Rg3 : a rising star in the ginseng world
1. PANAX GINSENG & GINSENOSIDES
Asian ginseng is one of the most famous medicinal plants in the world. Praised for a myriad of health benefits, its roots are widely consumed for nutraceutical and therapeutical purposes. The potency of ginseng root is linked to the presence of specific molecules. Among them, ginsenosides are recognised as the main active constituents. Consequently, ginsenosides content is considered to be a key aspect of ginseng quality and performance.
However, the nature of ginsenosides is equally important. Indeed, not every ginsenoside are "born equal" in terms of potency. For instance, if Rb1 and Rg1 are considered as the most common ginsenosides, they show poor bioavailability. Yet, they are precursors of more bioactive ginsenosides (like Rg3) and are partially converted by gut microflora (ex: Rb1 is converted in Rg3). Alternatively, ginsenosides can be transformed by drying, cooking and other processes. For instance, the steam cooking process applied to produce red ginseng, converts some ginsenosides into more bioavailables ones. It is also true for the process of black ginseng (cooked nine times) that is promoted as a more bioactive version of red ginseng due to a higher convertion rate [1-2].
2. Rg3: A COVETED MOLECULE
2.1. Rg3: a rare ginsenoside
Due to its high health potential, Rg3 is one of the rising star among ginsenosides. Unfortunately, if Rb1 or Rg1 are considered to be ubiquitous, Rg3 is considered to be a rare (frequently called "rares ginsenosides" or "nobles ginsenosides" in the litterature). In fact, Rg3 is almost absent from white ginseng and is generally exclusive of premium cooked ginseng. Wild ginseng is also considered to be more effective than field ginseng through a better ginsenoside profile, however, this depends on growth conditions (some wild ginseng are poor in ginsenosides of interest and some cultivated ginseng are good).
2.2. Ginsenosides bioconversion
As explained before, Rb1 can be "bioactivated" in Rg3 by the gut microflora. However, depending on the microbiota, the converted fraction can be quite low, leading to poor bioavailability and consequently poor health benefits. Due to the rise of interest for the nutraceutical and therapeutical potential of Rg3, it is now highly coveted. Indeed, a lot of energy is devoted to find ways to "bioactivate" classical ginsenosides Rg3.
The investigations about conversion processes involve cooking optimisations. As mentioned, the black ginseng trend is based on this principle. Ginseng fermentation is also an emerging trend that opens the opportunity to "bioactive" ginsenosides [3-4].
More recently, tuning of growth conditions through indoor vertical farming is appearing as an opportunity to optimise ginsenosides content. Combined with cooking optimisation, it leads to the development of ideal ginsenosides profiles with strong nutraceutical and therapeutical potentials.
3. NUTRACEUTICAL POTENTIAL OF Rg3
Ginseng is traditionally considered as a natural tonic. Unsurprisingly, it is widely found in energizing food and beverage. These ergogenic and anti-fatigue effects can, at least partially, be explained by the activity of Rg3. Indeed, Rg3 has been reported to have positive impact on fatigue, both from a metabolic standpoint  and a neurological perspective . Moreover, Rg3 has been reported to "mimic exercise training" on cardiac mitochondrial system , offering new opportunities for sport nutrition.
3.2. Immune booster
In European pharmacies, ginseng is usually combined with vitamins for products destined to support natural defenses against "common cold". This use seems to be related, in part, to Rg3 which has has been reported to not only to potentiate immune response, but also to inhibit virus infection.
Indeed, Rg3 has be highlighted as an immune booster [8-10] to the point that it was even evaluated in a chemotherapy context to support immune defenses recovery [11-12]. It has also been identified as an inhibitor of virus infection [13-16]. Combined with the data on ergogenic properties, Rg3 becomes a true "health booster".
In Shénnóng běncǎo jīng, ginseng benefits are described as follow: "Consumed over a long time, it lightens the body and extends the years". Since then, ginseng roots are considered as a medicinal plant for longevity. Neuroprotection is therefore a core element in ginseng neurological properties.
According to existing data, not only does Rg3 show neuroprotective properties [17-24] but it also has been identified as a "shield" against cognitive deterioration in multiple experimental models [25-26]. Finally, the benefits of Rg3 on Alzheimer related mechanisms is also really promising [27-30].
