RESEARCH

Acanthopanax

Eleutheroside B or E, the main component of Acanthopanax, can relieve fatigue, enhance memory, and improve human cognition. Numerous studies have confirmed that high doses of acetylcholine significantly attenuate clinical symptoms and delay the progression of Alzheimer's disease. The present study replicated a rat model of aging induced by injecting quinolinic acid into the hippocampal CA1 region. At 4 weeks after administration, behavioural tests showed that the escape latencies and errors in searching for the platform in a Morris water maze were dose-dependently reduced in rats treated with medium and high-dose eleutheroside B or E [1]. 

Hippocampal homogenates showed enhanced cholinesterase activity, and dose-dependent increases in acetylcholine content and decreases in choline content following eleutheroside B or E treatment, like those seen in the Huperzine A group. These findings indicate that eleutheroside B or E improves learning and memory in aged rats. These effects of eleutheroside B or E may be mediated by activation of cholinesterase or enhanced reuse of choline to accelerate the synthesis of acetylcholine in hippocampal neurones [2].

There have been many studies on the activities of eleutherosides B and E. Eleutherosides B and E have been reported to have protective effects against amyloid β (25–35)-induced neuritic atrophy in cultured rat cortical neurons [3], neuroprotective effects against transient global cerebral ischemia in rats, protective effects in dopaminergic neurons in Parkinson’s disease mice, and antioxidant properties [5]. There have been many studies determining the effects of eleutherosides B and E. The quantitative analysis of eleutherosides B and E from Acanthopanax species has been reported from various parts of members of Acanthopanax species [6,7], including A. sessiliflorus fruits and fermented wine made from them [8] and in the roots of A. senticosus [9].

EB and EE showed obvious protective effects against neuritic atrophy and nerve cell death [10,11]. Furthermore, EE exerted significant anti-inflammatory effects by suppressing the gene expression of inflammatory proteins and protective effects in ischemia heart [12]. In addition, EE has the potential abilities to alleviate behavioural alterations induced by sleep deprivation [13] and fatigue both in physical and mental fatigue [14].

References

Eleutheroside B or E enhances learning and memory in experimentally aged rats. Neural Regen Res. 2013 Apr 25;8(12):1103-12. doi: 10.3969/j.issn.1673-5374.2013.12.005.

Effect of recombinant human erythropoietin on the expression of TNF-α in cerebral ischemia-reperfusion mice. Zhongguo Yike Daue Xuebao. 2012;41(5):396–398.

Neuroprotective effects of Eleutherococcus senticosus bark on transient global cerebral ischemia in rats. Journal of Ethnopharmacology, vol. 139, no. 1, pp. 6–11, 2012.

Protective effect of extract of Acanthopanax senticosus harms on dopaminergic neurons in Parkinson's disease mice. Phytomedicine, vol. 19, no. 7, pp. 631–638, 2012.

Antioxidant activities of Acanthopanax senticosus stems and their lignan components. Archives of Pharmacal Research, vol. 27, no. 1, pp. 106–110, 2004.

Quantitative determination of eleutherosides B and E from Acanthopanax species by high performance liquid chromatography. Archives of Pharmacal Research, vol. 24, no. 5, pp. 407–411, 2001.

Determination of eleutherosides B and E in various parts of Acanthopanax species. Korean Journal of Pharmacognosy, vol. 36, no. 2, pp. 70–74, 2005.

Analysis of lignans in Acanthopanax sessiliflorus fruits and their fermented wine by HPLC. Korean Journal of Medicinal Crop Science, vol. 14, pp. 289–292, 2006.

Quality control of roots of Eleutherococcus senticosus by HPLC. Phytochemical Analysis, vol. 16, no. 1, pp. 55–60,

Inhibitory effects of Eleutherococcus senticosus extracts on amyloid beta (25–35)-induced neuritic atrophy and synaptic loss. J Pharmacol Sci. 2008;3(107):329–339. [PubMed] [Google Scholar]

Active components from Siberian ginseng (Eleutherococcus senticosus) for protection of amyloid beta (25–35)-induced neuritic atrophy in cultured rat cortical neurons. J Nat Med. 2011;3–4(65):417–423. 

