Product name: Ginsenoside Rh3
Synonym name:
Catalogue No.: BP0669
Cas No.: 105558-26-7
Formula: C₃₆H₆₀O₇
Mol Weight: 604.869
Botanical Source: Panax ginseng
Physical Description: White powder
Type of Compound: Triterpenoids

Purity: 95%~99%
Analysis Method: HPLC-DAD or/and HPLC-ELSD
Identification Method: Mass, NMR
Packing: Brown vial or HDPE plastic bottle

Storage: Store in a well closed container, protected from air and light. Put into refrigerate or freeze for long term storage.
Whenever possible, you should prepare and use solutions on the same day. However, if you need to make up stock solutions in advance, we recommend that you store the solution as aliquots in tightly sealed vials at -20℃. Generally, these will be useable for up to two weeks.

The product could be supplied from milligrams to grams, up to kilograms
Inquire for bulk scale.

Descriptions:
Ginsenoside Rh3 is a bacterial metabolite of Rg5, which is the main constituent of heat-processed ginseng, has anti-inflammatory effect in microglia by modulating AMPK and its downstream signaling pathways.[1]
Ginsenosides Rh3 and Rg5 can suppress swelling of oxazolone-induced mouse ear contact dermatitis, they also reduce mRNA expressions of cyclooxygenase-2, interleukin (IL)-1β, tumor necrosis factor (TNF)-α and interferon (IFN)-γ; the inhibition of ginsenoside Rh3 was more potent than that of ginsenoside Rg5, suggests that ginsenoside Rh3 metabolized from ginsenoside Rg5 may improve chronic dermatitis or psoriasis by the regulation of IL-1β and TNF-α produced by macrophage cells and of IFN-γ produced by Th cells.[2]
Ginsenoside-Rh2 and Rh3 can induce differentiation of HL-60 cells into granulocytes and modulation of PKC isoform levels may contribute to differentiation of HL-60 cells by G-Rh2.[3]
Ginsenosides Rg5 and Rh3 inhibit acetylcholinesterase activity in a dose-dependent manner, with IC50 values of 18.4 and 10.2 uM, respectively; the inhibitory potency of ginsenoside Rh3 is comparable with that of donepezil (IC50=9.9 uM); ginsenoside Rh3 can potently protect memory deficit; suggests that they may protect memory deficit by inhibiting AChE activity and increasing BDNF expression and CREB activation.[4]


References:
[1] Lee Y Y, Park J S, Lee E J, et al. J Agr Food Chem, 2015, 63(13):3472-80.
[2]Yong W S, Bae E A, Dong H K. Arch Pharm Res, 2006, 29(8):685-90.
[3] Kim Y S, Dong S K, Kim S I. Int J Biochem Cell Biol, 1998, 30(3):327-38.
[4] Kim E J, Jung I H, Le T K V, et al. J Ethnopharmacol, 2013, 146(1):294-9.
[5] Wang J Y, Li X Q,Yang X Q. Chinese Herbal Medicine,2008 (02): 225-6.

Storage conditions：Short-term storage at 2~8℃, long-term storage at -20 ~ -80℃

Introduction/Overview

As a traditional precious Chinese medicinal herb, ginseng's pharmacological activity lies in a class of structurally diverse triterpenoid saponins - ginsenosides. With the advancement of separation and identification techniques, numerous rare ginsenosides have gradually been discovered, among which ginsenoside Rh3 (CAS: 105558-26-7), as a metabolic product of the original ginsenoside Rg5 after intestinal microbiota or in vitro biotransformation, has attracted much attention due to its unique chemical structure and significant biological activity. Early studies have revealed that it can effectively activate nuclear factor E2 related factor 2 (Nrf2) in human retinal cells, suggesting its strong antioxidant stress potential. In recent years, the research focus has further expanded to the field of metabolic diseases, especially in improving insulin resistance, showing multi-target regulatory characteristics involving multiple key signaling molecules such as CDC25B, PTPN1, STAT3, SIRT1, etc. This article aims to systematically review the chemical properties, sources, pharmacological activities, molecular mechanisms of action, and medicinal properties of ginsenoside Rh3, in order to provide scientific basis for the deep development and clinical application of this natural product.

