Comprehensive understanding and underlying molecular mechanisms of the adaptogenic effects of Panax ginseng

Abstract

Panax ginseng Meyer, a traditional herbal remedy with a long history, has been widely used worldwide. Phytochemical studies have shown that its physiological activity is due to a variety of active compounds, and extensive research has demonstrated the adaptogenic potential of ginseng in various physiological and pathological contexts. However, the molecular mechanisms supporting its adaptogenic effects remain inadequately elucidated, leading to undervaluation of its adaptogenic properties. This review uses a comprehensive literature analysis to examine five major health benefits attributed to ginseng extracts or derivatives: anti-inflammatory, antioxidant, anti-fatigue, cardiovascular protection, and cognitive enhancement. Moreover, it categorizes the biomarkers identified in each efficacy study and analyzes their interaction networks using KEGG pathway information. In that way, four key biomarkers pivotal to the adaptogenic attributes of P. ginseng are identified: superoxide dismutase, tumor necrosis factor, nuclear factor erythroid 2-related factor 2, and caspase-1. These biomarkers play an integral role in the manifestation of P. ginseng's five major effects, contributing significantly to its adaptogenic efficacy. This novel approach to understanding adaptogenic mechanisms is intended to offer innovative insights into the pharmacological effects of P. ginseng and its derivatives.

Graphical abstract

1. Introduction

Panax ginseng Meyer, a medicinal plant for thousands of years, is one of the herbal remedies most widely used around the world. Phytochemical investigations have revealed that its physiological activity stems from a diverse array of active constituents, including ginsenosides, polysaccharides, peptides, alkaloids, polyacetylenes, and phenolic compounds [1]. Among those constituents, ginsenosides, also known as ginseng saponins, are the predominant bioactive components. Korean ginseng has more than 30 distinct ginsenoside variants. Ginsenosides are typically categorized into two groups, protopanaxadiols (PPDs) and protopanaxatriols, based on their backbone structures [2]. The chemical structures of ginsenosides are depicted in Fig. 1. Extensive in vitro and in vivo investigations have underscored the therapeutic potential of P. ginseng across a spectrum of conditions, including immune-related diseases [3], neurodegenerative disorders [4], and hormonal and metabolic regulation [5]. Ginseng is renowned for its adaptogenic properties, meaning that it helps the body adapt to stress and maintain homeostasis.

Fig. 1.

Chemical structures of ginsenosides.

Adaptogens, characterized as anti-stress agents, enhance both mental and physical health by increasing a body's resilience to stressors in a nonspecific manner. These compounds are expected to confer broad resistance to various stressors by helping to restore a body from a pathological state to normalcy without disrupting regular bodily functions [6]. The term adaptogen was first introduced by the Russian pharmacologist Israel I. Brekhman in 1968, and ginseng is one of the herbs most extensively researched for its adaptogenic properties [7]. The demand for adaptogens is increasing, fueled by growing stress levels and increasing consumer awareness about healthy eating. According to the “Adaptogens Global Market Report 2024,” the global market for adaptogens is projected to reach $17.11 billion by 2028.

Ginseng has been used as a general adaptogen in Asian countries for thousands of years, but scientific literature supporting its adaptogenic activity remains limited [8]. To enhance ginseng's competitiveness in the adaptogen market, it is essential to identify consistent efficacy biomarkers that can scientifically validate its adaptogenic properties and elucidate its underlying mechanisms of action. The efficacy of ginseng-derived adaptogens relies on a multitude of pharmacological functions, including immunity promotion, antioxidant effects, fatigue alleviation, blood circulation improvement, and memory enhancement. Consequently, a holistic perspective that considers these diverse effects is imperative to comprehensively understand its adaptogenic function. To summarize the adaptogenic activities of ginseng, a comprehensive PubMed search was conducted using the keywords Panax ginseng extract, ginsenoside, immune response, inflammation, antioxidant, fatigue recovery, memory, neurodegenerative diseases, blood circulation, and cardiovascular diseases. The search results were reviewed with a focus on in vivo, in vitro, and clinical studies involving P. ginseng extract or major ginsenosides. Additionally, we categorized the biomarkers identified in each efficacy study and analyzed their interaction networks using KEGG pathway information. This review delineates the five key effects of ginseng extracts and ginseng-derived components. Furthermore, we organize and analyze the target biomarkers associated with each effect and provide compelling evidence elucidating the molecular mechanisms that underlie ginseng's adaptogenic properties.

2. Beneficial effects of P. ginseng and its components on the immune system

2.1. Immune system

The immune system is the body's defense, acting as a shield against all manner of biological threats. Such threats can come from within, such as abnormal cells, or from outside, such as viruses and bacteria. Generally, immunity can be divided into innate and adaptive systems. These two systems work together closely to protect the body and foster healthy, normal function. The innate immunity, often referred to as the nonspecific or general immune system, constitutes the first line of defense against foreign substances attempting to enter the body. It includes physical barriers (skin and mucous membranes), biological barriers (endocytic, phagocytic, cytokines, inflammation, etc.), and chemical barriers (acid in the stomach and chemical mediators) [9], and it acts quickly to eliminate and destroy external pathogens. However, the innate immune response cannot inhibit infection from spreading, and it has no immunological memory and cannot prevent the same pathogen from re-entering the body [10]. The innate immune system is activated when a diverse set of pattern-recognition receptors (PRRs) recognize pathogens. These PRRs are encoded in an organism's germline DNA and can directly detect pathogen-associated molecular patterns (PAMPs) [11]. When PRRs detects PAMPs, they trigger various signaling pathways that regulate the expression of immune-response genes.

