreductase-1 (NQO1) to prevent accumulation of reactive oxidative species in the liver [30]. According to a Hungarian research, black garlic also improves superior postischemic cardiac function, infarct size reduction, and HO1 and inducible NOS (iNOS) levels after ischemia/reperfusion, which in turn exerts a cardioprotective effect [31]. Moreover, antioxidant effect of black garlic has also been proved in clinical study. In previous study, Wang and collaborators performed a double-blind, parallel design study with a population of untrained males with similar age and body mass index during 14 days to compare the effect of black garlic and placebo on exercise-induced oxidative stress and recovery of muscle function [32]. They found that black garlic improved the recovery rate of circumference of biceps brachii after eccentric exercise and diminished reactive oxygen metabolites (dROMs), lipid peroxide, and 8-iso prostaglandin F2α concentrations, a new indicator of oxidative stress and related with atherosclerosis [32, 33]. Recently, Liu and collaborators have demonstrated the beneficial effect of black garlic on coronary heart disease patient. Black garlic exhibits an augmentation on chronic heart failure by increasing the left ventricular ejection fraction value and the scores of the quality of life and circulating antioxidant levels along with a decline of brain natriuretic peptide (BNP) precursor N-terminal, a biomarker for severity of heart failure [34]. Note that some research implies that the processing method has a remarkable effect on antioxidant of black garlic [8, 15, 35]. The temperature and moisture are the most important parameters that determine the quality and antioxidant capacity of black garlic. In Sun and Wang's work, scavenging DPPH free radical activity of black garlic produced at 85°C in 85% humidity was higher than ones generated at 75 and 60°C in the same humidity after fermentation. The authors observed that at the same temperature, the indicated humidity (75%) would produce black garlic with highest Trolox equivalent antioxidant capacity followed by 85, 80, and 70% humidity [35]. The separation of garlic cloves also has positive correlation with antioxidant capacity. Angeles and collaborators proposed that peeled black garlic cloves exhibited a higher antioxidant capacity than whole black garlic bulbs fermented at same condition in the end of production [15].

### **3.4 Black garlic and its anti-inflammatory effect**

Inflammation is a process by which our immune system responds to injury, infection, and toxin. Inflammation plays a vital role not only in wound healing and repairing process but also in protecting our body from foreign invaders, including viruses and bacteria. However, chronic inflammation may have a negative impact on our health which has been manifested in a variety of chronic diseases from heart disease to rheumatoid arthritis and lupus. Consumption of anti-inflammatory ingredients or foods, such as ώ-3 polyunsaturated fatty acid, monounsaturated fatty acids, β-cryptoxanthin, quercetin, kaempferol, malvidin, peonidin, daidzein, genistein, extra virgin olive oil, tomato juice, walnut, red wine, flaxseed flour, and cherry, may help combat certain diseases related to chronic inflammation [36]. Recently, some reports have suggested black garlic as a prominent agent for treatment of inflammation and septicemia-related diseases. Aqueous extract of black garlic hinders the production of nitric oxide (NO) and proinflammatory cytokines, including tumor necrosis factor α (TNFα) and prostaglandin (PG)-E2, and suppresses NO synthase and TNFα and cyclooxygenase-2 expression through a mechanism-related mitogen-activated protein kinase and nuclear factor-ΚB in liposaccharide (LPS)-stimulated murine macrophages. Furthermore, black garlic extract supplement impedes serum TNFα, interleukin-6 (IL6), and interleukin-1 β (IL1β) production and prevents mice from LPS-induced death [37, 38]. These findings are identical with the results from Zhang and Jilg experiments, in which six different black garlic extracts, including hot aqueous extract, ethanol supernatant extract, ethanol precipitate extract, deproteinized ethanol supernatant extract, and deproteinized ethanol precipitate extract, not only ameliorate regulatory effect of LPS on macrophages growth inhibition but also abate TNF α, IL-6, and IL1β generation in LPS-treated macrophages [39]. Moreover, the chloroform extract of black

**89**

effects [48].

**3.6 Hepatoprotective effect of black garlic**

*Black Garlic and Its Therapeutic Benefits DOI: http://dx.doi.org/10.5772/intechopen.85042*

**3.5 Neuroprotective effect of black garlic**

pathway [42].

garlic inhibits TNFα-induced reactive oxygen species (ROS) formation, mRNA and protein expression of vascular cell adhesion molecule-1 (VCAM1), and activation of NFΚB pathway and reduces adhesiveness of THP-1 monocytes to human umbilical vein endothelial cells (HUVECs) [40]. In previous research, hexane extract of black garlic also regulates human endometrial stromal cell proliferation and cell progression via suppression of c-Jun N-terminal kinase (JNK) and extracellular signalregulated kinase (ERK). Moreover, Kim and collaborators demonstrate that hexane extract of black garlic has potential to render the NFΚB and activator protein 1 (AP1) activation, which in turn decreases VCAM1 and ICAM1 expression [41]. Fermented black garlic, a product of fermentation of *Lactobacillus rhamnosus,* also hinders production of inflammatory mediators, such as TNF α, IL-6, IL1β, iNOS, and COX2, and retards an inflammatory signal transduction pathway, the NFΚB