Chemical structure and physicochemical properties

The molecular formula of ginsenoside Rh3 is C36H60O7, with a molecular weight of 604.8690. Its chemical structure belongs to the dammarane type tetracyclic triterpenoid saponin, which is a derivative of protopanaxadiol (PPD) type saponins. Specifically, it is composed of hydrophobic glycosides (PPD type) and hydrophilic glycosides, with the sugar chain typically connected to the C-3 position of the glycosides. However, compared to common saponins, it has fewer glycosides or its structure has been modified, which directly affects its physicochemical properties.

From the analysis of parameters related to medicinal properties, ginsenoside Rh3 exhibits typical natural saponin compound characteristics. The logarithmic (LogP) value of its lipid water partition coefficient is 4.9508, indicating that the compound has a moderately high lipophilicity, which is beneficial for its penetration of cell membranes, but may also affect its dispersion in the aqueous phase. Its topological polar surface area (TPSA) is 119.6100 Å ², reflecting the size of the polar regions (mainly from hydroxyl and glycosyl oxygen atoms) in the molecule. The water solubility data is 0.0042 (usually measured in mg/mL or mol/L, which is a relative or specific value under certain conditions), confirming its extremely low water solubility, which is one of the main challenges faced by most ginsenosides in formulation development. These physical and chemical properties collectively determine its absorption, distribution, and metabolic behavior in living organisms.

Plant sources and extraction methods

Ginsenoside Rh3 has extremely low content in natural ginseng, American ginseng and other plants of the Araliaceae family, and belongs to rare ginsenosides. Its main source is not directly extracted from plants, but obtained through the following two ways:

1. Biotransformation method This is currently the most important and effective method for obtaining ginsenoside Rh3. The precursor substance ginsenoside Rg5 has been generated during the steaming and processing of ginseng (such as red ginseng preparation), but its content is still limited. By using specific microorganisms (such as intestinal bacteria, fungi) or enzyme preparations to carry out targeted biotransformation of relatively abundant main saponins (such as Rb1, Rc, Rd) or Rg5, Rh3 can be efficiently and specifically obtained. This method has mild conditions and high selectivity, making it an important strategy for large-scale preparation of rare saponins.

2. Chemical synthesis and semi synthesis Ginsenoside Rh3 can be synthesized by selectively linking sugar groups through chemical methods using original ginsenediol or related sapogenins as starting materials. However, this method is cumbersome in steps, difficult to control stereoselectivity, and costly. Currently, it is mainly used for the preparation of standard samples and structural modification research.

3. Direct extraction and separation Directly extracted from processed products such as red ginseng, but with extremely low yield. Usually, alcohol (such as methanol, ethanol) reflux extraction is used. After concentration, the extract is separated and purified systematically using macroporous adsorption resin column chromatography, silica gel column chromatography, reverse phase high performance liquid chromatography (RP-HPLC), or high-speed countercurrent chromatography (HSCCC), etc., ultimately obtaining high-purity ginsenoside Rh3 monomer.

Pharmacological activity research

The pharmacological activity research of ginsenoside Rh3 has expanded from its initial antioxidant activity to multiple fields such as anti-inflammatory, anti-tumor, neuroprotective, and metabolic regulation. Among them, research on improving insulin resistance and related metabolic disorders is particularly prominent.

1. Improve insulin resistance and anti diabetes activity Numerous in vitro and animal model studies have shown that ginsenoside Rh3 can significantly improve insulin sensitivity. In insulin resistant liver cell, adipocyte, and skeletal muscle cell models, Rh3 treatment can promote glucose uptake, reduce fasting blood glucose, and improve glucose tolerance. Its function is closely related to regulating fat metabolism, reducing lipid accumulation, and inhibiting chronic low-grade inflammation.

2. Antioxidant and Nrf2 activation activity As a classic Nrf2 activator, ginsenoside Rh3 can induce Nrf2 translocation from the cytoplasm to the nucleus, thereby upregulating the expression of phase II detoxifying enzymes and antioxidant proteins such as heme oxygenase-1 (HO-1) and quinone oxidoreductase 1 (NQO1), clearing reactive oxygen species (ROS), and protecting various cells such as retinal cells, neurons, and liver cells from oxidative stress damage.

3. anti-inflammatory effect Rh3 can inhibit the overexpression of pro-inflammatory cytokines (such as TNF - α, IL-6, IL-1 β) induced by inflammatory stimuli such as lipopolysaccharide (LPS), and its mechanism involves the regulation of classic inflammatory signaling pathways such as NF - κ B and MAPK.