The adaptive immune system, commonly referred to as acquired immunity, constitutes the secondary line of defense responses. It relies on the function of B and T cells, which originate from hematopoietic stem cells in the bone marrow [10]. The distinction between the adaptive and innate immunity is the ability of the adaptive system to distinguish between self and non-self antigens and establish immunological memory to create a state of readiness to invoke a stronger response upon re-exposure to pathogens, offering long-lasting immunity throughout an individual's lifetime [10].

Despite the existence of both the innate and adaptive immune systems, harm that disrupts immune system homeostasis can compromise the efficiency of the body's defenses. In such instances, external supports are needed to help regulate and enhance the immune system. Currently, natural resources are gaining attention as potential immunomodulators. Among them, P. ginseng has emerged as a noteworthy natural immunomodulatory agent with the potential to modulate both the adaptive and innate immune systems.

2.2. Anti-inflammatory effects of P. ginseng and its polysaccharides

Yang et al. reported the anti-inflammatory effects of a ginseng root extract in RAW264.7 cells stimulated with lipopolysaccharide (LPS) and in mice treated with dextran sulfate sodium (DSS) to induce colitis [12]. Ginseng root extract significantly reduced nitric oxide, tumor necrosis factor-alpha (TNF-α), and interleukin (IL)-6 levels. Additionally, it increased IL-10 mRNA level while downregulating the IL-6 and IL-1β mRNA levels induced by LPS. This extract also showed inhibitory effects on the activity of nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) and mitogen-activated protein kinase (MAPK) phosphorylation.

Further protein expression analysis showed that the immunoprotective effect of P. ginseng's polysaccharides was due to activation of MAPK and NF-κB signaling pathways. Several studies have used RAW264.7 cells to investigate the immunomodulatory capabilities of P. ginseng polysaccharides [13,14]. Those results revealed that polysaccharide treatment increased nitric oxide synthase expression and production in RAW264.7 cells and enhanced mRNA levels of immunoregulatory genes.

A separate investigation researched the anti-neuroinflammatory properties of a chloroform extract of cultured P. ginseng root. Its in vitro MTT and ELISA experiments revealed that the extract significantly increased the level of the anti-inflammatory gene IL-10 in LPS-stimulated BV2 microglial cells [15].

Cyclophosphamide (CY) is commonly used to establish an animal model of immunosuppressive conditions for in vivo evaluation of a drug's immune-enhancing activity. For example, a report by Nam et al. about the immunomodulatory effect of polysaccharides from P. ginseng berries used a CY-induced immunosuppression mouse model and found that administration of crude polysaccharides activated natural killer (NK) cells, increased splenic lymphocyte proliferation, and significantly stimulated the mRNA expression of the immune-associated genes IL-1β, IL-2, IL-4, TNF-α, interferon-gamma (IFN-γ), toll-like receptor 4 (TLR-4), and cyclooxygenase-2 (COX-2) [16].

Another experiment using CY-induced mice compared the effects of total ginsenosides and ginseng extract [17]. Both samples protected the hematopoietic function of bone marrow, maintained the balance of Th1 and Th2 cells, and safeguarded the bone marrow, thymus, and liver. Moreover, both protected the intestinal bacteria of the CY-induced immunosuppressed mice [17].

DSS is another drug used to trigger inflammation for modeling, specifically in the intestinal context. In a 2021 study, the intestinal anti-inflammatory activity of a polysaccharide isolated from P. ginseng was investigated using DSS-treated rats, fecal microbiota transplantation (FMT), and LPS-stimulated HT-29 cells [18]. In vitro and in vivo studies of P. ginseng extract and polysaccharide are summarized in Supplementary Tables 1 and 2, respectively.

2.3. Immunomodulatory role of ginsenosides

Ginsenosides are acknowledged to have a diverse spectrum of biological activities. Below, we compiled several studies that explore the immunomodulatory abilities of ginsenosides. The ginsenoside Rg1 is known for its ability to enhance intestinal immunity in mice. Administration of Rg1 increased the spleen index; the numbers of T cells, B cells, and dendritic cells; and IgA production in dexamethasone-induced mice [19]. Moreover, it regulated the levels of immune-related genes (IL-2, IL-4, IL-10, and IFN-γ), positively influencing intestinal microbiota and improving the immune state of colonic tissue.

Another study highlighted the role of Rg1 in treating chronic inflammatory neurodegenerative diseases [20]. It revealed that Rg1 significantly improved LPS-induced neural damage in mice by reducing the expression of inflammation-related genes and inhibiting the AIM2 inflammasome. That study further elucidated that the mechanism of Rg1 effects was regulated by the activation of Nrf2 and its downstream antioxidant-related enzymes [20].

