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This work aimed at improving the water solubility of Ginsenoside (G)-Re by forming an inclusion complex. The solubility parameters of G-Re in alpha (α), beta (β), and gamma (γ) cyclodextrin (CD) were investigated. The phase solubility profiles were all classified as AL-type that indicated the 1:1 stoichiometric relationship with the stability constants Ks which were 22 M−1 (α-CD), 612 M−1 (β-CD), and 14,410 M−1 (γ-CD), respectively. Molecular docking studies confirmed the results of phase solubility with the binding energy of −4.7 (α-CD), −5.10 (β-CD), and −6.70 (γ-CD) kcal/mol, respectively. The inclusion complex (IC) of G-Re was prepared with γ-CD via the water-stirring method followed by freeze-drying. The successful preparation of IC was confirmed by powder X-ray diffraction (XRD), Fourier transform-infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), and scanning electron microscopy (SEM). In-vivo absorption studies were carried out by LC-MS/MS. Dissolution rate of G-Re was increased 9.27 times after inclusion, and the peak blood concentration was 2.7-fold higher than that of pure G-Re powder. The relative bioavailability calculated from the ratio of Area under the curve AUC0–∞ of the inclusion to pure G-Re powder was 171%. This study offers the first report that describes G-Re’s inclusion into γ-CD, and explored the inclusion complex’s mechanism at the molecular level. The results indicated that the solubility could be significantly improved as well as the bioavailability, implying γ-CD was a very suitable inclusion host for complex preparation of G-Re.

Ginsenoside Re is a protopanaxatriol-type saponin extracted from the berry, leaf, stem, flower bud, and root of Panax ginseng . In recent years, ginsenoside Re (Re) has been attracting attention as a dietary phytochemical. In this review, studies on Re were compiled by searching a combination of keywords, namely “pharmacology,” “pharmacokinetics,” and “toxicology,” in the Google Scholar, NCBI, PubMed, and Web of Science databases. The aim of this review was to provide an exhaustive overview of the pharmacological activities, pharmacokinetics, and toxicity of Re, focusing on clinical evidence that has shown effectiveness in specific diseases, such as diabetes mellitus, nervous system diseases, inflammation, cardiovascular disease, and cancer. Re is also known to eliminate virus, enhance the immune response, improve osteoporosis, improve skin barrier function, enhance intracellular anti-oxidant actions, regulate cholesterol metabolism, alleviate allergic responses, increase sperm motility, reduce erectile dysfunction, promote cyclic growth of hair follicles, and reduce gastrointestinal motility dysfunction. Furthermore, this review provides data on pharmacokinetic parameters and toxicological factors to examine the safety profile of Re. Such data will provide a theoretical basis and reference for Re-related studies and future applications.

Accumulation of amyloid-β (Aβ), which results in the formation of senile plaques that cause oxidative damage and neuronal cell death, has been accepted as the major pathological mechanism of Alzheimer’s disease (AD). Hence, inhibition of Aβ-induced oxidative damage and neuronal cell apoptosis represents the effective strategies in combating AD. Ginsenoside Re (Re) has pharmacological effects against Aβ-induced neurotoxicity. However, its molecular mechanism remains elusive. The present study evaluated the effect of Re against Aβ-induced cytotoxicity and apoptosis in SH-SY5Y cells, and investigated the underlying mechanism. We demonstrate that Re inhibits the Aβ-triggered mitochondrial apoptotic pathway, as indicated by maintenance of mitochondrial functional, elevated Bcl-2/Bax ratio, reduced cytochrome c release, and inactivation of caspase-3/9. Re attenuated Aβ-evoked reactive oxygen species (ROS) production, apoptosis signal-regulating kinase 1 (ASK1) phosphorylation, and JNK activation. ROS-scavenging abrogated the ability of Re to alter ASK-1 activation. Simultaneously, inhibition of JNK abolished Re-induced Bax downregulation in Aβ-challenged SH-SY5Y cells. In addition, Re enhanced activation of the nuclear factor-E2-related factor 2 (Nrf2) in Aβ-induced SH-SY5Y cells. Knockdown of Nrf2 by small interfering RNA targeting Nrf2 abolished the protective effect of Re. Our findings indicate that Re could be a potential therapeutic approach for the treatment of AD.

