Panax ginseng C.A. Meyer (Panax ginseng) is an ancient Chinese medicinal material used in Asian nations for over 2,000 years (Kennedy and Scholey, 2003). It has been listed as a medicinal herb in Shennong Bencao Jing, a standard Chinese herbal dictionary. P. ginseng, Panax quinquefolius L., and P. notoginseng (Burk) F.H. Chen (P. notoginseng), all from the Araliaceae family, are widely used herbs. Several studies over the past few decades have shown that P. ginseng and P. notoginseng have various pharmacological effects on immunological and neurological system disorders (Liu et al., 2020). The kinds and concentrations of their primary active ingredients, saponins, may be altered throughout the steaming process, and the therapeutic efficacies of raw and steaming P. ginseng and P. notoginseng vary. These variations in saponins are causally significant (Zhang et al., 2019). Meanwhile, according to traditional Chinese medicine (TCM) theory, their uses differ, since P. ginseng strengthens vital energy while P. notoginseng encourages blood circulation (Xiong et al., 2022).

P. ginseng is often processed into white ginseng (WG) and traditional red ginseng (TRG), most well-used in clinical applications for their great pharmacological activity. In TCM, the steaming method of P. ginseng is initially listed in the Complete Manual of Experience in the Treatment of Sores. The character of TRG is detailed and described in The Ming dynasty’s Enlightening Primer of Materia Medica. In steaming processing, the quality of TRG improves with an increase of P. ginseng cultivation age. Typically, TRG is produced by six-year-old ginseng in Korea. In addition, the unique and advanced processing technology makes Korean red ginseng (KRG) predominate the world ginseng market. With the development of steaming, fermenting, and puffing technology, many new red ginseng products are being produced, including sun ginseng (SG), black ginseng (BG), fermented red ginseng (FRG), and puffed red ginseng (PRG). These process conditions directly influence the pharmacological activity of red ginseng.

It is widely known ginsenosides can be classified into three types: the protopanaxadiol type (Rb1, Rc, Rb2, and Rd); the protopanaxatriol type (ginsenoside Rg1 and Re); and the oleanolic acid type (ginsenoside Ro and polyacetylene ginsenoside Ro) according to different aglycones (Xu et al., 2014). The various structures of ginsenosides endow them with rich pharmacological activities, such as antioxidation, anti-inflammation, anti-apoptosis, and so on (Choi et al., 2014; Li et al., 2014). Additionally, ginsenosides can be divided into major and rare ginsenosides according to the different content of ginseng, which all have significant pharmacological activities (Wei et al., 2011).

The major ginsenosides occur in WG, TRG, and other new types of red ginseng. In contrast, rare ginsenosides are present in TRG at a trim level, including Rg2, Rg3, Rh1, and Rh2. However, compared with TRG, the rare ginsenosides are abundant in the new types of red ginseng. The types and contents of ginsenosides in different red ginseng products result in various pharmacological activities, and the relationship between ginsenosides and their bioactivities help in the application of red ginseng products in clinical settings.

We aimed to review the relevant clinical studies of red ginseng products and summarize the discovered ginsenoside components of red ginseng. Furthermore, we discuss the structure–functional relationship of ginsenosides. The transformation law of ginsenosides in red ginseng processing are revealed to illustrate the medicinal composition transformation. The other pharmacological activities of red ginseng, such as TRG, SG, BG, FRG, and PRG, are also discussed. We summarize the process and character of the new type of red ginseng, which provides the basis for further research to facilitate the development of red ginseng industrialization in the future.

Generally, TRG is steamed at 90°C–100°C for 2-3 h and then dried (Chung et al., 2014). The large-scale application of TRG began in the Qing Dynasty. According to TCM theory, WG is used to “supply qi and promote the production of body fluids” and enhance physical fitness and disease resistance. In contrast, TRG is often used to “boost yang” and replenishing vital essence with the “warming effect” (Zhang et al., 2012).

During TRG processing, one ginsenoside can be transformed into another by demalonylating, decarboxylating, deglycosylating, and dehydrating (Figure 1). Compared with WG, the rare ginsenosides are the characteristic compound with significant pharmacological activities. TRG exhibits more potent anticancer activity than WG due to the abundance of rare ginsenosides generated from processing (Li et al., 2011; Kim J. H. et al., 2014), which has been further developed into drugs and health products. The pharmacological activity of TRG focuses on anti-aging (Peng et al., 2021), treating erectile dysfunction (Jang et al., 2008), immune-modulating (Kim et al., 2021), the antidepressant effect (Lee et al., 2020), and anti-inflammation (Min et al., 2022). In addition, TRG can inhibit tau aggregation and promote tau dissociation in vitro, which can be a potential therapeutic agent to treat neurodegenerative diseases (Shin et al., 2020).

