Network Pharmacology Analysis and In Vitro Validation of the Active Ingredients and Potential Mechanisms of Gynostemma Pentaphyllum Against Esophageal Cancer.

BACKGROUND: Esophageal cancer (EC) is one of the deadliest malignancies worldwide. Gynostemma pentaphyllum Thunb. Makino (GpM) has been used in traditional Chinese medicine as a treatment for tumors and hyperlipidemia. Nevertheless, the active components and underlying mechanisms of anti-EC effects of GpM remain elusive. OBJECTIVE: This study aims to determine the major active ingredients of GpM in the treatment of EC and to explore their molecular mechanisms by using network pharmacology, molecular docking, and in vitro experiments. METHODS: Firstly, active ingredients and potential targets of GpM, as well as targets of EC, were screened in relevant databases to construct a compound-target network and a protein-protein interaction (PPI) network that narrowed down the pool of ingredients and targets. This was followed by gene ontology (GO) functional and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Next, molecular docking, ADME and toxicity risk prediction, cell viability assays, in vitro scratch assays, Transwell cell invasion assays, and Western blotting analysis were subsequently applied to validate the results of the network analysis. RESULTS: The screening produced a total of 21 active ingredients and 167 ingredient-related targets for GpM, along with 2653 targets for EC. The PPI network analysis highlighted three targets of interest, namely AKT1, TP53, and VEGFA, and the compound-target network identified three possible active ingredients: quercetin, rhamnazin, and isofucosterol. GO and EKGG indicated that the mechanism of action might be related to the PI3K/AKT signaling pathway as well as the regulation of cell motility and cell migration. Molecular docking and pharmacokinetic analyses suggest that quercetin and isoprostanoid sterols may have therapeutic value and safety for EC. The in vitro experiments confirmed that GpM can inhibit EC cell proliferation, migration, and invasion and suppress PI3K and AKT phosphorylation. CONCLUSION: Our findings indicate that GpM exerts its anti-tumor effect on EC by inhibiting EC cell migration and invasion via downregulation of the PI3K/AKT signaling pathway. Hence, we have reason to believe that GpM could be a promising candidate for the treatment of EC.

Probabilistic double hierarchy linguistic Maclaurin symmetric mean-MultiCriteria Border Approximation area Comparison method for multi-criteria group decision making and its application in a selection of traditional Chinese medicine prescriptions.

Traditional Chinese medicine (TCM) has gradually played an indispensable role in people's health maintenance, especially in the treatment of chronic diseases. However, there is always uncertainty and hesitation in the judgment and understanding of diseases by doctors, which affects the status recognition and optimal diagnosis and treatment decision-making of patients. In order to overcome the above problems, we lead into probabilistic double hierarchy linguistic term set (PDHLTS) to accurately describe language information in traditional Chinese medicine and make decisions. In this paper, a multi-criteria group decision making (MCGDM) model is constructed based on the MSM-MCBAC (Maclaurin symmetric mean-MultiCriteria Border Approximation area Comparison) method in the PDHL environment. Firstly, a PDHL weighted Maclaurin symmetric mean (PDHLWMSM) operator is proposed to aggregate the evaluation matrices of multiple experts. Then, combined with the BWM and maximizing deviation method, a comprehensive weight determination method is put forward to calculate the weights of criteria. Furthermore, we propose PDHL MSM-MCBAC method based on the Multi-Attributive Border Approximation area Comparison (MABAC) method and the PDHLWMSM operator. Finally, an example of a selection of TCM prescriptions is used and some comparative analyses are made to verify the effectiveness and superiority of this paper.

Curcumin attenuates collagen-induced rat arthritis via anti-inflammatory and apoptotic effects.

Curcumin is a natural herbal product that has been popularly used to treat autoimmune diseases in China; however, its effects on rheumatoid arthritis and its mechanism are not clear. The main purposes of this study are to explore the therapeutic effects of curcumin on collagen-induced arthritis (CIA) rats and the pharmacological mechanism. In the present study, CIA rats were established by injecting bovine type II collagen. Curcumin and methotrexate were then orally administered daily, and the swelling degree of the hind limb joints was scored every two days. Histopathological changes were observed by hematoxylin-eosin staining. The levels of cytokines (TNF-α, IL-1ß, IL-17 and TGF-ß) were detected by radioimmunoassay, while the expression of IκBα and COX-2 was detected by Western blot. In addition, cell viability was detected by CCK-8 assay, and the effect of curcumin on macrophage apoptosis was detected by flow cytometry and TUNEL assay. The results indicated that in vivo curcumin attenuated the degree of joint swelling of rats and the further development of joint histopathology. Moreover, it downregulated the levels of cytokines. In vitro curcumin inhibited the degradation of IκBα and reduced the production of COX-2 in LPS-induced inflammatory RAW264.7 cells. Importantly, curcumin significantly induced macrophage apoptosis. In conclusion, in this study, we have demonstrated that curcumin exerts therapeutic effects on arthritis in CIA rats and has a strong pharmacological activity on reducing the inflammatory response in macrophages. Its mechanism may be related to the inhibition of the NF-κB signaling pathway and the promotion of macrophage apoptosis.

