Advances in research on HBV inhibitors based on new targets (1): capsid protein inhibitors / 药学学报

Hepatitis B virus (HBV) capsid protein plays an important role in the life cycle, thus becoming an ideal target for drug design. Capsid protein inhibitors can exert a synergistic antiviral effect with nucleoside drugs by inhibiting the replication of HBV. This paper reviews the research progress of capsid protein inhibitors with different structural types from the perspective of medicinal chemistry.

Progress of screening methods in vitro for HIV-1 capsid protein inhibitors / 中国药理学通报

Human immunodeficiency virus type 1 (HIV-1) infection is highly dependent on its conical fullerene capsid, which is composed of approximately 1 500 capsid proteins. In recent years, capsid protein has been recognized as an ideal target for design and screening drugs for AIDS therapy. Screening methods are the key to develop HIV-1 capsid inhibitors. A variety of screening approaches for HIV-1 capsid protein inhibitor, which have been reported in the literature are reviewed in the article.

Epigenetic Modifications: Novel Therapeutic Approach for Thyroid Cancer

The incidence of thyroid cancer is growing the fastest among all cancers in the United States, especially in women. The number of patients with thyroid neoplasm is part of an even larger number of patients who often need to undergo an operation to exclude a cancer diagnosis. While differentiated thyroid cancer (papillary thyroid cancer and follicular thyroid cancer) accounts for most cases of thyroid cancer and has a relatively good prognosis, effective treatments for patients with de-differentiated and anaplastic thyroid cancer are still gravely needed. Despite progress in the identification of genetic changes in thyroid cancer, the impact of aberrant epigenetic alterations on thyroid cancer remains to be fully elucidated. Understanding of the roles of epigenetic changes in thyroid cancer could open new opportunities for the identification of innovative molecular targets for novel treatment modalities, especially for anaplastic thyroid cancer for which treatment is very limited. This article briefly reviews the studies that exemplify the potential for and promise of using epigenetic regulators in the treatment of thyroid cancer.

Effect of PIAS1 on Epithelial-mesenchymal Transition of Gastric Cancer under Inflammatory Microenvironment / 胃肠病学

Background:Protein inhibitor of activated STAT 1( PIAS1 )is an important regulator for inflammatory signaling network,which is low expressed in gastric cancer and associated with development of cancer,but its mechanism has not been elucidated. Aims:To investigate the effect of PIAS1 on epithelial-mesenchymal transition( EMT)of gastric cancer under inflammatory microenvironment. Methods:Recombinant adenovirus Ad5/F35-PIAS1 and Ad5/F35-null were constructed and transfected into gastric cancer cell line SGC-7901,mRNA and protein expressions of PIAS1 were detected by RT-PCR and Western blotting,respectively. SGC-7901 cells were divided into IL-6 treatment group,Ad5/F35-PIAS1﹢IL-6 treatment group and Ad5/F35-null﹢IL-6 treatment group. Cell proliferation was measured by MTT method,migration and invasion capacities were assessed by wound healing test and Transwell chamber invasion assay. Protein expressions of E-cadherin,Snail,Twist,Vimentin and P-p38MAPK were assessed by Western blotting. Results:The transfection of Ad5/F35-PIAS1 significantly increased the expressions of PIAS1 mRNA and protein in SGC-7901 cells. Compared with IL-6 treatment group and Ad5/F35-null﹢IL-6 treatment group,capacities of cell proliferation,migration and invasion were significantly decreased(P ﹤0. 01);protein expressions of Snail,Twist,Vimentin and P-p38MAPK were significantly decreased while expression of E-cadherin protein was significantly increased in Ad5/F35-PIAS1 ﹢IL-6 treatment group ( P﹤0. 01). No significant differences in above-mentioned indices were found between IL-6 treatment group and Ad5/F35-null﹢IL-6 treatment group(P﹥0. 05). Conclusions:PIAS1 could inhibit EMT of gastric cancer cells under inflammatory microenvironment,and may play an important role in inhibition of tumor invasion and metastasis.

