What Are the Health Benefits of Ginseng Extract Ginsenoside?

Ginseng is a traditional precious Chinese medicinal herb with a complex chemical composition and a wide range of biological activities. With the advancement of modern separation and analysis techniques, the chemical composition of ginseng has been further elucidated. Ginsenosides are considered to be the main active substances in ginseng, accounting for about 4%. According to the different saponins, ginsenosides are divided into protopanaxadiol saponins, protopanaxatriol saponins and oleanolic acid saponins. So far, more than 40 ginsenoside monomers have been isolated and identified. In recent years, the pharmacological effects and mechanisms of ginsenosides have been widely studied. This article reviews the progress of pharmacological research on ginsenosides at home and abroad.

1 Anti-tumor effects of ginsenosides

In the past 30 years, research into the anti-tumor activity of ginseng and its relatives has continued to deepen, and various anti-tumor active ingredients such as ginsenosides Rg3, Rg1, Rh1, Rh2, and Rb1 have been discovered. These ingredients have shown certain clinical application potential in promoting apoptosis of tumor cells, inhibiting proliferation of tumor cells, inhibiting invasion and metastasis of tumor cells, inhibiting tumor angiogenesis, reversing multidrug resistance of tumors, affecting the expression of genes related to tumor signal transduction, and enhancing the immunity of patients with tumor radiotherapy. In particular, they are especially prominent in reducing the side effects of radiotherapy and chemotherapy in tumor patients and enhancing the sensitivity of tumor cells to therapeutic drugs.

Jin Yan et al. [1, 2] found that ginsenoside Rb1 can significantly improve natural killer (NK) cell function and tumor necrosis factor (TNF)-α content when exploring the effect of ginsenoside Rb1 and Rg1 in combination with 5-fluorouracil on the apoptosis of splenic lymphocytes in S180 tumor-bearing mice induced by dexamethasone. and antagonized the inhibitory effect of 5-fluorouracil (P< 0.05). Jie Jian et al. [3] studied the effect of ginsenoside Rg3 on the expression of the proto-oncogene Pim-3 and the phosphorylated Bad protein pBad (Ser112) and (Ser136) expression. It was found that ginsenoside Rg3 can downregulate the expression of Pim-3 and phosphorylated Bad protein in pancreatic cancer cells PANC-1, thereby inhibiting PANC-1 cell proliferation and inducing apoptosis. 

Yoo JH et al. [4] studied the inhibitory effect of ginsenoside KG-135 on the proliferation of human prostate cancer cell lines DU145 and PC-3 and tumor-bearing mice. They found that KG-135 can significantly inhibit the proliferation of DU145 and PC-3 cells by causing the cell cycle to arrest at the G1 phase. Immunohistochemical analysis showed that KG-135 could reduce the expression of proliferating cell nuclear antigen (PCNA). Its mechanism of action may involve cell cycle inhibition and regulation of the expression of TNFRSF25 and ADRA2A genes. Liu TG et al. [5] studied the inhibition of angiogenesis and mouse lung cancer by the combined application of ginsenoside Rg3 and gemcitabine. The results showed that the combination of the two not only inhibited tumor growth and improved the survival rate and quality of life of mice with lung cancer, but also significantly mediated tumor necrosis, while inhibiting vascular endothelial growth factor (VEGF) expression in the blood and tumor tissue. Lee SY et al. [6] studied the effect of ginsenoside Rd on inhibiting colon cancer cells HT29, found that ginsenoside Rd mediated the regulation of 14 mitotic proteins (Stathmin 1, microtubule-associated protein RP/EB family and Stratifin) and was closely related to apoptosis-related proteins (Rho GDP dissociation inhibitor, Tropomyosin 1 and Annexin 5). Therefore, it is speculated that the inhibition of proliferation of the colon cancer cell HT29 by ginsenoside Rd is related to the above proteins.

2 The anti-Alzheimer's disease (AD) effect of ginsenosides

AD is a neurodegenerative disease that mainly occurs in early old age and old age. The main clinical manifestations of AD patients are memory loss and cognitive impairment. Ginsenosides, the main active ingredient in ginseng, have anti-aging, memory-enhancing and geriatric disease-treating properties. They can increase the amount of acetylcholine (Ach) in the brain, increase the number of cholinergic nerve M receptors, and have a bidirectional regulatory effect on the central nervous system. They also have anti-inflammatory and antioxidant properties, protect nerve cells, reduce their apoptosis, and promote the synthesis of nucleic acids and proteins. In recent years, ginsenoside treatment of AD has been receiving increasing attention. Its mechanism is mainly related to promoting the activity of β-secretase and γ-secretase, which promote the formation of β-amyloid (Aβ), as well as protein phosphatase 2A, anti-oxidation and elimination of free radicals.