The Suppressive Effects of the Petroleum Ether Fraction from Atractylodes lancea (Thunb.) DC. On a Collagen-Induced Arthritis Model.

In Chinese traditional medicine, the rhizome of Atractylodes lancea (Thunb.) DC. (A. lancea) is used extensively for the treatment of several diseases such as rheumatic diseases, but its actions on rheumatoid arthritis have not been clarified. The purpose of this article was to investigate the pharmacological effect of an A. lancea rhizome extract on collagen-induced arthritis (CIA) in rats. The CIA model was induced by the injection of bovine type II collagen. The rats were orally administered the petroleum ether (PE) fraction of the A. lancea rhizome (0.82 and 1.64 mg/kg), methotrexate (0.3 mg/kg body weight), or a vehicle from day 7 to day 15 after the model was established. The histological examination and radiological observation showed that the PE fraction significantly reduced the inflammatory responses and collagen loss in the joints of the rats with CIA. The PE fraction inhibited the production of tumor necrosis factor-α, interleukin (IL)-1ß, IL-17, and IL-6 in the sera. Moreover, the treatment with the PE fraction in vivo was able to reduce the level of Beclin 1 protein in the synovial tissue of the rats. These results highlight the antiarthritic potential of the PE fraction of the A. lancea rhizome and provide further evidence of the involvement of Beclin 1 inhibition in the effects of the PE fraction of the A. lancea rhizome. Copyright © 2016 John Wiley & Sons, Ltd.

FLLL31, a derivative of curcumin, attenuates airway inflammation in a multi-allergen challenged mouse model.

Signal transducer and activator of transcription protein 3 (STAT3), one of the major regulators of inflammation, plays multiple roles in cellular transcription, differentiation, proliferation, and survival in human diseases. Dysregulation of STAT3 is related to the severe airway inflammation associated with asthma. FLLL31 is a newly developed compound based on the herbal medicine curcumin, which specifically suppresses the activation of STAT3. However, the function of FLLL31 on inflammatory diseases, especially on the regulation of airway inflammation, has not been fully studied. In our prior investigations, we developed a mouse model that was challenged with a mixture of DRA allergens (including house dust mite, ragweed, and Aspergillums species) to mimic the severe airway inflammation observed in human patients. In this study, we performed a series of experiments on the inflammatory regulation activities of FLLL31 in both in vitro cultured cells and our in vivo DRA-challenged mouse model. Our results show that FLLL31 exhibits anti-inflammatory effects on macrophage activation, lymphocyte differentiation, and pro-inflammatory factor production. Importantly, FLLL31 significantly inhibited airway inflammation and recruitment of inflammatory cells in the DRA-challenged mouse model. Based on these results, we conclude that FLLL31 is a potential therapeutic agent that can be used against severe airway inflammation diseases.

Multi-allergen challenge stimulates steriod-resistant airway inflammation via NF-κB-mediated IL-8 expression.

Neutrophilic airway inflammation associated with multiple allergens has been related to steroid-resistant asthma. However, most animal models use only one allergen, which cannot simulate asthma closely as seen in patients. To determine the mechanism of inflammatory process involved in this severe condition, BALB/c mice were repetitively challenged with the pooled extract of dust mite, ragweed, and Aspergillus species (DRA). We found that DRA increased interleukin (IL)-10 and TGF-ß levels and neutrophil recruitment in bronchial alveolar lavage fluid. We also found that although dexamethasone suppressed the release of these two cytokines, mast cells recruitment, and mucus hypersecretion, it actually increased neutrophil infiltration and the level of keratinocyte-derived chemokine (mKC), a functional homolog of human IL-8. Treatment of human lung alveolar A549 cells with Der p1, an extract of house dust mite Dermatophagoides pteronyssinus, increased the expression of IL-8 and activity of NF-κB. The elevated IL-8 level was suppressed by BAY11-7082, a selective NF-κB inhibitor, but not by dexamethasone. These results suggest that increased IL-8 (mKC) levels may be involved in steroid-resistant neutrophilic airway inflammation through an NF-κB-dependent pathway.