Identifying the catalytic regioselectivity of enzymes remains a challenge. Compared to experimental trial-and-error approaches, computational methods like molecular dynamics simulations provide valuable insights into enzyme characteristics. However, the massive data generated by these simulations hinder the extraction of knowledge about enzyme catalytic mechanisms without adequate modeling techniques. Here, we propose a computational framework utilizing graph-based active learning from molecular dynamics to identify the regioselectivity of ginsenoside hydrolases (GHs), which selectively catalyze C6 or C20 positions to obtain rare deglycosylated bioactive compounds from Panax plants. Experimental results reveal that the dynamic-aware graph model can excellently distinguish GH regioselectivity with accuracy as high as 96-98% even when different enzyme-substrate systems exhibit similar dynamic behaviors. The active learning strategy equips our model to work robustly while reducing the reliance on dynamic data, indicating its capacity to mine sufficient knowledge from short multi-replica simulations. Moreover, the model\'s interpretability identified crucial residues and features associated with regioselectivity. Our findings contribute to the understanding of GH catalytic mechanisms and provide direct assistance for rational design to improve regioselectivity. We presented a general computational framework for modeling enzyme catalytic specificity from simulation data, paving the way for further integration of experimental and computational approaches in enzyme optimization and design.

Medicinal plant-derived vesicle-like nanoparticles can carry chemical components and exert intercellular activity due to the encapsulation of nanostructures. American ginseng is well known as a traditional herb and is commonly used in clinical decoctions. However, the nano-characteristics and chemical composition of American-ginseng-derived vesicle-like nanoparticles (AGVNs) in decoctions are unclear. In this study, the gradient centrifugation method was used to extract and isolate AGVNs. A metabolomic method based on high-resolution mass spectrometry was established to analyze small molecules loaded in AGVNs. Zebrafish and RAW264.7 cells were employed to investigate the anti-inflammatory effects of AGVNs. The results showed that the particle size of AGVNs was generally 243.6 nm, and the zeta potential was -14.5 mV. AGVNs were found to contain 26 ginsenosides (14 protopanaxadiols, 11 protopanaxatriols, and 1 oleanolic acid). Ginsenoside Rb1 and malonyl-ginsenoside Rb1 tended to be enriched in AGVNs. Moreover, AGVNs were found to exert anti-inflammatory effects by reducing macrophage migration in zebrafish and regulating inflammatory factor (NO, TNF-α, IL-6, IL-10) secretion in RAW 264.7 cells. The characterization and analysis of AGVNs provide references and data that support the development of nanoscale anti-inflammatory substances from medicinal plants.

UNASSIGNED: This research main objective was to evaluate a proliposomes (PLs) formulation for the enhancement of oral bioavailability of ginsenosides, using ginsenoside Rg3 (Rg3) as a marker.
UNASSIGNED: A novel PLs formulation was prepared using a modified evaporation-on-matrix method. Soy phosphatidylcholine, Rg3-enriched extract, poloxamer 188 (Lutrol® F 68) and sorbitol were mixed and dissolved using a aqueous ethanolic solution, followed by the removal of ethanol and lyophilization. The characterization of Rg3-PLs formulations was performed by powder X-ray diffractometry (PXRD), transmission electron microscopy (TEM) and in vitro release. The enhancement of oral bioavailability was investigated and analyzed by non-compartmental parameters after oral administration of the formulations.
UNASSIGNED: PXRD of Rg3-PLs indicated that Rg3 was transformed from crystalline into its amorphous form during the preparation process. The Rg3-encapsulated liposomes with vesicular-shaped morphology were generated after the reconstitution by gentle hand-shaking in water; they had a mean diameter of approximately 350 nm, a negative zeta potential (-28.6 mV) and a high entrapment efficiency (97.3%). The results of the in vitro release study exhibited that significantly more amount of Rg3 was released from the PLs formulation in comparison with that from the suspension of Rg3-enriched extract (control group). The pharmacokinetic parameters after oral administration of PLs formulation in rats showed an approximately 11.8-fold increase in the bioavailability of Rg3, compared to that of the control group.
UNASSIGNED: The developed PLs formulation could be a favorable delivery system to improve the oral bioavailability of ginsenosides, including Rg3.

Ginsenosides in ginseng are known for their potential health benefits, including antioxidant properties and their potential to exhibit anticancer effects. Besides a various range of coding genes, ginsenosides impose their efficacy by targeting noncoding RNAs. Long noncoding RNA ( lncRNA) has gained significant attention from both basic and clinical oncology fields due to its involvement in various cancer cell activities such as proliferation, apoptosis, metastasis, and autophagy. These events can be achieved either by lncRNA alone or in association with microRNAs or proteins. This review aims to summarize the diverse activities of lncRNAs that are regulated by ginsenosides, focusing on their role in regulating target genes through signaling pathways in human diseases. We highlight the results of studies on the expression profiles of lncRNAs induced by ginsenosides in efforts to inhibit cancer cell proliferation. Finally, we discuss the potential and challenges of utilizing lncRNAs as diagnostic markers for disease treatment.