Fluorescent carbon-based nanomaterials have promising properties such as biosensing, cell imaging, tracing and drug delivery. However, carbon dots (CDs) with specific inherent biological functions have not been investigated. Ginsenosides are the components with multiple bioactivities found in plants of the genus , which have attracted a lot of attention for their anticancer effect. In this study, we prepared a kind of novel photoluminescent CDs from ginsenoside Re by one-step hydrothermal synthesis method. The conventional methods including transmission electron microscopy, Fourier transform infrared spectroscopy, HPLC and fluorescence spectrum were used for characterization of CDs. In vitro anticancer effect was investigated by cytotoxicity assay, flow cytometry and Western blot analysis. The as-prepared Re-CDs had an average diameter of 4.6±0.6 nm and excellent luminescent properties. Cellular uptake of Re-CDs was facilitated by their tiny nanosize, with evidence of their bright excitation-dependent fluorescent images. Compared with ginsenoside Re, the Re-CDs showed greater inhibition efficiency of cancer cell proliferation, with lower toxicity to the normal cells. The anticancer activity of Re-CDs was suggested to be associated with the generation of large amount of ROS and the caspase-3 related cell apoptosis. Hopefully, the dual functional Re-CDs, which could both exhibit bioimaging and anticancer effect, are expected to have great potential in future clinical applications.

Despite the rapid advancement of glycosidase biotechnology, ginsenoside-transforming rhamnosidases remain underexplored due to a lack of research. In this study, we aimed to bridge this gap by evaluating eight putative rhamnosidases for their ability to transform ginsenosides. Among them, a novel rhamnosidase (C118) from Bifidobacterium was identified as being efficient at hydrolyzing ginsenoside Re. This enzyme was expressed well in Escherichia coli and exhibited optimal activity at pH of 6.0 and 45 °C. Protein structural predictions revealed that the potential active hydrophobic area near an active pocket may influence the ginsenoside-transforming activities compared to non-active screened rhamnosidases. This enzyme’s thermal stability exceeded that of the only previously known ginsenoside-transforming rhamnosidase, BD890. Additionally, the kcat/Km value of C118 was 1.45 times higher than that of BD890. Using recombinant C118 from E. coli, all ginsenoside Re in a PPT-type ginsenoside mixture (2.25 mg/mL) was converted after 12 h of reaction. To the best of our knowledge, this is the most efficient ginsenoside Re-transforming α-L-rhamnosidase reported to date, enhancing our understanding of rhamnosidase–substrate interactions and potentially improving the efficiency and specificity of the conversion process. These findings offer promising implications for the production of pharmacologically active ginsenosides in the pharmaceutical, cosmetic, and functional food industries.

Ginsenoside Re was the major bioactive component found rich in Panax ginseng C. A. Meyer, which exerted excellent cardiovascular protection, anti-inflammatory, and anti-oxidation effects. The generation of unexpected degradation products (DPs) may influence the therapeutic effect of Re, or even bring toxic effects to patients. However, to date, only a few reports were available about the stability of Re. The present study aims to systematically investigate the degradation behaviors of Re under different stress conditions, including hydrolysis (acidic, basic, and neutral), oxidation, humidity, thermal, and photolytic (ultraviolet and visible light) conditions. A total of thirteen DPs were putatively identified, and among them, nine were discovered for the first time in our study. The results showed that Re was sensitive to exposure to acidic, basic, and oxidation conditions. It underwent a series of chemical degradation reactions, including deglycosylation, dehydration, addition, oxidation at the double bond, and isomerization under various stress conditions. Structural characterization of these DPs was carried out by UHPLC-DAD-CAD and LC-LTQ/Orbitrap. A plausible mechanism of their formation was proposed to support the structures of all DPs of Re. In silico toxicity prediction and metabolism behavior assessment were done by Derek Nexus and Meteor Nexus software. Re and DP-1 to DP-6 were predicted to possess potential skin irritation/corrosion toxicity. DP-11 and DP-12 bear the potential for carcinogenicity, mutagenicity, irritation, hepatotoxicity, and skin sensitization. The observation of these DPs updates our knowledge regarding the stability of Re, which provides valuable information for quality control and to choose suitable storage conditions.

[This corrects the article DOI: 10.3389/fphar.2020.00695.].