Wang YH et al. [7] studied the inhibitory effect of ginsenoside Rg1 on β-secretase activity and its protective effect on Aβ-induced cytotoxicity in PC12 cells in vitro. The results showed that ginsenoside Rg1 can inhibit β-secretase activity and protect PC12 cells from the damage caused by Aβ, such as lactate dehydrogenase (LDH) release, nitric oxide (NO) release, reactive oxygen species (ROS) production, lipid peroxidation, intracellular calcium elevation, and apoptosis. Li Yongkun et al. [8] established an animal model of Tau protein hyperphosphorylation by injecting Okadaic acid into the dorsal hippocampus, and investigated whether ginsenoside Rb1 has a relieving effect on Tau protein hyperphosphorylation.

The results showed that ginsenoside Rb1 can reduce the overphosphorylation of Tau protein induced by okadaic acid in rat hippocampal neurons, and the mechanism may be related to the increase in protein phosphatase 2A activity. Shi YQ et al. [9] studied the effect of ginsenoside Rg1 on Aβ deposition and cognitive ability in rapidly aging mice (SAMP8), found that after long-term administration of ginsenoside Rg1, SAMP8 mice had significantly less Aβ deposition in the hippocampus, and significantly lower levels of PKARIIα in the hippocampus, while the levels of phosphorylated cyclic adenosine monophosphate response element binding protein (CREB) and brain-derived neurotrophic factor (BDNF) were significantly higher. In addition, the learning and memory abilities of SAMP8 mice were also correspondingly improved. Zhuang Ying et al. [10] investigated the effects of ginsenoside Rg2 on the learning and memory abilities and senile plaque (SP) formation in an AD rat model induced by Aβ25-35. The results showed that the learning and memory abilities of rats in the preventive administration group were enhanced compared with the model group at each dose of ginsenoside Rg2, indicating that ginsenoside Rg2 has a certain protective effect on the learning and memory abilities of AD rats and can prevent the formation of SP. 

3. The protective effect of ginsenosides on cerebral ischemia

Ischemic stroke is a common disease that threatens human health, with the characteristics of high incidence, high disability rate and high mortality rate. Ginseng total saponins, ginsenoside diol or ginsenoside monomers have varying degrees of anti-ischemic brain damage. The currently accepted mechanisms include anti-free radical lipid peroxidation, regulation of NO activity, increase in cerebral blood flow, reduction of excitatory amino acid neurotoxicity, and inhibition of neuronal apoptosis.

Chen LM et al. [11] studied the neuroprotective effect of ginsenoside Re on cerebral ischemia-reperfusion injury in rats. The results showed that compared with the sham operation group, neurological symptoms in the model group were significantly increased, but after administration of different doses of ginsenoside Re, the symptoms were alleviated to varying degrees. It was also detected that Re could significantly reduce mitochondrial swelling and increase adenosine triphosphatease activity. Studies have shown that ginsenoside Re has good neuroprotective potential against cerebral ischemia-reperfusion injury. Bao Cuifen et al. [12] investigated the effects and significance of ginsenoside Rg1 on the expression of membrane proteins (Fas) and cysteine proteases (Caspase-3) in the brain tissue of rats with ischemic stroke. The results showed that the number of positive cells expressing Fas and Caspase-3 in the brain tissue of rats in each dose group of ginsenoside Rg1 and the positive drug group was significantly lower than that in the model group, indicating that the mechanism of ginsenoside Rg1 in preventing and treating rat ischemic stroke damage may be related to inhibiting the expression of Fas and Caspase-3 in brain tissue. Hu Yu et al. [13] studied the protective effect of three doses of ginsenoside Rb3 on focal cerebral ischemia in rats. The results showed that ginsenoside Rb3 had a significant protective effect on focal cerebral ischemia in rats. The high, medium and low dose groups all significantly alleviated the behavioral symptoms of rats with cerebral ischemia, reduced the degree of cerebral edema, lowered the malondialdehyde (MDA) content in the serum, increased the superoxide dismutase (SOD) content, and reduced the area of cerebral infarction and alleviated the histopathological damage.