FIGURE 1. Various types of red ginseng.

SG is prepared by steaming fresh ginseng at a temperature of 120°C or higher, which is a higher temperature than during TRG processing (Figure 1). SG contains approximately equal amounts of three major ginsenosides, Rg3, Rg5, and Rk1, in a higher concentration than TRG. One study (Kim et al., 2000) first reported this processed red ginseng, which is more potent in its ability to induce endothelium-dependent relaxation and free radical scavenging activity.

Compared with TRG, SG contains an abundance of ginsenosides Rg3, Rg5, and Rk1 (Kwon et al., 2001). In addition, new acetylated ginsenosides (Rs4, Rs5, Rs6, and Rs7) and dammarane glycosides (Rk1, Rk2, and Rk3) have been isolated from SG (Park et al., 2002a; Park et al., 2002b). These different types and amounts of ginsenosides endow SG with more potent pharmacological effects than TRG under certain pathological conditions. SG reportedly serves several functions, including free radical scavenging (Kang et al., 2006), peroxynitrite scavenging (Kang et al., 2009), antitumor-promoting (Song et al., 2012), antihyperglycemic (Jiao et al., 2014), and cytoprotection activities (Lee C. S. et al., 2012). Moreover, SG has memory-enhancing activities (Lee C. H. et al., 2013), and enhances cognitive function in patients with moderately severe Alzheimer’s disease (Heo et al., 2012).

Due to repeated steaming and drying processes, BG is named according to its surface color change (Figure 1). The nine-time repeated steaming and drying is a typical method in TCM, mainly to rectify the properties and increase the components of Chinese medicine. Observations indicate that BG improves at temperatures of 95°C or higher, at least from the appearance (Oh et al., 2021). Multiple steaming and drying can enhance the antibacterial activity of BG (Lee H. W. et al., 2021). Compared with the TRG, the total saponins of BG are absorbed faster in the gut and exposed more widely (Yoo et al., 2021). In recent years, this method has been used to manufacture functional food.

After nine repeated steaming cycles, ginseng gradually becomes BG, with increased Rg3 content (Kim, 2015). Nineteen ginsenosides (Rg1, Re, Rf, Rb1, Rc, Rb2, Rd, F4, Rg6, Rk3, Rh4, 20(S)-, 20(R)-Rg3, 20(S)-, 20(R)-Rs3, Rk1, Rg5, Rs4, and Rs5) have been determined to be found in BG; among them, the ginsenosides Rg3, Rg5, and Rk1 are the main components (Sun et al., 2009). Research has also revealed that the total ginsenosides increase with number of steam cycles (Lee H. et al., 2012), and that the fructose in BG is 44 times that present in WG and 18.3 times that in RG (Zhu et al., 2019).

In animal and cell culture models, BG plays a role in the prevention and treatment of diseases such as cognitive impairment (Park et al., 2011), obesity (Park et al., 2019), fetal alcohol syndrome (Lee et al., 2009), and breast cancer (Kim and Kim, 2015). BG is a potential anti-aging supplementation, which can reduce the activation of p53-dependent p21 and p16 classical aging pathways in the liver, skeletal muscle, and white fat (Lee S. et al., 2022). BG can prevent liver injury by resisting oxidative stress, regulating lipid and glucose metabolism, and reducing inflammation and TLR4/NF-κB axis (Jiang et al., 2021; Wei et al., 2022). BG may maintain endothelial integrity by activating Akt, reducing vascular protein leakage, leukocyte infiltration, and proinflammatory factor release in alveolar lavage fluid, and thus plays a protective role against particle-induced lung injury and vascular hyperpermeability (Lee et al., 2019; Kim et al., 2022).

Fermenting food through edible microorganisms can produce other active small molecular compounds, which has aroused the interest of most food scientists and dietitians (Oh et al., 2015). Similarly, the fermentation applied in the red ginseng process, which is called FRG, produces a significant change in ginsenoside derivatives and possesses great pharmacological activity (Irfan et al., 2022), such as anti-inflammatory (Kim et al., 2018; Bae et al., 2021), antioxidant (Saba et al., 2018), anti-allergy (Kim et al., 2019), anti-diabetes (Jang et al., 2017), anti-anxiety (Han et al., 2020), and so on. There is another FRG, which involves ginseng steaming, extracting, fermenting, and freeze-drying. The pharmacodynamic function of ginseng after fermentation is improved, which may be related to the increase in ingestion rates and absorption levels of P. ginseng (Lee et al., 2015).

