Product name: Chikusetsusaponin IVa
Synonym name: Calenduloside F; Glucopyranosiduronic acid; Momordin IIb; Silphioside G; Hericiumsaponin S1
Catalogue No.: BP0675
Cas No.: 51415-02-2
Formula: C₄₂H₆₆O₁₄
Mol Weight: 794.976
Botanical Source: Panax japonicus C.A.Mey.
Physical Description:
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.

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

Description:

Chikusetsusaponin IVa is a novel AMPK activator, can induce insulin secretion from βTC3 cells via GPR40 mediated calcium and PKC pathways, may be developed into a new potential for therapeutic agent used in T2DM patients.Chikusetsusaponin IVa exerts antithrombotic effects, including minor hemorrhagic events.

References:

Biochem Biophys Res Commun. 2015 Apr 17;459(4):591-6.    

Chikusetsusaponin IVa methyl ester induces cell cycle arrest by the inhibition of nuclear translocation of β-catenin in HCT116 cells.   

We demonstrate that Chikusetsusaponin IVa methyl ester (CME), a triterpenoid saponin from the root of Achyranthes japonica, has an anticancer activity. 

METHODS AND RESULTS:

We investigate its molecular mechanism in depth in HCT116 cells. CME reduces the amount of β-catenin in nucleus and inhibits the binding of β-catenin to specific DNA sequences (TCF binding elements, TBE) in target gene promoters. Thus, CME appears to decrease the expression of cell cycle regulatory proteins such as Cyclin D1, as a representative target for β-catenin, as well as CDK2 and CDK4. As a result of the decrease of the cell cycle regulatory proteins, CME inhibits cell proliferation by arresting the cell cycle at the G0/G1 phase. 

CONCLUSIONS:

Therefore, we suggest that CME as a novel Wnt/β-catenin inhibitor can be a putative agent for the treatment of colorectal cancers.    

J Med Food. 2012 Dec;15(12):1073-80.    

Antithrombotic effect of chikusetsusaponin IVa isolated from Ilex paraguariensis (Maté).   

The triterpene Chikusetsusaponin IVa was isolated from the fruit of Ilex paraguariensis. 

METHODS AND RESULTS:

Using biochemical and pharmacological methods, we demonstrated that Chikusetsusaponin IVa (1) prolongs the recalcification time, prothrombin time, activated partial thromboplastin time, and thrombin time of normal human plasma in a dose-dependent manner, (2) inhibits the amidolytic activity of thrombin and factor Xa upon synthetic substrates S2238 and S2222, (3) inhibits thrombin-induced fibrinogen clotting (50% inhibition concentration, 199.4 ± 9.1 μM), and (4) inhibits thrombin- and collagen-induced platelet aggregation. The results also indicate that Chikusetsusaponin IVa preferentially inhibits thrombin in a competitive manner (K(i)=219.6 μM). Furthermore, when administered intravenously to rats, Chikusetsusaponin IVa inhibited thrombus formation in a stasis model of venous thrombosis, although it did not induce a significant bleeding effect. Chikusetsusaponin IVa also prolonged the ex vivo activated partial thromboplastin time. 

CONCLUSIONS:

Altogether, these data suggest that Chikusetsusaponin IVa exerts antithrombotic effects, including minor hemorrhagic events. This appears to be important for the development of new therapeutic agents. 

HPLC of Chikusetsusaponin IVa

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

Introduction/Overview

Natural products, as an important source of drug discovery, play an irreplaceable role in the history of human disease prevention and treatment. Among them, saponin compounds have always been a hot topic in medicinal chemistry and pharmacology research due to their structural diversity and wide range of biological activities. Chikusetsu saponin IVa (Cs IVa), CAS number 51415-02-2, is a triterpenoid saponin of oleanane type isolated from the traditional medicinal plant Chikusetsu. In recent years, with the deepening of research technology, the pharmacological activity spectrum of Cs IVa has been continuously expanded, and its mechanism of action has extended from traditional anti-inflammatory and hepatoprotective effects to cutting-edge fields such as regulating cell fate, metabolic balance, and tumor microenvironment. Research has shown that Cs IVa is not only an orally active protein kinase activator, but also binds to the key effector molecule YAP in the Hippo pathway, and exerts multiple biological effects such as anti-inflammatory, antiviral, anti-tumor, blood glucose regulation, and bone and liver protection through multi-target and multi pathway synergy. This article aims to systematically review the chemical properties, plant sources, pharmacological activities, molecular mechanisms of action, pharmacological evaluation, and clinical application potential of Cs IVa, in order to provide comprehensive scientific references for the deep development and transformation research of this natural product.