4. Antitumor activity: Studies have shown that ginsenoside Rh3 can inhibit the proliferation and induce apoptosis of a variety of cancer cells (such as colon cancer, lung cancer, breast cancer), and can enhance the sensitivity of some chemotherapy drugs. Its mechanism is related to cell cycle arrest, activation of apoptosis pathway and inhibition of tumor related signal pathways.

5. Neuroprotective effect In addition to its antioxidant pathway, Rh3 may also exhibit protective effects in neurodegenerative disease models such as Alzheimer's disease and Parkinson's disease by regulating neurotransmitters, inhibiting neuroinflammation, and reducing mitochondrial dysfunction.

Mechanism of action and molecular targets

The pharmacological activity of ginsenoside Rh3 in improving insulin resistance depends on its diverse regulation of complex cellular signaling networks. Existing research has identified multiple key molecular targets:

1. Insulin signaling pathway related targets：

   • PTPN1 (protein tyrosine phosphatase 1B)PTPN1 is a key negative regulator of insulin signaling, which dephosphorylates insulin receptors and their substrates, terminating signal transduction. Rh3 may enhance insulin receptor tyrosine phosphorylation and promote insulin signaling by inhibiting PTPN1 activity.
   • STAT3 (Signal Transduction and Transcription Activation Factor 3)Chronic STAT3 activation is closely related to insulin resistance and inflammation. Rh3 may regulate the phosphorylation status of STAT3, inhibit its abnormal activation, improve insulin sensitivity, and alleviate inflammation.
   • PRKCA/CD (protein kinase C alpha/delta subtypes)A high sugar and high-fat environment can activate PKC, especially PKC - α and PKC - δ, thereby interfering with insulin signaling. Rh3 may restore the normal function of the insulin signaling pathway by inhibiting the activity of these PKC subtypes.

2. Metabolic and energy sensing regulatory targets：

   • SIRT1 (Silent Information Regulatory Factor 1)SIRT1 is an NAD+- dependent deacetylase involved in energy metabolism, inflammation, and stress response. Rh3 may activate SIRT1, which in turn deacetylates and activates downstream factors such as PGC-1 α and FOXO1, promoting mitochondrial biosynthesis, fatty acid oxidation, and gluconeogenesis inhibition, comprehensively improving metabolic homeostasis.
   • NR1H4 (farnesol X receptor, FXR）As a bile acid receptor, FXR plays an important role in regulating glucose and lipid metabolism. Rh3 may act as a regulator of FXR, affecting the expression of hepatic glucose and lipid metabolism genes.
   • SHBG (Sex Hormone Binding Globulin)The level of SHBG in the blood is negatively correlated with the risk of insulin resistance. Rh3 may affect the level or function of SHBG through some mechanism, indirectly improving metabolic status.

3. Core targets of antioxidant stress：

   • NFE2L2（Nrf2）As mentioned earlier, Rh3 is an effective activator of Nrf2. By activating the Keap1-Nrf2-ARE pathway, we enhance cellular antioxidant defense capabilities and alleviate oxidative stress damage to the insulin signaling pathway.

4. Other related targets：

   • CDC25B (Cyclin 25B)Related to cell cycle regulation, it may play a role in the anti-tumor activity of Rh3, or participate in metabolic regulation by affecting the proliferation of metabolically active cells.
   • ABCB1 (P-glycoprotein)As a drug efflux pump, its regulation may affect the pharmacokinetics of Rh3 itself or the efficacy of other drugs, especially in the study of tumor multidrug resistance.

These targets do not exist in isolation, but form an interconnected network. For example, SIRT1 activation can enhance PGC-1 α activity and inhibit NF - κ B, while also interacting with the Nrf2 pathway; Inhibition of PTPN1 and abnormal PKC activity can directly enhance insulin signaling. Ginsenoside Rh3 synergistically improves insulin resistance and regulates overall metabolism through this "multi-target, fine-tuning" mode.