4 The protective effect of ginsenosides on bone

With the aging of society and population, the incidence of osteoarthritis and osteoporosis is increasing day by day. Many studies have confirmed that ginsenosides have estrogen-like effects and are classified as phytoestrogens [14]. They can cause cell mitogen-activated protein kinase (MAPK) activation through non-genomic effects of estrogen receptor activation, resulting in an osteogenic effect. Lv Zhenchao et al. [15] observed the effects of ginsenosides Rg1 and Rb1 on IL-1-induced apoptosis of chondrocytes in vitro and compared the differences in their effects on cells. The results showed that ginsenosides Rg1 and Rb1 had a significant inhibitory effect on chondrocyte apoptosis and could inhibit the occurrence and development of knee osteoarthritis. Liu J et al. [16] studied the effect of ginsenoside Rh2 on osteoclast-mediated bone resorption. The results showed that ginsenoside 20(R)-Rh2 had a selective inhibitory effect on bone resorption without any cytotoxicity. Yang Renxuan et al. [17] investigated the effects of ginsenoside Rg1 on the proliferation and expression of chondrocytes in vitro. The results showed that ginsenoside Rg1 could increase cell proliferation, antagonize interleukin (IL)-1α, reduce SOD and degrade type II collagen, indicating that ginsenoside Rg1 could promote the proliferation of chondrocytes in vitro and the expression of their phenotype.

5. The immunomodulatory effect of ginsenosides

Modern pharmacological studies have shown that ginsenosides have the effect of regulating the immune function of the body, and can improve the non-specific and specific immune functions (including cellular immunity and humoral immunity) of experimental animals. Clinical observations have shown that ginsenosides can improve or regulate the immune function of the body, and can be used or used in conjunction with immune disorders. Zhang Shanyu et al. [18] studied the effect of astragalus polysaccharide (APS) and ginsenoside (TG) on the proliferation of peripheral blood T cells in normal people and on the immune function of mice treated with cyclophosphamide (CY). They found that the combination of APS and TG can promote the proliferation of peripheral blood T cells in normal people and enhance the immune function of mice, and has a certain synergistic effect. Song X et al. [19] studied the adjuvant effect of ginsenoside Re on the immune response of mice induced by inactivated H3N3 subtype influenza virus. The results showed that administration of ginsenoside Re significantly enhanced the immune response of serum-specific antibodies IgG, IgG1, IgG2a and IgG2b. At the same time, the humoral immune index (HI) and lymphocyte proliferation also increased significantly, indicating that both Th1 and Th2 cells were activated.

6 Other

As one of the main active ingredients of ginseng, ginsenosides have diverse pharmacological effects. In addition to the pharmacological effects mentioned above, ginsenosides also have other effects, such as lowering blood sugar. Lai DM et al. [20] used a streptozotocin-induced diabetic rat model to observe the effect of ginsenoside Rh2 on blood sugar. The experiment showed that after Rh2 was intravenously injected into fasted model rats for more than 120 minutes, blood sugar decreased, and this hypoglycemic effect was dose-dependent. Research into the mechanism of the hypoglycemic effect suggests that ginsenoside Rh2 may work by increasing the secretion of β-endorphin. β-Endorphin activates the opioid μ-receptor, which can lead to increased expression of glucose transporter type 4 (GLUT4). Ginsenosides also promote the healing of burn wounds. Kimura Y et al. [21] showed that that ginsenoside Rb1 isolated from red ginseng strongly promotes the healing of burn wounds in mice at low concentrations. This promoting effect may be related to the increased expression of hypoxia-inducible factor (HIF) in keratinocytes and the increased IL-β content caused by the accumulation of macrophages at burn wounds.

7 Summary

Ginsenosides, the main active substance in ginseng, have a wide range of pharmacological effects, including anti-tumor activity, nervous system activity, and cardiovascular system activity. At present, most research on ginsenosides is preclinical, and more in-depth research is needed on their clinical effects.

References

[ 1 ]    Jin Yan, Qu Tingting, Liu Yuedong, et al. Experimental study on the effects of ginsenosides Rb1 and Rg1 and 5-fluorouracil on the apoptosis of splenic lymphocytes in dexamethasone-induced S180 tumor-bearing mice [J]. Journal of Traditional Chinese Medicine, 2006, 24 (7): 1 272.

[2] Qu Tingting, Jin Yan, Liu Yuedong, et al. Effects of ginsenosides Rb1 and Rg1 and 5-fluorouracil on the immune function of tumor-bearing mice [J]. Research in Chinese Medicine, 2006, 19(5): 16.

[ 3 ]    Jian Jie，Hu Zhi-Fang，Huang Yuan. Effect of ginsenoside Rg3 on Pim-3 and Bad proteins in human pancreatic  cancer cell line PANC-1[J].Chin J Cancer，2009，28（5）： 461.