Triple negative breast cancer (TNBC) has the characteristics of low immune cell infiltration, high expression of tumor programmed death ligand 1 (PD-L1), and abundant cancer stem cells. Systemic toxicity of traditional chemotherapy drugs due to poor drug selectivity, and chemotherapy failure due to tumor drug resistance and other problems, so it is particularly important to find new cancer treatment strategies for TNBC with limited treatment options. Both the anti-tumor natural drugs curcumin and ginsenoside Rg3 can exert anti-tumor effects by inducing immunogenic cell death (ICD) of tumor cells, reducing PD-L1 expression, and reducing cancer stem cells. However, they have the disadvantages of poor water solubility, low bioavailability, and weak anti-tumor effect of single agents. We used vinyl ether bonds to link curcumin (Cur) with N-O type zwitterionic polymers and at the same time encapsulated ginsenoside Rg3 to obtain hyperbranched zwitterionic drug-loaded micelles OPDEA-PGED-5HA@Cur@Rg3 (PPH@CR) with pH response. In vitro cell experiments and in vivo animal experiments have proved that PPH@CR could not only promote the maturation of dendritic cells (DCs) and increase the CD4+ T cells and CD8+ T cells by inducing ICD in tumor cells but also reduce the expression of PD-L1 in tumor tissues, and reduce cancer stem cells and showed better anti-tumor effects and good biological safety compared with free double drugs, which is a promising cancer treatment strategy.

Notoginseng saponin R1; ginsenosides Rg1, Re, Rb1, and Rd; the sum of the five saponins; and underground-part fresh weight (UPFW) of single plants were used as quality evaluation indices for Panax notoginseng (Burk.) F. H. Chen (P. notoginseng). Comprehensive evaluation of P. notoginseng samples from 30 production areas was performed using that MaxEnt model. Spatial pattern changes in suitable P. notoginseng habitats were predicted for current and future periods (2050s, 2070s, and 2090s) using SSP126 and SSP585 models. The results revealed that temperature, precipitation, and solar radiation were important environmental variables. Suitable habitats were located mainly in Yunnan, Guizhou, and Sichuan Provinces. The distribution core of P. notoginseng is predicted to shift southeast in the future. The saponin content decreased from the southeast to the northwest of Yunnan Province, which was contrary to the UPFW trend. This study provides the necessary information for the protection and sustainable utilization of P. notoginseng resources, and a theoretical reference for its application in the quality evaluation of Chinese medicinal products.

Current evidence suggests a beneficial role of herbal products in free radical-induced diseases. Panax notoginseng (Burk.) F. H. Chen has long occupied a leading position in traditional Chinese medicine because of the ergogenic, nootropic, and antistress activities, although these properties are also acknowledged in the Western world. The goal of this paper is to review the pharmacological and toxicological properties of P. notoginseng and discuss its potential therapeutic effect. A literature search was carried out on Pubmed, Scopus, and the Cochrane Central Register of Controlled Trials databases. The following search terms were used: \"notoginseng\", \"gut microbiota\", \"immune system\", \"inflammation\", \"cardiovascular system\", \"central nervous system\", \"metabolism\", \"cancer\", and \"toxicology\". Only peer-reviewed articles written in English, with the full text available, have been included. Preclinical evidence has unraveled the P. notoginseng pharmacological effects in immune-inflammatory, cardiovascular, central nervous system, metabolic, and neoplastic diseases by acting on several molecular targets. However, few clinical studies have confirmed the therapeutic properties of P. notoginseng, mainly as an adjuvant in the conventional treatment of cardiovascular disorders. Further clinical studies, which both confirm the efficacy of P. notoginseng in free radical-related diseases and delve into its toxicological aspects, are mandatory to broaden its therapeutic potential.