Bacteria and fungi, such as Lactobacillus, Bifidobacterium, Saccharomyces cerevisiae, and Red-Koji, mainly perform the fermentation. These microbes are essential in transforming ginseng components (Lee, et al., 2015; Choi et al., 2016). Moreover, mushroom mycelia can provide the microbial environment needed in ginseng fermentation (Bae et al., 2011). Interestingly, fermentation creates a new small molecule, Compound K (CK). CK is transformed from Rb1, Rb2, Rc, and Rd, the metabolite of FRG digested by intestinal microorganisms, and has considerable activity against diabetes, cancer, and immune stimulation (Jung et al., 2019; Kim et al., 2020). In addition, a large amount of Rg3 is fermented into Rh2 by lactic acid bacteria, which have obvious anti-tumor, anti-allergic, and anti-inflammatory activities (Bae et al., 2004; Trinh et al., 2007).

Purple-red ginseng is prepared by fresh ginseng and then through fermentation, steam ripening, and low-temperature ripening. This processing uses bilberry, sugar, and bulgaricus. The ginsenoside, Rg5, is the most abundant ingredient of this FRG. In addition, this FRG might be a beneficial therapeutic supplementary substitute for metabolic syndrome with the efficacy to improve insulin sensitivity and lower postprandial glucose levels (Kho et al., 2016; Lee S. J. et al., 2022).

After puffing, the texture of ginseng is loose and porous, and easy to dehydrate. The process goes through rapid heating at atmospheric pressure and immediate pressure reduction, and the product is what we often call PRG (Hoseney, 1986).

The red ginseng was puffed with rice to avoid a burning phenomenon at high temperatures (An et al., 2011). PRG shows higher extraction yield and crude saponin content than non-puffed ginseng (Kim et al., 2008). The primary ginsenosides (Rb1, Rb2, Rc, Rd, Re, and Rg1) are effectively converted into minor ginsenosides (F2, Rg3, Rk1, and Rg5) by puffing, which is similar to the effect of the steaming process on the content of transformed ginsenosides. However, the time required for the transformation of ginsenosides by steaming (4–36 days) is much longer than by puffing (less than 30 min) (Shin et al., 2019). During in vitro experiments, the ethanolic extract of PRG shows a more vital antioxidant capacity than TRG. In addition, more robust antioxidant properties are observed in bulk oil and oil-water emulsions (Lee et al., 2018).

Ginsenosides are the main active components in red ginseng. So far, about 100 ginsenosides have been discovered in red ginseng (Table 1), and the number is still increasing. In red ginseng products, protopanaxadiol (PPD), protopanaxatriol (PPT), and oleanane (OLE) ginsenosides are the main classification of ginsenosides (Figure 2). Ginsenoside is a triterpenoid saponin with a dammarane skeleton. The ether bond combines carbon-3, carbon-6, or carbon-20 with glycosyl residue. Carbon-20 is a chiral carbon atom presenting the 20(S) and 20(R) epimers, such as ginsenoside Rg3, Rh2, Rs3, Rg2, and Rh1. Furthermore, dehydration in the carbon-20 can present positional isomers of the double bond at carbon-20 (21) or carbon-20 (22), while the double bond at carbon-20 (22) also presents cis-trans isomers, such as Rg9, F4, Rs6, Rh4, Rs4, Rg5, and Rh3.

TABLE 1. Ginsenosides in red ginseng products.

FIGURE 2. Structure of protopanaxadiol (PPD), protopanaxatriol (PPT), and oleanolic acid (OA).

The structure of ginsenoside is directly related to anticancer activities. Interestingly, in red ginseng processing, the position of sugar chain hydrolysis (carbon-3 > carbon-6 > carbon-20) results in different degrees of anticancer activity (Kai et al., 2015). The 20(S)-ginsenosides have more substantial anticancer potential than their 20(R)-stereoisomers (Wang et al., 2007; Seoyoung et al., 2009). Ginsenosides with a double bond at C-20 (21) exhibit more effective anticancer activities than those at C-20 (22) (Kai, et al., 2015).

During red ginseng processing, the polar compounds transform into less polar compounds, which exhibit different pharmacological activity from other red ginseng products. TRG, SG, BG, FRG, and PRG have many ginsenosides in common, such as the major ginsenosides Rb1, Rb2, Rc, Rd, Re, and Rg1. In contrast, the minor ginsenosides are different in content and variety. So, red ginseng product pharmacological activity is significantly different from the diverse ingredients.