A growing body of literature indicates that black garlic has beneficial effects to memory and nerve system through antiamnesic effect, improvement of cognitive impairment, and prevention from neuroinflammation and neurotoxicity. In previous study, Nurmasitoh and collaborators demonstrated that ethanol extract of black garlic has manifested a strong protection of murine medial prefrontal cortex from monosodium glutamate-induced oxidative stress via improvement of the working memory performance and prevention of the pyramidal neurons from modification of neuronal architecture [43]. Furthermore, a variety of doses of black garlic extracts (from 2.5 to 10 mg/200 g body weight) also inhibit deleterious effect of monosodium glutamate on spatial memory and total number of pyramidal neurons in CA1 region of the hippocampus [44]. These findings are identical with the results from Indonesian report, in which black garlic improves motor coordination function and the number of Purkinje cells in the cerebellar cortex of the rat brain [45]. The protection effect of black garlic on nerve system from neuroinflammation, a pathological evidence of Alzheimer's disease, and cognitive impairment has been well documented [46]. Β amyloid (Aβ) deposition leads to inflammation of the neuron, which triggers a host defense response to neuronal damage and eventually neuronal degeneration. Nillert and collaborators had established a neuronal degenerative model by treatment with 1 μl of aggregated Aβ(1–42) in the lateral ventricles; eventually they observed that ethanol extract-aged black garlic, a variant form of black garlic produced by aging the fresh garlic in room temperature, could ameliorate short-term recognition memory and inhibit activation of microglia as well as production of IL1β, a proinflammatory cytokine [46]. Additionally, ethyl acetate fraction of aged garlic extract protects PC12 neuron-like cells and ICR mice from neurotoxicity and amnesia induced by Aβ(25–35) [47]. Note that both aged and black garlics are rich of S-allyl-cysteine content, a stable bioactive organosulfur compound which also exerts anti-inflammatory, neuroprotective, and antioxidant

The liver is a vital organ which exerts detoxicity, protein biosynthesis, and digestive biochemical production. However, the liver is vulnerable with medications, chemicals, alcohol, solvents, infection, and nutritional supplement. Black garlic has proved to protect the liver from side effects including hepatoxicity and apoptosis of cyclophosphamide, an anticancer medicine [49]. Ahmed indicated that black garlic supplement at the dose 200 mg/kg body weight recovers the histological

#### *Black Garlic and Its Therapeutic Benefits DOI: http://dx.doi.org/10.5772/intechopen.85042*

*Medicinal Plants - Use in Prevention and Treatment of Diseases*

**3.4 Black garlic and its anti-inflammatory effect**

parallel design study with a population of untrained males with similar age and body mass index during 14 days to compare the effect of black garlic and placebo on exercise-induced oxidative stress and recovery of muscle function [32]. They found that black garlic improved the recovery rate of circumference of biceps brachii after eccentric exercise and diminished reactive oxygen metabolites (dROMs), lipid peroxide, and 8-iso prostaglandin F2α concentrations, a new indicator of oxidative stress and related with atherosclerosis [32, 33]. Recently, Liu and collaborators have demonstrated the beneficial effect of black garlic on coronary heart disease patient. Black garlic exhibits an augmentation on chronic heart failure by increasing the left ventricular ejection fraction value and the scores of the quality of life and circulating antioxidant levels along with a decline of brain natriuretic peptide (BNP) precursor N-terminal, a biomarker for severity of heart failure [34]. Note that some research implies that the processing method has a remarkable effect on antioxidant of black garlic [8, 15, 35]. The temperature and moisture are the most important parameters that determine the quality and antioxidant capacity of black garlic. In Sun and Wang's work, scavenging DPPH free radical activity of black garlic produced at 85°C in 85% humidity was higher than ones generated at 75 and 60°C in the same humidity after fermentation. The authors observed that at the same temperature, the indicated humidity (75%) would produce black garlic with highest Trolox equivalent antioxidant capacity followed by 85, 80, and 70% humidity [35]. The separation of garlic cloves also has positive correlation with antioxidant capacity. Angeles and collaborators proposed that peeled black garlic cloves exhibited a higher antioxidant capacity than whole black garlic bulbs fermented at same condition in the end of

Inflammation is a process by which our immune system responds to injury, infection, and toxin. Inflammation plays a vital role not only in wound healing and repairing process but also in protecting our body from foreign invaders, including viruses and bacteria. However, chronic inflammation may have a negative impact on our health which has been manifested in a variety of chronic diseases from heart disease to rheumatoid arthritis and lupus. Consumption of anti-inflammatory ingredients or foods, such as ώ-3 polyunsaturated fatty acid, monounsaturated fatty acids, β-cryptoxanthin, quercetin, kaempferol, malvidin, peonidin, daidzein, genistein, extra virgin olive oil, tomato juice, walnut, red wine, flaxseed flour, and cherry, may help combat certain diseases related to chronic inflammation [36]. Recently, some reports have suggested black garlic as a prominent agent for treatment of inflammation and septicemia-related diseases. Aqueous extract of black garlic hinders the production of nitric oxide (NO) and proinflammatory cytokines, including tumor necrosis factor α (TNFα) and prostaglandin (PG)-E2, and suppresses NO synthase and TNFα and cyclooxygenase-2 expression through a mechanism-related mitogen-activated protein kinase and nuclear factor-ΚB in liposaccharide (LPS)-stimulated murine macrophages. Furthermore, black garlic extract supplement impedes serum TNFα, interleukin-6 (IL6), and interleukin-1 β (IL1β) production and prevents mice from LPS-induced death [37, 38]. These findings are identical with the results from Zhang and Jilg experiments, in which six different black garlic extracts, including hot aqueous extract, ethanol supernatant extract, ethanol precipitate extract, deproteinized ethanol supernatant extract, and deproteinized ethanol precipitate extract, not only ameliorate regulatory effect of LPS on macrophages growth inhibition but also abate TNF α, IL-6, and IL1β generation in LPS-treated macrophages [39]. Moreover, the chloroform extract of black

**88**

production [15].

garlic inhibits TNFα-induced reactive oxygen species (ROS) formation, mRNA and protein expression of vascular cell adhesion molecule-1 (VCAM1), and activation of NFΚB pathway and reduces adhesiveness of THP-1 monocytes to human umbilical vein endothelial cells (HUVECs) [40]. In previous research, hexane extract of black garlic also regulates human endometrial stromal cell proliferation and cell progression via suppression of c-Jun N-terminal kinase (JNK) and extracellular signalregulated kinase (ERK). Moreover, Kim and collaborators demonstrate that hexane extract of black garlic has potential to render the NFΚB and activator protein 1 (AP1) activation, which in turn decreases VCAM1 and ICAM1 expression [41]. Fermented black garlic, a product of fermentation of *Lactobacillus rhamnosus,* also hinders production of inflammatory mediators, such as TNF α, IL-6, IL1β, iNOS, and COX2, and retards an inflammatory signal transduction pathway, the NFΚB pathway [42].