Progress in ATP-competitive Kinesin Spindle Protein Inhibitors as Anticancer Agents / 中国药师

Kinesin spindle protein ( KSP) inhibitors is an important direction for the discovery of anticancer agents. Several KSP in-hibitors have been studied in clinic trials. The discovery of ATP-competitive KSP inhibitors may be a new approach for searching novel a-gents to overcome the mutation-mediated resistance to the allosteric inhibitors. The progress in the discovery of ATP-competitive KSP in-hibitors was reviewed in the paper to provide reference for the further development of KSP inhibitors.

Absorption characteristics of the total alkaloids from Mahonia bealei in an in situ single-pass intestinal perfusion assay / 中国天然药物

AIM@#To investigate the absorption characteristics of the total alkaloids from Mahoniae Caulis (TAMC) through the administration of monterpene absorption enhancers or protein inhibitors.@*METHOD@#The absorption behavior was investigated in an in situ single-pass intestinal perfusion (SPIP) assay in rats.@*RESULTS@#The intestinal absorption of TAMC was much more than that of a single compound or a mixture of compounds (jatrorrhizine, palmatine, and berberine). Promotion of absorption by the bicyclic monoterpenoids (borneol or camphor) was higher than by the monocyclic monoterpenes (menthol or menthone), and promotion by compounds with a hydroxyl group (borneol or menthol) was higher than those with a carbonyl group (camphor or menthone). The apparent permeability coefficient (Papp) of TAMC was increased to 1.8-fold by verapamil, while it was reduced to one half by thiamine. The absorption rate constant (Ka) and Papp of TAMC were unchanged by probenecid and pantoprazole.@*CONCLUSION@#The intestinal absorption characteristics of TAMC might be passive transport, and the intestinum tenue was the best absorptive site. In addition, TAMC might be likely a substrate of P-glycoprotein (P-gp) and organic cation transporters (OCT), rather than multidrug resistance protein (MRP) and breast cancer resistance protein (BCRP). Compared with a single compound and a mixture of compounds, TAMC was able to be absorbed in the blood circulation effectively.

Baixa digestibilidade proteica e presença de antinutricionais em produtos tipo mix de cereais / Low protein digestibility and anti-nutritional factors in cereal mix like products

Products composed of cereal mixes and other ingredients such as guarana, gelatin and cocoa powders; yeast; and soybean, flaxseed and sesame extracts have presented increased sales while receiving ever-growing criticism. Amongst the ingredients that could compose this cereal mix, most are of vegetable origin, wholegrain and not thermally processed. Therefore, they may present anti-nutritional factors, which are recognized to harm the bioavailability of nutrients, such as proteins. In this study, we aimed to evaluate the protein quality of these products, sold in the municipality of Uberaba, Brazil. The protein digestibility, tannins and trypsin inhibitors of the 14 samples were assessed. All samples showed trypsin inhibition activity and tannins. These results suggest that those products present low potential for nutrient utilization, especially with regards to proteins.

Productos compuestos por mezclas de cereales y otros ingredientes, como guaraná en polvo, gelatina en polvo, cacao en polvo, levadura de cerveza, extracto de soja, linaza y ajonjolí, presentan creciente comercialización, al mismo tiempo que aumentan los cuestionamientos al respecto. Estos productos están compuestos de variados ingredientes, la mayoría de origen vegetal, integral y sin procesamiento térmico previo, y podrían presentar antinutricionales, reconocidamente capaces de perjudicar la biodisponibilidad de nutrientes, tales como las proteínas. Este estudio evaluó la calidad proteica de productos listos para el consumo, compuestos por mezclas de cereales y otros componentes, comercializados en la ciudad de Uberaba-MG, determinando sus niveles antinutricionales y su digestibilidad proteica in vitro. Todas las muestras analizadas presentaron inhibición en la actividad de tripsina y de taninos. Las muestras presentaron muy claramente bajos valores de digestibilidad proteica in vitro. Los resultados sugieren que estos productos presentan bajo potencial de utilización de sus nutrientes, muy especialmente con respecto a sus proteínas.

