Latest ArticlesFragments of the human indoleamine 2, 3-dioxygenase 1 (IDO1) gene 5'-UTR (untranslated 1 245 bp region) promoters were amplified by PCR and cloned into pGL4.20 vector in the construction of reporter vector pGL4-IDO1-luc. A549 cells were transfected with the constructed plasmid and IDO1 inhibitor screening model was established with dual-luciferase reporter assay. Based on the model, we screened natural small molecules which could down-regulate the expression of IDO1 on tumor cells. The anti-tumor activities were examined by MTT, Western blotting and lactic dehydrogenase (LDH) release assays. Toosendanin (NS-180) down regulated the IDO1 expression and inhibited IFN-γ-induced STAT1 and STAT3 phosphorylation in A549 cells. Moreover, NS-180 significantly increased the cytotoxicity of co-cultured NK cells on A549 cells in LDH release assays. In summary, NS-180 is a novel and potent IDO1 inhibitor, which has an antitumor activity for cancer immunotherapies.
The present study was aimed to investigate the role and mechanisms of kallistatin in protection against oxidative stress-induced hepatic stellate cell damage. The effects of kallistatin on the viability, the intracellular superoxide level and Akt, eNOS molecules were investigated in human hepatic stellate cell line LX-2 and the incompletely activated primary rat hepatic stellate cells. Two different oxidative-stress related models, the hydrogen peroxide model and the iron-overload model were used in the experiments. The results show that kallistatin protected the hepatic stellate cells from oxidative damage and repaired the cell damage by oxidative stress. The main mechanism is antioxidant activity of kallistatin, which can remove the oxidized substances inside the cells. On the other way, kallistatin activates Akt and eNOS molecules to generate the antioxidant effect. Our results help to explore new anti-fibrotic targets.
To investigate the difference of Gegen Qinlian Decoction (GQD) piece and boiled powder in the treatment of type 2 diabetes (T2DM), the characteristic of overall metabolite profile was examined in the serum of T2DM rats with 1H NMR-based metabolomics combined with the multivariate statistical analysis. A rat model of T2DM was established by feeding of high glucose and high fat diet followed by a streptozotocin (STZ) treatment. The general condition, body weight and fasting blood glucose (FBG) of rats were monitored. GQD piece and boiled powder exhibited activities in the improvement of these parameters. The results of the principal component analysis showed that there was a significant difference in the metabolic profile of the normal control group, the model group, the positive group, the herbal decoction group and the boiled powder group. Totally 15 potential biomarkers were identified by OPLS-DA binding univariate analysis. Compared with normal control group, the serum samples of T2DM showed a higher level of 3-HB, TMAO, glycine, β-glucose and α-glucose accompanied by lower level of lactate, VLDL, acetate, glutamate, methionine, glutamine, pyruvate, creatine, choline and glycerol. The above results also demonstrated that both piece and boiled powder of GQD could restore 14 of these markers. These results suggested that the disrupted metabolic pathways including energy metabolism, lipid metabolism and amino acid metabolism, were restored by GQD piece and boiled powder. The two formula did not show a significant difference. The results of this study provide experimental data and theoretical basis for the equal activities of GQD piece and boiled powder in clinical application.
In the era of genome-wide association study (GWAS), a large number of drug response-related loci have been identified in the non-coding sequences. The interpretation of these loci in mechanism is concerned with the effects on the mRNA expression level of these genes. Expression quantitative trait loci (eQTL) studies indicate the relationship of genome variants and the level of mRNA. Its elucidation of the relationship between genetic variation and gene expression, gene interaction and gene regulatory network provides an efficacious mean for pharmacogenomics. The effects of gene polymorphism on drug responses have been unraveled thoroughly in studies which combined pharmacogenomics with eQTL and GWAS.
Fibronectin extra-domain B (ED-B) has been a good target in new drug development, several relevant antibody drugs are in phase Ⅱ or Ⅲ clinical trials for metastatic melanoma, soft-tissue sarcoma and so on. Some data of phase Ⅱ clinical trials shows that ED-B antibody drugs (L19-IL2 and L19-TNF α) for melanoma are significantly superior to PD-1 antibody drugs. This article describes several aspects of ED-B, such as biological characteristics, the development of targeted drugs, and the potential therapeutic applications, including modifying protein drug structure, constructing fusion protein, expanding indications, developing companion diagnostics and individual treatments. We also discuss how to promote original innovation in drug discovery, which might help to find new development focus.