Rg1 also has been shown to mitigate chronic inflammatory injury in the liver in an LPS-induced mouse model. Rg1 treatment decreased the level of inflammatory factors and alleviated hepatocellular injury and apoptosis in mice. Its immunomodulatory mechanism was suggested to be mediated through the dissociation of Nrf2 from Keap1 and the further activation of Nrf2 signaling, which inhibited the inflammasome in liver cells [21].

A study used both in vivo and in vitro experiments to delve into Rg1's immunomodulatory role in attenuating ulcerative colitis [22]. Rg1 treatment ameliorated DSS-induced oxidative stress and increased inflammation-related genes by activating the Nrf2/HO-1/NF-κB pathway [22].

Another major ginsenoside, Rb2, showed potential immune-enhancing activity in CY-induced immunosuppressed mice [23]. Rb2 treatment enhanced the spleen index and reduced spleen damage. Moreover, Rb2 promoted the proliferation of splenic lymphocytes, NK cell viability, and macrophage activity and upregulated serum levels of IFN-γ, TNF-α, IL-2, and IgG, consistently and positively regulating the mRNA expression of immune-related genes (IL-4, SYK, IL-2, TNF-α, and IL-6).

Rh4, a minor ginsenoside of P. ginseng, showed promising immune protection abilities in several studies. A study by To et al. demonstrated the anti-inflammatory activity of Rh4 [24]. In that study, the potential target signal of Rh4 was elucidated through a network database search and computer simulation. The network pharmacology approach revealed that JAK-STAT, TNF, NF-κB, and PI3K-AKT signaling pathways might be involved in the anti-inflammatory effects of Rh4. That hypothesis was supported by in vitro experiments using LPS-stimulated RAW264.7 cells. In that model, Rh4 decreased the levels of proinflammatory cytokines (IL-6, TNFα, and IL-1β), reduced the levels of inflammatory enzymes [inducible nitric oxide synthase (iNOS) and COX-2] and inflammatory mediators (NO and PGE2), and suppressed the activation of NF-κB and STAT3. Rh4 has also been shown to have an immunoprotective effect against gastric mucosal damage [25]. In a murine model of ethanol-induced gastric ulcers, Rh4 reduced mucosal injury by inhibiting proinflammatory factors (IL-6, COX2, and MAPK/NF-κB signaling). The immunomodulatory effects of ginsenosides are summarized in Supplementary Table 3.

3. Antioxidant activity of P. ginseng and its components

3.1. Antioxidative system

Reactive oxygen species (ROS) are commonly generated as byproducts of cellular metabolism and function as secondary messengers in a range of normal physiological processes [26]. However, excess ROS production promotes oxidative stress, which can cause cellular and tissue damage and the onset of numerous diseases [27,28]. To maintain cellular ROS homeostasis, oxidative stress is neutralized by antioxidant defense mechanisms. A prominent mediator of those defenses is the erythroid 2-related factor 2 (Nrf2) pathway [29]. Nrf2, a transcription factor, binds the antioxidant response element (ARE) to regulate the expression of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), heme oxygenase 1 (HO-1), and glutathione peroxidase (GPx) [30,31]. Moreover, exogenous antioxidants, such as vitamins, glutathione, and phytochemicals sourced from herbal extracts, augment antioxidant defenses, either by activating signaling pathways associated with antioxidants or by directly scavenging ROS [32]. Extensive research has been devoted to examining the antioxidant attributes of P. ginseng, and considerable attention has been paid to elucidating the antioxidant mechanisms of ginsenosides.

3.2. Antioxidant activities of ginsenosides

3.2.1. Antioxidant activities in neurodegenerative diseases

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3.2.2. Antioxidant activities in aging

A study investigated the oxidative protective effects of ginsenoside Rb1, particularly its potential to mitigate age-related injury, in ovarian granulosa cells [33]. Administration of Rb1 resulted in significant reduction in malondialdehyde (MDA) and lactate dehydrogenase (LDH) levels in the cells, accompanied by a decrease in ROS. The researchers attributed the antioxidative effect to activation of AKT and facilitation of binding between phosphorylated Akt and FoxO1 [33]. Rb1 has also been shown to mitigate sarcopenia, a condition characterized by elevated oxidative stress in aging skeletal muscle that leads to progressive loss of function and mass [34]. Rb1 inhibited ROS accumulation, protecting skeletal muscle tissue from oxidative stress–induced cytotoxicity triggered by H₂O₂. Moreover, Rb1 exhibited preventive action against oxidative stress–induced apoptosis by inhibiting the activation of caspase-3/9. These findings underscore the antioxidant capability of Rb1 and suggest its potential as a protective agent against age-related sarcopenia.

The potential of Rg1 to delay testicular aging was examined in a mouse model of D-galactose-induced aging [35]. Those findings revealed that treatment with Rg1 notably elevated the testis index, serum testosterone level, active SOD content, and total antioxidant capacity. That study ascribed Rg1's protective effects against aging to its antioxidant properties and downregulation of the p18/p53/p21 signaling pathway. During the aging process, prolonged exposure to UVB radiation is an external factor that contributes to oxidative stress. Intriguingly, the antioxidative capabilities of Rg1 have been shown to combat UVB radiation [36]. Pre-treating UVB-irradiated HaCaT cells with Rg1 increased their expression of the glucocorticoid receptor and rescued UVB-induced degradation of histone deacetylase 2 (HDAC2). Furthermore, Rg1 led to a reduction in ROS production. This protective effect was suggested to be mediated through the Nrf2/HDAC2 pathway and highlights Rg1's potential as an antioxidant that could mitigate the effects of UVB radiation.