Anti-inflammatory effect of eleutheroside E from Acanthopanax senticosus. Foods Food Ingred J Jpn. 2006;7(211):576–582. 

The effect of Eleutheroside E on behavioral alterations in murine sleep deprivation stress model. Eur J Pharmacol. 2011;2–3(658):150–155. 

 Bioactivity-guided fractionation for anti-fatigue property of Acanthopanax senticosus. J Ethnopharmacol. 2011;1(133):213–219.

Beneficial effects of Panax ginseng for the treatment and prevention of neurodegenerative diseases: past findings and future directions. J Ginseng Res. 2018 Jul;42(3):239-247. doi: 10.1016/j.jgr.2017.03.011.

Therapeutic Potential and Cellular Mechanisms of Panax Notoginseng on Prevention of Aging and Cell Senescence-Associated Diseases. Aging Dis. 2017 Dec 1;8(6):721-739. doi: 10.14336/AD.2017.0724.

Taking a "good" look at free radicals in the aging process. Trends Cell Biol, 2011 21: 569-576

Metabolic syndrome, aging and involvement of oxidative stress. Aging Dis, 2015. 6: 109-120

Telomeres in aging and disease: lessons from zebrafish. Dis Model Mech, 2016 9: 737-748

Aging-Induced Stem Cell Mutations as Drivers for Disease and Cancer. Cell Stem Cell, 2015 16: 601-612

Ginsenosides

Ginseng contains many active ingredients including steroidal saponins, protopanaxadiols, and protopanaxatriols, collectively known as ginsenosides. In the last few decades, the antioxidative and anticancer effects of ginseng, in addition to its effects on improving immunity, energy and sexuality, and combating cardiovascular diseases, diabetes mellitus, and neurological diseases, have been studied in both basic and clinical research [1]

Active compounds of Panax quinquefolius (PQ) are ginsenosides, saponins of the glycosides group that are abundant in roots, leaves, stem, and fruits of the plant. Ginsenosides are suggested to be primarily responsible for health-beneficial effects of PQ ginsenosides. PQ ginsenosides acts on the nervous system; it was reported to improve the cognitive function in a mouse model of Alzheimer’s disease, display anxiolytic activity, and neuroprotective effects against neuronal damage resulting from ischemic stroke in animals, demonstrate anxiolytic activity, and induce neuroprotective effects against neuronal damage.

PQ ginsenosides displays anti-cancer effect by induction of apoptosis of cancer cells and reducing local inflammation. It exerts antimicrobial effects against several pathogenic strains of bacteria. Therefore, PQ ginsenosides presents a high potential to induce beneficial health effects in humans and should be further explored to formulate precise nutritional recommendations, as well as to assess its value in prevention and therapy of some disorders, including cancer [2].

Numerous preclinical studies have demonstrated the great potential of G-Rh2 in the treatment of a wide range of carcinomatous diseases in vitro and in vivo. G-Rh2 can inhibit proliferation, induce apoptosis and cell cycle arrest, retard metastasis, promote differentiation, enhance chemotherapy and reverse multi-drug resistance against multiple tumor cells. The present review mainly summarizes the anticancer effects and related mechanisms of G-Rh2 in various models as well as the recent advances in G-Rh2 delivery systems and structural modification to ameliorate its anticancer activity and pharmacokinetics characteristics [3].