Chemical structure and physicochemical properties

The chemical name of Zhujie ginseng saponin IVa is 3-O - [β - D-glucopyranosyl (1 → 2) - β - D-glucopyranosyl] - oleanolic acid-28-O - β - D-glucopyranosyl ester. Its molecular formula is C₄₂H₆₆O₁₄The molecular weight is 794.9760. Structurally, it takes oleanolic acid as the aglycone and connects a disaccharide chain consisting of a glucose group (1 → 2) glucuronic acid at the C-3 position, while esterifying a glucose unit at the C-28 position. This unique glycosylation pattern has a decisive impact on its biological activity and solubility.

The physicochemical properties parameters show that the calculated lipid water partition coefficient LogP is 2.9232, indicating that the compound has a certain lipophilicity, but not highly hydrophobic. The topologically polar surface area (TPSA) is as high as 232.9000 Å ², mainly attributed to the abundant hydroxyl groups in the molecule and multiple oxygen atoms on the sugar chain, indicating its strong ability to form hydrogen bonds. The water solubility value is 0.0699 (usually measured in mg/mL or mol/L, relative here), indicating that it belongs to the category of slightly soluble to poorly soluble compounds, which is related to its larger molecular weight and more polar groups, and is also a common challenge faced by most saponin compounds. These basic physicochemical parameters provide important basis for subsequent formulation research and pharmacokinetic behavior.

Plant sources and extraction methods

Zhujie Ginseng Saponin IVa is mainly derived from Zhujie Ginseng, a plant of the Panax genus in the Araliaceae family（Panax japonicus C. Dry rhizomes of A. Mey. Zhujie ginseng, as a traditional Chinese medicine, is commonly used in Asia to treat cough, hemoptysis, traumatic injuries, and rheumatism. Except for bamboo ginseng, in the same genus of plants such as pearl ginseng（Panax japonicus var. major）There is also a high content in it.

Its extraction and separation usually follow the conventional process of natural product chemistry. Firstly, the dried roots and stems of bamboo ginseng are crushed and subjected to heating reflux or ultrasound assisted extraction using methanol, ethanol, or ethanol water mixed solvents to obtain the crude extract of total saponins. Subsequently, macroporous adsorption resins (such as D101, AB-8) were used for preliminary enrichment and decolorization, followed by gradient elution with water and different concentrations of ethanol to collect saponin rich fractions. Further purification relies on techniques such as normal or reverse phase silica gel column chromatography and preparative high-performance liquid chromatography (HPLC). The combination of a reverse phase C18 chromatographic column with acetonitrile water or methanol water system is a key step in separating and obtaining high-purity Cs IVa. Modern technologies such as high-speed countercurrent chromatography (HSCCC) have also been applied to the efficient preparation and separation of such saponins due to their advantages of not requiring solid carriers and high recovery rates. The optimization of extraction process is usually based on the yield and purity of Cs IVa, involving multiple factors such as solvent type, concentration, temperature, time, and solid-liquid ratio.

Pharmacological activity research

A large number of pharmacological studies both in vitro and in vivo have revealed the extensive and significant biological activities of saponins IVa from Panax ginseng.

1. Anti inflammatory and immune regulatory effects Cs IVa exhibits strong activity in various inflammatory models. It can significantly inhibit the expression of nitric oxide (NO) and key inflammatory mediators such as interleukin-6 (IL-6), IL-10, and cyclooxygenase-2 (COX-2) in macrophages induced by lipopolysaccharide (LPS). This anti-inflammatory effect is an important basis for its hepatoprotective and bone protective effects.
2. Antiviral activity Research has confirmed that Cs IVa has activity against H9N2 avian influenza virus (AIV). It may exert antiviral effects by interfering with the virus replication cycle or regulating the host immune response, providing candidate molecules for the development of novel anti influenza drugs.
3. Antitumor activity Cs IVa has growth inhibitory and apoptosis inducing effects on various cancer cell lines. Especially in the study of endometrial cancer, it can effectively inhibit cancer cell proliferation and induce apoptosis. Its pro apoptotic effect is closely related to promoting the generation of reactive oxygen species (ROS).
4. Metabolic regulation and anti hyperglycemic potential Although direct research on the hypoglycemic effects of Cs IVa is still ongoing, its related target network (such as AMPK, SGLT2, GCK, etc.) strongly suggests its potential in regulating glucose homeostasis. The activation of AMPK is a key pathway for improving insulin resistance and glucose metabolism.
5. Organ protection function：
   • Hepatoprotective effect In the chemical liver injury model, Cs IVa can alleviate liver tissue inflammation and oxidative stress, and protect liver function.
   • Bone protective effect In the osteoporosis model, Cs IVa exhibits dual potential of inhibiting bone resorption and promoting bone formation, which may be achieved by regulating the balance between osteoblasts and osteoclasts.