### **3.5 Neuroprotective effect of black garlic**

A growing body of literature indicates that black garlic has beneficial effects to memory and nerve system through antiamnesic effect, improvement of cognitive impairment, and prevention from neuroinflammation and neurotoxicity. In previous study, Nurmasitoh and collaborators demonstrated that ethanol extract of black garlic has manifested a strong protection of murine medial prefrontal cortex from monosodium glutamate-induced oxidative stress via improvement of the working memory performance and prevention of the pyramidal neurons from modification of neuronal architecture [43]. Furthermore, a variety of doses of black garlic extracts (from 2.5 to 10 mg/200 g body weight) also inhibit deleterious effect of monosodium glutamate on spatial memory and total number of pyramidal neurons in CA1 region of the hippocampus [44]. These findings are identical with the results from Indonesian report, in which black garlic improves motor coordination function and the number of Purkinje cells in the cerebellar cortex of the rat brain [45]. The protection effect of black garlic on nerve system from neuroinflammation, a pathological evidence of Alzheimer's disease, and cognitive impairment has been well documented [46]. Β amyloid (Aβ) deposition leads to inflammation of the neuron, which triggers a host defense response to neuronal damage and eventually neuronal degeneration. Nillert and collaborators had established a neuronal degenerative model by treatment with 1 μl of aggregated Aβ(1–42) in the lateral ventricles; eventually they observed that ethanol extract-aged black garlic, a variant form of black garlic produced by aging the fresh garlic in room temperature, could ameliorate short-term recognition memory and inhibit activation of microglia as well as production of IL1β, a proinflammatory cytokine [46]. Additionally, ethyl acetate fraction of aged garlic extract protects PC12 neuron-like cells and ICR mice from neurotoxicity and amnesia induced by Aβ(25–35) [47]. Note that both aged and black garlics are rich of S-allyl-cysteine content, a stable bioactive organosulfur compound which also exerts anti-inflammatory, neuroprotective, and antioxidant effects [48].

### **3.6 Hepatoprotective effect of black garlic**

The liver is a vital organ which exerts detoxicity, protein biosynthesis, and digestive biochemical production. However, the liver is vulnerable with medications, chemicals, alcohol, solvents, infection, and nutritional supplement. Black garlic has proved to protect the liver from side effects including hepatoxicity and apoptosis of cyclophosphamide, an anticancer medicine [49]. Ahmed indicated that black garlic supplement at the dose 200 mg/kg body weight recovers the histological change, DNA damage, and blood biochemical parameter alteration (bilirubin, alanine transaminase (ALT), aspartate transaminase (AST)) as well as increases the hepatic antioxidant enzyme levels (CAD, SOD, GSH-Px) as compared with cyclophosphamide-treated group. According to Lee's research, black garlic could prevent rat clone-9 hepatocytes from hepatic damage induced by tert-butyl hydroperoxide in vitro [50]. One of explanations for hepatoprotective effect of black garlic is that black garlic could improve cell death and reduce lipid peroxidation, oxidative stress, and inflammation through regulation of JNK signaling cascade. Note that black garlic exerts the hepatoprotective effect not only in acute toxicity but also in chronic conditions. One study from Korea reports that black garlic decreases the fat accumulation, epididymal, total fat pad, and liver weight alteration and reduces elevation of hepatic enzymes (ALT, AST, alkaline phosphatase (ALP), and lactate dehydrogenase (LDH)) and blood lymphocyte DNA damage in chronic alcohol-induced hepatic damage model [51]. They also observed a decrease of TBARS content in the liver, heart, and plasma and reduction of cytochrome P450 2E1 activity companion with a rise of hepatic GSH level and antioxidant enzyme activities such as GSH-Px, CAT, and glutathione reductase in black garlic-treated group. From these evidences, the authors imply that the strong antioxidant effect of black garlic is related to the mechanism of protection against liver damage induced by chronic alcohol exposure. Moreover, Shin and collaborators suggested that black garlic supplement not only protects the liver from acute toxicity induced by carbon tetrachloride or D-galactosamine but also improves lipid profile and liver injury in hepatic steatosis model [52]. A Vietnamese report also proved the hepatoprotective effect of single-clove black garlic on liver injury in sub-chronic toxicity model (**Figure 3**) [14].

#### **Figure 3.**

*Liver sections from carbon tetrachloride (CCl4)-intoxicated mice and CCl4 treated with single-clove black garlic extract mice. Carbon tetrachloride treatment (1 ml of mixture of CCl4 in 50% olive oil/kg body weight, twice per week, for 28 days) not only alters the gross appearance of the liver (swelling liver, hard texture, pale brown with coarse surface) but also results in a severe hepatic inflammation and necrosis in microscopic level (panels A and B, respectively). Supplement with single-clove black garlic extract (200 mg/kg body weight) could improve liver morphology (semihard texture, redness, slight coarse surface) and histological structure of the liver along with reduction of inflammation (panels C and D, respectively).*

**91**

**Author details**

provided the original work is properly cited.

Minh City, Ho Chi Minh City, Vietnam

Gia-Buu Tran\*, Tan-Viet Pham and Ngoc-Nam Trinh

\*Address all correspondence to: trangiabuu@iuh.edu.vn

*Black Garlic and Its Therapeutic Benefits DOI: http://dx.doi.org/10.5772/intechopen.85042*

**4. Conclusions**

of black garlic.

**Acknowledgements**

**Conflict of interest**

this work.

assistance during this project.

commercial, or not-for-profit sectors.