Several in vitro, in vivo, and clinical studies suggest that ginseng has some degree of anti-inflammatory activity (see figure below) [4-6]. Dong-Hyun Kim et al found that ginsenosides Re and Rp1 can suppress the NF-κB signaling pathway [7]. In another study, Yu et al revealed that ginsenoside Rc can inhibit the expression of macrophage-derived cytokines [8.9]. Moreover, it can suppress the activation of tumor necrosis factor receptor-associated factor family member-associated NF-kappa-B activator (TANK)-binding kinase-1/IκB kinase ε/interferon regulatory factor-3 and p38/ATF-2 signaling in activated RAW264.7 macrophages, human synovial cells, and HEK293 cells [10]. In 2006, Rhule et al examined the immunomodulatory effects of a P. notoginseng extract on cultured macrophages (RAW264.7 cells) [and found that it inhibited the lipopolysaccharide (LPS)-induced production of tumor necrosis factor (TNF)-α and interleukin (IL)-6 in a concentration-dependent pattern [11]. Interestingly, a clinical study reported that patients who took ginseng after curative surgery had up to a 35% higher chance of disease-free living for 5 years and up to a 38% higher survival rate than those patients who did not take it [12].

Evidence for the medicinal and health benefits of Panax ginseng and its components in preventing neurodegeneration has increased significantly in the past decade. The beneficial effects of P. ginseng on neurodegenerative diseases have been attributed primarily to the antioxidative and immunomodulatory activities of its ginsenoside components. Mechanistic studies on the neuroprotective effects of ginsenosides revealed that they act not only as antioxidants but also as modulators of intracellular neuronal signaling and metabolism, cell survival/death genes, and mitochondrial function [11].

The most common treatment strategy in Alzheimer's disease involves acetylcholine (ACh), an important neurotransmitter in cognition and memory processes that is known to be decreased in Alzheimer's disease. Treatment options include the use of ACh precursors, ACh-releasing agents, and acetylcholinesterase (AChE) inhibitors [12]. Other therapeutic interventions, although with fewer proven beneficial effects, also involve antioxidative agents that scavenge free radicals and anti-inflammatory agents that treat the amyloid β cascade.

ginseng extracts have been reported to exert neuroprotective effects by ameliorating the advanced glycation end product-induced memory impairment and mitigating the Alzheimer-like pathophysiological changes through downregulation of the RAGE/NF-κB pathway [13]. Moreover, ginsenosides attenuated d-galactose- and aluminium chloride (AlCl3)- induced spatial memory impairment and Alzheimer-like pathophysiological changes in male Wistar rats through restoration of amyloid β formation, tau phosphorylation, and function of various neurotransmitters including glutamate (Glu), aspartate (Asp), gamma-aminobutyric acid (GABA), acetylcholine (ACh), dopamine (DA), glycine (Gly), and 5-hydroxytryptamine (5-HT) [14]. Ginsenosides are reported to improve memory loss in C57BL/6J mice with severe hippocampal damage and in aged SAMP8 mice (senescence-accelerated mouse) by upregulating plasticity-related proteins such as postsynaptic density protein-95 (PSD-95), gamma isotype of protein kinase C (PKCγ), and brain-derived neurotrophic factor (BDNF) [15].

Ginsenosides act not only as antioxidant metal chelators, but also as modulators of intracellular neuronal signaling and metabolism, cell survival/death genes, and mitochondrial function. It has been shown that ginsenosides modulate caspase-dependent and caspase-independent programmed cell death. Indeed, several ginsenosides significantly inhibit the activation of caspase-3, a key apoptotic player, and can modulate mitogen-activated protein kinases known to play an important role in neuronal apoptosis [15].

Panax notoginseng (PN) has been extensively employed in China to treat microcirculatory disturbances, inflammation, trauma, internal and external bleeding due to injury, and as a tonic [16]. Several major theories including the mitochondrial free radical theory [17], deregulated metabolic and immune responses [18], genetic and epigenetic regulation of aging, telomere shortening theory [19] and stem cell theory [20] are thought to play a significant role in aging. lowering the serum cholesterol and antioxidant therapy could prevent vascular aging and reduce the incidence of cardiovascular and cerebrovascular diseases [20]. Panax notoginseng has been used for the treatment of microcirculatory disturbances, inflammation, and internal and external bleeding due to injury.

