The effects of ginseng on the metabolic syndrome: An updated review

Abstract Metabolic syndrome is a group of risk factors including high blood glucose, dyslipidemia, high blood pressure, and high body weight. It can increase the risk of diabetes and cardiovascular disorders, which are the important reasons for death around the world. Nowadays, there are numerous demands for herbal medicine because of less harmful effects and more useful effects in comparison with chemical options. Ginseng is one of the most famous herbs used as a drug for a variety of disorders in humans. The antihyperlipidemia, antihypertension, antihyperglycemic, and anti‐obesity effects of ginseng and its active constituents such as ginsenosides have been shown in different studies. In this review article, the different in vitro, in vivo, and human studies concerning the effects of ginseng and its active constituents in metabolic syndrome have been summarized. According to these studies, ginseng can control metabolic syndrome and related diseases.

Panax ginseng belonging to the genus Panax and the family Araliaceae is one of the popular pharmaceutical and perennial plant species. The plant is cultivating in China, Japan, and Korea .
Its curative function for the first time was seen in the Chinese medicine monograph (Yun, 2001). Ginseng is one of the most famous herbs used as a drug and nutritional supplements for a variety of disorders in humans (Liu et al., 2019b).
"Panax" taken from the word "panacea" in Greek which means "cure-all." Ginseng has been proven to have a wide variety of therapeutic effects. Red ginseng and white ginseng are two prevalent products of ginseng. Red ginseng provided during the process of steaming, and dried white ginseng provided by air-drying (Karmazyn et al., 2011). Red ginseng has shown efficacy for the remedy of a wide range of disorders including hyperglycemia (Nam et al., 2019).
The important bioactive structures in ginseng are ginsenosides, the different types of triterpene saponins including oleanane-type ones and dammarane-type ones, that classified according to their chemical skeleton structures (Han et al., 2006). Until now, over than 150 ginsenosides have been purified from ginseng; in Panax ginseng, 40 kinds of ginsenosides have been found (Christensen, 2008). Some of the most active constituents of ginseng are structurally shown in Figure 1. Ginsenosides are the principal group of effective compounds in ginseng. They demonstrate unique biological activity and broad pharmacological properties including anticancer, antiinflammatory, antioxidant, and anti-apoptotic effects (Razgonova et al., 2019).
According to the modern pharmacological, preclinical, and clinical studies, ginseng has marvelous beneficial effects in multiple neurological and neurodegenerative diseases and it has various biological activities such as antihypertension, antitumor, anti-anxiety, and immune-modulatory activities, so it has several protective mechanisms (Liu et al., 2019b). Furthermore, ginseng has wide curative potentials including diminishing blood glucose, modifying blood lipids, and enhancing insulin sensitivity (Imanshahidi & Hosseinzadeh, 2008). Therefore, ginseng is effective in the treatment of different components of metabolic syndrome.
In this review, different relevant studies to realize the role of ginseng and its active components in metabolic syndrome risk factors including hypertension, hyperglycemia, hyperlipidemia, and obesity have been explained.

