Latest ArticlesThe hepatotoxicity of gefitinib is an important factor limiting its clinical application. In order to control the toxicity, we conducted this study to find the gene variation that can explain and predict the occurrence and severity of hepatotoxicity of gefitinib. Ninety patients with non-small cell lung cancer were included in the retrospective clinical study. Detailed hepatotoxicity induced by gefitinib and epidemiological characteristics were recorded. Twenty-six candidate single-nucleotide polymorphisms of molecular targets, metabolic enzymes, transporters and chemokines were genotyped by matrix-assisted laser desorption/ionization time-of-flight platform. Various confounding factors, such as age, gender and smoking status, were included in the follow-up analysis and variability in the extent of hepatotoxicity was best explained by a multivariate logistic regression model incorporating. The severity of hepatotoxicity was associated with mitogen-activated protein kinase 1 rs13515 (OR=9.467, P=0.074). The research about pharmacogenomic of gefitinib identified the determinants of the drug-induced liver injury. These findings provide a basis to design clinical trials targeting a particular toxicity of gefitinib or similarly targeted agents to benefit patients on long-term gefitinib treatment.
Interleukin-6 (IL-6)/janus kinase (JAK)/signal transducers and activators of transcription 3 (STAT3) is a pivotal signaling pathway in the regulation of cell proliferation, survival, differentiation and T cell activation. Aberration of this pathway is involved in multiple autoimmunity diseases and cancers, therefore the pathway is considered as a hot target for drug development. In our study, we validated a cell-based model of IL-6/JAK/STAT3 and used it in screening of its inhibitors. HEK-Blue IL-6 cells of Invivogen Inc. were used to stably express IL-6 receptor and STAT3-induced secreted embryonic alkaline phosphatase (SEAP) report gene. After stimulation by IL-6, SEAP was secreted from cells and reacted with QUANTI-Blue. The product can be detected at 655 nm. The inhibitory effect of compounds on STAT3 signaling showed as IC50 was calculated by OD value. The results shown that IL-6 specifically activated the cells, which could be applied to screen the inhibitors for IL-6/JAK/STAT3 signaling pathway. The optimized screening conditions were described as below:50 000 cells/well, 1 ng·mL-1 IL-6 incubation for 20 h and reaction with QUANTI-Blue for 1 h. Based on this condition, we screened 14 natural products based on this cell model and arctigenin, cryptotanshinone and curcumin showed potential inhibitory activities on STAT3 signaling pathway with IC50 of 1.28, 2.96 and 6.61 μmol·L-1. Our study suggests that HEK-Blue IL-6 cells were suitable for screening inhibitors for the IL-6/JAK/STAT3 signaling pathway.
Primary hepatocellular carcinoma as the main pathological type of liver cancer is one of the common malignant tumors in our country. Liver cancer stem cells (LCSCs) have the characteristics of multidrug resistance, anti-radiotherapy and high tumorigenicity in addition to the characteristics of stem cells, namely, self-renewal, multi-directional differentiation and unlimited proliferation. Based on the above features, relapse and metastasis often occur after the patients being treated with conventional methods, which results in poor prognosis. Effective treatment targeting LCSCs has the potential to cure hepatocellular carcinoma (HCC) completely. This article reviews the common biomarkers used in identification of LCSCs and development of stem cell-targeted therapy for HCC.
Hepatic fibrosis is an important pathological process in the development of liver cirrhosis and liver cancer from chronic liver damage. So far there is no effective chemical drug in clinic for treatment of hepatic fibrosis. Therefore, the research in anti-hepatic fibrosis drugs is a hot topic. For drugs currently under research and development, most of the mechanisms of action are related to inhibition of factors that could cause or deteriorate liver fibrosis, including activation and proliferation of hepatic stellate cells, inflammation, oxidative stress and production of extracellular matrix, et al. In this review, we briefly analyze targets and drugs related to the mechanisms mentioned above in order to provide a reference to the future research and development of anti-hepatic fibrosis drugs.
Jasmonic acid (JA) can promote the biosynthesis of artemisinin.To have an insight into the JA signaling in Artemisia annua, two new genes belonging to JAZ family, namely AaJAZ5 and AaJAZ6, were cloned from Artemisia annua, which might be the negative regulators involved in the JA signaling pathway.Bioinformatic analysis showed that AaJAZ5 and AaJAZ6 contained the conserved domains of ZIM and Jas specific to JAZ family.According to tissue profile analysis, AaJAZ5 had the highest expression level in leaf and AaJAZ6 had the highest expression level in root.The expression levels of both AaJAZ5 and AaJAZ6 were markedly elevated by methyl jasmonate and mechanical wounding.The BiFC results indicated that AaJAZ5, as well as AaJAZ6, physically interacted with AaMYC2.Importantly, only AaJAZ5 could interact with AaCOI1.The interaction assays given by BiFC suggested that AaJAZ5 might play a crucial role in JA signaling.This study facilitated the further analysis of the functional divergence of JAZ-family members and the understanding of molecular mechanism on JA signaling to regulate the artemisinin biosynthesis.