Bromodomain and extraterminal (BET) proteins are a class of proteins that can interpret epigenetic codes and play an important role in regulating gene transcription through identifying and binding acetylated histones or non-histones proteins. The BET inhibitors have emerged with good therapeutic effects in preclinical disease models such as cancer and inflammation. Some of them have entered clinical studies, demonstrating that there is considerable prospect for drug development with BET as a potential therapeutic target. This review briefly describes the structures and functions of the BET proteins, the BET inhibitors in various diseases, as well as molecular mechanisms involved.
This study was designed to investigate the synergistic analgesic effect between choline (Cho) and acetaminophen (Ace). Mice were treated with 0.6% acetic acid solution by intraperitoneal injection to build acetate writhing model. The KM mice were randomly divided into four groups:control group (n=10), Cho group (n=50), Ace group (n=50), combination group (Cho+Ace group, n=40), then the writhing times were counted respectively. OriginPro8.5 was used to calculate ED 50. The isobolographic analysis was used to test the interaction of Cho and Ace. To explore the mechanism, forty KM mice were randomly divided into control group, Cho group, Ace group and Cho + Ace group. Blood was collected for detection of TNF-α, IL-6, PGE2 and NF-κB content using ELISA kits. The result ED 50 was calculated as followings. ED50 of Cho and Ace was 19.47 mg·kg-1 and 20.56 mg·kg-1. The concentrations were 2.94 mg·kg-1 for Cho and 3.15 mg·kg-1 for Ace in the combination test. The levels of TNF-α, IL-6, PGE2 and NF-κB in Cho group and Ace group were lower than those in the control group (P < 0.05). Compared to the Cho group and Ace group, the levels of TNF-α, IL-6, PGE2, NF-κB in Cho + Ace group were reduced further (P < 0.05). The results revealed that Cho and Ace have synergistic analgesic effects, which may associate with inhibition of the NF-κB signaling pathway.
Three sesquiterpenoids were isolated from the dichloromethane extract of the roots of Stelleropsis tianschanica Pobed through a combination of various chromatographic approaches, including silica gel, Sephadex LH-20, reverse phase C18 and so on. On the basis of spectroscopic data analysis, they were identified as (+)-guaia-l(10), ll-dien-9-one-5α-hydroxy (1), 4β, 5βH-guai-9, 7(11)-dien-12, 8-olide-1α, 8α-diol (2), 4α, 5βHguai-9, 7(11)-dien-12, 8-olide-1α, 8α-diol (3). The compound 1 is a new sesquiterpenoid, and the compound 3 was isolated for the first time from the genus Stelleropsis.
Poly(2-ethyl-2-oxazoline) (PEOz), a hydrophilic long-chain polymer synthesized by living cationic ring-opening isomerization polymerization of 2-ethyl-2-oxazoline, has the characteristics of low toxicity, biocompatibility, flexible chain, and modified expediently. PEOz is a potential substitute of polyethylene glycol (PEG) to render the ability of long-circulation, enhance cellular uptake and endosomal escape behaviors to PEOz modified drug delivery system. In this review, we summarized recent literature for the research progress of physicochemical properties, synthetic methods and the application of PEOz in drug delivery system.
To a certain extent, the drug effect is determined by its blood concentration. It is generally accepted that the blood concentrations of constituents of Chinese medicines are very low. There is no sufficient experimental bases and references on its degree and the possibility of taking effect. In this study, 69 papers were collected and analyzed by searching the database of Scifinder, Pubmed, CNKI. The minimum effective blood concentrations of 73 common Western medicines and the maximum blood concentrations of 211 in vivo constituents of 40 Chinese medicines (single herb or compound Chinese medicine) were summarized. It was found that the maximum blood concentrations of the most in vivo constituents of Chinese medicines were much less than the minimum effective blood concentrations of the Western medicines. Specifically, the minimum effective blood concentrations of 17 Western medicines (23% of total) and the maximum blood concentrations of the 143 in vivo constituents of Chinese medicines (68% of total) were less than 100 ng ·mL-1; the minimum effective blood concentrations of 31 Western medicines (42% of total) and the maximum blood concentrations of the 20 in vivo constituents of Chinese medicines (9% of total) were more than 1 000 ng·mL-1. In this paper, a systematic summary and comparison of the blood concentrations in traditional Chinese medicines and Western medicines were conducted, which could provide a new ideas and references for the study of the pharmacodynamical material basis and its mechanism in traditional Chinese medicine.
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