3.2.3. Antioxidant activities in hepatic disorders

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3.2.4. Antioxidant role in diabetic tissue damage

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3.2.5. Antioxidant activities in pulmonary disease

Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation that leads to respiratory difficulties. Long-term exposure to cigarette smoke is a significant risk factor for COPD. A study was conducted to elucidate the potential mechanisms underlying the antioxidative properties of ginsenoside Rb1 in the context of a cigarette smoke exposure (CSE) model [37]. Specifically, the study used in vitro human bronchial epithelium BEAS-2B cells and in vivo COPD rat models and revealed that Rb1 treatment effectively attenuated the oxidative reactions induced by CSE by activating the Nrf2 signaling pathway. Those findings suggest that oxidative stress might play a role in the pathogenesis of CSE-induced COPD and provide further insight into the protective effects and antioxidant efficacy of Rb1.

3.2.6. Antioxidant activities in exercise-induced oxidative stress

To further substantiate the potent antioxidant abilities of ginsenoside Rb1, its effects on oxidative stress induced by a swimming exercise were investigated in male mice [38]. Rb1 treatment significantly reduced MDA content and increased the activities of SOD, CAT, and GPx in the livers of the experimental mice, highlighting the potential of Rb1 as an antioxidant agent. Similarly, Yu et al. evaluated the antioxidant defense effects of ginsenoside Rg1 in skeletal muscle, specifically in the context of mitigating the oxidative stress induced by exhaustive exercise [39]. In an in vivo study of 40 weight-matched rats, long-term administration of Rg1 effectively alleviated the increased oxidative stress caused by exercise, as evidenced by elevated levels of glutathione reductase and glutathione S-transferase (GST) in Rg1-treated animals following exercise. The antioxidant activities of ginsenosides in each disease model are summarized in Supplementary Table 4.

3.3. Clinical studies on the antioxidant capacity of P. ginseng

In addition to in vitro and in vivo investigations, numerous clinical studies have provided evidence supporting the antioxidant effects of P. ginseng. One study analyzed 82 healthy volunteers in a double-blind, randomized controlled design, dividing the participants into three groups: the control and those receiving 1 or 2g/day of P. ginseng extract for 4 weeks. The consumption of P. ginseng produced a significant decrease in ROS and MDA levels and a significant increase in the total glutathione and glutathione reductase content, demonstrating P. ginseng's ability to enhance antioxidant defense mechanisms in a healthy population [40].

P. ginseng has also been suggested to possess antioxidant properties and reduce oxidative stress in postmenopausal females. This proposition was substantiated by a double-blind, placebo-controlled trial; a significant increase in SOD level and a decrease in MDA level were observed after 12 weeks of P. ginseng supplementation [41]. Similarly, a clinical trial of postmenopausal females with hand osteoarthritis yielded results consistent with the previous findings: consumption of P. ginseng for 12 weeks led to an increase in SOD level and a decrease in MDA level [42]. Chung et al. evaluated the clinical antioxidant effect of P. ginseng in postmenopausal females in a double-blind, placebo-controlled clinical trial with 63 participants. They found that P. ginseng significantly increased total antioxidant status. Moreover, administration of P. ginseng improved fatigue symptoms and increased the mitochondrial DNA copy number in postmenopausal females [43].

Although most studies have focused on the antioxidant efficacy of ginseng mediated by Nrf2 pathway activation, the MAPK and PI3K/AKT signaling pathways have also been implicated in the antioxidant mechanisms of P. ginseng. Therefore, it is anticipated that exploring the effects of ginseng on MAPK and PI3K/AKT signals from an antioxidant perspective could yield new insights into the antioxidant efficacy of P. ginseng [44].

Clinical studies on the antioxidant effects of P. ginseng are summarized in Supplementary Table 5.

4. Anti-fatigue effects of P. ginseng and its components

4.1. Physical fatigue and its mechanisms

Fatigue is a common experience for most individuals and can typically be relieved through adequate rest and exercise. However, in extreme cases, those measures might not be sufficient, and fatigue can significantly affect overall quality of life [45]. When fatigue symptoms persist for six months or longer, they can be categorized as chronic fatigue, which requires a combination of at least four symptoms to diagnose [46]. Fatigue assessment can be approached subjectively or objectively. A subjective evaluation involves an individual's self-reported perception of fatigue on tests such as the Mental Self-Rating Numeric Scale (NRS), the Visual Analogue Scale (VAS), the Fatigue Assessment Scale, or the Brief Fatigue Inventory [47,48]. On the other hand, objective measurement relies on quantitative assessment of markers associated with anti-fatigue effects and their correlations with certain physiological factors that have been linked to fatigue. For example, elevated levels of low-density lipoprotein cholesterol, total cholesterol, and triglycerides are commonly associated with fatigue [49,50].