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Institute of Biotechnology and Food-Technology, Industrial University of Ho Chi

Black garlic is a well-known garlic preparation which is fermented in regulated high humidity and temperature not only to remove strong unpleasant flavor of fresh garlic but also to improve its nutrient composition, bioactivites, and taste values. After being introduced in the market in last few decades, black garlic has become an emerging functional food on account of its wide-range biological functions, including antioxidant, anti-inflammatory, anticancer, lowering hyperlipidemia, antiobesity, hepatoprotective, and neuroprotective effects. Its bioactivities and therapeutic benefits have been the subjects to a numerous extensive researches in both in vitro and in vivo levels. In recently, there are only a few clinical studies which prove the health benefits of black garlic on cardiovascular diseases. Therefore, further researches focused on other medical application and safety aspect of black garlic are required to provide a comprehensive overview about therapeutic effects

The authors thank their colleagues from the Institute of Biotechnology and Food Technology, Industrial University of Ho Chi Minh City, for their facility and

This project received no specific grant from any funding agency in the public,

The authors declare there are no conflicts of interest regarding the publication of

## **4. Conclusions**

*Medicinal Plants - Use in Prevention and Treatment of Diseases*

change, DNA damage, and blood biochemical parameter alteration (bilirubin, alanine transaminase (ALT), aspartate transaminase (AST)) as well as increases the hepatic antioxidant enzyme levels (CAD, SOD, GSH-Px) as compared with cyclophosphamide-treated group. According to Lee's research, black garlic could prevent rat clone-9 hepatocytes from hepatic damage induced by tert-butyl hydroperoxide in vitro [50]. One of explanations for hepatoprotective effect of black garlic is that black garlic could improve cell death and reduce lipid peroxidation, oxidative stress, and inflammation through regulation of JNK signaling cascade. Note that black garlic exerts the hepatoprotective effect not only in acute toxicity but also in chronic conditions. One study from Korea reports that black garlic decreases the fat accumulation, epididymal, total fat pad, and liver weight alteration and reduces elevation of hepatic enzymes (ALT, AST, alkaline phosphatase (ALP), and lactate dehydrogenase (LDH)) and blood lymphocyte DNA damage in chronic alcohol-induced hepatic damage model [51]. They also observed a decrease of TBARS content in the liver, heart, and plasma and reduction of cytochrome P450 2E1 activity companion with a rise of hepatic GSH level and antioxidant enzyme activities such as GSH-Px, CAT, and glutathione reductase in black garlic-treated group. From these evidences, the authors imply that the strong antioxidant effect of black garlic is related to the mechanism of protection against liver damage induced by chronic alcohol exposure. Moreover, Shin and collaborators suggested that black garlic supplement not only protects the liver from acute toxicity induced by carbon tetrachloride or D-galactosamine but also improves lipid profile and liver injury in hepatic steatosis model [52]. A Vietnamese report also proved the hepatoprotective effect of single-clove black garlic on liver injury in sub-chronic toxicity model

*Liver sections from carbon tetrachloride (CCl4)-intoxicated mice and CCl4 treated with single-clove black garlic extract mice. Carbon tetrachloride treatment (1 ml of mixture of CCl4 in 50% olive oil/kg body weight, twice per week, for 28 days) not only alters the gross appearance of the liver (swelling liver, hard texture, pale brown with coarse surface) but also results in a severe hepatic inflammation and necrosis in microscopic level (panels A and B, respectively). Supplement with single-clove black garlic extract (200 mg/kg body weight) could improve liver morphology (semihard texture, redness, slight coarse surface) and histological structure of* 

*the liver along with reduction of inflammation (panels C and D, respectively).*

**90**

**Figure 3.**

(**Figure 3**) [14].

Black garlic is a well-known garlic preparation which is fermented in regulated high humidity and temperature not only to remove strong unpleasant flavor of fresh garlic but also to improve its nutrient composition, bioactivites, and taste values. After being introduced in the market in last few decades, black garlic has become an emerging functional food on account of its wide-range biological functions, including antioxidant, anti-inflammatory, anticancer, lowering hyperlipidemia, antiobesity, hepatoprotective, and neuroprotective effects. Its bioactivities and therapeutic benefits have been the subjects to a numerous extensive researches in both in vitro and in vivo levels. In recently, there are only a few clinical studies which prove the health benefits of black garlic on cardiovascular diseases. Therefore, further researches focused on other medical application and safety aspect of black garlic are required to provide a comprehensive overview about therapeutic effects of black garlic.

### **Acknowledgements**

The authors thank their colleagues from the Institute of Biotechnology and Food Technology, Industrial University of Ho Chi Minh City, for their facility and assistance during this project.

This project received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

### **Conflict of interest**

The authors declare there are no conflicts of interest regarding the publication of this work.

### **Author details**

Gia-Buu Tran\*, Tan-Viet Pham and Ngoc-Nam Trinh Institute of Biotechnology and Food-Technology, Industrial University of Ho Chi Minh City, Ho Chi Minh City, Vietnam

\*Address all correspondence to: trangiabuu@iuh.edu.vn

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[20] Yang GQ, Wang D, Wang YS, Wang YY, Yang K. Radiosensitization effect of black garlic extract on lung cancer cell line Lewis cells. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2013;**33**(8):1093-1097

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[17] Shin DY, Yoon MK, Choi YW, Gweon OC, Kim JI, Choi TH, et al. Effects of aged black garlic extracts on the tight junction permeability and cell invasion in human gastric cancer cells. Journal of Life Sciences. 2010;**20**(4): 528-534. DOI: 10.3892/mmr.2011.588

[18] Dong M, Yang G, Liu H, Liu X, Lin S, Sun D, et al. Aged black garlic extract inhibits Ht29 colon cancer cell growth via the PI3K/Akt signaling pathway. Biomedical Reports. 2014;**2**:250-254. DOI: 10.3892/br.2014.226