Mechanism of action and molecular targets

The multiple pharmacological activities of bamboo ginseng saponin IVa stem from its precise regulation of complex cellular signaling networks, and its mechanism of action has been studied at the molecular target level.

1. Core target: Hippo YAP/TAZ pathway Surface plasmon resonance (SPR) and other techniques have confirmed that Cs IVa can directly bind to the downstream transcription co activator YAP in the Hippo pathway, with a dissociation constant KD value of 0.388 mM. Through this interaction, Cs IVa can inhibit the transcriptional activity of YAP and its homologous protein TAZ. The Hippo YAP/TAZ pathway is crucial in regulating cell proliferation, apoptosis, stem cell characteristics, and organ size, and its abnormal activation is closely related to tumorigenesis, fibrosis, and other diseases. The inhibition of this pathway by Cs IVa is one of the core mechanisms underlying its anti-tumor effects, such as endometrial cancer.
2. Regulating MAPK and JAK/STAT pathways Cs IVa can inhibit the mitogen activated protein kinase (MAPK) signaling pathway, which is involved in the regulation of inflammation, stress response, and cell proliferation. At the same time, it can also regulate the Janus kinase/signal transduction and transcriptional activator (JAK/STAT) pathway, which is the center of cytokine signaling and closely related to immune inflammation and tumorigenesis.
3. Activate Nrf2 antioxidant pathway Cs IVa can upregulate the activity of nuclear factor E2 related factor 2 (Nrf2). Nrf2 is a central regulatory factor of cellular antioxidant response, which can drive the expression of a series of antioxidant enzymes and phase II detoxifying enzymes, thereby combating oxidative stress. This is closely related to its anti-inflammatory and hepatoprotective effects.
4. Inducing oxidative stress and apoptosis Cs IVa can promote the generation of ROS in tumor cells. Moderately elevated ROS levels can lead to mitochondrial dysfunction, activate endogenous apoptotic pathways (such as caspase cascade), and selectively induce cancer cell apoptosis.
5. Potential association with targets related to hyperglycemia Although direct evidence needs to be supplemented, bioinformatics and target prediction analysis suggest that Cs IVa may exert regulatory effects by affecting a series of targets related to glucose metabolism, such as activating AMPK to improve energy metabolism and insulin sensitivity; Potential impact on the activity of sodium glucose cotransporter 2 (SGLT2) and glucokinase (GCK); Or indirectly affect blood glucose homeostasis by acting on epigenetic and signaling regulatory factors such as EHMT2 and PTPN1.

Evaluation of drug properties and pharmacokinetics

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

• Absorption and oral activity Despite its large molecular weight (~795 Da) and high TPSA, studies have confirmed its oral activity, indicating that it can be absorbed to some extent in the gastrointestinal tract. Its LogP value (~2.92) is within the range of drug like properties, which is conducive to transmembrane absorption, but its high polarity may limit its passive diffusion efficiency. Its slight solubility may be the main limiting factor for oral bioavailability.
• distribution Predict that its blood-brain barrier (BBB) penetration is "low", which is consistent with the characteristics of most hydrophilic macrosaponins, meaning that it may not easily enter the central nervous system, reducing the risk of central side effects for the treatment of peripheral diseases. However, for targeted brain diseases (such as intervening in Alzheimer's disease through APP or BACE1 targets), structural modifications or special administration strategies are required.
• Metabolism and excretion As a saponin compound, it may undergo metabolic processes such as hydrolysis (especially glycosidic bonds), oxidation, and binding in the body. The hydrolysis of glycans by gut microbiota may be an important link in their metabolism and activation. Further pharmacokinetic studies are needed to clarify the specific metabolites, major metabolic enzymes, and excretion pathways.
• Preliminary Safety Assessment The data shows that it has no hERG inhibitory activity ("no"), which is an important positive signal indicating that it may not have potential cardiac toxicity (QT interval prolongation risk). The Ames test result is 0.0, indicating that there is no mutagenicity in this testing system, but a more complete genotoxicity combination test is needed for verification. Overall, the preliminary safety parameters are relatively ideal, but a comprehensive preclinical safety evaluation (such as acute toxicity, chronic toxicity, reproductive toxicity, etc.) is essential.

