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The inhibition of Na⁺/K⁺-ATPase by versatile steroid-like compounds contributes to the putative therapeutic effects of many Chinese medicinal cardiac products via the same molecular mechanism triggered by cardiac glycosides. Five major steroid-like compounds, antcin A, B, C, H, and K were isolated from Niuchangchih (Antrodia camphorata), a unique Taiwan mushroom, and all inhibited Na⁺/K⁺-ATPase. Antcin A exhibited significantly higher inhibitory potency than the other four antcins, though weaker than ginsenoside Rh2. In contrast, cortisone (an analogous steroid with anti-inflammatory effects stronger than antcin A) showed no detectable inhibitory potency. Molecular modeling has shown that antcins bind to Na⁺/K⁺-ATPase with the steroidal skeleton structurally upside-down in comparison with ginsenoside Rh2. The inhibitory potency of antcin A is attributed to steroidal hydrophobic interaction within the binding pocket and the formation of three hydrogen bonds between its carboxyl group and two cationic residues around the cavity entrance of Na⁺/K⁺-ATPase. The presence of an additional carbonyl or hydroxyl group at C7 of the other four antcins leads to severe repulsion in the hydrophobic pocket, and thus significantly reduces inhibitory potency. It is proposed that antcin A is a bi-functional compound that exerts anti-inflammatory effects and that enhances blood circulation via two different molecular mechanisms.

The total amount of ginsenoside in fermented red ginseng (FRG) is increased by microbial fermentation. The aim of this study was to evaluate whether fermentation time and temperature affect the ginsenoside content during fermentation using an appliance for the preparation of red ginseng. The FRG and fermented red ginseng extracts (FRG-e) were prepared using an appliance for the preparation of red ginseng. The temperature was recorded and time points for sampling were scheduled at pre-fermentation (0h) and 18, 36, 48, 60 and 72h after the addition of the microbial strains. Samples of FRG and FRG-e were collected to identify changes in the ginsenoside contents at each time point during the fermentation process. The ginsenoside content was analyzed using high performance liquid chromatography (HPLC). The levels of ginsenoside Rh1, Rg3, and compound Y, which are known to have effective pharmacological properties, increased more than three-fold in the final products of FRG relative to samples prior to fermentation. Although the ginsenoside constituents of FRG-e decreased or increased and then decreased during fermentation, the total amount of ginsenoside in FRG-e was even higher than those in FRG; the total amounts of ginsenoside in FRG-e and FRG were 8282.8 and 738.0mg, respectively. This study examined the changes in composition of ginsenosides and suggests a method to manufacture high-content total ginsenosides according to the fermentation temperature and process time. Reducing the extraction time is expected to improve the decrease of ginsenosides in FRG-e as a function of the fermentation time.

Angiogenesis is a regulated process integral to many physiological and pathological situations, including carcinogenesis and tumor growth. The majority of the angiogenic processes are related to inflammation. The interplay is not only important in the case of pathogen entry but also influential in chronic inflammatory diseases, tumor growth and tissue regeneration. Modulating the interaction between inflammation and angiogenesis could be an important target for cancer treatment and wound healing alike. Ginseng has a wide range of pharmacological effects, including anti-inflammatory and angiogenesis-modulating activities. This paper presents the recent research progresses on the inhibition of angiogenesis by ginseng and its active constituents, with a particular focus on processes mediated by inflammation. The modulatory role of ginseng compounds in inflammation-mediated angiogenesis involving hypoxia and microRNAs are also discussed. With the potential to modulate the angiogenesis at the transcriptional, translational and protein signaling level via various different mechanisms, ginseng could prove to be effective in cancer therapeutics.

The present study was designed to assess the effects and potential mechanisms of ginsenosides on 17$\alpha$-ethynyelstradiol (EE)-induced intrahepatic cholestasis (IC). Ginsenoside at doses of 30, 100, 300mg/kg body weight was intragastrically (i.g.) given to rats for 5 days to examine the effect on EE-induced IC. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bile acid (TBA) were measured. Hepatic malondialdehyde (MDA) content and superoxide dismutase (SOD) activity were determined. Protein expression of proinflammatory cytokines TNF-$\alpha$, IL-6 and IL-1$\beta$ was analyzed by immunohistochemistry and Western blot. Results indicated that ginsenosides remarkably prevented EE-induced increase in the serum levels of AST, ALT, ALP and TBA. Moreover, the elevation of hepatic MDA content induced by EE was significantly reduced, while hepatic SOD activities were significantly increased when treated with ginsenosides. Histopathology of the liver tissue showed that pathological injuries were relieved after treatment with ginsenosides. In addition, treatment with ginsenosides could significantly downregulate the protein expression of TNF-$\alpha$, IL-6 and IL-1$\beta$ compared with EE group. These findings indicate that ginsenosides exert the hepatoprotective effect on EE-induced intrahepatic cholestasis in rats, and this protection might be attributed to the attenuation of oxidative stress and inflammation.

