Latest ArticlesFree fatty acid receptor 1 (FFAR1), also known as G protein-coupled receptor 40 (GPR40), is a receptor for diverse free fatty acids. This review aims at summarizing effects and mechanisms of FFAR1 on insulin secretion and related blood glucose and lipids metabolism. FFAR1 is involved in the occurrence and development of type 2 diabetes, but its specific mechanism has not been clarified. FFAR1 is expressed in the wide variety of issues, especially β-cells in the pancreatic islets, as well as α-cells in islets, central nervous tissue, subcutaneous fat, skeletal muscle, gastrointestinal tract, etc. FFAR1 can act on islet β-cells to promote the secretion of insulin, promote α-cells on glucagon secretion, and regulate the secretion of endocrine cells in the gastrointestinal tract to balance the level of glucose and lipids. Existing research found that FFAR1 agonists have significant advantages. They promote insulin release, reduce weight and protect pancreatic β-cells, and have no risk of hypoglycemia. To in-depth understand the role of FFAR1 as a drug target in the treatment of diabetes, further pharmacological studies are still needed in order to obtain safer and more effective drugs against type 2 diabetes.
Pulmonary hypertension (PH) is a progressive cardiopulmonary disease with high mortality and increased prevalence. The target therapy of pulmonary hypertension is mainly dependent on vasodilation, but how to improve vascular remodeling with stem cell therapy has not been fully understood. Over the past ten years, the researches on endothelial progenitor cells, mesenchymal stem cells and pluripotent cells have brought the hope to patients with pulmonary hypertension. This article mainly introduces the latest progress of stem cell technology in the intervention of pulmonary hypertension, and discusses the problems in the application.
Indoleamine 2, 3-dioxygenase 1 (IDO1) is a key enzyme of L-tryptophan metabolic oxidation pathway, in which the L-tryptophan is transformed into N-formyl kynurenine by oxidative cleavage. IDO1 is considered as a potential target for the development of cancer immunotherapeutic molecules. Up to now, at least 10 drug candidates have been advanced into clinical research. In this review, the binding mode and structure-activity relationships of the representative IDO1 small molecule inhibitors were summarized according the characteristics of chemical structures. Hopefully, this review could provide some insights for further development of novel IDO1 inhibitors.
Multidrug resistance (MDR) seriously affects the clinical efficacy of chemotherapeutic drugs. One of the main mechanisms of MDR is the overexpression of P-glycoprotein (P-gp) in tumor cells that reduces the intracellular drug concentrations and limits the effective use of chemotherapeutic drugs. Accordingly, application of P-gp inhibitors that can reverse tumor MDR is an effective strategy to enhance the anti-tumor effect of chemotherapeutic drugs. In recent years, D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) has been widely applied as the potential P-gp inhibitor for its excellent P-gp inhibition effect as well as good safety. In this paper, we reviewed the P-gp inhibitors, the mechanisms of TPGS in reversing P-gp-mediated MDR and the application of TPGS-based nano-drug delivery system.
Chinese material medica (CMM) is the foundation for treating disease using traditional Chinese medicine (TCM), which is not only guided by the basic theory of TCM but also follows the general rules of drug action. There are both toxicity and efficacy in TCM. For TCM the integrated regularities of its toxicity and efficacy were demonstrated in their prescription, which were qualitatively characterized by compatible experiences such as "seven emotions", "Yin" and "Yang" compatibility, etc. When the toxicity is still produced by oral administration according to the prescription of TCM theory or administration is not abided by original requirement, the integral regularities of toxicity and efficacy that depends on experience appears to be at a loss what to do. Especially in recent years, with the modernization of TCM and the continuous advantages in new medicinal innovation, the CMM safety incidents occurred frequently. It is very urgent for us how to establish a set of integrated methods that are adequately situated to multiple components for TCM. With the combination of the biological supramolecular chemistry and the basic theory of TCM, an integrated model of toxicity and efficacy based on TCM supramolecular "imprinting template" has begun to take shape. The CMM and the human body are both biological supramolecular bodies that follow the autonomic action rules of their "imprinting template". The integrated trends of toxicity and efficacy are able to build on systematical results of single components in CMM based on the theory of TCM to treat diseases by prescription on syndromes. It is also the systematic actions resulting from single effective components in CMM by the supramolecular "imprinting template" self-acted regularities. Through the qualitative and quantitative analysis of supramolecular "imprinting templates" characteristics and actions and their network chromatotoxicometrology (chromatopharmacometrology), a toxic and effective integrated analysis methods will be established on an integrated "therapeutic window" for components in the CMM. This effort will finally permit the description of the components of the pharmacokinetic overlaid law of "therapeutic window", plotted to lower-overflow, entering and higher-overflow profiles.
