Ginseng's hidden gems: Rare ginsenosides emerge as potent players in the future of medicine

In a recent review published in the Journal of Advanced Research, researchers summarized the structural and functional characteristics, traditional and modern applications, mechanisms of action, toxicity, and current production strategies of rare ginsenosides (RGs). RGs are the deglycosylated secondary metabolic derivatives of major ginsenosides, bioactive compounds obtained from Panax ginseng.

This review encapsulates more than 350 publications on these compounds and reveals that 144 RGs have been discovered with clinical applications, including immunoregulatory, anti-aging, anti-cancer, cerebrovascular, and cardiovascular. This work further explores the advances in large-scale production of RGs and may form the basis for future research into the applications of these remarkable compounds.

Review: Rare ginsenosides: a unique perspective of ginseng research. Image Credit: Light Stock / ShutterstockReview: Rare ginsenosides: a unique perspective of ginseng research. Image Credit: Light Stock / Shutterstock

Novel knowledge for an ancient medicine

Gingseng is the common name for the root of plants from the genus Panax. It has been used in traditional Chinese and Korean medicine and cuisine for thousands of years to treat chronic ailments ranging from erectile dysfunction to memory loss. However, due to inconsistencies in modern clinical research, the use of ginseng and its extracts remains contentious, and the plant has yet to receive approval from the United States (US) Food and Drug Administration (FDA) as a prescription drug.

Ginsenosides are a class of dammarane-type triterpenoids obtained from any of the three ginseng species – Panax ginseng, P. notoginseng, or P. quinquefolius, and comprise the majority of clinically and pharmacologically beneficial metabolites of these herbs. Based on their relative abundance, ginsenosides are divided into the significantly more abundant primary (macro) saponins and the rare ginsenosides (RGs), which are naturally found in concentrations less than 0.1% by volume. RGs are industrially produced from primary saponins via processes including steaming, microbial transformation, and acid/alkali treatment.

Until the last decade, most research on the clinically relevant effects of ginseng and its products focused on primary saponins, predominantly due to RGs seemingly having poor in vivo bioavailability. Recent research, however, challenged this notion and revealed that the discrepancies between the potential pharmacological effects of RGs and their poor in vivo performance are due to intestinal microbiome-mediated digestion. This opened the floodgates of studies into RG's potential medical benefits, most notably treating cancers, cerebrovascular diseases, and cardiovascular ailments.

While research on RGs has been rapidly growing, a review summarizing the holistic effects of these compounds remains lacking. The present review aims to bridge this gap by synthesizing available information on RG research archived in the Web of Science core collection between 2001 and 2021.

Classification of ginsenosides and their production

Recent bioprospecting refinements have revealed more than 500 Panax genus saponins, most of which are primary saponins. While naturally occurring RGs are limited in number, advances in natural product chemistry have discovered 144 RGs derived from primary saponins via transformations including steaming, bio-, and chemical transformations. Encouragingly, these processes rely on the stems and leaves of ginseng as their raw materials, which is cost-effective given that, historically, ginseng roots have been the most expensive herb components.

High temperature steaming allowed for the identification of Rk1, Rg5, Rg6, F4, 20(R/S)-Rs3, Rh4, Rs5, 20(R/S)-Rg3, Rk3, and Rs4. However, the yield and quality of obtained RGs depend upon temperature and time, making acid/alkali chemical transformation the more reliable method for batch RG production.

"Strong acid hydrolysis shows a higher conversion efficiency, leading to not only deglycocylation of ginsenosides, but also the side chain derivatization such as dehydration, cyclization, and double bond displacement, especially configuration inversion at C-20 of aglycones. In contrast, alkali hydrolysis has the advantages of high conversion, mild reaction conditions which cause no epimerization and no cyclization of the side chain."

Most recently, biotransformation by microorganisms is being explored as the next step in RG production, given its environmental benefits. Thus far, K, Rh2, Mc, F2, F1, and aglycones have been successfully produced using microorganisms or their enzymes.

Pharmacological benefits

Traditionally, red ginseng P. ginseng has documentation of use for almost 2000 years since its description in the famous Bencao Mengquan, a traditional Chinese medicine (TCM) monograph. Now known to be rich in RGs (via steaming), the herb was valued for its observed pharmacological effects, including immunity boosting, memory improvement, and fatigue relief. More recent investigations have revealed that derivatives of red ginseng present potent anti-cancer, cognitive improvement, and cardiovascular disease-fighting effects.