Inflammation and endoplasmic reticulum (ER) stress have been documented to contribute to the development of atherosclerosis. Ginsenoside Rb2 has been reported to exhibit antidiabetic effects. However, the effects of Rb2 on atherosclerotic responses such as inflammation and ER stress in endothelial cells and monocytes remain unclear. In this study, the expression of inflammation and ER stress markers was determined using a Western blotting method. Concentrations of tumor necrosis factor alpha (TNF$\alpha$) and monocyte chemoattractant protein-1 (MCP-1) in culture media were assessed by enzyme-linked immunosorbent assay (ELISA) and apoptosis was evaluated by a cell viability assay and a caspase-3 activity measurement kit. We found that exposure of HUVECs and THP-1 monocytes to Rb2 attenuated inflammation and ER stress, resulting in amelioration of apoptosis and THP-1 cell adhesion to HUVECs under lipopolysaccharide (LPS) condition. Increased AMPK phosphorylation and heme oxygenase (HO)-1 expression, including GPR120 expression were observed in Rb2-treated HUVECs and THP-1 monocytes. Downregulation of both, AMPK phosphorylation and HO-1expression rescued these observed changes. Furthermore, GPR120 siRNA mitigated Rb2-induced AMPK phosphorylation. These results suggest that Rb2 inhibits LPS-mediated apoptosis and THP-1 cell adhesion to HUVECs by GPR120/AMPK/HO-1-associated attenuating inflammation and ER stress. Therefore, Rb2 can be used as a potential therapeutic molecule for treatment of atherosclerosis.

Ginsenosides of orally administered red ginseng (RG) extracts are metabolized and absorbed into blood. Here, we examined the pharmacokinetic profiles of ginsenosides Rd and Rg3 in mice orally gavaged with RG, then investigated the correlations between these and gut microbiota composition. RG water extract (RGw), RG ethanol extract (RGe), or fermented RGe (fRGe) was orally gavaged in mice. The plasma concentrations of the ginsenosides were determined, and the gut microbiota composition was analyzed. RGe and fRGe-treated mice showed higher plasma concentration levels of ginsenoside Rd compared with RGw-treated mice; particularly, ginsenoside Rd absorbed was substantially high in fRGe-treated mice. Oral administration of RG extracts modified the gut microbiota composition; the modified gut microbiota, such as Peptococcaceae, Rikenellaceae, and Hungateiclostridiaceae, were closely correlated with the absorption of ginsenosides, such as Rd and Rg3. These results suggest that oral administration of RG extracts can modify gut microbiome, which may consequently affect the bioavailability of RG ginsenosides.

The endothelium covers the internal lumen of the entire circulatory system and plays an important modulatory role in vascular homeostasis. Endothelium dysfunction, characterized by a vasoconstrictive, pro-inflammatory, and pro-coagulant state, usually manifests as a significant pathological process of vascular diseases, including hypertension, atherosclerosis (AS), stroke, diabetes mellitus, coronary artery disease, and cancer. Therefore, there is an urgent necessity to seek promising therapeutic drugs or remedies to ameliorate endothelial dysfunction-induced vascular ailments and complications. Recently, much attention has been attached to ginsenosides, the most significant active components of ginseng, which have always been referred to as “all-healing” and widely used for its extensively medicinal value. Surprisingly, ginsenosides have diverse biological activity which might be related to inflammation, apoptosis, oxidative stress, and angiogenesis. In this review, a brief introduction about endothelial dysfunction and ginsenosides was demonstrated, and the emphasis was put on summarizing multi-faceted pharmacological effects and underlying molecular mechanisms of ginsenosides on the endothelium, including vasorelaxation, anti-oxidation, anti-inflammation, and angio-modulation. Beyond that, nanotechnology to improve efficacy and the existing clinical trials of ginsenosides were concluded. Hopefully, our work will give suggestions for promoting clinical application of traditional Chinese medicine, e.g., hypertension, AS, diabetes, ischemic stroke, and cancer. This review provides a comprehensive base of knowledge for ginsenosides to prevention and treatment of vascular injury- related diseases with clinical significance.