| EFFEC T ON DYS LIPIDEMIA
Hyperlipidemia is found as an important risk factor for heart and vessel disorders, which is one of the important reasons for human mortality (Mueller et al., 2011).
Recently, there has been an enhancing interest in the usage of medicinal herbs with more efficiency and lower adverse effects than chemical drugs for a variety of disorders including hyperlipidemia.
According to the studies focused on the plants with hypolipidemic effects, some plants including Allium sativum, Nigella sativa, Curcuma longa, Anethum graveolens, and Commiphora mukul showed the best hypolipidemic effect (Mollazadeh et al., 2019).
Numerous studies have been shown that ginseng could decline total cholesterol (TC), triglyceride (TG), and low-density lipoproteins (LDL) and increase high-density lipoprotein (HDL) level.
A study on male and female rats intoxicated with ethanol for two weeks indicated that the administration of 150 mg/kg of ginseng for six weeks improved the serum lipid profiles. Ginseng lowered the serum level of TC, TG, LDL-C, and atherogenic index and elevated the serum level HDL-C (Ayaz & Alnahdi, 2018). In another study in mice receiving the alcoholic extract of North American ginseng at 4 and 32 weeks of age, a decrease in hepatic and intestinal lipoprotein secretion and the level of blood lipid has been shown. Treatment by ginseng protected the mice against fatty liver. Moreover, ginseng reduced the expression of genes involved in the adjustment of fatty acid and triglyceride secretion by the lipoproteins. On the other hand, ginseng stimulated lipolysis (Singh et al., 2017). The protective effects of ginseng on dyslipidemia may be related to the increased phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase. Also, the different gene expressions related to lipolysis and uptake of fatty acids such as peroxisome proliferator-activated receptorα and CD36 were enhanced. These results have shown that ginseng improved hyperlipidemia by stimulating lipolysis through AMPK activation (Yuan et al., 2010). Administration of fermented red ginseng for eight weeks could reduce the levels of ALT, AST, TC, TG, and LDL-C and hepatic MDA levels in high-fat diet-treated rats.
Moreover, ginseng improved the HDL-C level and hepatic SOD, CAT, and GSH-Px activity induced by a high-fat diet. These results demonstrated that ginseng modified lipid profiles, prevented lipid peroxidation, and increased antioxidant activities . Also, Saba et al. showed that the administration of aqueous and ethanolic extracts of ginseng decreased the cholesterol and LDL levels in HFDtreated rats. It also downregulated the important genes responsible for lipogenesis, such as acetyl-coenzyme A (CoA) acetyltransferase 2, 3-hydroxy-3-methyl-glutaryl-CoA reductase, and sterol regulatory element-binding protein 2 (Saba et al., 2016). According to these studies, it could be concluded that ginseng could modify the lipid profile and inhibit atherosclerosis (Table 1).

| EFFEC T ON HI G H B LOOD PRE SSURE
Hypertension is an additional important metabolic risk factor for cardiovascular disease (Organization, 2007). High blood pressure increases the risk of myocardial infarction and cerebrovascular disease as well as heart failure, peripheral vascular disease, stroke, and coronary artery disease (Leong et al., 2013).
Medicinal herbs are accessible, cheap, and useful for both prevention and treatment of hypertension. Furthermore, some medicinal plants such as Ginkgo biloba (Eisvand et al., 2020), Aloe vera (Shakib et al., 2019), Crataegus pinnatifida (Dehghani et al., 2019), Silybum marianum (Tajmohammadi et al., 2018), Capsicum annuum According to animal and human studies, ginseng can reduce hypertension. In a study, the administration of ginseng to spontaneously hypertensive rats improved endothelium-dependent vasodilatation.
Ginseng treatment for 6 weeks increased the serum NO levels and decreased the mean aortal intima-media width in comparison with control. Furthermore, ginseng mediated the expressions of cyclooxygenase (COX)-2 in endothelial cells (Park et al., 2014b). Clinical investigations also demonstrated that the daily consumption of capsules of ginseng is helpful for blood flow during exercise. Ginseng reduced peripheral vascular resistance and improved oxygen transfer to activate atrophied muscles (Zaheri & Marandi, 2016). In another animal study, concurrent treatment with ginseng reduced the blood pressure in spontaneously hypertension rat by the inhibition of angiotensin-I-converting enzyme and release of NO (Lee, Bae, Park, Park, Lee, 2016). A study on prehypertensive subjects revealed that treatment by ginseng decreased lipoprotein-associated phospholipase A 2 (Lp-PLA 2) and lysophosphatidylcholines (lysoPCs) and increased dihydrobiopterin levels, which caused a notable decrease in diastolic and systolic blood pressure (Cha et al., 2016). Besides, the oral administration of ginseng to healthy volunteers for two separate appointments with a 7-day washout course demonstrated that

↓ Hypertriglyceridemia
Several in vivo and clinical studies reported the antihypertension effect of ginseng and its protection against hypertensive complications such as cardiac hypertrophy (Table 2).