Oxidative damage has also been recognized as a factor contributing to fatigue, and parameters such as ROS, MDA, and F2-isoprostane levels are elevated in individuals experiencing chronic fatigue, while antioxidant parameters such as SOD and GPx are reduced [51]. Furthermore, chronic fatigue often correlates with immune-mediated inflammatory diseases. In many cases of fatigue, the body releases excessive amounts of pro-inflammatory cytokines such as IL-1, IL-6, IL-10, TLR-4, and TNF-α [52]. This interplay of various factors influencing fatigue underscores the complexity of this condition.

Numerous studies have investigated the potential of P. ginseng to prevent or alleviate fatigue. For example, in a 2023 study by Zhang et al., subcutaneous administration of an ethanol extract of P. ginseng roots to Sprague-Dawley rats resulted in a significant increase in swimming endurance compared with the control group [53]. Furthermore, the ethanol extract was noted to significantly reduce serum triglycerides and total cholesterol levels. These outcomes could be linked to the beneficial effects of the ethanol extract in promoting ATPase activity and the PI3K/AKT/mTOR pathway. Such findings suggest that an ethanol extract of P. ginseng roots might confer anti-fatigue efficacy by modulating biochemical processes associated with energy regulation.

4.2. Anti-fatigue activity of ginsenosides

The principal components of P. ginseng most often hailed for their anti-fatigue effects are ginsenoside Rb1, a primary protopanaxadiol saponin, and ginsenoside Rg3, a derivative of protopanaxadiol [54]. Tan et al. investigated the potential anti-fatigue properties of Rb1 in post-operative fatigue syndrome induced in aged rats by a major small intestinal resection (MSIR) [55]. Administration of Rb1 to the aged rats subjected to MSIR significantly enhanced their grip strength and ameliorated negative changes in their biochemical parameters. Subsequently, the researchers expanded their investigation to include an open field test, and they observed that the Rb1-treated group exhibited significantly reduced resting times, along with improvements in exploratory and nurturing behavior. The researchers attributed those effects to activation of the PI3K/Akt pathway, which leads to nuclear translocation of Nrf2 and subsequent induction of antioxidant enzymes [56]. Their observations suggest that antioxidant activity is a plausible underlying mechanism for the anti-fatigue properties of Rb1.

In a study by Yang et al., aged mice with post-fatigue syndrome were treated with ginsenoside Rg3. Those researchers used an open-field test to assess mouse behavior and activity, and they found that Rg3 significantly increased the distance traveled and the frequency of rearing. Additionally, Rg3 elevated blood levels of total cholesterol, serum triglycerides, and LDH, while also increasing the SOD concentration and reducing the release of MDA from skeletal muscles. They attributed those effects to an increase in sirtuin 1 (SIRT1) deacetylase activity [57].

Fatigue is known to diminish dopamine levels in the brain by influencing the expression and phosphorylation of tyrosine hydroxylase. Interestingly, a study by Xu et al. reported that Rg3 can counteract those fatigue-induced changes by modulating the activity of proteins such as PKAα, ERK1/2, AKT, and α-synuclein [58]. That information enhances our understanding of the effects of Rg3 on biochemical parameters that can affect and alleviate fatigue in the brain, particularly within the dopaminergic system.

A study published in 2023 explores ginsenoside Rg1 as an anti-fatigue agent, specifically for treating chronic fatigue syndrome [59]. Rg1 can regulate the metabolic pathway to reverse metabolic imbalance in rats with chronic fatigue syndrome. The researchers found that taurine and mannose 6-phosphate are key biomarkers in this regulation and identified AKT1, VEGFA, and EGFR as Rg1 targets to alleviate fatigue.

Several studies have underscored the anti-fatigue effects of polysaccharides derived from P. ginseng (WGP). For instance, one study investigated the effects of neutral polysaccharides (WGPN) and acidic polysaccharides (WGPA) on anti-fatigue activity using the forced swim test in mice [60]. Notably, WGPA exhibited significantly more potent anti-fatigue effects than WGPN. Building upon that initial experiment, the researchers aimed to identify the active components and elucidate the mechanisms by which they mitigated chronic fatigue syndrome (CFS) [61]. In a subsequent study, they continued their investigation with WGPA, fractionating it into the neutral polysaccharide fraction (WGPA-N) and the acidic polysaccharide fraction (WGPA-A). Again, using the forced swim test in mice, they discovered that both WGPA-A and WGPA could prolong swimming times, whereas WGPA-N could not. Furthermore, they observed increase in serum MDA and LDH levels, coupled with decrease in SOD and GPx levels. Those findings suggest that WGPA-A is the active component of WGP and has potential therapeutic effects for CFS. The involvement of antioxidants in this process is likely, as indicated by the changes observed in relevant biochemical markers.

A 2021 publication reported an experiment using acid heteropolysaccharides extracted from steamed ginseng [62]. Those polysaccharides exhibited distinct molecular weights, denoted as S3 (MW < 30,000 Da) and G3 (MW > 30,000 Da). The researchers found that treatment with S3 significantly extended the swimming time of fatigued mice. Furthermore, S3 treatment increased the levels of liver and muscle glycogen and elevated the levels of enzymes associated with fatigue mitigation, such as SOD and CAT. Conversely, no significant differences were observed with G3 treatment. Those findings suggest that polysaccharides with molecular weight in the S3 range could have anti-fatigue effects, as indicated by their positive effects on various fatigue-related markers.