Sepsis-induced acute lung injury (SALI) poses a significant threat with high incidence and mortality rates. Ginsenoside Rg1 (GRg1), derived from Ginseng in traditional Chinese medicine, has been found to reduce inflammation and protect lung epithelial cells against tissue damage. However, the specific roles and mechanisms by which GRg1 mitigates SALI have yet to be fully elucidated. In this context, we employed a relevant SALI mouse model, alongside network pharmacology, molecular docking, and molecular dynamics simulation to pinpoint GRg1\'s action targets, complemented by in vitro assays to explore the underlying mechanisms. Our research shows that GRg1 alleviates CLP-induced SALI, decreasing lung tissue damage and levels of serum proinflammatory factor IL-6, TNF-α, and IL-1β, also enhancing the survival rate of CLP mice. A total of 116 common targets between GRg1 and ALI, with specific core targets including AKT1, VEGFA, SRC, IGF1, ESR1, STAT3, and ALB. Further in vitro experiments assessed GRg1\'s intervention effects on MLE-12 cells exposed to LPS, with qRT-PCR analysis and molecular dynamics simulations confirming AKT1 as the key target with the favorable binding activity for GRg1. Western blot results indicated that GRg1 increased the Bcl-2/Bax protein expression ratio to reduce apoptosis and decreased the high expression of cleaved caspase-3 in LPS-induced MLE-12 cells. More results showed significant increases in the phosphorylation of PI3K and AKT1. Flow cytometric analysis using PI and Annexin-V assays further verified that GRg1 decreased the apoptosis rate in LPS-stimulated MLE-12 cells (from 14.85 to 6.54%, p < 0.05). The employment of the AKT1 inhibitor LY294002 confirmed these trends, indicating that AKT1\'s inhibition negates GRg1\'s protective effects on LPS-stimulated MLE-12 cells. In conclusion, our research highlights GRg1\'s potential as an effective adjunct therapy for SALI, primarily by inhibiting apoptosis in alveolar epithelial cells and reducing pro-inflammatory cytokine secretion, thus significantly enhancing the survival rates of CLP mice. These beneficial effects are mediated through targeting AKT1 and activating the PI3K-AKT pathway.

BACKGROUND: The ginseng endophyte Paenibacillus polymyxa Pp-7250 (Pp-7250) has multifaceted roles such as preventing ginseng diseases, promoting growth, increasing ginsenoside accumulation, and degrading pesticide residues, however, these effects still have room for improvements. Composite fungicides are an effective means to improve the biocontrol effect of fungicides, but the effect of Pp-7250 in combination with its symbiotic bacteria on ginseng needs to be further investigated, and its mechanism of action has not been elucidated. In this study, a series of experiments was conducted to elucidate the effect of Paenibacillus polymyxa and Bacillus cereus co-bacterial agent on the yield and quality of understory ginseng, and to investigate their mechanism of action.
RESULTS: The results indicated that P. polymyxa and B. cereus co-bacterial agent (PB) treatment improved ginseng yield, ginsenoside accumulation, disease prevention, and pesticide degradation. The mechanism is that PB treatment increased the abundance of beneficial microorganisms, including Rhodanobacter, Pseudolabrys, Gemmatimonas, Bacillus, Paenibacillus, Cortinarius, Russula, Paecilomyces, and Trechispora, and decreased the abundance of pathogenic microorganisms, including Ellin6067, Acidibacter, Fusarium, Tetracladium, Alternaria, and Ilyonectria in ginseng rhizosphere soil. PB co-bacterial agents enhanced the function of microbial metabolic pathways, biosynthesis of secondary metabolites, biosynthesis of antibiotics, biosynthesis of amino acids, carbon fixation pathways in prokaryotes, DNA replication, and terpenoid backbone biosynthesis, and decreased the function of microbial plant pathogens and animal pathogens.
CONCLUSIONS: The combination of P. polymyxa and B. cereus may be a potential biocontrol agent to promote the resistance of ginseng to disease and improve the yield, quality, and pesticide degradation.

BACKGROUND: Oxidative stress may contribute to cardiac ryanodine receptor (RyR2) dysfunction in diabetic cardiomyopathy. Ginsenoside Rb1 (Rb1) is a major pharmacologically active component of ginseng to treat cardiovascular diseases. Whether Rb1 treat diabetes injured heart remains unknown. This study was to investigate the effect of Rb1 on diabetes injured cardiac muscle tissue and to further investigate its possible molecular pharmacology mechanisms.
METHODS: Male Sprague-Dawley rats were injected streptozotocin solution for 2 weeks, followed 6 weeks Rb1 or insulin treatment. The activity of SOD, CAT, Gpx, and the levels of MDA was measured; histological and ultrastructure analyses, RyR2 activity and phosphorylated RyR2(Ser2808) protein expression analyses; and Tunel assay were performed.
RESULTS: There was decreased activity of SOD, CAT, Gpx and increased levels of MDA in the diabetic group from control. Rb1 treatment increased activity of SOD, CAT, Gpx and decreased the levels of MDA as compared with diabetic rats. Neutralizing the RyR2 activity significantly decreased in diabetes from control, and increased in Rb1 treatment group from diabetic group. The expression of phosphorylation of RyR2 Ser2808 was increased in diabetic rats from control, and were attenuated with insulin and Rb1 treatment. Diabetes increased the apoptosis rate, and Rb1 treatment decreased the apoptosis rate. Rb1 and insulin ameliorated myocardial injury in diabetic rats.
CONCLUSIONS: These data indicate that Rb1 could be useful for mitigating oxidative damage, reduced phosphorylation of RyR2 Ser2808 and decreased the apoptosis rate of cardiomyocytes in diabetic cardiomyopathy.