[19] Park C, Park S, Chung YH, Kim GY, Choi YW, Kim BW, et al. Induction of apoptosis by a hexane extract of aged black garlic in the human leukemic U937 cells. Nutrition Research and Practice. 2014;**8**(2):132-137. DOI: 10.4162/ nrp.2014.8.2.132

[20] Yang GQ, Wang D, Wang YS, Wang YY, Yang K. Radiosensitization effect of black garlic extract on lung cancer cell line Lewis cells. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2013;**33**(8):1093-1097

[21] Sunkara R, Verghese M. Functional foods for obesity management. Food and Nutrition Sciences. 2014;**5**: 1359-1369. DOI: 10.4236/fns.2014. 514148

[22] Ha AW, Ying T, Kim WK. The effects of black garlic (*Allium sativum*) extracts on lipid metabolism in rats fed a high fat diet. Nutrition Research and Practice. 2015;**9**(1):30-36. DOI: 10.4162/ nrp.2015.9.1.30

[23] Chen YC, Kao TH, Tseng CY, Chang WT, Hsu CL. Methanolic extract of black garlic ameliorates diet-induced obesity via regulating adipogenesis, adipokine biosynthesis, and lipolysis. Journal of Functional Foods. 2014;**9**: 98-108. DOI: 10.1016/j.jff.2014.02.019

[24] Seo DY, Lee S, Figueroa A, Kwak YS, Kim N, Rhee BD, et al. Aged garlic extract enhances exercise-mediated improvement of metabolic parameters in high fat diet-induced obese rats. Nutrition Research and Practice. 2012;**6**(6):513-519. DOI: 10.4162/nrp.2012.6.6.513

[25] Jung ES, Park SH, Choi EK, Ryu BH, Park BH, Kim DS, et al. Reduction of blood lipid parameters by a 12-wk supplementation of aged black garlic: A randomized controlled trial. Nutrition. 2014;**30**(9):1034-1039. DOI: 10.1016/j. nut.2014.02.014

[26] Jung YM, Lee SH, Lee DS, You MJ, Chung IK, Cheon WH, et al. Fermented garlic protects diabetic, obese mice when fed a high-fat diet by antioxidant effects. Nutrition Research. 2011;**31**(5):387-396. DOI: 10.1016/j. nutres.2011.04.005

[27] Lee HS, Lim WC, Lee SJ, Lee SH, Lee JH, Cho HY. Antiobesity effect of garlic extract fermented by *Lactobacillus plantarum* BL2 in diet-induced obese mice. Journal of Medicinal Food. 2016;**19**(9):823-829. DOI: 10.1089/ jmf.2016.3674

[28] Wang W, Sun Y. In vitro and in vivo antioxidant activities of polyphenol extracted from black garlic. Food Science and Technology. 2017;**37**(4): 681-685. DOI: 10.1590/1678-457x.30816

[29] Lee YM, Gweon OC, Seo YJ, Im J, Kang MJ, Kim MJ, et al. Antioxidant effect of garlic and aged black garlic in animal model of type 2 diabetes mellitus. Nutrition Research and Practice. 2009;**3**(2):156-161. DOI: 10.4162/nrp.2009.3.2.156

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*Medicinal Plants - Use in Prevention and Treatment of Diseases*

Food and Drug Analysis. 2017;**25**(1): 62-70. DOI: 10.1016/j.jfda.2016.11.003

[9] Choi IS, Cha HS, Lee YS. Physicochemical and antioxidant properties of black garlic. Molecules. 2014;**19**:16811-16823. DOI: 10.3390/

[10] Kim JS, Kang OJ, Gweon OC. Comparison of phenolic acids and flavonoids in black garlic at different thermal processing steps. Journal of Functional Foods. 2013;**5**(1):80-86. DOI:

[11] Bae SE, Cho SY, Won YD, Lee SH, Park HJ. Changes in S-allyl cysteine contents and physicochemical properties of black garlic during heat treatment. LWT-Food Science and Technology. 2014;**55**(1):397-402. DOI:

[12] Zhang X, Li N, Lu X, Liu P, Qiao X. Effects of temperature on the quality of black garlic. Journal of the Science of Food and Agriculture. 2016;**96**(7): 2366-2372. DOI: 10.1002/jsfa.7351

molecules191016811

10.1016/j.jff.2012.08.006

10.1016/j.lwt.2013.05.006

[13] Kang OJ. Physicochemical characteristics of black garlic after different thermal processing steps. Preventive Nutrition and Food Science. 2016;**21**(4):348-354. DOI: 10.3746/

[14] Tran GB, Dam SM, Le TNT. Amelioration of single clove black garlic aqueous extract on dyslipidemia and hepatitis in chronic carbon tetrachloride intoxicated Swiss albino mice. International Journal of Hepatology. 2018;**2018**:9383950. DOI:

[15] Toledano-Medina MA, Pérez-Aparicio J, Moreno-Rojas R, Merinas-Amo T. Evolution of some physicochemical and antioxidant properties of black garlic whole bulbs

pnf.2016.21.4.348

10.1155/2018/9383950

**References**

nure.12012

[1] Bayan L, Koulivand PH, Gorji A. Garlic: A review of potential

10.22038/ajp.2014.1741

1274 p. (In Vietnamese)

journal.pone.0079730

Al-Soudi SA, D'souza MR.

therapeutic effects. Avicenna Journal of Phytomedicine. 2014;**4**(1):1-14. DOI:

[2] Ried K, Toben C, Fakler P. Effect of garlic on serum lipids: An updated meta-analysis. Nutrition Reviews. 2013;**71**(5):282-299. DOI: 10.1111/

[3] Adaki S, Adaki R, Shah K, Karagir A. Garlic: Review of literature. Indian Journal of Cancer. 2014;**51**(4):577-581. DOI: 10.4103/0019-509X.175383

[4] Do TL, editor. Vietnamese Medicinal Plants and Remedies. 12th ed. Hanoi: Hanoi Medical Publishing House; 2004.