| EFFEC T ON OB E S IT Y
Obesity is an important global issue that is characterized by an imbalance between lipogenic and lipolytic processes, which causes the accumulation of excess body fat in the form of triglyceride in adipose tissue and is associated with several diseases including diabetes and heart disease (Langin, 2006).
As the approved anti-obesity drugs have poorly documented effects, so, there is an immediate need for novel and effective antiobesity medicines .
The research reported that ginseng exhibited an anti-obesity effect by different mechanisms. Several studies have shown that ginseng in animals exhibited anti-obesity effects.
Ginseng decreased adipose tissue mass and obesity in high-fat diet-induced obese mice and this effect mediated through the reduction of angiogenesis and extracellular matrix metalloproteinase (MMP) activity . In high-fat diet-induced obese mice, administration of 125 and 500 mg kg −1 day −1 of ginseng for 12 weeks decreased body and liver weight, epidermal adipose tissue weight through the downregulation of PPARγ expression, and upregulation of PPARα, PGC-1α, UCP-1, and UCP-3 genes in adipose tissues .
The body weight-lowering effect of ginseng extract (0.8% and 1.6% w/w) on obesity induced by a high-fat diet in mice was investigated for 8 weeks. A significant decrease in plasma TG levels, body weight gains, and white adipose tissue were observed. The possible mechanism is through the regulation of lipogenesis-related gene expression in white adipose tissue and delays in intestinal fat absorption . In a study on obese rats received a high-fat diet, ginseng significantly reduced epididymal and abdominal adipose tissue mass and total body weight . In this regard, another experiment revealed that high hydrostatic pressure extract of ginseng (PEG) reduced the protein expression of adipogenic genes such as PPARγ and aP2. The results of this study showed PEG may have more useful than water extract ginseng on obesity and inflammation. This effect is mediated through the increase of fecal triacylglycerol and adjustment of gene expression (Jung et al., 2014).
A study on the anti-obesity effect of ginseng in 3T3-L1 cells showed that ginsenoside Rg2 decreased adipocyte differentiation and the accumulation of intracellular lipids (Liu et al., 2019b). Ginseng decreased adipose tissue and adipocyte size, triglyceride, cholesterol, and body weight without changing food intake in high-fat diet mice (Shin & Yoon, 2018).
Based on these studies, the anti-obesity effect of ginseng and its active constituents is moderate to very strong. Furthermore, ginseng may have important roles in the treatment and prevention of obesity through several mechanisms (Table 3).

| EFFEC T ON HI G H B LOOD G LUCOS E
Diabetes is known as a metabolic disease that outcomes from failure in insulin action or insulin production or both (Mahadeva Rao & Adinew, 2011). Diabetes is one of the major reasons for human death, morbidity, and hospital cost around the world. According to the universal reports about diabetes, the number of people suffering from diabetes has been over 422 million in 2014 and the number of people with diabetes is increasing every day around the world (Collaboration, 2016). So, diabetes is a serious universal health problem, which is guessed to reach 592 million by 2035 and will be the seventh reason for mortality in 2035 (Das et al., 2014).
Many animal and human studies have shown useful effects of phytotherapy for the treatment of diabetes (Ghorbani, 2013a(Ghorbani, , 2013b (Razavi & Hosseinzadeh, 2014). Flavonoids such as rutin are useful in the treatment of many diseases such as diabetes (Hosseinzadeh & Nassiri-Asl, 2014). The results of studies revealed that grape poly- In summary, ginseng can be suggested for the treatment of diabetic patients because it can decrease blood glucose levels with several effective mechanisms, such as insulin sensitivity improvement, the enhancement of tissues glucose uptake, and the reduction of insulin resistance and glucose tolerance. Numerous studies regarding the antidiabetic effect of the ginseng have been conducted on

↓ BG
we need more clinical research projects (Table 4).

| CON CLUS ION
The use of herbal medicines as supplementary drugs is prevalent and gaining global popularity. Ginseng has wide curative potentials including decreasing blood glucose level, blood lipids level, and blood pressure and enhancing insulin sensitivity. This review article summarizes a variety of in vitro, in vivo, and human studies on the role of ginseng and its active constituents in metabolic syndrome. The results of different studies have indicated that this plant exhibits useful effects in several components of metabolic syndrome including blood glucose, dyslipidemia, blood pressure, and obesity ( Figure 2).
Ginseng stimulates AMPK and activates lipolysis, so, it can improve hyperglycemia. Ginseng decreases adipose tissue mass and obesity.
The possible mechanism is through the regulation of lipogenesis-

TA B L E 4 (Continued)
F I G U R E 2 Schematic effects of ginseng in metabolic syndrome side effects, so it can be used as an herbal medicine for the treatment of various components of metabolic syndrome. However, more clinical studies need to be done for confirming the beneficial effects of ginseng in metabolic syndrome.

ACK N OWLED G M ENTS
We thank the Vice-Chancellor of Research, Mashhad University of Medical Sciences, Iran.

CO N FLI C T O F I NTE R E S T S TATE M E NT
The authors declare that there are no conflicts of interest.