The increasing demographic aging of society is a great challenge to the healthcare sector and raises the socio-economic burden. Therefore, elucidating the mechanisms of aging and developing safe effective anti-aging products to prolong people’s healthy lifespan are paramount nowadays. Panax ginseng has been highly regarded since ancient times for its ability to enhance health and prolong life. However, its main active substances of anti-aging and their mechanisms are not fully understood. In this research, Caenorhabditis elegans was used as a model organism to explore and confirm the key active substances from Panax ginseng and the mechanisms that exert anti-aging effects. Various ginsenoside compounds were evaluated based on longevity, anti-stress, physiological function, etc. Ginsenoside Re, which has powerful anti-aging activity, was screened. In the follow-up trials, transcriptomics and RT-qPCR techniques were used to investigate the mechanism of Re in exerting its anti-aging properties. Differential genes were enriched in the Insulin/Insulin-like Growth Factor-1 Signaling (IIS) pathway, the neuropeptide signaling pathway, and lipid metabolism. A significant increase in the expression levels of daf-16, sgk-1, skn-1, hsf-1, hsp-16.2, sod-3, gst-4, fil-2, lips-11, cyp-35A4, and aex-2 genes, and a significant decrease in the expression levels of daf-2, age-1, and akt-2 genes were verified. These suggest that ginsenoside Re exerts its life-extending influence by regulating lipid metabolism and the IIS pathway.

Ginsenoside Re (G-Re) is a panaxatriol saponin and one of the pharmacologically active natural constituents of ginseng (Panax ginseng C.A. Meyer). G-Re has antioxidant, anti-inflammatory and antidiabetic effects. The present study aimed to investigate the effects of G-Re on neuroinflammatory responses in lipopolysaccharide (LPS)-stimulated microglia and its protective effects on hippocampal neurons. Cytokine levels were measured using ELISA and reactive oxygen species (ROS) levels were assessed using flow cytometry and fluorescence microscopy. Protein levels of inflammatory molecules and kinase activity were assessed by western blotting. Cell viability was assessed by MTT assay; apoptosis was estimated by Annexin V apoptosis assay. The results revealed that G-Re significantly inhibited the production of IL-6, TNF-α, nitric oxide (NO) and ROS in BV2 microglial cells, and that of NO in mouse primary microglia, without affecting cell viability. G-Re also inhibited the nuclear translocation of NF-κB, and phosphorylation and degradation of IκB-α. In addition, G-Re dose-dependently suppressed LPS-mediated phosphorylation of Ca2+/calmodulin-dependent protein kinase (CAMK)2, CAMK4, extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinases (JNK). Moreover, the conditioned medium from LPS-stimulated microglial cells induced HT22 hippocampal neuronal cell death, whereas that from microglial cells incubated with both LPS and G-Re ameliorated HT22 cell death in a dose-dependent manner. These results suggested that G-Re suppressed the production of pro-inflammatory mediators by blocking CAMK/ERK/JNK/NF-κB signaling in microglial cells and protected hippocampal cells by reducing these inflammatory and neurotoxic factors released from microglial cells. The present findings indicated that G-Re may be a potential treatment option for neuroinflammatory disorders and could have therapeutic potential for various neurodegenerative diseases.

Ginsenoside Rg3 (Rg3) is an adjuvant antitumor drug, while ginsenoside Re (Re) is an adjuvant antidiabetic drug. Our previous studies demonstrated that Rg3 and Re both have hepatoprotective effects in db/db mice. The present study aimed to observe the renoprotective effects of Rg3 on db/db mice, with Re as the control. The db/db mice were randomly assigned to receive daily oral treatment with Rg3, Re or vehicle for 8 weeks. Body weight and blood glucose were examined weekly. Blood lipids, creatinine, and BUN were examined by biochemical assay. Hematoxylin and eosin and Masson staining were used for pathological examination. The expression of peroxisome proliferator-activated receptor gamma (PPAR[gamma]) and inflammation and fibrosis biomarkers was examined by immunohistochemical and reverse transcription-quantitative PCR. Although neither had a significant effect on body weight, blood glucose or lipids, Rg3 and Re were both able to decrease the creatinine and blood urea nitrogen levels of db/db mice to levels similar to those of wild type mice and inhibit pathological changes. The expression of PPAR[gamma] was upregulated and biomarkers of inflammation and fibrosis were downregulated by Rg3 and Re. The results showed that the potential of Rg3 as a preventive treatment of diabetic kidney disease was similar to that of Re.