Ginsenosides can cause a structure change during red ginseng processing. Malonyl-ginsenoside is an initial form of ginseng before processing, after which deglycosylation, decarboxylation, and dehydration will occur. For example, Rg2, Rh1, and Rg3 are deglycosylated from Re, Rg1, and Rd; Rg3 and Rg2 are dehydrated to form Rg5 and Rg6; and malonyl-ginsenoside Rb2 and Rc are decarboxylated to create Rs1 and Rs2 (Chen et al., 2020). Previous research has indicated that ginsenoside Rb1 and Rb2 can transform into ginsenoside Rg3, and ginsenoside Re can transform into ginsenoside Rg2 (Lee et al., 2008; Kim Y. J. et al., 2014). The Maillard reaction is also the primary chemical reaction in red ginseng processing, whereby products are generated whenever reducing sugars are heated with amino acids, peptides, or proteins (Chen and Kitts, 2012). These products are a significant source of compounds that enhance antioxidant activity through heat treatment (Chen and Kitts, 2011). In the Maillard reaction, ginsenosides provide the reducing sugars and then transform into other ginsenosides (Yamabe et al., 2013).

Before being processed into red ginseng, malonyl-20(S)-ginsenoside is a natural compound of ginseng. The deglycosylate in carbon-20 easily occurs after processing; however, the location of the 20(S) and 20(R) epimers remains to be determined. The 20(R)-ginsenosides are present through the OH group selective attack after the glycosyl residue elimination at carbon-20 during red ginseng processing (Kang et al., 2007). For example, the ginsenoside Rg3, Rh2, Rs3, Rg2, Rh1, and Rf both have the 20(S) and 20(R) epimers.

TRG processing is mainly conducted by decarbonylation, decarboxylation, and the first deglycosylation in carbon-20 of the dammarane skeleton. SG, BG, and PRG promote these reactions. The second deglycosylation is mainly conducted in carbon-20 of the dammarane skeleton and dehydration in this position. However, the FRG processes some characteristic ginsenosides, such as ginsenoside CK, for microbial metabolism. At the same time, the amount of some minor ginsenosides, such as ginsenoside Rh2, Rg1, and Rh1, also increase with the fermentation process. The conversion pathway of oleanane ginsenosides is similar to dammarane ginsenosides. The demethylation, debutylization, and deglycosylation of ester bonds can easily occur at carbon-3 and carbon-28. The ether bond is stable at carbon-3 in the oleanane skeleton, which is also stable between sugars in this position (Figures 3–6).

FIGURE 3. Structure of protopanaxadiol ginsenosides. (ara(f):α-L-arabinofuranosyl; ara(p):α-L-arabinopyranosyl; rha:α-L-ahamnopyranosyl; glc:β-D-glucopyranosyl; xyl:β-D-xylopyranosyl; mal:malonyl; Ac:acetyl).

FIGURE 4. Structure of protopanaxatriol ginsenosides. (ara(f):α-L-arabinofuranosyl; rha:α-L-ahamnopyranosyl; glc:β-D-glucopyranosyl; xyl:β-D-xylopyranosyl; mal:malonyl; bu:butyl; Ac:acetyl).

FIGURE 5. Structure of oleanolic acid ginsenosides. (glcA: β-D-glucuronosyl; glc: β-D-glucopyranosyl; me: methyl; bu: butyl).

FIGURE 6. Transformation of ginsenosides in red ginseng products. (ara(f):α-L-arabinofuranosyl; ara(p):α-L-arabinopyranosyl; rha:α-L-ahamnopyranosyl; glc:β-D-glucopyranosyl; glcA: β-D-glucuronosyl; xyl:β-D-xylopyranosyl; mal:malonyl; bu: butyl. The red arrow represents biotransformation).

In an in vitro study, the stereochemistry of the hydroxyl group at C-20 may play an important role in preventing rotavirus infection, and anticancer and osteoclastogenesis inhibitory activity. Ginsenoside Rb2 and its hydrolytic product; 20(S)-ginsenoside Rg3, but not 20(R)-ginsenoside Rg3, prevent rotavirus infection (Yang et al., 2018). The regulation of DNA methylation may play an important role in the inhibitory effect of ginsenoside Rg3 on the growth of the HepG2 cell line. The inhibitory effect of 20(S)-ginsenoside Rg3 is stronger than that of 20(R)-ginsenoside Rg3 (Teng et al., 2017). 20(S)-Ginsenoside Rh2 potently protects HepG2 cells cytotoxicity treated with tert-butyl hydroperoxide, but 20(S)-ginsenoside Rg3 weakly protects it (Lee et al., 2005). The ginsenoside 20(R)-ginsenoside Rh2, but not ginsenoside 20(S)-ginsenoside Rh2, shows selective osteoclastogenesis inhibitory activity without any cytotoxicity on osteoclastogenesis using RAW264 cells (Liu et al., 2009).