[5] Chen S, Shen X, Cheng S, Li P, Du J, Chang Y, et al. Evaluation of garlic cultivars for polyphenolic content and antioxidant properties. PLoS One. 2013;**8**(11):e79730. DOI: 10.1371/

[6] Naji KM, Al-Shaibani ES, Alhadi FA,

Hepatoprotective and antioxidant effects of single clove garlic against CCl4-induced hepatic damage in rabbits. BMC Complementary and Alternative Medicine. 2017;**17**(1):411. DOI: 10.1186/s12906-017-1916-8

[7] Santos FCC, Carvalho NUM. Alcoholic tincture of garlic (*Allium sativum*) on gastrointestinal endoparasites of sheep-short communication. Ciência Animal Brasileira. 2014;**15**(1):115-118. DOI:

[8] Kimura S, Tung YC, Pan MH, Su NW, Lai YJ, Cheng KC. Black garlic: A critical review of its production, bioactivity, and application. Journal of

10.5216/cab.v15i1.23284

[30] Ha AW, Kim WK. Antioxidant mechanism of black garlic extract involving nuclear factor erythroid 2-like factor 2 pathway. Nutrition Research and Practice. 2017;**11**(3):206-213. DOI: 10.4162/nrp.2017.11.3.206

[31] Czompa A, Szoke K, Prokisch J, Gyongyosi A, Bak I, Balla G, et al. Aged (black) versus raw garlic against ischemia/reperfusion-induced cardiac complications. International Journal of Molecular Sciences. 2018;**19**(4):1017. DOI: 10.3390/ijms19041017

[32] Wang L, Mimura K, Fujimoto S. Effects of black garlic supplementation on exercise-induced physiological responses. The Journal of Physical Fitness and Sports Medicine. 2012;**1**(4):685-694. DOI: 10.7600/jpfsm.1.685

[33] Mueller T, Dieplinger B, Gegenhuber A, Haidinger D, Schmid N, Roth N, et al. Serum total 8-isoprostaglandin F2α: A new and independent predictor of peripheral arterial disease. Journal of Vascular Surgery. 2004;**40**(4):768-773. DOI: 10.1016/j.jvs.2004.07.044

[34] Liu J, Zhang G, Cong X, Wen C. Black garlic improves heart function in patients with coronary heart disease by improving circulating antioxidant levels. Frontiers in Physiology. 2018;**9**:1435. DOI: 10.3389/ fphys.2018.01435

[35] Sun YE, Wang W. Changes in nutritional and bio-functional compounds and antioxidant capacity during black garlic processing. Journal of Food Science and Technology. 2018;**55**(2):479-488. DOI: 10.1007/ s13197-017-2956-2

[36] Galland L. Diet and inflammation. Nutrition in Clinical Practice. 2010;**25**(6):634-640. DOI: 10.1177/0884533610385703

[37] Kim MJ, Yoo YC, Kim HJ, Shin SK, Sohn EJ, Min AY, et al. Aged black garlic exerts anti-inflammatory effects by decreasing no and proinflammatory cytokine production with less cytotoxicity in LPS-stimulated raw 264.7 macrophages and LPS-induced septicemia mice. Journal of Medicinal Food. 2014;**17**(10):1057-1106. DOI: 10.1089/jmf.2013.3043

[38] Oh HL, Kim MJ, You BR, Kim MR. Anti-inflammatory action of black garlic through downregulation of NF-κB activation and MAP kinase phosphorylation. The FASEB Journal. 2012;**26**(1\_supplement):823-833

[39] Zhang J, Hao J. Antioxidant and anti-inflammatory activities of black garlic extracts. Journal of Food Safety and Quality. 2017;**8**(7):2635-2643

[40] Lee EN, Choi YW, Kim HK, Park JK, Kim HJ, Kim MJ, et al. Chloroform extract of aged black garlic attenuates TNF-α-induced ROS generation, VCAM-1 expression, NF-κB activation and adhesiveness for monocytes in human umbilical vein endothelial cells. Phytotherapy Research. 2011;**25**(1): 92-100. DOI: 10.1002/ptr.3230

[41] Kim KH, Park JK, Choi YW, Kim YH, Lee EN, Lee JR, et al. Hexane extract of aged black garlic reduces cell proliferation and attenuates the expression of ICAM-1 and VCAM-1 in TNF-α-activated human endometrial stromal cells. International Journal of Molecular Medicine. 2013;**32**(1):67-78. DOI: 10.3892/ijmm.2013.1362

[42] Tak HM, Kang MJ, Kyoung MK, Kang D, Han S, Shin JH. Antiinflammatory activities of fermented black garlic. Journal of the Korean Society of Food Science and Nutrition. 2014;**43**:1527-1534. DOI: 10.3746/ jkfn.2014.43.10.1527

[43] Nurmasitoh T, Sari DCR, Partadiredja G. The effects of black garlic on the working memory and pyramidal cell number of

**95**

*Black Garlic and Its Therapeutic Benefits DOI: http://dx.doi.org/10.5772/intechopen.85042*

> against hepatotoxicity induced by cyclophosphamide. The Journal of Basic and Applied Zoology. 2018;**79**:8. DOI:

[50] Lee K, Teng C, Shen C, Huang W, Lu C, Kuo H, et al. Protective effect of black garlic extracts on tert-butyl hydroperoxide-induced injury in hepatocytes via a c-Jun N-terminal kinase-dependent mechanism. Experimental and Therapeutic Medicine. 2018;**15**:2468-2474. DOI:

[51] Kim MH, Kim MJ, Lee JH, Han JI, Kim JH, Sok DE, et al. Hepatoprotective effect of aged black garlic on chronic alcohol-induced liver injury in rats. Journal of Medicinal Food. 2011;**14** (7-8):732-738. DOI: 10.1089/