Misturas de cereais e outros ingredientes, como guaraná em pó, gelatina em pó, cacau em pó, levedo de cerveja, extrato de soja, linhaça e gergelim, vêm apresentando crescente comercialização, concomitantemente com crescentes questionamentos a seu respeito. Dentre os ingredientes variados que podem compor estes produtos, a maioria é de origem vegetal, integral e sem processamento térmico prévio, e poderiam apresentar antinutricionais, reconhecidamente capazes de prejudicar a biodisponibilidade de nutrientes, como proteínas. Este trabalho buscou avaliar a qualidade proteica de produtos prontos para o consumo, compostos por misturas de cereais e outros componentes, comercializados no município de Uberaba-MG, determinando seus teores de antinutricionais e sua digestibilidade proteica in vitro. Todas as amostras analisadas apresentaram atividade de inibição de tripsina e teores de taninos, e baixa digestibilidade in vitro.

The relationship between expression of PIAS3 and malignancy of human brain meningioma / 中国基层医药

Objective To explore the relationship between PIAS3 expression and the degree of malignancy of meningiomas.Methods 72 cases of different degree of malignant meningioma and 13 cases of surgical specimens of normal brain tissue were extracted the total RNA,and detected the levels of PIAS3 in different degree of meningioma and normal brain tissue through comparative control study by using real-time fluorescence quantitative PCR.Results PIAS3 was low expressed in normal brain tissue,however,high expressed in the human brain meningioma with significant differences(P＜0.01).There were also significant differences found in expression level of PIAS3 between meningiomas grade I and Ⅱ,or Ⅲ level(P＜0.05),but the differences between meningiomas grade Ⅱ and Ⅲ were not obvious(P＞0.05).And PIAS3 expression was not related with the depth of infiltration in invasive meningiomas(P＞0.05).Conclusion PIAS3 was overexpression in meningiomas,and was be closely related to the occurrence and development of meningiomas.

Effect of oxymatrine on the expression of p-STAT3 and PIAS3 in human mesangial cells / 中华肾脏病杂志

Objective To study the effect of oxymatrine on p-STAT3 and PIAS3 signaling molecule and it's mRNA expression in the proliferation of the human mesangial cells (HMCs) induced by lipopolysaccharide(LPS) and to explore their relationship. Methods HMCs were divided into three groups: control group, LPS group and oxymatrine group. HMC proliferation was detected by methyl thiazolyl tetrazolium (MTT) assay. Type Ⅳ collagen in the supernatants of the cultured HMCs was detected by ELISA at 12, 24, 48 hours respectively. At the same time, the protein and mRNA expressions of p-STAT3 and PIAS3 were measured by Western blot and real-time quantitative RT-PCR. Results The cell proliferation, the mRNA and protein expression of type Ⅳ collagen, p-STAT3 in LPS group were increased compared with the control group (P<0.01), but they were decreased in oxymatrine group (P < 0.01). The expressions of protein and mRNA of PIAS3 in LPS group were decreased significantly compared with control group (P<0.01), but they were increased in oxymatrine group (P<0.01). Conclusion Oxymatrine can down-regulate the expression of p-STAT3 and up-regulate the expression of PIAS3, which plays an important role in the process of LPS-induced HMCs proliferation.

PIAS1 interacts with the KRAB zinc finger protein, ZNF133, via zinc finger motifs and regulates its transcriptional activity

Zinc finger protein 133 (ZNF133) is composed of a Kruppel-associated box (KRAB) domain and 14 contiguous zinc finger motifs. ZNF133 is regarded as a transcriptional repressor because the KRAB domain has potent repressor activity and the zinc finger motifs usually act in binding to DNA. However, we found that the zinc finger motifs of ZNF133 also possessed transcriptional repressor activity. By two-hybrid screening assay, we found that the zinc finger motifs of ZNF133 interacted with protein inhibitor of activated STAT1 (PIAS1). PIAS1 enhanced the transcriptional repression activity of ZNF133 through the zinc finger motifs. This effect of PIAS1 was relieved by an inhibitor of the histone deacetylases (HDACs). These results demonstrate that the transcriptional repressor activity of ZNF133 is regulated by both the KRAB domain and the zinc finger motifs, and that the repressive effect by zinc finger motifs is mediated by PIAS1.