Fluorinated compounds, which now make up 20%-25% of all marketed chemical drugs, are playing significant role and showing great potential in medicinal chemistry. Fluorine substitution is always utilized to change the physicochemical properties of the compounds to improve the ADME/T properties. In addition, fluorine substitution leads to improvement of the ligand binding affinity. With respect to molecular level, organofluorine can form various intermolecular interactions with the target proteins, e.g., hydrogen bond, halogen bond, C-F…π interaction, polar interaction and so on. These interactions display unique properties or nature due to the specificity of fluorine atom, which are at the center of attention. This paper reviews the related research background, followed by the research progress of hydrogen bond, halogen bond, C-F…π interaction, polar interaction and some other interactions involved organofluorine.
Neural stem cell is a cell type with the ability of self-renewing and the potential to differentiate into neurons, astrocytes or oligodendrocytes. Neurogenesis is beneficial for the recovery of many neurological diseases, such as stroke, Alzheimer's disease and so on. Neurogenesis capacity can maintain through the whole life, which includes the proliferation, migration and differentiation of neural stem cell, as well as the incorporation into the neuronal network of newborn neurons. The self-renewal and differentiation activities of neural stem cell are regulated by the microenvironment, which is defined as neural stem cell niche. Components of neural stem cell niche include cell-cell interactions, cytokines, extracellular matrix and vascular niche. Illustration of neural stem cell niche impact is far more significant for the treatment of certain nervous system diseases. This review summarizes the current understanding of the relationship between neural stem cell niche and the fate of neural stem cell.
Mesoporous silica nanoparticles (MSNs) have been widely used as drug carriers in the diagnosis and treatment of diseases due to their specific characteristics, which include a large surface area, ordered mesoporous structures, easy surface modification and feasible sustained release action for encapsulated drugs. With the research development of MSNs, the biodegradability and removability of mesoporous silica nanomaterials have attracted considerable attention in the clinical application of the MSNs-based formulations. This paper was prepared to emphasize the preparation approaches of biodegradable mesoporous silica nanoparticles through the metal oxide doping method and the organic compound doping method. We discussed the biodegradable mechanism and process of such nanoparticles, and finally, provided an insightful and helpful review of the prospective application of the biodegradable mesoporous silica nanoparticles in medical field.
This study was designed to investigate the impacts of particle shape of micelles on cell uptake and tumor imaging applications. We designed and synthesized an ultra-pH sensitive PEG-iPDPA diblock polymer, and prepared it into wormlike micelles and spherical micelles by thin-film dispersion method and modified solvent evaporation method, respectively. Firstly, the pH responsiveness of two kinds of micelles was investigated in vitro. Both forms of micelles responded to pH sensitively, and each of them could reach 100 times of ON/OFF fold after conjugated with BDP fluorescent probe. Moreover, the cellular uptake of two forms of micelles depended on the concentration and incubation time. However, the amount of cellular uptake of spherical micelles was much higher than that of the wormlike micelles, which proved that the shape of nanoparticles had a great influence on the cellular uptake. The results of in vivo imaging revealed that the spherical micelles had a better tumor accumulation as well as tumor imaging outcomes. Finally, the biosafety of micelles was tested by MTT assay and H & E staining, which indicated that none of the two kinds of micelles had obvious toxicity. Collectively, these results suggest that the spherical micelles could be a better carrier compared with wormlike micelles in terms of cellular uptake, tumor accumulation and tumor detection.
Tumor microenvironment (TME) is the internal environment of tumor. As a functional unit, the microenvironment determines the occurrence and development of tumors. Hypoxia, inflammation and immunosuppression are three major characteristics of TME. Hypoxia signals involve in multiple immunosuppressive pathway. There is communication among the gut microbiota, chronic inflammation and immunity. The three characteristics are associated with each other to form a complex network affecting the metastasis of the tumor. TME also influences the development of immunotherapy and efficacy of drugs in solid tumor. Therefore, it is important to identify the valuable biomarkers to predict disease progression, to elucidate the mechanistic networks in the microenvironment, to develop microenvironment targeting drugs and effective drug combination strategies to improve the drug efficacy. All of these have a profound clinical value.
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