[52] Shin JH, Lee CW, Oh SJ, Yun J, Kang MR, Han SB, et al. Hepatoprotective effect of aged black garlic extract in rodents. Toxicological Research. 2014;**30**(1):49-54. DOI: 10.5487/

10.1186/s41936-018-0017-7

10.3892/etm.2018.5719

jmf.2010.1454

TR.2014.30.1.049

medial prefrontal cortex of rats exposed to monosodium glutamate. Drug and Chemical Toxicology. 2018;**41**(3):324-329. DOI: 10.1080/01480545.2017.1414833

[44] Hermawati E, Sari DCR, Partadiredja G. The effects of black garlic ethanol extract on the spatial memory and estimated total number of pyramidal cells of the hippocampus of monosodium glutamate-exposed adolescent male Wistar rats. Anatomical Science International. 2015;**90**:275. DOI:

10.1007/s12565-014-0262-x

10.1007/s12565-014-0233-2

[46] Nillert N, Pannangrong W, Welbat JU, Chaijaroonkhanarak W, Sripanidkulchai K, Sripanidkulchai B. Neuroprotective effects of aged garlic extract on cognitive dysfunction and neuroinflammation induced by β-amyloid in rats. Nutrients. 2017;**9**(1):24. DOI: 10.3390/nu9010024

[47] Jeong JH, Jeong HR, Jo YN, Kim HJ, Shin JH, Heo HJ. Ameliorating effects of aged garlic extracts against Aβ-induced neurotoxicity and cognitive impairment. BMC Complementary and Alternative Medicine. 2013;**13**:268. DOI:

[48] Colín-González AL, Ali SF, Túnez I, Santamaría A. On the antioxidant, neuroprotective and anti-inflammatory properties of S-allyl cysteine: An update. Neurochemistry International.

[49] Ahmed RA. Hepatoprotective and antiapoptotic role of aged black garlic

10.1186/1472-6882-13-268

2015;**89**:83-91. DOI: 10.1016/j.

neuint.2015.06.011

[45] Aminuddin M, Partadiredja G, Sari DCR. The effects of black garlic (*Allium sativum* L.) ethanol extract on the estimated total number of Purkinje cells and motor coordination of male adolescent Wistar rats treated with monosodium glutamate. Anatomical Science International. 2015;**90**:75. DOI: *Black Garlic and Its Therapeutic Benefits DOI: http://dx.doi.org/10.5772/intechopen.85042*

medial prefrontal cortex of rats exposed to monosodium glutamate. Drug and Chemical Toxicology. 2018;**41**(3):324-329. DOI: 10.1080/01480545.2017.1414833

*Medicinal Plants - Use in Prevention and Treatment of Diseases*

exerts anti-inflammatory effects by decreasing no and proinflammatory cytokine production with less cytotoxicity in LPS-stimulated raw 264.7 macrophages and LPS-induced septicemia mice. Journal of Medicinal Food. 2014;**17**(10):1057-1106. DOI:

[38] Oh HL, Kim MJ, You BR, Kim MR. Anti-inflammatory action of black garlic through downregulation of NF-κB activation and MAP kinase phosphorylation. The FASEB Journal. 2012;**26**(1\_supplement):823-833

[39] Zhang J, Hao J. Antioxidant and anti-inflammatory activities of black garlic extracts. Journal of Food Safety and Quality. 2017;**8**(7):2635-2643

[40] Lee EN, Choi YW, Kim HK, Park JK, Kim HJ, Kim MJ, et al. Chloroform extract of aged black garlic attenuates TNF-α-induced ROS generation, VCAM-1 expression, NF-κB activation and adhesiveness for monocytes in human umbilical vein endothelial cells. Phytotherapy Research. 2011;**25**(1): 92-100. DOI: 10.1002/ptr.3230

[41] Kim KH, Park JK, Choi YW, Kim YH, Lee EN, Lee JR, et al. Hexane extract of aged black garlic reduces cell proliferation and attenuates the expression of ICAM-1 and VCAM-1 in TNF-α-activated human endometrial stromal cells. International Journal of Molecular Medicine. 2013;**32**(1):67-78.

DOI: 10.3892/ijmm.2013.1362

[43] Nurmasitoh T, Sari DCR, Partadiredja G. The effects of black garlic on the working memory and pyramidal cell number of

jkfn.2014.43.10.1527

[42] Tak HM, Kang MJ, Kyoung MK, Kang D, Han S, Shin JH. Anti-

inflammatory activities of fermented black garlic. Journal of the Korean Society of Food Science and Nutrition. 2014;**43**:1527-1534. DOI: 10.3746/

10.1089/jmf.2013.3043

[30] Ha AW, Kim WK. Antioxidant mechanism of black garlic extract involving nuclear factor erythroid 2-like factor 2 pathway. Nutrition Research and Practice. 2017;**11**(3):206-213. DOI:

[31] Czompa A, Szoke K, Prokisch J, Gyongyosi A, Bak I, Balla G, et al. Aged (black) versus raw garlic against ischemia/reperfusion-induced cardiac complications. International Journal of Molecular Sciences. 2018;**19**(4):1017.

[32] Wang L, Mimura K, Fujimoto S. Effects of black garlic supplementation on exercise-induced physiological

responses. The Journal of Physical Fitness and Sports Medicine. 2012;**1**(4):685-694.

Gegenhuber A, Haidinger D, Schmid N, Roth N, et al. Serum total 8-isoprostaglandin F2α: A new and independent predictor of peripheral arterial disease. Journal of Vascular Surgery. 2004;**40**(4):768-773. DOI:

[34] Liu J, Zhang G, Cong X, Wen C. Black garlic improves heart function in patients with coronary heart disease by improving circulating antioxidant levels. Frontiers in

Physiology. 2018;**9**:1435. DOI: 10.3389/

[36] Galland L. Diet and inflammation.