At present, there is still a lack of publicly available data on the pharmacokinetics of the Cs IVa system, such as absolute bioavailability, half-life, tissue distribution, plasma protein binding rate, etc. This is a key information gap that must be filled as it moves towards drug development.

Clinical application prospects and prospects

The multi-target and multi pathway pharmacological properties exhibited by bamboo ginseng saponin IVa provide broad prospects for its application in multiple disease fields.

1. Inflammatory related diseases Its strong anti-inflammatory and immune regulatory abilities make it a promising candidate for treating chronic or acute inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Its dual effects of Nrf2 antioxidant and inhibition of MAPK/NF - κ B inflammatory pathway are particularly attractive.
2. tumor therapy Targeting the anticancer activity of solid tumors such as endometrial cancer, combined with its unique mechanism of regulating Hippo YAP/TAZ, an emerging anti-cancer target, Cs IVa has the potential to be developed as a novel anti-tumor drug or adjuvant therapy. Combining it with existing chemotherapy and targeted therapies may result in synergistic effects and reversal of drug resistance.
3. Metabolic diseases: In view of its association with multiple diabetes related targets such as AMPK, in-depth research on the regulatory effect of Cs IVa on blood glucose and lipids may provide new natural candidate drugs for the treatment of type 2 diabetes and its complications (such as diabetes nephropathy and liver disease).
4. Organ fibrosis The YAP/TAZ pathway is a key factor driving liver, lung, and kidney fibrosis. Cs IVa, as a YAP inhibitor, has important exploratory value in the field of anti organ fibrosis.
5. Bone and joint diseases Its bone protective effect suggests that it may have practical value in the prevention and treatment of diseases such as osteoporosis and osteoarthritis.

However, its clinical translation still faces challenges:First Poor water solubility and potential low bioavailability are the primary pharmaceutical challenges that require improvement through strategies such as nano formulations (such as liposomes, polymer micelles), prodrug modification, and eutectic technology.secondly Systematic preclinical pharmacokinetic and toxicological studies need to be conducted to clarify its in vivo fate and safety window.Again Its multi-target nature is a double-edged sword. While it brings comprehensive therapeutic effects, it may also increase the complexity of the mechanism of action and the risk of unpredictable side effects, requiring more precise mechanism research and disease model validation.finally It is necessary to ensure stable and sufficient drug sources are obtained from natural sources, or to develop feasible chemical synthesis or synthetic biology preparation routes.

Conclusion

Zhujie ginseng saponin IVa, as a natural triterpenoid saponin derived from traditional Chinese medicine, has become a star molecule in modern natural product pharmacology research due to its unique chemical structure and multidimensional pharmacological activity. From directly combining YAP to regulate cell growth and apoptosis, to synergistically exerting anti-inflammatory and antioxidant effects through multiple pathways such as MAPK, Nrf2, JAK/STAT, the mechanism network of action is becoming increasingly clear. The potential demonstrated in antiviral, anti-tumor, metabolic regulation, and organ protection has laid a solid foundation for its application in new drug development, especially in the development of drugs for complex multifactorial diseases such as cancer, chronic inflammation, and metabolic syndrome. Although there are still key scientific issues that need to be addressed in terms of drug formulation, systemic pharmacokinetics, and clinical translation, with the advancement of formulation technology and the continuous deepening of molecular mechanism research, Zhujie Ginsenoside IVa is expected to gradually move from an excellent pharmacological tool molecule to a candidate drug with clear clinical application value, demonstrating the enduring vitality of natural products in innovative drug discovery. Future research should focus on optimizing its structure, precise target validation, and comprehensive efficacy evaluation based on modern disease models to accelerate its transition from laboratory to clinical use.