Aging-induced immune senescence occurs in the brain as microglia senescence, which functions abnormally and promotes neurodegeneration [19,20] Panax notoginseng contains many active ingredients and is shown to have a role of anti-brain aging.

Panax quinquefolius saponin (PQS) is the main active component of Panax quinquefolius. Emerging evidence suggests that PQS exerts beneficial effects against cardiovascular diseases. The present study used calcification medium containing 3 mM inorganic phosphate (Pi) to induce rat VSMCs calcification. They investigated the effects of PQS on VSMCs calcification using alizarin red staining and alkaline phosphatase (ALP) activity assays. The intracellular reactive oxygen species (ROS) levels and the transcriptional activity of nuclear factor-erythroid 2-related factor 2 (Nrf2) were determined. The mRNA and protein expression levels of Nrf2, the antioxidant gene heme oxygenase-1 (HO-1), osteogenic markers, including runt-related transcription factor 2 (Runx2) and bone morphogenetic protein 2 (BMP2), and Kelch-like ECH-associated protein 1 (Keap1) were also measured.

Treatment with Pi significantly increased intracellular calcium deposition and ALP activity, which were suppressed by PQS in a concentration-dependent manner. During VSMCs calcification, PQS inhibited the mRNA and protein expression of Runx2 and BMP2. PQS treatment reduced intracellular ROS production and significantly upregulated Nrf2 transcriptional activity and the expression of Nrf2 and its target antioxidant gene HO-1. PQS suppressed the Pi-induced protein expression of Keap1, which is an endogenous inhibitor of Nrf2. Keap1 siRNA treatment induced Nrf2 expression and downregulated Runx2 expression in the presence of Pi and PQS.

Taken together, these findings suggest that PQS could effectively inhibit VSMCs calcification by ameliorating oxidative stress and regulating osteogenic genes via the promotion of Nrf2 expression. In summary, the results of the present study revealed that activation of Nrf2 signaling was likely a crucial pathway for the PQS-mediated inhibition of VSMCs calcification. PQS effectively inhibited VSMCs calcification by ameliorating oxidative stress and regulating osteogenic genes via the promotion of Nrf2 expression. Therefore, PQS against oxidative stress may offer a greater therapeutic benefit for vascular calcification with an improved side-effect profile [21]

Reference

References

Pharmacological potential of ginseng and its major component ginsenosides. J Ginseng Res. 2021 Mar;45(2):199-210. doi: 10.1016/j.jgr.2020.02.004.

American Ginseng (Panax quinquefolium) as a Source of Bioactive Phytochemicals with Pro-Health Properties. Nutrients. 2019 May 9;11(5):1041. doi: 10.3390/nu11051041. 

Potential of ginsenoside Rh2and its derivatives as anti-cancer agents. Chinese Journal of Natural Medicines. Volume 20, Issue 12, December 2022, Pages 881-901. https://doi.org/10.1016/S1875-5364(22)60193-6

Role of ginsenosides, the main active components of Panax ginseng, in inflammatory responses and diseases. J Ginseng Res. 2017;41:435–443.

Antinociceptive and anti-inflammatory effects of ginsenoside Rf in a rat model of incisional pain. J Ginseng Res. 2018;42:183–191.

Ginsenoside Rg3 promotes inflammation resolution through M2 macrophage polarization. J Ginseng Res. 2018;42:68–74.

Ginsenoside Rc from Panax ginseng exerts anti-inflammatory activity by targeting TANK-binding kinase 1/interferon regulatory factor-3 and p38/ATF-2. J Ginseng Res. 2017;41:127–133.

Ginsenoside Rc from Panax ginseng exerts anti-inflammatory activity by targeting TANK-binding kinase 1/interferon regulatory factor-3 and p38/ATF-2. J Ginseng Res. 2017;41:127–133.

AKT-targeted anti-inflammatory activity of Panax ginseng calyx ethanolic extract. J Ginseng Res. 2018;42:496–503.