[ 4 ]    Yoo JH，Kwon HC，Kim YJ，et al. KG-135，enriched with selected ginsenosides，inhibits the proliferation of hu- man prostate cancer cells in culture and inhibits xenograft growth in athymic mice[J]. Cancer Lett，2010，289（1）：99.

[ 5 ]    Liu TG，Huang Y，Cui DD，et al. Inhibitory effect of ginsenoside Rg3 combined with gemcitabine on angiogenesis  and growth of lung cancer in mice[J]. BMC Cancer，2009， 23（9）：250.

[ 6 ]    Lee SY，Kim GT，Roh SH，et al. Proteome changes related to the anti-cancer activity of HT29 cells by the treat- ment of ginsenoside Rd[J]. Pharmazie，2009，64（4）：242.

[ 7 ]    Wang YH，Du Gh. Ginsenoside Rg1 inhibits beta-secretase activity in vitro and protects against Abeta-induced cy-  totoxicity in PC12 cells[J]. J Asian Nat Prod Res，2009，11 （7）：604.

[8] Li Yongkun, Chen Xiaochun, Zhu Yuanyi, et al. Ginseng saponin Rb1 reduces the overphosphorylation of Tau protein induced by okadaic acid in rat hippocampal neurons [J]. Acta Physiologica Sinica, 2005, 57 (2): 154.

[ 9 ]    Shi YQ，Huang TW，Chen LM，et al. Ginsenoside Rg1 at- tenuates amyloid-beta content，regulates PKA/CREB ac- tivity ，and  improves  cognitive  performance  in  SAMP8 mice[J]. J AlzheimersDis，2010，19（3）：977.

[ 10 ]   Zhuang Ying, Shi Bo, Tian Xin, et al. Effects of ginsenoside Rg2 on learning and memory ability and senile plaque formation in rats with Alzheimer's disease model [J]. Chinese Journal of Gerontology, 2010, 30(2): 202.

[ 11]    Chen LM，Zhou XM，Cao YL，et al. Neuroprotection of ginsenoside Re in cerebral ischemia-reperfusion injury in rats[J]. J Asian Nat Prod Res，2008，10（5～6）：439.

[12] Bao Cuifen, Liu Xia, Liang Jia, et al. Effects of ginsenoside Rg1 on the expression of Fas and Caspase-3 proteins in the brain tissue of rats with ischemic stroke [J]. Journal of Liaoning University of Traditional Chinese Medicine, 2009, 11(5): 211.

[13] Hu Yu, Chen Haofan, Zang Linquan, et al. Protective effect of ginsenoside Rb3 on focal cerebral ischemia in rats [J]. Journal of Guangdong Pharmaceutical University, 2008, 24(5): 590.

[ 14]    Chan RY，Chen WF，Dong A，et al.Estrogen-like effects of ginsenoside Rg1 derived from Panax notoginseng[J]. J ClinEndocrinol Metab，2002，87（8）：3 691.

[15] Lv Zhenchao, Guo Yanxing, Cao Xiangyang, et al. Effects of ginsenosides Rg1 and Rb1 on the apoptosis of knee cartilage cells cultured in vitro [J]. World Journal of Integrative Medicine, 2010, 5(1): 32.

[16]    Liu J，Shiono J，Yu H，et al. 20（R）-ginsenoside Rh2，not  20（S）， is a selective osteoclastgenesis inhibitor without  any cytotoxicity[J].Bioorg Med Chem Lett，2009，19（12）： 3 320.

[17] Yang Renxuan, Wang Zhaopei, Xu Shucai, et al. Effects of ginsenoside Rg1 on the proliferation and phenotype of chondrocytes [J]. New Chinese Medicine and Clinical Pharmacology, 2004, 15 (1): 4. [18] Zhang Shanyu, Pu Huisun, Shen Yingai. A preliminary study on the immunomodulatory effect of astragalus polysaccharide in combination with ginseng saponins [J]. Chinese Pharmacy, 2005, 16 (21): 1 620.

[19]    Song X，Chen J，Sakwiwatkul K，et al. Enhancement of immune responses to influenza vaccine（H3N2）by ginsen- oside Re[J]. Int Immunopharmacol，2010，10（3）：351.

[20]    Lai DM，Tu YK，Liu M，et al. Mediation of β-endorphin by ginsenoside Rh2 to lower plasma glucose in streptozoto- cin-induced diabetic rats[J].PlantaMed，2006，72（1）：9.

[21]    Kimura Y，Sumiyoshi M，Kawahira K，et al.  Effects  of  ginseng saponins isolated from Red Ginseng roots on burn  wound healing in mice[J]. Br JPharmacol，2006，148（6）： 860.