Evaluation of drug properties and pharmacokinetics

Based on the provided parameters and existing research, the preliminary evaluation of the pharmacological properties of ginsenoside Rh3 is as follows:

• Absorption and distribution Moderate LogP values and low TPSA suggest that it has certain membrane permeability, which is beneficial for oral absorption. However, the extremely low water solubility is the main limiting factor for its oral bioavailability, which may require the use of solubilization technologies such as nanomaterials, phospholipid complexes, and cyclodextrin inclusion complexes. The prediction of "blood-brain barrier: low" suggests that it may be difficult to freely enter the central nervous system through the blood-brain barrier, which may pose a challenge to the action of central targets, but also reduces the potential risk of central side effects.
• Metabolism and excretion As a saponin compound, it may undergo metabolic processes such as hydrolysis (deglycosylation), oxidation, and binding in the body to generate aglycones or other secondary metabolites. The metabolism of gut microbiota is a key step in the conversion of its precursor Rg5 to Rh3, and it is also one of its important activation pathways.
• Preliminary Safety Assessment According to the data, "hERG inhibition: No" means that in existing predictive models, it does not inhibit hERG potassium channels, indicating a lower risk of causing QT interval prolongation and apical torsion type ventricular tachycardia. Ames test: 0.0 "usually indicates that no mutagenicity has been shown in the standard Ames test, and the preliminary genetic toxicity risk is low. But this still requires complete preclinical toxicology studies to confirm.
• Current status of pharmacokinetic research Currently, there are relatively few reports on pharmacokinetic studies of the ginsenoside Rh3 system. Limited animal studies have shown that its oral absorption is slower, plasma concentration is lower, it is widely distributed, and metabolism is faster. Its absolute bioavailability needs to be accurately determined. Developing appropriate drug delivery systems and dosage forms is key to improving their pharmacokinetic properties.

Clinical application prospects and prospects

Ginsenoside Rh3 exhibits broad clinical application potential, especially in the field of metabolic diseases:

1. Type 2 diabetes and insulin resistance syndrome As a multi target insulin sensitizer and antioxidant anti-inflammatory agent, Rh3 is expected to be developed as a new type of anti diabetes drug or dietary supplement to improve blood sugar control, reduce the burden of pancreatic islet β cells and prevent and treat complications of diabetes.
2. Non alcoholic fatty liver disease (NAFLD/NASH)Its regulation of lipid metabolism, anti-inflammatory and anti fibrotic activities make it promising for the treatment of NAFLD/NASH.
3. Adjuvant anti-tumor therapy Its direct anti-tumor activity and possible chemotherapy sensitization effect can be considered as an adjuvant therapy for tumors to improve efficacy and reduce the side effects of radiotherapy and chemotherapy.
4. Neurodegenerative diseases and retinopathy Based on its Nrf2 activation and neuroprotective properties, it has exploratory value in the prevention and treatment of oxidative stress related diseases such as Alzheimer's disease, Parkinson's disease and diabetes retinopathy.

However, its clinical application still faces many challenges: ① Low solubility and bioavailability It is the primary bottleneck that urgently needs advanced drug delivery systems to solve; ② Complex mechanism of action network The weights between each target and the dominant pathways in vivo need to be further clarified; ③ The preclinical pharmacodynamics, pharmacokinetics, and toxicology data of the system are not yet complete It is necessary to conduct standardized GLP research; ④ The evidence of high-quality human clinical trials is completely blank Future research should focus on optimizing its drug properties through structural modification or formulation techniques; Deeply elucidate its multi-target action map using systems biology and chemical biology methods; Carry out standardized preclinical research and exploratory clinical trials, gradually promoting their transition from laboratory to clinical practice.

Conclusion

Ginsenoside Rh3, as a rare ginsenoside with a unique structure, has become a hot topic in natural product pharmacology research due to its multiple pharmacological activities such as activating Nrf2, improving insulin resistance, and anti-inflammatory. It exhibits the advantage of multi pathway synergistic effects in the prevention and treatment of metabolic diseases by regulating the network composed of key targets such as PTPN1, SIRT1, STAT3, Nrf2, etc. Despite challenges in terms of physicochemical properties (especially water solubility) and systemic pharmacokinetics, these obstacles are expected to be overcome with the continuous development of medicinal chemical modifications and novel drug delivery systems. In the future, through interdisciplinary in-depth cooperative research, ginsenoside Rh3 is expected to develop from a potential lead compound to an innovative drug for the treatment of diabetes, metabolic syndrome and related complications, and contribute modern wisdom of traditional medicine to human health.