This study is aimed to investigate the potential mechanisms of herceptin-acquired resistance and curcumin to reverse resistance in NCI N87/R gastric cancer cells. Western blot was used to evaluate the effect of curcumin on the expression of IκBα, NF-κBp65, HER-2, caspase-3, Bcl-2 and Bax in herceptin resistant cells; Annexin V-FITC/PI was exploited to analyze the effect of curcumin on cell apoptosis; Caspase kit was used to evaluate the effect of curcumin on the enzymatic activity of caspase-3, 8 and 9. The results showed a low expression of IκBα in the cytoplasm and a high expression of NF-κBp65 in the nucleus of NCI N87/R cells. Correspondingly, inhibition of NF-κB pathway by EVP4593, a specific NF-κB inhibitor, preferentially reduced cell viability of NCI N87/R cells, indicating the activation of NF-κB pathway in NCI N87/R cells. Curcumin preferentially reduced cell proliferation and inhibited NF-κB signaling pathway of NCI N87/R cells, downregulated the expression of HER-2 and Bcl-2, upregulated the expression of Bax, increased the activity of caspase-3, 8 and 9. Taken together, our study demonstrates the correlation between herceptin resistance acquirement of NCI N87 cells and the activation of NF-κB pathway. Moreover, curcumin reverses herceptin resistance of NCI N87 cells possibly by inhibiting NF-κB pathway and inducing cell apoptosis.
Rabdosia japonica(Burm.f.) Hara var.glaucocalyx(Maxim.) Hara is a traditional Chinese medicine, and is known to have anti-tumor effects. This study aims to investigate the effect of glaucocalyxin A (GLA), a diterpenoids extracted from Glaucocalyx Hara, on apoptosis of glioma cells and its mechanism. This study investigated the molecular signaling mechanism of GLA-induced glioma cell apoptosis by analyzing survival rate of C6 rat glioma cells, cell morphology, colony formation ability, interference ribonucleic acid, polymerase chain reaction, and Western blot. The result showed that in the presentce of GLA, the survival rate of C6 rat glioma cells decreased significantly, while the expression of guanine nucleotide-exchange factor-H1 was up-regulated, causing phosphorylation of extracellular regulated protein kinases proteins and apoptosis. Hence, the mechanism of GLA-induced glioma cell apoptosis was the GEF-H1/ERK pathway.
Forsythia suspensa is a herbal medicine that widely used for heat-clearing and detoxification in clinical practice. However, the molecular mechanism of its heat-clearing and detoxifying effect is still unclear. Based on the theory and methods of network pharmacology, the efficacy of the heat-clearing and detoxification of Forsythia suspensa was analyzed in this study. A total of 114 of compounds in Forsythia suspensa were collected, and 15 of effective compounds were obtained by analyzing the bioavailability (OB) and drug-like properties (DL). Then 26 corresponding targets were obtained using reverse pharmacophore-docking method. Using the BioGPS database, the organ location of the target initially was revealed. The compound-targetdisease network model of Forsythia suspensa was constructed by using the Cytoscape, which showed that the material basis of the heat-clearing and detoxification of Forsythia suspensa was to synthesize and synergize the effects by combining various active ingredients of multiple targets, simultaneously. This study explains the scientific mechanism of the heat-clearing and detoxification of Forsythia suspensa, and provides a theoretical foundation for clinical rational usage of Forsythia suspensa.
The Chinese herbal Radix Scrophulariae is the main medicine for nourishing yin and reducing fire. It can be used to treat hyperthyroidism due to yin deficiency and fire hyperactivity, but its mechanism is not clear. The present study was aimed to explore the mechanism of Radix Scrophulariae treatment of hyperthyroidism due to yin deficiency and fire hyperactivity. The urine metabolomic approach was conducted using the method of UPLC-TOF-MS. The results showed that Radix Scrophulariae has good therapeutic effects on hyperthyroidism rat model of yin deficiency. After treatment with Radix Scrophulariae, through metabolic profiling and protocol analysis, 6 potential metabolic markers may be closely related with the treatment mechanism of Radix Scrophulariae on this disease, including proline betaine, estrone, thymidine, 5-hydroxyindoleacetic acid, cyclic AMP and L-dopa. The strongest metabolic pathways were associated with tryptophan metabolism, pyrimidine metabolism, tyrosine metabolism, purine metabolism and steroid hormone biosynthesis. The urine metabolomic approach can be applied to clarify the therapeutic mechanism of Radix Scrophulariae on hyperthyroidism rat of yin deficiency, and provide the theoretical basis for the clinical practice of Radix Scrophulariae on nourishing yin to reduce pathogenic fire.
In this study, twenty containing ethylenediamine groups derivatives of oleanolic acid (OA) were synthesized, their structures were determined by 1H NMR, 13C NMR and HR-MS. The anti-tumor activities in HepG2 and SGC7901 cells were evaluated by MTT assay. The results showed that all compounds exhibited anti-tumor activity, compounds Ⅰ6, Ⅰ8 and Ⅰ9 exhibited significant anti-tumor activities with IC50 values of 16.7, 9.8 and 6.3 μmol·L-1, respectively. Molecular docking studies showed that compounds Ⅰ6-Ⅰ9 produce higher combining ability with VEGFR. Compound Ⅰ6-Ⅰ9 were further evaluated for the inhibitory activity against VEGFR-2, the result showed Ⅰ9 had a strong inhibitory effect on VEGFR with IC50 values of 0.56 μmol·L-1.
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