While a number of coding genes have explained the anticancer activity of ginsenoside Rh2, little is known about noncoding RNAs. This study was performed to elucidate the regulatory activity of long noncoding RNA (lncRNA) CFAP20DC-AS1, which is known to be downregulated by Rh2. MiR-3614-3p, which potentially binds CFAP20DC-AS1, was screened using the LncBase Predicted program, and the binding was verified by assaying the luciferase activity of a luciferase/lncRNA recombinant plasmid construct. The competitive endogenous RNA (ceRNA) relationship of the two RNAs was further validated by quantitative PCR after deregulation of each RNA using siRNA. The effect of miRNA and target genes on the MCF-7 cancer cell growth was determined by monitoring proliferation and apoptosis in the presence of Rh2 after deregulating the corresponding gene. The miRNA decreased the luciferase activity of the luciferase/CFAP20DC-AS1 fusion vector, confirming the binding. SiRNA-based deregulation of CFAP20DC-AS1 attenuated the expression of miR-3614-3p and vice versa. In contrast to CFAP20DC-AS1, miR-3614-3p was upregulated by Rh2, inhibiting proliferation but stimulating apoptosis of the MCF-7 cells. Target genes of miR-3614-3p, BBX and TNFAIP3, were downregulated by Rh2 and the miRNA but upregulated by the lncRNA. Rh2 inhibits CFAP20DC-AS1, which obscures the association of the lncRNA with miR-3614-3p, resulting in the suppression of oncogenic BBX and TNFAIP3. Taken together, the Rh2/CFAP20DC-AS1/miR-3614-3p/target gene axis contributes to the antiproliferation activity of Rh2 in cancer cells.

Gut microbiota are significantly associated with the occurrence and development of inflammatory bowel disease (IBD). Panax notoginseng saponins (PNS) could be used for colitis and to modulate gut microbiota. However, the mechanism behind the effects of PNS on anti-colitis that are pertinent to gut microbiota is largely unknown. This study aimed to evaluate the anti-colitis effects of PNS and explore the involved mechanism as it is related to gut microbiota. Results showed that PNS significantly alleviated dextran sulfate sodium (DSS)-induced colitis. Meanwhile, after PNS treatment, the tight junction proteins were enhanced and proinflammatory cytokines, such as TNF-$\alpha$, IL-6, IL-1$\beta$, and IL-17, were decreased. Furthermore, Bacteroides spp. were significantly increased after modeling, while PNS reduced their abundance and significantly increased the amount of Akkermansia spp. in vivo. Importantly, Akkermansia spp. and Bacteroides spp. were correlated with the IBD disease indicators. Moreover, fecal microbiota transplantation (FMT) experiments confirmed that PNS-reshaped gut microbiota significantly alleviated DSS-induced colitis, while A. muciniphila significantly reduced the levels of the LPS-induced cellular inflammatory factors IL-1$\beta$ and TNF-$\alpha$. In conclusion, PNS alleviated colitis pertinent to the upregulation of Akkermania spp. and downregulation of Bacteroides spp. in the gut.

Ginseng is a valuable medicinal plant in Asian countries with thousands of years of history. Ginsenosides, one of the active components of ginseng, are considered to be of potential value in the treatment of various diseases. The antitumor effects of ginsenosides, such as Rg3, Rh2, Rg5, and CK, are well known, and their potential mechanisms are thought to be related to inducing apoptosis, enhancing the immune response, reversing drug resistance to chemotherapy, and regulating signaling pathways, such as MAPK, PI3K/Akt/mTOR, Wnt/$\beta$-catenin, NF-$\kappa$B, ASK-1/JNK, AMPK, and EGFR/Akt/SOX2. On the other hand, ginsenosides also have anti-inflammatory effects, including reducing the release of inflammatory factors, regulating the balance of immune cells, regulating the diversity of intestinal flora, and activating MAPK, NF-$\kappa$B, and NLRP3 inflammasomes. These data suggest that ginsenosides may provide new insights as promising drugs for the treatment of malignant tumors and inflammatory diseases.