During in vivo experiments, ginsenoside isomers showed significant differences in improving immunity, survival ability, and alleviating diabetes symptoms. 20(R)- ginsenoside Rg3 has a more potent adjuvant activity of the immune response than 20(S)-ginsenoside Rg3 with highly upregulated serum IFN-γ and IL-5 (Wei et al., 2012). The novel characteristics of 20(S)-ginsenoside Rg3 exhibited higher pharmacological effects in insulin secretion and AMPK activation than 20(R)-ginsenoside Rg3, suggesting that ginsenoside Rg3 epimers show differential activities; 20(S)- ginsenoside Rg3 may be a valuable candidate for an anti-diabetic agent (Park et al., 2008). 20(S)-ginsenoside Rg3 promotes angiogenesis by activating the AKT/ERK-eNOS signal pathway, and its activity is significantly more potent than that of 20(R)-ginsenoside Rg3 (Kwok et al., 2012). In addition, ginsenosides can also maintain body growth with a supplement of 20(S)-, but not 20(R)-ginsenoside Rg3 in a cholesterol-deprived medium (Lee et al., 2011).

The hydroxyl stereochemistry at C-20 has a great influence on the activity of ginsenosides. In the production process, the processing method of red ginseng should be changed according to the actual demand to achieve the maximum transformation of the target ginsenosides. For example, under optimum reaction conditions, the actual 20(R)-ginsenoside Rg3 converts PPD ginsenosides (Sun et al., 2013). As mentioned, ginsenoside Rg3, Rh2, Rs3, Rg2, Rh1, and Rf have the 20(S) and 20(R) epimers. There are few studies regarding the structure-activity relationship of other ginsenosides, which is still an urgent problem to be solved. In the future, these problems should be explored to determine the greater value of red ginseng.

ClinicalTrials.gov is a database of privately and publicly funded clinical studies conducted worldwide. Through the ClinicalTrials.gov platform (https://clinicaltrials.gov/), a search of the term “red ginseng” found 78 research projects; while the exclusion of all other forms of ginseng other than red ginseng obtained 39 clinical studies (Figure 7); only six of these research projects were successfully concluded and the results were reported. These results suggest that KRG is efficacious as an adjuvant treatment for patients experiencing residual symptoms of major depression (Jeong et al., 2015), reducing proinflammatory cytokines and fatigue in overweight patients with non-alcoholic fatty liver disease (Hong et al., 2016), and protecting subjects from contracting acute respiratory illness (Lee S. A. et al., 2012). KRG may have beneficial effects for dry mouth in women, especially in those of menopausal age, but not in men (Park et al., 2010). There is no evidence that KRG has an effect on blood pressure, fasting blood glucose, or arterial stiffness in subjects with metabolic syndrome (Park et al., 2012). Based on mostly low certainty evidence, ginseng may only have trivial effects on erectile function or satisfaction with intercourse compared to a placebo when assessed using validated instruments (Lee Y. S. et al., 2021). South Korea and Canada lead the studies. Twenty-eight institutions from seven countries participated, including the Clinical Trial Center for Functional Foods Chonbuk National University Hospital, Clinical Nutrition and Risk Factor Modification Centre, and Clinical Trial Center for Functional Foods. Red ginseng is mainly used as a dietary supplement, and a small part is used in drug research. There are 31 research directions, primarily focusing on diabetes mellitus type 2, health, hypertension, and blood pressure, etc. Given this, clinical studies of red ginseng mainly focus on Korea and Canada and the use of dietary supplements in human clinical studies of type II diabetes, health, hypertension, and other neurological diseases.

FIGURE 7. Analysis of clinical trials of red ginseng.

During red ginseng processing, the polar compounds are transformed into less polar compounds; demalonylation and decarboxylation easily occur, and the malonyl-ginsenosides decarboxylate into acetyl-ginsenosides; the Maillard reaction is also a reaction in red ginseng processing (Figure 1). The different process influences the content and variety of minor ginsenosides. Usually, the ginsenoside transformation of the new type of red ginseng is more vital than TRG. So, the amount of minor ginsenosides is minimal in TRG but abundant in the new type of red ginseng. With a further understanding of the structure and efficacy of ginsenosides, rare ginsenosides, such as Rg3 and Rh2, have been found to have significant pharmacological activities. The species and proportion of ginsenosides are different during red ginseng processing, which suggests that processing is crucial for the efficacy of red ginseng products. The processing of TCM expands the scope of the application thereof, which is the charm of TCM.

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