Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory disorder including mainly ulcerative colitis (UC) and Crohn's disease (CD). In China, IBD has become a common disease of the digestive system with an dramatic increase in incidence in recent years. The pathogenesis of IBD is not yet clear, and no drugs can completely cure IBD. Compared with monoclonal antibody drugs, small molecule drugs have the advantages of low cost, easy development as oral agents, and absence of immunogenicity. This review summarizes the recent research and development of small molecule immunosuppressants for IBD.

MCT is an important key enzyme in the terpenoid biosynthesis in MEP pathway. In this study, Gateway technology was used to construct RNAi vector of TwMCT, and a vector fragment with a size of 484 bp was obtained. The TwMCT RNAi vector was transferred into the suspension cells of Tripterygium wilfordii by gene gun. Accumulation of terpenoids was assayed by UPLC, and the result showed that the content of triptolide and celastrol in cells decreased by 23.4% and 42.8%, respectively, compared with the control group pK7GWIWG2D. Moreover, the gene expression of TwMCT and major genes in terpenoid biosynthesis pathway was detected by qRT-PCR, which demonstrated that the expression of TwMCT reduced by 29.2% relative to that of the control group pK7GWIWG2D, and the relative expression of TwDXR, TwGGPS, TwHMGR and TwHMGS diminished by 36.3%, 31.3%, 62.2%, and 29.1%, respectively, but the expression of TwDXS was up-regulated by 114.2%, and there was no significant change in TwFPS. Thus, it was verified in vivo that interference with TwMCT expression significantly inhibited the accumulation of triptolide and celastrol in Tripterygium wilfordii, laying a foundation for further exploring the regulation mechanism of MCT gene on the terpenoid biosynthesis in Tripterygium wilfordii.

Tripterygium wilfordii 3-hydroxy-3-methylglutaryl coenzyme-A reductase (TwHMGR) is an important regulation site in terpenoids metabolic pathway in cytoplasm which is the first speed limit enzyme of MVA pathway. In order to investigate the effects of TwHMGR on the biosynthesis of triptolide and celastrol in Tripterygium wilfordii, the overexpression of TwHMGR (OE-HMGR) was studied in this paper. We cloned the full-length of TwHMGR to construct overexpression vector by Gateway technology then delivered the expression vector into Tripterygium wilfordii suspension cells by gene gun. qRT-PCR was used to detect the expression of TwHMGR:the expression of TwHMGR was increased to 1.75 folds over the control group (empty vector:pH7WG2D) in the overexpression group. The accumulation of triptolide and celastrol in the suspension cells of Tripterygium wilfordii was detected by UPLC, revealing that:the contents of triptolide and celastrol were increased to 163.93% and 190.04% of over the control group in the overexpression group. Based on these findings, the positive effect on the accumulation of active terpenoids, triptolide and celastrol in Tripterygium wilfordii was found and the results laid a foundation of the synthetic biology research on important active terpenoids in Tripterygium wilfordii.

Diterpene synthases from plants are key enzymes in diterpene biosynthesis, which catalyzed the initial cyclization cascade of (E, E, E,)-geranylgeranyl pyrophosphate, and generated diverse carbon skeletons. Recent research show that the structural and stereo chemical differences lead to diverse natural diterpene compounds of plants. The structures of diterpene synthases play a crucial role in cyclization function. This article mainly reviews the mechanisms, functional characteristics, and structural information of diterpene synthases according to the crystal structures and functions.

This study was designed to investigate the effects of icariin on bone metabolism in osteoprotic mice induced by iron overload, the model of iron overload mice was established by intraperitoneal injection of iron dextran (100 mg·kg^-1). Sixty 2-month-old C57/BL6 male mice were randomly divided into six groups, including normal control group, model group, N-acetyl-L-cysteine (NAC)-treated group, icariin (50, 100 and 200 mg·kg^-1)-treated group. Except for the mice in control group, the mice were intraperitoneal injected weekly with iron dextran (100 mg·kg^-1) to establish the model of iron overload mice. The NAC and icariin were suspended in 0.5% CMC-Na solution, and administered orally for six times one week according to body weight. The mice in normal group and model group were given the same volume of 0.5% CMC-Na solution. Three months later, the organs, serum and femurs of mice were collected. Serum biochemical parameters were detected with an ELISA kit, the distal femur bone density and trabecular bone microstructure were analyzed by Micro-CT, and the mechanical properties of femur were measured by universal mechanical analyzer. Compared with the normal control group, iron overload decreased the bone mineral density and deteriorated the micro-architecture structure and bone mechanical properties in femur of mice, increased the level of iron, phosphorus and activity of tartrate resistant acid phosphatase-5b (TRACP-5b), reduced the level of osteocalcin (OCN) in serum, decreased the activity of superoxide dismutase (SOD) of liver tissues, increased the content of malondialdehyde (MDA) of liver tissues. Icariin increased bone mineral density, improved the micro-architecture and mechanical properties of bone tissue, reduced the levels of iron and phosphorus, decreased the activity of TRACP-5b and enhanced the levels of OCN in serum, and also decreased the activity of MDA in liver tissue of iron overload mice. These results suggest that icariin is able to reduce bone loss and improve bone microstructure and mechanical properties in iron overload mice through regulation of bone metabolism via anti-oxidation.