Tu et al. extracted and isolated a homogeneous ginseng polysaccharide named APS-1 [63] and investigated its potential for fatigue mitigation and its underlying molecular mechanisms. They found that treating mice with APS-1 significantly extended their fatigue tolerance time and reduced the accumulation of fatigue-related markers. Furthermore, it boosted antioxidant enzyme activities, decreasing oxidative damage. Mechanistically, they confirmed that APS-1 exerted its anti-fatigue effects by activating the AMPK signaling pathway, enhancing glucose uptake and improving mitochondrial function.

In vitro and in vivo studies on the anti-fatigue roles of P. ginseng and ginsenosides are summarized in Supplementary Table 6.

4.3. Clinical studies on the anti-fatigue capability of P. ginseng

4.3.1. Clinical studies on chronic fatigue

The anti-fatigue effects of P. ginseng have been firmly established by a substantial body of clinical evidence that extends beyond in vivo and in vitro studies. These comprehensive clinical investigations demonstrate the efficacy of P. ginseng as a potent anti-fatigue agent.

A notable study conducted by Kim et al., in 2013 investigated the effects of a 20 % ethanol extract of P. ginseng in 90 subjects with idiopathic chronic fatigue [64]. They found that P. ginseng led to a reduction in both the NRS and VAS scores commonly used to measure pain. Furthermore, treatment with the extract decreased the serum levels of ROS and MDA.

In contrast, another research group conducted a randomized, double-blind, placebo-controlled trial of 50 subjects with chronic fatigue (CF) to assess the effects of P. ginseng [65]. They found no significant difference between the treated and placebo groups. A subsequent subgroup analysis indicated that individuals with initial VAS scores below 80 and those older than 50 years experienced a notable reduction in their initial fatigue levels. Therefore, although P. ginseng might not have definitive anti-fatigue effects for CF patients overall, it could have therapeutic potential for middle-aged individuals experiencing moderate fatigue.

4.3.2. Clinical studies of cancer-related fatigue

Numerous studies have investigated the utility and advantages of P. ginseng as a therapeutic for cancer-related fatigue (CRF), which is commonly experienced by patients undergoing cancer treatment. A study conducted by Pourmohamadi et al. underscores the potential of P. ginseng as an effective agent for alleviating CRF and enhancing quality of life (QoL) in non-metastatic cancer patients [66]. Clinical assessments, including the Beck Depression Inventory test and a researcher-designed questionnaire encompassing aspects such as muscular discomfort, emotional well-being, and sleep quality, were used to evaluate the participants. P. ginseng had a significantly positive effect on the QoL and mood of the participants (p-value <0.0001) compared with those in the placebo group (p-value 0.887).

Another study investigated the anti-fatigue properties of P. ginseng in colorectal cancer patients undergoing the mFOLFOX-6 regimen [67]. That study suggested that daily consumption of 2000 mg of ginseng water extract powder for a 16-week period could be beneficial in alleviating CRF. Significant improvements in the Brief Fatigue Inventory, usual fatigue, mood, interpersonal relationships, and physical capabilities were observed in the group receiving daily ginseng extract.

Clinical studies on the anti-fatigue effects of P. ginseng are summarized in Supplementary Table 7.

5. Cardiovascular benefits of P. ginseng and its components

5.1. Molecular signaling pathways related to cardiac function

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5.2. Pathological molecular mechanisms of cardiovascular diseases (CVDs)

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5.3. Cardioprotective effects of ginsenosides

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6. Efficacy of P. ginseng for cognitive improvement

6.1. Pathological mechanisms of neurodegenerative disease

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6.2. Effects of ginsenosides on cognitive activity and neurodegenerative diseases

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6.3. Clinical investigations of the cognitive enhancement effects of P. ginseng

6.3.1. Clinical studies targeting individuals suffering from subjective memory impairment (SMI)

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6.3.2. Clinical evaluation of cognitive improvement in patients with early-stage AD

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7. Exploring an integrated network to understand the adaptogenic activity of P. ginseng

P. ginseng has long been esteemed as an adaptogen. However, its exceptional adaptogenic qualities have been undervalued due to the lack of scientific evidence substantiating the mechanisms underlying its sporadically observed beneficial effects across various pathological conditions. To overcome those limitations, extensive research is needed to delineate the pivotal elements that contribute to the multifaceted potency of ginseng and comprehend its efficacy as an adaptogen at the molecular level.

To comprehensively analyze the mechanisms underlying ginseng's adaptogenic activity, a literature search was conducted in PubMed using relevant keywords, including Panax ginseng extract, ginsenoside, immune response, inflammation, antioxidant, fatigue recovery, memory, neurodegenerative diseases, blood circulation, and cardiovascular diseases. This search yielded studies summarizing molecular targets that have been experimentally employed to demonstrate the health-promoting effects of ginseng or ginsenosides. Among these, 37 overlapping genes were identified as being simultaneously involved in at least two of the five biological functions of ginseng discussed in this review (Fig. 2).

Fig. 2.

Flowchart outlining the process for identifying target biomarkers associated with the adaptogenic effects of ginseng.