Panax notoginseng attenuates LPS-induced pro-inflammatory mediators in RAW264. 7 cells. J Ethnopharmacol. 2006;106:121–128.

The immunomodulator ginsan induces resistance to experimental sepsis by inhibiting Toll-like receptor-mediated inflammatory signals. Eur J Immunol. 2006;36:37–45.

Beneficial effects of Panax ginseng for the treatment and prevention of neurodegenerative diseases: past findings and future directions. J Ginseng Res. 2018 Jul;42(3):239-247. doi: 10.1016/j.jgr.2017.03.011

Ginseng improves cognitive deficit via the RAGE/NF-κB pathway in advanced glycation end product-induced rats. J Ginseng Res. 2015;39:116–124.

Ginsenosides attenuate d-galactose-and AlCl 3-inducedspatial memory impairment by restoring the dysfunction of the neurotransmitter systems in the rat model of Alzheimer's disease. J Ethnopharmacol. 2016;194:188–195.

Long-term ginsenoside consumption prevents memory loss in aged SAMP8 mice by decreasing oxidative stress and up-regulating the plasticity-related proteins in hippocampus. Brain Res. 2009;1256:111–122

Therapeutic Potential and Cellular Mechanisms of Panax Notoginseng on Prevention of Aging and Cell Senescence-Associated Diseases. Aging Dis. 2017 Dec 1;8(6):721-739. doi: 10.14336/AD.2017.0724.

Taking a "good" look at free radicals in the aging process. Trends Cell Biol, 2011 21: 569-576

Metabolic syndrome, aging and involvement of oxidative stress. Aging Dis, 2015 6: 109-120

Telomeres in aging and disease: lessons from zebrafish. Dis Model Mech, 2016 9: 737-748

Aging and Neurodegeneration: A Tangle of Models and Mechanisms. Aging Dis, 7: 111-113

Panax quinquefolius saponin inhibits vascular smooth muscle cell calcification via activation of nuclear factor-erythroid 2-related factor 2. BMC Complement Med Ther 23, 129 (2023). https://doi.org/10.1186/s12906-023-03961-6

Additional information: Chemotherapy

Cyclophosphamide (CTX), used in cancer chemotherapy, a high dose of which would cause immunosuppressive effect and intestinal mucosa damage. American ginseng (Panax quinquefolius L.) has a long history of functional food use for immunological disorder, colitis, cancer, and so on. This study aimed to illustrate the underlying mechanism of American ginseng's immunomodulatory effect in CTX-induced mice.

The synergistic effect of polysaccharides and ginsenosides (AGP_AGG group) restored the gut microbiota composition and increased various beneficial mucosa-associated bacterial taxa Clostridiales, Bifidobacterium, and Lachnospiraceae, while decreased harmful bacteria Escherichia-Shigella and Peptococcaceae. Also, AGP_AGG group altered various fecal metabolites such as uric acid, xanthurenic acid, acylcarnitine, 9,10-DHOME, 13-HDoHE, LysoPE15:0, LysoPC 16:0, LysoPI 18:0, and so on, that associated with immunometabolism or protective effect of gut barrier. These results suggest AG, particularly co-treated of polysaccharide and ginsenoside may be used as immunostimulants targeting microbiome-metabolomics axis to prevent CTX-induced side effects in cancer patients.

Reference

The Synergistic Effects of Polysaccharides and Ginsenosides from American Ginseng (Panax quinquefolius L.) Ameliorating Cyclophosphamide-Induced Intestinal Immune Disorders and Gut Barrier Dysfunctions Based on Microbiome-Metabolomics Analysis. Front Immunol. 2021 Apr 22;12:665901. doi: 10.3389/fimmu.2021.665901.

Figure 1 - Free radical scavenging activity of ginseng as an antioxidant

Figure 2 Anti-inflammatory, NF-kB, AP-1, iNOS, COX-2, IL-6