The orexin system was discovered in 1998 with two G-protein coupled receptors (GPCRs):orexin-1 (OX₁R) and orexin-2 (OX₂R) receptors that bind the neuropeptides orexin-A (OX-A) and orexin-B (OX-B).The causal link between the orexin system and obesity, anxiety, and sleep/wake disorders as a potential therapeutic target has drawn much attention in the field of pharmaceuticals.The developments of dual antagonism of the receptors by small molecules are clinically efficacious in the treatment of insomnia, where the most advanced molecule suvorexant has been approved by FDA in August, 2014.The small molecule orexin receptor antagonists (ORA) between January 2010 and August 2017 are summarized in this review and we focus on their chemical structures, mechanism and human clinical trials.

This study is designed to investigate the effect of triptolide on the function and expression of P-glycoprotein (P-gp) in HNE1 nasopharyngeal cancer cells. MTT assay was used to test cell viability. Intracellular doxorubicin content was evaluated with flow cytometry. Rhodamine 123 (Rh) was used to detect the excretion function of P-gp. The expression of P-gp was analyzed by Western blot. ATP levels were evaluated. JC-1 staining was used to determining mitochondrial membrane potential (MMP). Triptolide, doxorubicin and the combination treatment all had the inhibitory effect to HNE1 cells, and the combination treatment had the best effect. Triptolide increased intracellular concentration of doxorubicin and Rh (P < 0.05 or P < 0.01), inhibited the excretion function of P-gp. The expression of P-gp was reduced greatly in the middle and high dose group of triptolide. The ATP levels were decreased significantly (P < 0.05). JC-1 staining showed that triptolide mediated the down-regulation of MMP in HNE1 cells. Triptolide could increase intracellular drug content and enhance cytotoxicity of chemotherapeutics by inhibition of the expression and the excretion function of P-gp.

UHPLC-QTOF-MS was applied to non-targeted metabolomics study of mice infected with K. pneumoniae ATCC^® BAA 2146 to discover potential biomarkers and metabolic pathways that are associated with sepsis. Fifty-eight metabolites were identified by principal components analysis (PCA) and partial least-squares discriminant analysis (OPLS-DA), which was combined with variable projection importance (VIP) and nonparametric test. Eighteen of the 58 metabolites were further found to be involved in 8 metabolic pathways, including nicotinate and nicotinamide metabolism, pyrimidine metabolism, vitamin B6 metabolism, taurine and hypotaurine metabolism, arginine and proline metabolism, alanine, aspartate and glutamate metabolism, D-glutamine and D-glutamate metabolism and glycerophospholipid metabolism.

Pancreatic cancer is a highly-malignant digestive system neoplasm. The anticancer efficacies of the chemotherapeutic drugs for pancreatic cancer treatment, such as gemcitabine, are greatly limited by their poor targetability to tumor and low drug concentration in the tumor tissue. Drug delivery system plays an important role in improvement of therapeutic efficacy and reduction of adverse effects. Enhancement of the tumor targeting capacity of nanomedicine and promotion of the delivery efficiency are the key issues in the research field of pharmaceutics. In this review article, we survey recent progress in targeted drug delivery nanosystems for treatment of pancreatic cancer by targeting cancer cells, pancreatic tumor stroma, pancreatic cancer-associated cells, and pancreatic cancer stem-like cells, which will provide a new insight into clinical treatment of pancreatic cancer.

In this study, the thermoresponsive micelles were synthesized with random copolymerization method and the photosensitizer indocyanine green (ICG) was loaded on micelles through the physical adsorption. The light energy was converted into heat energy to increase the temperature after irradiation with near-infrared light. When the phase transition temperature was reached, the micelle was disassembled and the targeted therapy was achieved. The nanoparticles were characterized with a transmission electron microscopy, Fourier transform infrared spectrometer, nuclear magnetic resonance spectrometer and other characterization were used to investigate. The critical micelle concentration (CMC), upper critical solution temperature, the photothermal properties of the carrier and the release of drug triggered by light were investigated after the doxorubicin (DOX) loaded. The carrier was evaluated for toxicity, cellular uptake, the effect of photothermal, the combination of photothermal and chemotherapy; the p(AAm-co-AN)-g-PEG (PAAP) was spherical in shape with a particle size of about 45 nm and a phase transition temperature was about 43℃. The critical micelle concentration was 24 μg·mL^-1. The particle size increased to 88 nm after loaded with ICG and DOX which the photothermal effect was obvious. The cumulative release of the drug under the irradiation of near-infrared light (808 nm, 2 W·cm^-2, 2 min·h^-1) was increased to 59.4% (pH 5.0) after 5 h. The results of the cell experiment indicated that ICG-PAAP was almost non-toxic and uptaken by the lysosomal pathway. The cell killing effect was stronger with combination of chemotherapy (DOX as 20 μg·mL^-1) with more than 70% of the cells killed. The results showed that the prepared micelle with low toxicity was thermoresponsive and could be used in combined therapy of tumor under the irradiation of near-infrared light.