However, some of these genes lacked well-defined biological roles, and certain molecular markers had been investigated only in a limited number of ginseng studies. To refine the selection, an additional literature search was conducted to exclude these genes and retain only those with well-established roles in the five biological functions. For this, a PubMed search was performed using keywords, including the names of the 37 genes, their corresponding protein names, and terms related to immune response, inflammation, antioxidant activity, fatigue recovery, memory, neurodegenerative diseases, blood circulation, and cardiovascular diseases. Through this process, four genes—SOD, TNF, nuclear factor erythroid 2-related factor 2 (NFE2L2), and caspase-1 (CASP1)—were identified as key factors (Fig. 2).

All those genes are related to antioxidant or anti-inflammatory mechanisms. Thus, P. ginseng can exert adaptogenic effects, such as reducing fatigue, enhancing cognitive function, and improving blood circulation, primarily through its antioxidant and anti-inflammatory properties.

7.1. SOD

7.1.1. Role of SOD in antioxidation and fatigue

SOD is a gene encoding superoxide dismutase, an antioxidant enzyme that acts as a defense against oxidative stress. The enzyme decomposes hydrogen peroxide, which can be converted into highly reactive hydroxyl radicals, water, and molecular oxygen [68].

Fatigue is a physiological phenomenon that can be caused by oxidative stress [69]. Indeed, clinical trials have demonstrated that oxidative stress levels are elevated among individuals in exhausted test cohorts, such as those engaged in overnight work or individuals afflicted with CFS [70]. One factor that contributes to heightened oxidative stress is a reduction in antioxidant enzymes, such as SOD and CAT. Therefore, enhancing antioxidant enzymes is a viable strategy for fatigue alleviation. Notably, daily consumption of a SOD-melon concentrate has been shown to mitigate both physical and mental fatigue [71]. Furthermore, a plethora of antioxidants has demonstrated efficacy in combating fatigue. For instance, phytochemicals such as curcumin and epigallocatechin gallate have exhibited favorable outcomes in addressing CFS [72].

7.1.2. The adaptogenic potential of ginseng or ginseng-derived components targeting SOD

In an in vivo study in mice, ginsenoside Rb1 was found to ameliorate postoperative fatigue syndrome through enhanced SOD-mediated antioxidant efficacy [73]. Additionally, under conditions of normal fatigue, ginsenoside Re and ginseng oligopeptides showed anti-fatigue efficacy that was accompanied by observed improvements in SOD activity within skeletal muscle [74]. Those findings suggest that antioxidant activity is a central mechanism underlying ginseng's tonic effect in alleviating fatigue. Beyond SOD, various antioxidant signaling pathways such as Nrf2, WNT, AKT, and NF-κB, as well as antioxidant substances such as GSH-px, are expected to have anti-fatigue efficacy. Currently, pharmacological efficacy evaluations predominantly rely on in vitro and in vivo studies. Therefore, additional theoretical and experimental investigations at the clinical level are needed to comprehensively elucidate the tonic action mechanism of ginseng, which exhibits antioxidant and anti-fatigue effects across both normal and pathological fatigue.

7.2. TNF

7.2.1. Role of TNF in the inflammatory response

TNF is a gene encoding TNF-α, a pro-inflammatory cytokine synthesized primarily by activated macrophages, that is crucially involved in inflammation. P. ginseng extract, or KRG, exhibits anti-inflammatory properties by downregulating the expression of inflammatory cytokines, including TNF-α, across diverse inflammatory disease models: non-alcoholic steatohepatitis [75], obesity induced by high-fat diet [76], atopic dermatitis [77], and sepsis [78].

7.2.2. Role of TNF in the antioxidant response

Interestingly, cytokines have been reported to participate in inflammatory reactions and influence antioxidant activity by regulating the activity of antioxidant enzymes. Specifically, treatment with recombinant TNF-α has been shown to decrease CAT activity in the liver [79]. In pharmacological studies examining the effects of ginseng treatment, ginseng extract and ginseng-derived components have been found to lower the levels of cytokines such as TNF-α and interleukins in models of CCL4-induced liver injury [80], radiation-induced lung injury [81], fibroblast damage caused by cigarette smoke extract [82], and acute liver failure [83]. This reduction in cytokine levels has been associated with increased CAT and SOD activity. Therefore, it is hypothesized that Korean ginseng enhances the production and activity of antioxidant enzymes by lowering TNF-α level during periods of external stress.

7.2.3. Role of TNF in fatigue

The concentration of TNF-α is intricately linked to fatigue, particularly pathological fatigue. Elevated levels of TNF-α have been observed in individuals diagnosed with CFS [84]. Furthermore, patients suffering from irritable bowel syndrome have shown a positive correlation between serum TNF level and fatigue [85]. Notably, fatigue alleviation has been documented in rheumatoid arthritis patients undergoing anti-TNF treatment [86]. These findings imply that the fatigue-relieving effects attributed to ginseng's anti-inflammatory action could involve the inhibition of TNF-α.