3.4. Stress & anxiety
Ginseng is rarely considered as a first choice for stress management. However, numerous ginsenosides have shown positive effects on anxiety and depression models. Rg3 is no exception and has been identified as beneficial in multiple experiments [31-36]. Interestingly, Rg3 has shown quicker and stronger effect at lower dosage compared to other ginsenosides , illustrating one more time the fact that Rg3 can be considered as a "bioactivated" form of ginsenoside. Finally, it should be noted that Rg3 has been identified as an activator of GABAergic pathway  which opens opportunities for products destined to sleep. It should be noted that a growing number of data seem to correlate the anti-stress effect with the nootropic action of ginseng.
Menopause is a complex phenomenon with potential adverse effects (irritability, sleep troubles, hot flashes, etc.) and associated with increased risks of cardiovascular issues, osteoporosis, metabolic syndrom, depression, etc. Even if ginseng is not traditionally considered as an asset on this matter, clinical data indicate that ginseng could be a great asset in supporting menopausal women [39-40]. Moreover, some highlighted biological properties of Rg3 suggest that it could bring an even more global support.
On one hand, Rg3 could potentially be beneficial in case of hypertension (a frequent condition in menopausal women)  and has been identified as cardioprotective  and vasculoprotective . It also has been identified in experimental models as beneficial in cases of atherosclerosis [44-45]. On the other hand, Rg3 seems to have beneficial effect on osteoporis-related mechanisms [46-48].
4. THERAPEUTIC PERSPECTIVES OF Rg3
But, beyond nutraceutical benefits, the real cause of "Rg3 rush" is more than probably related to its potential therapeutical properties.
Ginseng is usually considered in phytotherapy to have a balancing effect on blood sugar. Scientific data on Rg3 seem to not only validate this virtue [49-52] but also to have potential benefits on complications related to the condition [53-56]. Obviously, this does not means that Rg3 is a treatment against diabetes. However, these results invites to consider it as a adjuvant treatment or a support tool for glycemic balance.
Oncology is probably the most studied topic for Rg3. It would be too long to make a exhaustive compendium of every cancer model where Rg3 where evaluated (see main examples below). Even from a general perspective, Rg3 is involved through many physiological processes (Epigenetical impact , Angiogenesis inhibition , etc.). Its interest has been evaluated in lots of different cancer models:
- Colon Cancers: Rg3 has shown fascinating results on different cell lines of colon cancers. The identified effects range from direct antiproliferative effects [59-62] to inhibition of angiogenesis  and migration [64-65]. Rg3 has also been shown to potentiate treatments like docetaxel  or radiotherapy .
- Breast Cancers: Rg3 has been reported to have significant impact on different breast cancer models [68-70] (including triple negative ) through multiple mechanisms [72-73]. Like data on colon cancer, that includes impact on migration  and potantiation of treatments like paclitaxel  or capecitabine .
- Liver Cancers: Rg3 has been evaluated in the context of liver cancers through different models. Like other types of cancer described above, Rg3 seems to inhibit proliferation/stimulate apoptosis of cancer cells [77-82], limit migration  and potentiate treatments like sorafenib  and Doxorubicin .
- Lung Cancers: Rg3 has shown results in lung cancers [86-87] including impact on invasiveness [88-90]. Moreover, there is a lot of studies on the potentiation of other treatment using Rg3 like osimertinib , icotinib , gefitinib , cisplatin [94-95], gemcitabine , cyclophosphamide  and even radiation treatment .
These are only some examples among many other like skin cancers [99-103], ovarian cancers [104-108] or brain cancers [109-112]. Like the data on diabetes, this does not mean that Rg3 can be considered as a cancer treatment. However, the health potential of the molecule begs to investigate the opportunity of using it to support patients.
Rg3 is widely considered as the flagship molecule of Panax ginseng roots both for nutraceutical and therapeutical applications. However, even if it is present in very limited quantities in red ginseng and in reasonnable quantities in black ginseng, Rg3 is still a rare ginsenoside. Based on this premise, a lot of industrial actors are looking to produce pure Rg3 by other means, thereby giving up on the beneficial properties of other constituents of ginseng roots.
BOTALYS is exploring another path. By applying a unique indoor vertical farming approach to ginseng culture, it has total control over growth conditions and has optimized them to produce a red ginseng naturally rich in Rg3 (>15 mg/g) among other rare ginsenosides like Rg5 & Rk1.
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