[37] Kim MJ, Yoo YC, Kim HJ, Shin SK, Sohn EJ, Min AY, et al. Aged black garlic

Nutrition in Clinical Practice. 2010;**25**(6):634-640. DOI: 10.1177/0884533610385703

[35] Sun YE, Wang W. Changes in nutritional and bio-functional compounds and antioxidant capacity during black garlic processing. Journal of Food Science and Technology. 2018;**55**(2):479-488. DOI: 10.1007/

10.4162/nrp.2017.11.3.206

DOI: 10.3390/ijms19041017

DOI: 10.7600/jpfsm.1.685

10.1016/j.jvs.2004.07.044

fphys.2018.01435

s13197-017-2956-2

[33] Mueller T, Dieplinger B,

**94**

[44] Hermawati E, Sari DCR, Partadiredja G. The effects of black garlic ethanol extract on the spatial memory and estimated total number of pyramidal cells of the hippocampus of monosodium glutamate-exposed adolescent male Wistar rats. Anatomical Science International. 2015;**90**:275. DOI: 10.1007/s12565-014-0262-x

[45] Aminuddin M, Partadiredja G, Sari DCR. The effects of black garlic (*Allium sativum* L.) ethanol extract on the estimated total number of Purkinje cells and motor coordination of male adolescent Wistar rats treated with monosodium glutamate. Anatomical Science International. 2015;**90**:75. DOI: 10.1007/s12565-014-0233-2

[46] Nillert N, Pannangrong W, Welbat JU, Chaijaroonkhanarak W, Sripanidkulchai K, Sripanidkulchai B. Neuroprotective effects of aged garlic extract on cognitive dysfunction and neuroinflammation induced by β-amyloid in rats. Nutrients. 2017;**9**(1):24. DOI: 10.3390/nu9010024

[47] Jeong JH, Jeong HR, Jo YN, Kim HJ, Shin JH, Heo HJ. Ameliorating effects of aged garlic extracts against Aβ-induced neurotoxicity and cognitive impairment. BMC Complementary and Alternative Medicine. 2013;**13**:268. DOI: 10.1186/1472-6882-13-268

[48] Colín-González AL, Ali SF, Túnez I, Santamaría A. On the antioxidant, neuroprotective and anti-inflammatory properties of S-allyl cysteine: An update. Neurochemistry International. 2015;**89**:83-91. DOI: 10.1016/j. neuint.2015.06.011

[49] Ahmed RA. Hepatoprotective and antiapoptotic role of aged black garlic

against hepatotoxicity induced by cyclophosphamide. The Journal of Basic and Applied Zoology. 2018;**79**:8. DOI: 10.1186/s41936-018-0017-7

[50] Lee K, Teng C, Shen C, Huang W, Lu C, Kuo H, et al. Protective effect of black garlic extracts on tert-butyl hydroperoxide-induced injury in hepatocytes via a c-Jun N-terminal kinase-dependent mechanism. Experimental and Therapeutic Medicine. 2018;**15**:2468-2474. DOI: 10.3892/etm.2018.5719

[51] Kim MH, Kim MJ, Lee JH, Han JI, Kim JH, Sok DE, et al. Hepatoprotective effect of aged black garlic on chronic alcohol-induced liver injury in rats. Journal of Medicinal Food. 2011;**14** (7-8):732-738. DOI: 10.1089/ jmf.2010.1454

[52] Shin JH, Lee CW, Oh SJ, Yun J, Kang MR, Han SB, et al. Hepatoprotective effect of aged black garlic extract in rodents. Toxicological Research. 2014;**30**(1):49-54. DOI: 10.5487/ TR.2014.30.1.049

**97**

**Chapter 6**

**Abstract**

better antifungal therapy.

**1. Introduction to fungal disease**

fungal infections

Medicinal Plants Having

*Koushlesh Kumar Mishra, Chanchal Deep Kaur,* 

*Saraswati Prasad Mishra and Shweta Dutta*

*Anil Kumar Sahu, Rajnikant Panik, Pankaj Kashyap,* 

**Keywords:** antifungal, phytocompounds, fungicidal, antifungal therapy,

position and it accounts for the majority of death also [2].

Fungal infections are one of the most deadly infections accounting in excess of 1.5 million deaths annually worldwide. The major reason that makes fungal infections more life threatening because they are been neglected by the society. Though in last 20 years there are many developments in the diagnosis and treatment of fungal disease but still majority of population are devoid of the benefits of these developments [1]. Among all the fungal diseases, infection of skin hold the 4th

Plant kingdom has always been a hub for many natural compounds with novel structure and this keep the investigators interested in doing research about many plants species till today. Results of new researchers showed that plants are enrich of many bioactive secondary metabolites such as saponins, alkaloids and terpenoids which characterized by antifungal property. Depending on that, these plants can be considered as a potent future source for anti-fungal drugs [3]. When recent scenario regarding fungal diseases and antifungal drugs are taken into consideration it

In the past few decades, a worldwide increase in the incidence of fungal infections has been observed as well as rise in the resistance of some species of fungi to different fungicidal used in medicinal practice. Besides, fungi are the one of the most neglected pathogens as demonstrated by the fact that the amphotericin B and other sold treatments are still used as gold standard as antifungal therapy. The majority of used antifungal treatments have various drawbacks in terms of toxicity, efficacy as well as cost and their frequent use has also led to the emergence of resistant strains. Hence, there is a great demand for developing an antifungal belonging to a wide range of structural classes, selectively acting on new targets with least side effects. Natural products, either as pure phytocompounds or as standardized plant extracts, provide unlimited opportunities for new drug lads because of their having normally matchless chemical diversity. Present chapter focused on the work done in the field of antifungal activities of various plant components and novel approaches which will be the future prospective for the new drug discoveries and providing

Antifungal Properties

### **Chapter 6**