7.2.4. The adaptogenic potential of ginseng targeting TNF

Despite the multifaceted involvement of TNF-α in inflammatory responses, antioxidant activity, and fatigue, researchers have yet to explore the relationships among ginseng's related effects. Moreover, although numerous studies have independently demonstrated the antioxidant and anti-inflammatory properties of ginseng-derived components, few have investigated the correlation among those effects from an integrated perspective. Given the current understanding of the role of TNF-α, there is a pressing need for integrated research that examines all three of these functionalities and emphasizes the importance of TNFα-mediated central mechanisms in ginseng's adaptogenic activity.

7.3. NFE2L2

7.3.1. Role of NFE2L2 (Nrf2) in antioxidant and inflammatory responses

NFE2L2 is a gene that codes for Nrf2, a crucial transcription factor pivotal in orchestrating antioxidant processes by governing the expression of genes involved in antioxidant defense mechanisms. Nrf2 activation concurrently serves as a mechanism within several anti-inflammatory pathways. For instance, Nrf2 can regulate the innate immune response by impeding the activity of NF-κB, a prominent transcriptional regulator intricately involved in modulating the innate immune system response [87]. At the same time, Nrf2 exerts anti-inflammatory properties by counteracting the activity of ROS, a trigger for NLRP3-mediated inflammasome activation, via its antioxidant functions [88]. Additionally, Nrf2 contributes to anti-inflammatory responses through diverse mechanisms, as extensively discussed in a comprehensive review paper [89].

7.3.2. Role of Nrf2 in cognitive ability improvement

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7.3.3. Role of Nrf2 in cardiovascular improvement

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7.3.4. The adaptogenic potential of ginseng targeting Nrf2

The evidence supporting the anti-inflammatory and antioxidant effects of ginseng and ginsenosides through Nrf2 activation has been well-established in numerous studies [90]. Recent in vitro and in vivo investigations in mice have further revealed that ginsenosides Re and RK1 enhance cognitive function by modulating the Nrf2 pathway in mice subjected to chronic restraint stress and in an AD mouse model [91]. Additionally, the consumption of ginseng extract by rats has been shown to protect myocardial tissue through antioxidant action when cardiac infarction is induced by isoproterenol [92]. Those experimental findings suggest that Nrf2 activation mediates the anti-inflammatory, antioxidant, cognitive function enhancement, and cardiovascular protection effects of ginseng, underscoring Nrf2 as a pivotal regulatory mechanism integral to its adaptogenic properties.

7.4. CASPs

7.4.1. Role of CASPs (caspases) in inflammatory responses

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7.4.2. Role of CASPs in blood circulation improvement

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7.4.3. The adaptogenic potential of ginseng targeting CASPs (or inflammasomes)

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8. Conclusion and suggestions for further research

The mechanisms underlying the adaptogenic effects of ginseng are believed to stem from the collective effects of its diverse components. The in vivo and clinical studies conducted have revealed that ginseng and its derivatives hold promise as novel therapeutic interventions because they target specific signaling and metabolic pathways. However, the precise mechanisms underlying the synergistic or adaptogenic effects remain elusive. Therefore, to reassess our understanding of ginseng from an adaptogenic standpoint, a systematic and comprehensive analysis is warranted to elucidate the intricate relationships among its various effects and unveil the associated mechanisms.

Our analysis of the literature in this review suggests that SOD, TNF, NFE2L2, and CASP1 serve as pivotal genes in the mechanisms underlying the adaptogenic effects of P. ginseng (Fig. 3). However, because we primarily examined biomarkers based on findings from existing studies that focused on individual effects, we face inherent limitations in our ability to fully elucidate the mechanisms of ginseng's adaptogenic action. To address those limitations, we propose the establishment of a comprehensive database of target biomarkers for ginseng extracts and individual components derived from ginseng. The acquisition and mapping of biomarker profiles that intersect with each area of efficacy would be integral to this strategy. Our analysis, supported by existing bioinformatics data, can anticipate the feasibility of ginseng's adaptogenic efficacy and identifying the genes pivotal for this effect and their intricate correlations. However, further validation through in vitro, in vivo, and clinical investigations is essential because this approach is primarily a hypothesis about the core mechanism of adaptogenic efficacy. Specifically, longitudinal clinical trials are needed to validate the therapeutic benefits of these ginseng derivatives over an extended period.

Fig. 3.

Potential mechanisms underlying the adaptogenic properties of ginseng.

Author contributions

JYC and JHK supervised, conceptualized, and designed the manuscript. NCS and NPQ wrote the original draft of the manuscript. JYC and JHK edited and revised the manuscript critically. NCS, NPQ, HWL, and MSL prepared the figures and supplementary tables. JYC acquired the funding for this project. NCS and NPQ contributed equally as first authors of the paper, preparing first drafts of the paper. All authors have read and agreed to the published version of the manuscript.

Funding

This research was supported by the National Research Foundation of Korea (NRF), the Ministry of Science and ICT, Republic of Korea (Grant No.: 2017R1A6A1A03015642 to J.Y. C.), by a Korea Basic Science Institute (National Research Facilities and Equipment Center) grant funded by the Ministry of Education, Republic of Korea (Grant No.: 2020R1A6C101A191 to J.Y.C.), and by Korea Ginseng Corporation (KGC), Republic of Korea.

Appendix A. Supplementary data

The following are the Supplementary data to this article: