Ginsenoside Rh2 Research Articles

Screening and Verification of Blood-Activating Effective Component Group of Panax notoginseng Based on Spectrum-Effect Relationships.

Panax notoginseng (P. notoginseng) is one of the most famous natural medicines and widely used to promote blood circulation in health care. However, the active component group of P. notoginseng for activating blood is not clear. We aim to screen and validate the pharmacodynamic component group (PCG), which could exert the same blood-activating effect as P. notoginseng. To clarify the active components, the chemical components were determined by liquid chromatography-tandem mass spectrometry, and the fingerprint of P. notoginseng was established. Twenty candidate active monomers were selected through the spectrum-effect relationship analysis. Eleven active monomers, including Ginsenoside Rg1, Rb1, Rd, F1, Rh1, Rg2, Rb2, Rg3, and Rk1 and Notoginsenoside R1 and R2, were screened out as the PCG through validation by platelet aggregation test. Among them, the antiplatelet aggregation activity of Ginsenoside Rh1 was directly confirmed for the first time. The active component group could exert similar efficacy to the P. notoginseng extract invitro and invivo through the validation of invitro platelet aggregation test and the rats with cerebral ischemia. This study laid the foundation for the quality evaluation of P. notoginseng and provided a reference for the research on the material basis of the pharmacodynamics of other Chinese herbs.

Functional characterization and site-directed mutagenesis of a novel UDP-glycosyltransferase from Panax japonicus var. major.

Ginsenosides R2 and F2 are key active components of Panax japonicus var. major which exhibit a wide range of pharmacological effects. However, few UDP-glycosyltransferases (UGTs) involved in Rh2 and F2 biosynthesis have been identified. In this study, 12 UGTs from Panax japonicus var. major were predicted and characterized. Among them, one UGT (PjvmUGT45) exhibited superior catalytic activities by catalyzing the C3 hydroxyl glycosylation of protopanaxadiol (PPD) and compound K to form Rh2 and F2, respectively. Especially, PjvmUGT45 showed certain substrate specificity and regional specificity at the C-3 sites of PPD-type ginsenosides. Site-directed mutagenesis showed that Gln334, His349, Ser354, and Asp373 were key residues for PjvmUGT45, and the K280A mutant highly improved its activity. Our results revealed the biosynthetic mechanism of ginsenosides in Panax japonicus var. major, providing a novel alternative UGT for ginsenoside Rh2 production by synthetic biological methods.

Structural Insights into the Substrate Recognition of Ginsenoside Glycosyltransferase Pq3-O-UGT2.

Ginsenosides are a group of tetracyclic triterpenoids with promising health benefits, consisting of ginseng aglycone attached to various glycans. Pq3-O-UGT2, an important UDP-dependent glycosyltransferase (UGT), catalyzes the production of Ginsenoside Rg3 and Rd by extending the glycan chain of Ginsenoside Rh2 and F2, respectively, with higher selectivity for F2. However, the mechanism underlying its substrate recognition remains unclear. In this study, the crystal structures of Pq3-O-UGT2 in complex with its acceptor substrates are solved. The structures revealed a Nα5-oriented acceptor binding pocket in Pq3-O-UGT2, shaped by the unique conformation of the Nα5-Nα6 linker. Hydrophobic interactions play a pivotal role in the recognition of both Rh2 and F2, while hydrogen bonds specifically aid in F2 recognition due to its additional glucose moiety. The hydrophobic nature of the acceptor binding pocket also enables Pq3-O-UGT2 to recognize flavonoids. Overall, this study provides novel insights into the substrate recognition mechanisms of ginsenoside UGTs, advancing the understanding of their function and specificity.

Boosting the catalytic efficiency of UGT51 for efficient production of rare ginsenoside Rh2.

Ginsenoside Rh2(S) is well-known for its therapeutic potential against diverse conditions, including some cancers, inflammation, and diabetes. The enzymatic activity of uridine diphosphate glycosyltransferase 51 (UGT51) from Saccharomyces cerevisiae plays a pivotal role in the glycosylation process between UDP-glucose (donor) and protopanaxadiol (acceptor), to form ginsenoside Rh2. However, the catalytic efficiency of the UGT51 has remained a challenging task. To this end, we employed site-directed mutagenesis on UGT51 to improve its catalytic efficiency for enhanced production of ginsenoside Rh2. The mutated structure, featuring four key mutations (E805A, S998A, R1031A, and L1032A), exhibited heightened stability, binding affinity, and active site accessibility for protopanaxadiol (PPD) compared to the wild type. Under in vitro conditions, three mutants (E805A, R1031A, and L1032A) demonstrated 10%, 58%, and 65% higher enzymatic activities compared to the wild strain. Notably, the double mutant R1031A/L1032A exhibited an 85% increase in activity. Employing a fed-batch technology with PPD as the substrate yielded a Rh2 production of 4.663g/L. The molecular dynamics (MD) simulations were employed to investigate the movements and dynamic dynamics of UGT51 mutations and PPD complexes. The root mean square deviation (RMSD) analysis revealed substantial alterations in structural conformation, particularly in the R1031A/L1032A mutations, correlating with boosted catalytic efficiency. Furthermore, the root mean square fluctuation (RMSF) simulation study aligned with both the RMSD and the solvent-accessible surface area (SASA) analyses. The computationally guided site-directed mutagenesis approach holds promise for extending its application to the development of commercially significant enzymes.

Inhibition of macrophage polarization and pyroptosis in collagen-induced arthritis through MSC-exo and ginsenoside Rh2

BackgroundRheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint inflammation, tissue damage, and fibrosis, significantly affecting the quality of life. While there are currently some effective treatments available, they often come with side effects. There is an urgent need to find new treatments that can further improve therapeutic outcomes and reduce side effects.MethodsOur study investigates the role of Mesenchymal Stem Cell exosomes (MSC-exo) combined with Ginsenoside Rh2 (Rh2) in the treatment of RA. We specifically focus on how this combined strategy influences macrophage polarization and pyroptosis. This research utilized a collagen-induced rat arthritis model.ResultsThe study findings reveal that the combination of MSC-exo combined with Rh2 can inhibit the polarization of M1 macrophages, increase the proportion of M2-like macrophages, and suppress M1-like macrophage pyroptosis via the NLRP3/Caspase11/GSDMD-N pathway. In the rat arthritis model, the combination of MSC-exo and Rh2 showed synergistic therapeutic effects.ConclusionThis research contributes to a deeper understanding of RA’s pathogenesis and presents new potential targeted therapeutic interventions. The combined application of MSC-exo and Rh2 offers promising insights for future innovative strategies in RA treatment, paving the way for more effective management of this autoimmune disease.

The molecular mechanism of ginsenoside Rh2 and its octyl ester derivative on anti-angiogenesis in cancer treatment: The battle between PI3K and ROS

The molecular mechanism of ginsenoside Rh2 and its octyl ester derivative on anti-angiogenesis in cancer treatment: The battle between PI3K and ROS

Progress of Ginsenosides on Immunomodulation and Inhibition of Lung Cancer

Ginseng is characterized by low toxicity, multi-targeting and enhancement of body immunity in its anti-cancer effects. Ginsenosides are natural effective anti-cancer components, mainly consisting of diol-type, triol-type, and oleanolic acid-type ginsenosides. Ginsenosides are bio absorbed by intestinal flora through "Rb1-Gibberellin XVII-F2-CK-PPD", "Rb2-Rd-F2-CK-PPD", "Rg3-Rh2-PPD" and other pathways. It can be converted into saponins ck, Rh1, Rh2, Rc, PPD and other active ingredients. Metabolites of ginsenosides are used in the treatment of many types of cancers and have been shown to be effective. They function by modulating various immune cells in the body, for example, ginsenoside Rh2 significantly increases T-lymphocyte activity and significantly induces differentiation of M2 macrophages towards the M1 phenotype. Ginsenoside Rg3 can act as a cytotoxic activator of NK cells, which inhibits the growth of tumor cells and induces apoptosis and autophagy of tumor cells, and plays an inhibitory and therapeutic role in lung cancer and a variety of tumors, with certain prospects for application development. This review introduces mechanism and function of ginsenosides and discusses application in lung cancer.

Preparation of Rare Dehydrated Protopanaxadiol Ginsenosides from Panax notoginseng Leaves by Confined Microwave-Driven Transformation.

Rare dehydrated ginsenosides barely exist in natural ginseng plants. Herein, the confined microwave technique was utilized to transform the main ginsenosides of Panax notoginseng leaves (PNL) into dehydrated ginsenosides. The main microwave-treated products of dried PNL are dehydrated ginsenoside Rk1, Rg5, notoginsenoside SFt3, and SFt4. Comparatively, the main microwave-treated products of water preimmersed PNL are dehydrated ginsenoside Rk2, Rh3, notoginsenoside SFt3, and SFt4. The impacts of solvent, solid-liquid ratio, microwave temperature and duration on the yield of dehydrated ginsenosides were explored. Based on theoretical calculation, primary ginsenosides in water preimmersed PNL are more prone to deglycosylation at the C-20 site and dehydration elimination reactions at the side chain during microwave treatment. Moreover, reference compounds were used to verify ginsenoside transformation pathway, and the dehydrated ginsenosides were individually purified and identified. In short, this study elucidates novel approach for preparing rare Δ20(21)- and Δ20(22)-dehydrated protopanoxadiol ginsenosides.

Metabolomics-based analysis of nitric oxide regulation of ginseng herb quality.

Ginsenosides, the primary active ingredients in Panax ginseng, are secondary metabolites. However, their content varies significantly across batches due to differences in environmental conditions and production methods. Ecological stress can increase the levels of reactive oxygen species (ROS) in plants, and ROS can enhance secondary metabolism. Nitric oxide (NO) can promote the production of O2 ·- and H2O2. This study utilized physiological and non-targeted metabolomics to investigate how NO regulates ginseng quality and how P. ginseng adapts to adversity. Sodium nitroprusside (SNP, an NO donor) at 0.5 mmol·L-1 significantly increased ROS levels, with O2 ·- increasing by 64.3% (P < 0.01) and H2O2 by 79.2% (P < 0.01). Nitric oxide influenced P. ginseng metabolism, with 24 metabolites showing significant differences. Rotenone, lactic acid, and gluconic acid, which are involved in ROS metabolism, increased significantly, whereas tyrosine decreased. Metabolites involved in secondary metabolic pathways, including campesterol, ginsenosides Rh1, Rb1, Rc, Rd, Rg3, phenylalanine, and tryptophan, increased markedly, whereas 2,3-oxidosqualene, glucose 1-phosphate, ferulic acid, and pyrogallol decreased. Isocitric acid, succinic acid, and 3-isopropylmalic acid, associated with respiratory metabolism, showed significant increases, but pyruvic acid decreased. Finally, 18:0 Lyso PC and 9-hydroxy-10E,12Z-octadecadienoic acid, linked to cell membrane protection, increased significantly, and mannose and raffinose decreased. Sodium nitroprusside enhances the physiological resilience of P. ginseng under stress and improves its quality. © 2024 Society of Chemical Industry.

Ginsenoside Rh2 promotes cell apoptosis in T-cell acute lymphocytic leukaemia by MAPK and PI3K/AKT signalling pathways

T-cell acute lymphoblastic leukaemia (T-ALL) is a common childhood malignant tumour, which has poor prognosis and high recurrence rate. Ginsenoside Rh2 (GRh2), a bioactive ingredient of Panax ginseng has significant anti-tumour effect. In this study, we found that gene expressions of Jurkat cells were significantly changed in the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT) signalling pathways after 35 µm GRh2 treatment, involving in JUN, PIEN, AKT3 and MAPK8IP2. Target proteins including PI3K, AKT, ASK, caspase 8 and caspase 9 were bind tightly with GRh2 by molecular docking. Moreover, the protein expression ratios of p-PI3K/PI3K and p-AKT/AKT were significantly reduced, and the expression ratios of p-ASK1/ASK1, p-JNK/JNK and p-c-JUN/c-JUN, Bax/Bcl-2, and the levels of cleaved caspase 8, 9, 3 were increased significantly in GRh2-treated Jurkat cells. The results imply that GRh2 induced T-ALL apoptosis by activating the MAPK pathway and inhibiting the PI3K-AKT pathway.

Therapeutic Effects of Ginsenoside Rh2 in the Treatment of Sepsis

Panax ginseng, a well-known traditional Chinese medicine (TCM) with a wide range of pharmacological activities, has been extensively investigated. However, its specific pharmacological mechanism in preventing and treating sepsis remains elusive. The study aims to investigate preventive effects of ginsenoside Rh2 (GRh2) on RAW264.7 cells and therapeutic effects of Panax ginseng in sepsis patients. The active ingredients of Panax ginseng were obtained from the TCMSP database. RAW 264.7 cells were incubated with the active ingredient of Panax ginseng at indicated concentrations for 1 hour and then stimulated with lipopolyssacharide (LPS). The therapeutic effects of Panax ginseng were validated in sepsis patients. We initially obtained 17 active ingredients of Panax ginseng including 20(S)-GRh2. No cytotoxicity conferred by 20(S)-GRh2 against RAW264.7 cells was found by cell viability assays. The treatment with 20(S)-GRh2 dramatically inhibited LPSinduced release of nitric oxide and production of pro-inflammatory factors in RAW264.7 cells. In sepsis patients, the administration of Sini Decoction supplemented with Panax ginseng resulted in lower SOFA scores and lower concentrations of pro-inflammatory factors in the sera compared to the control group (P &lt;0.05). Our study demonstrates the therapeutic effects of Panax ginseng in sepsis by its anti-inflammatory action and provides clinical evidence that Panax ginseng supplemented into Sini Decoction as a treatment strategy to prevent sepsis progression.

Ginsenoside Rh4 Ameliorates Cisplatin-Induced Intestinal Toxicity via PGC-1[Formula: see text]-Mediated Mitochondrial Autophagy and Apoptosis Pathways.

Cisplatin-evoked profound gastrointestinal symptomatology is one of the most common side effects of chemotherapy drugs, causing further gastrointestinal cell and intestinal mucosal injury. Ginsenoside Rh4 (G-Rh4), an active component extracted from red ginseng, possesses beneficial anti-oxidative and anti-apoptosis effects. This study aimed to assess the effectiveness of pharmacological intervention with G-Rh4 mitigating intestinal toxicity evoked by cisplatin in a murine model and in IEC-6 cells in vitro. Following oral administration for 10 days, G-Rh4 (10[Formula: see text]mg/kg and 20[Formula: see text]mg/kg) significantly increased the indicators of diamine oxidase (DAO) affected by cisplatin (20[Formula: see text]mg/kg) in mice, and histopathological analysis further indicated that G-Rh4 could effectively improve intestinal tissue morphology, as well as the expression of peroxisome proliferator-activated receptor-gamma coactivator 1 [Formula: see text] (PGC-1[Formula: see text] pathway and autophagy-related proteins. Moreover, in vitro experiments demonstrated that G-Rh4 exerted a concentration-dependent increase in cell viability, while also inhibiting cytotoxicity and abnormal rise of reactive oxygen species (ROS). Notably, ROS also activate PGC-1[Formula: see text] protein and mediate the occurrence of mitochondrial autophagy and apoptosis pathways. The molecular docking approach was employed to dock G-Rh4 with PGC-1[Formula: see text] and AMPK, revealing a binding energy of [Formula: see text]7.3[Formula: see text]kcal/mol and [Formula: see text]8.1[Formula: see text]kcal/mol and indicating a tight interaction between the components and the target. G-Rh4 could reduce the expression of autophagy-related protein p62/p53, reduce the accumulation of autophagy products, and promote the flow of autophagy. In conclusion, G-Rh4 exerted protective effects against cisplatin-induced intestinal toxicity, at least partially through PGC-1[Formula: see text]-mediated autophagy and apoptosis.

Green and Fast Synthesis of NiCo-MOF for Simultaneous Purification-Immobilization of Bienzyme to Catalyze the Synthesis of Ginsenoside Rh2.

Traditional metal-organic frameworks (MOFs) preparation is generally time-consuming, polluting, and lacking specificity for enzyme immobilization. This paper introduced a facile, rapid, and green method to produce three MOFs subsequently employed to purify and coimmobilize recombinant glycosyltransferase (UGT) and recombinant sucrose synthetase (SUSy) using histidine tag (His-tag) for the specific adsorption of Ni2+ and Co2+ from MOFs. This method simplified enzyme purification from crude extracts and enabled enzymes to be reused. The results demonstrated that NiCo-MOF exhibited a higher enzyme load (115.9 mg/g) than monometallic MOFs. Additionally, the NiCo-MOF@UGT&SUSy demonstrated excellent stability and efficiently produced the rare ginsenoside Rh2 by catalyzing a coupling reaction (95.6 μg/mL), solving the problem of the substrate cost of uridine diphosphate glucose (UDPG). The NiCo-MOF@UGT&SUSy retained 68.97% of the initial activity after 10 cycles. Finally, molecular docking studies elucidated the conversion mechanism of the target product Rh2. This technique is important in the industrialization of ginsenoside production and enzyme purification.

Review on the application of ginsenosides and their pharmaceutical preparations in the treatment of breast cancer

Ginsenosides, as the main active ingredients of ginseng, have shown great potential in the treatment of breast cancer. Studies have found that many types of ginsenosides, such as PPD ginsenosides Rh2, Rg3, CK and PPT ginsenosides Rg1, Rg2, have inhibitory effects on breast cancer cells. These components can effectively inhibit the development of breast cancer by directly inhibiting the proliferation of cancer cells, inducing apoptosis, enhancing the anticancer ability of NK cells, and remodeling the tumor microenvironment. In addition, the liposome and nanoparticle drug delivery system synthesized by ginsenoside showed great advantages in the application of drug formulations, providing a new strategy for the targeted transportation of antitumor drugs and improving the tumor killing ability. These research results not only provide a new strategy for breast cancer treatment, but also expand the application prospect of ginsenosides in cancer treatment. In the future, with the in-depth research, ginsenosides and their pharmaceutical preparations are expected to play a greater role in the treatment of breast cancer and bring more hope to patients.

Ginseng fruit rare saponins (GFRS) improved inflammatory response: In vitro and in vivo assessment

Inflammation is the body's protective immune response to tissue damage. Ginseng has a long history of medicinal use, and its active ingredient ginsenosides have anti-inflammatory effects. Ginseng fruit rare saponins (GFRS) is a transformation product of ginseng saponins and rich in a variety of rare saponins. We used HPLC-DAD method to study GFRS rare saponins with ginsenoside F4, R-Rg3, SRg3, Rk1, Rg6, Rg5, Rk3 and Rh4. However, there is no study on the use of GFRS to reduce skin inflammation. This study enriched the action pathway of GFRS through network pharmacology and revealed the anti-inflammatory effect of GFRS for the first time. In vitro experiments showed that GFRS could significantly reduce the release of NO in lipopolysaccharide (LPS) -induced RAW264.7 cells and HaCaT cells, and reduce the secretion and expression of inflammation-related factors Interleukin-6 (IL-6), Tumor necrosis factor-α (TNF-α) and Interleukin-17 A (IL-17 A), thereby reducing cell inflammatory damage. In the imiquimod (IMQ) -induced mouse inflammatory model, the therapeutic effect of GFRS on the pathogenesis of psoriasis-like dermatitis was studied. In vivo experiments showed that the skin erythema, scales, thickness and inflammatory infiltration of GFRS-treated mice were reduced, and the psoriasis area severity index score was significantly lower than that of IMQ group. GFRS restored IMQ-induced spleen size and reduced the secretion and expression of TNF-α, IL-6, Interferon-γ (IFN-γ) and IL-17 A in serum. In summary, our results demonstrate that GFRS alleviates IMQ-induced dermatitis symptoms, effectively reduces the secretion of inflammatory factors, and inhibits IL-17 A expression.

Ginsenoside Rh1 regulates the immune microenvironment of hepatocellular carcinoma via the glucocorticoid receptor

ObjectiveGinsenoside Rh1 (G-Rh1) has been confirmed to inhibit the growth of breast cancer and colon cancer, but its therapeutic effect on hepatocellular carcinoma (HCC) is unclear. This study investigates the therapeutic effect of G-Rh1 on HCC as well as the underlying mechanism. MethodsBioinformatics methods were used to analyze glucocorticoid receptor (GR) expression and the tumor microenvironment in HCC tissues from HCC patients. The effect of G-Rh1 on HCC cells was investigated in vitro using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method. The therapeutic effect of G-Rh1 was investigated in vivo using subcutaneous transplantation models in C57BL/6J and nude mice. Additionally, the proportion of infiltrating immune cells in tumors was analyzed using flow cytometry, the GR and major histocompatibility complex class-I (MHC-I) expression of HCC cells after G-Rh1 treatment was analyzed using Western blotting, and G-Rh1-treated Hepa1-6 cells were cocultured with bone marrow-derived dendritic cells and B3Z T cells to further analyze the ability of G-Rh1 to induce dendritic cell (DC) maturation and CD8+ T cell activation. ResultsGR expression was upregulated in HCC tissues, and high GR expression was associated with a worsened immune microenvironment. In vitro studies showed that G-Rh1 had no significant effect on the proliferation of HCC cells, while in vivo studies showed that G-Rh1 exerted antitumor effects in C57BL/6J mice but not in nude mice. Further research revealed that G-Rh1 ameliorated the immunosuppressive tumor microenvironment, thereby enhancing the antitumor effects of lenvatinib by increasing the infiltration of CD8+ T cells, mature DCs, and MHC-I-positive cells. MHC-I was upregulated by G-Rh1 via GR suppression. Moreover, overexpression of GR abolished the G-Rh1-mediated promotion of MHC-I expression in Huh7 cells, as well as the maturation of DCs and the activation of CD8+ T cells. ConclusionG-Rh1 can regulate the immune microenvironment of HCC by targeting GR, thus increasing the antitumor effect of lenvatinib.Please cite this article as: Wang XH, Fu YL, Xu YN, Zhang PC, Zheng TX, Ling CQ, Feng YL. Ginsenoside Rh1 regulates the immune microenvironment of hepatocellular carcinoma via the glucocorticoid receptor. J Integr Med. 2024; Epub ahead of print.

Remodeling the tumor immune microenvironment through hydrogel encapsulated G-Rh2 in situ vaccine and systemic immunotherapy

Ginsenoside Rh2 (G-Rh2) is a vital bioactive compound in Traditional Chinese Medicine, celebrated for its strong pharmacological properties, particularly its potent antitumor effects. However, its poor water solubility and limited bioavailability have necessitated the development of a novel drug delivery method. In this study, we utilized an indocyanine green carboxylic acid-hydroxypropyl cellulose-abietic acid-bovine serum albumin hydrogel (ICG-HPC-AA/BSA hydrogel) as a tumor in situ vaccine to enhance the permeability, retention, and tumor-targeted therapeutic efficacy of G-Rh2. We examined the therapeutic impact of a G-Rh2-loaded hydrogel combined with systemic PD-1 antibody treatment in murine models of H22 liver cancer and CT26 colon cancer. Additionally, we explored the immune microenvironment of the tumors influenced by this in situ vaccination strategy.

Ginsenoside Rh2 Alleviates LPS-Induced Inflammatory Responses by Binding to TLR4/MD-2 and Blocking TLR4 Dimerization.

Lipopolysaccharide (LPS) triggers a severe systemic inflammatory reaction in mammals, with the dimerization of TLR4/MD-2 upon LPS stimulation serving as the pivotal mechanism in the transmission of inflammatory signals. Ginsenoside Rh2 (G-Rh2), one of the active constituents of red ginseng, exerts potent anti-inflammatory activity. However, whether G-Rh2 can block the TLR4 dimerization to exert anti-inflammatory effects remains unclear. Here, we first investigated the non-cytotoxic concentration of G-Rh2 on RAW 264.7 cells, and detected the releases of pro-inflammatory cytokines in LPS-treated RAW 264.7 cells, and then uncovered the mechanisms involved in the anti-inflammatory activity of G-Rh2 through flow cytometry, fluorescent membrane localization, Western blotting, co-immunoprecipitation (Co-IP), molecular docking and surface plasmon resonance (SPR) analysis in LPS-stimulated macrophages. Our results show that G-Rh2 stimulation markedly inhibited the secretion of LPS-induced interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and nitric oxide (NO). Additionally, G-Rh2 blocked the binding of LPS with the membrane of RAW 264.7 cells through direct interaction with TLR4 and MD-2 proteins, leading to the disruption of the dimerization of TLR4 and MD-2, followed by suppression of the TLR4/NF-κB signaling pathway. Our results suggest that G-Rh2 acts as a new inhibitor of TLR4 dimerization and may serve as a promising therapeutic agent against inflammation.

Ginsenoside Rh2 suppresses ferroptosis in ulcerative colitis by targeting specific protein 1 by upregulating microRNA-125a-5p

BackgroundWorldwide, ulcerative colitis (UC) is becoming increasingly fast growing. Ginsenoside Rh2 has been reported to alleviate UC. However, the latent biological mechanism of Rh2 in the treatment of UC remains uncertain. In this study, the goal was to determine the therapeutic effect of Rh2 on dextran sulfate sodium (DSS)-induced UC.MethodsA DSS-induced UC mouse model was established and divided into 7 groups for Rh2 gavage and/or miR-125a-5p lentivirus injection (n = 10 per group). Colonic specimens were collected for phenotypic and pathological analysis. miR-125a-5p and specific protein 1 (SP1) expression, inflammation-related factors IL-6 and IL-10, and apoptosis were detected in mice. Human normal colon epithelial cell line NCM460 was treated with H2O2 and ferric chloride hexahydrate to construct an in vitro cell model of colitis and induce ferroptosis. Independent sample t-test was used to compare cell proliferation, cell entry, apoptosis, and oxidative stress between the two groups. One way analysis of variance combined with the least significant difference t test was used for comparison between groups. Multiple time points were compared by repeated measurement analysis of variance.ResultsDSS-induced UC mice had significantly decreased body weight, increased disease activity index, decreased colon length, and decreased miR-125a-5p expression (all P < 0.05). In the DSS-induced mouse model, the expression of miR-125a-5p rebounded and ferroptosis was inhibited after Rh2 treatment (all P < 0.05). Inhibition of miR-125a-5p or upregulation of SP1 expression counteracted the protective effects of Rh2 on UC mice and ferroptosis cell models (all P < 0.05).ConclusionsRh2 mitigated DSS-induced colitis in mice and restrained ferroptosis by targeting miR-125a-5p. Downregulating miR-125a-5p or elevating SP1 could counteract the protective impacts of Rh2 on ferroptotic cells. The findings convey that Rh2 has a latent application value in the treatment of UC.Graphical

20(S)-Ginsenoside Rh2 overcomes gemcitabine resistance in pancreatic cancer by inhibiting LAMC2-Modulated ABC transporters

IntroductionGemcitabine (GEM) is the first-line drug for pancreatic ductal adenocarcinoma (PDAC), but drug resistance severely restricts its chemotherapeutic efficacy. Laminin subunit γ2 (LAMC2) plays a crucial role in extracellular matrix formation in the development of GEM-resistance. However, the biological function of LAMC2 in GEM resistance and its molecular mechanisms are still unclear. 20(S)-Ginsenoside Rh2 (Rh2), one of the principal active components isolated from Ginseng Radix et Rhizoma, possesses strong anti-tumor effects. However, the effects of Rh2 on overcoming GEM resistance and its action mechanisms remain to be elucidated. ObjectivesThis study aimed to determine the efficacy of Rh2 on overcoming GEM resistance and to explore its underlying molecular mechanisms. MethodsClinical study, Western blotting, publicly available databasesand bioinformatic analyses were performed to investigate the protein expression of LAMC2 in the GEM-resistant PDAC patients and the acquired GEM-resistant PDAC cells. Then, the effects of Rh2 on overcoming the GEM resistance in PDAC were evaluated both in vitro and in vivo. Stable silencing or overexpression of LAMC2 in the GEM-resistant PDAC cells were established for validating the role of LAMC2 on Rh2 overcoming the GEM resistance in PDAC. ResultsThe protein expression of LAMC2 was markedly increased in the GEM-resistant PDAC patient biopsies compared to the sensitive cases. The protein expression of LAMC2 was significantly higher in the acquired GEM-resistant PDAC cells than that in their parental cells. Rh2 enhanced the chemosensitivity of GEM in the GEM-resistant PDAC cells, and inhibited the tumor growth of Miapaca-2-GR cell-bearing mice and Krastm4TyjTrp53tm1BrnTg (Pdx1-cre/Esr1*) #Dam/J (KPC) mice. Rh2 effectively reversed the GEM resistance in Miapaca-2-GR and Capan-2-GR cells by inhibiting LAMC2 expression through regulating the ubiquitin–proteasome pathway. Knockdown of LAMC2 enhanced the chemosensitivity of GEM and the effects of Rh2 on overcoming the GEM resistance in PDAC cells and the orthotopic PDAC mouse model. Conversely, LAMC2 overexpression aggravated the chemoresistance of GEM and abolished the effects of Rh2 on overcoming GEM resistance via modulating ATP-binding cassette (ABC) transporters leading to the active GEM efflux. ConclusionsLAMC2 plays an important role in the GEM resistance in PDAC, and Rh2 is a potential adjuvant for overcoming the chemoresistance of GEM in PDAC.