A clinical trial of 228 hepatocellular carcinoma (HCC) patients revealed that the rare ginsenoside Rg3 improved overall survival from 10.1 months to 13.2 months, most likely via vascular endothelial growth factor (VEGF) inhibition. Clinical trials on the cardiovascular benefits of red ginseng similarly revealed that herb extracts improved coronary flow reserve (CFR) and increased circulating angiogenic cells, thereby combatting acute myocardial infarction (AMI). Studies on patients with Alzheimer's disease showed that daily red ginseng extract consumption significantly improved Alzheimer's disease assessment scale (ADAS) scores and reduced clinical dementia.

"Rare ginsenosides also showed clinical potential for other diseases such as liver dysfunction, physical performance deficiency. In addition, the clinical pharmacokinetics study provided the evidence for drug administration, for instance, the plasma concentration of ginsenoside Rh2 reached steady state after oral administration of Rh2 twice daily for 5 days, which supported the twice-a-day dosing regimen."

Mechanisms of action

Research has identified numerous potential targets of RGs. Bile acid receptors, steroid hormone receptors, and platelet adenosine diphosphate (ADP) receptors have been independently elucidated, lending support to the characteristically claimed "adaptogen-like effect" of ginseng. This effect postulates that ginseng and its extracts can support homeostasis by up or down-regulating somatic imbalances from both internal and external disruptors.

"The genus name of Panax derived from "panacea" (heal-all diseases) may represent the ancient cognition of those herbs. The bidirectional regulation of immune system was considered undoubtedly as the peculiar way of ginseng and ginseng-related products participated in complex pharmacological network."

Surprisingly, in addition to their pharmacological and clinical benefits, RGs have been proven to have anti-aging properties in murine models via mechanisms of acetylcholinesterase (AChE) and malondialdehyde (MDA) suppression and superoxide dismutase (SOD) and catalase (CAT) overexpression in mice. Similarly, F1 and Rg3 were found to delay senescence (cell aging) by reducing NF-κB activation, thereby preventing oxidative aging and improving mitochondrial function.

Why take the trouble to produce RGs? Why not just use natural ginseng?

"The steamed P. ginseng, P. notoginseng, and P. quinquefolius showed superior efficacy in the treatment of cancer, CVDs, and cognitive disorders than raw ones, which were attributed to the production of rare ginsenosides."

Numerous studies have validated that RGs comprise most of natural ginseng's health and clinical benefits. Unfortunately, ginseng roots are expensive and contain less than 0.1% of RGs, necessitating the bulk production of the compounds. The added benefit of industrial-scale RG production is that ginseng leaves and stems are used – these components are traditionally considered waste and usually discarded, making their use in RG production cost-effective and environmentally beneficial.

What about toxicity? Are RGs safe?

While human clinical trials are scarce, research on animals has shown that ginseng extracts are generally safe at clinically administered concentrations. Even when these concentrations are exceeded or during long-term use, most side effects are temporary and can be reversed by dosage reductions. Human clinical trials are required to confirm these findings, but the centuries-long recommendations of traditional Chinese and Korean medicine imply that the benefits of the herb far outweigh any potential side effects of its overuse.

Challenges for the future

Future research should aim to investigate the specific protein targets of RGs, essential for their medically approved use in anti-cancer and cardiovascular therapies. Similarly, the role and extent of gut microbial transformations of ginseng extracts must be established before recommended clinical dosages of RGs can be evaluated. Finally, hitherto, microbial transformations of primary ginsenosides have remained in the lab-testing stage, with chemical transformations prevalent at the industrial scale. Upscaling these microbial and enzymatic methods would allow for safer and more environmentally conscious RG batch productions, bringing RGs to the forefront of future therapeutic interventions.

Journal reference:
Hugo Francisco de Souza

Written by

Hugo Francisco de Souza

Hugo Francisco de Souza is a scientific writer based in Bangalore, Karnataka, India. His academic passions lie in biogeography, evolutionary biology, and herpetology. He is currently pursuing his Ph.D. from the Centre for Ecological Sciences, Indian Institute of Science, where he studies the origins, dispersal, and speciation of wetland-associated snakes. Hugo has received, amongst others, the DST-INSPIRE fellowship for his doctoral research and the Gold Medal from Pondicherry University for academic excellence during his Masters. His research has been published in high-impact peer-reviewed journals, including PLOS Neglected Tropical Diseases and Systematic Biology. When not working or writing, Hugo can be found consuming copious amounts of anime and manga, composing and making music with his bass guitar, shredding trails on his MTB, playing video games (he prefers the term ‘gaming’), or tinkering with all things tech.

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