Latest ArticlesThe 26S proteasome is a 2.5 MDa complex of the protease family members and is central to a vast array of vital cellular processes including cell-cycle progression and antigen presentation. It has been proven to be a target for therapeutic agents in the treatment of cancers and autoimmune diseases. Most inhibitors are designed to target the 20S proteolytic core complex while the efforts to target the 19S regulatory particle subunits are less successful so far. This is, in part, due to the complexity of molecular architecture and poor understanding of the mechanism of this subcomplex. This review attempts to summarize the development of inhibitory molecules that target both the 20S and 19S subunits of the proteasome, especially highlight the recent progress in the proteasome structure and development of the new inhibitors.
Vascular endothelial growth factor receptor (VEGFR-2), a member of the super family of protein tyrosine kinase receptors, plays a vital role in the regulation of tumor metastasis and angiogenesis. Several VEGFR-2 inhibitors have been marketed as antitumor drugs and a range of inhibitors are undergoing clinical or preclinical studies. According to the principle of multi-targeted pharmacolgy, in the field of tumor treatment, nonselective drugs targeting on more than one kinase to inhibit different cell pathways can be more effective than drugs specific for one kinase. Multi-target treatment does not mean abandonment of selectivity, but a precise selectivity for several kinases related to tumor, which is also a big challenge in the development of small molecular antitumor drugs. This paper reviews briefly the advances in research of the VEGFR-2 inhibitors and selectivity strategy in recent years.
NMR-based metabolomics technique has been applied to botanical studies in recent years. The plant metabolites are complicated and various, metabolomics method can detect the global metabolomic profile of the plant to track valuable metabolites, and provide information for the research of plant physiology, metabolic pathways and functional genes. This paper reviews the application of NMR-based metabolomics technique in medicinal plants, including the biosynthetic mechanism and production of secondary metabolites, the improvement of yield or quality of medicinal plants, the development of effective active ingredient, the identification of medicinal plant species, and the quality control of herbal medicine. In addition, the potential development of this technique in future is discussed.
This study was designed to investigate the microRNA expression profile in human embryonic lung fibroblast 2BS cells upon salidroside (SAL) treatment, and predict the target genes of miRNAs and related pathways delaying cellular senescence. Samples were divided into three groups: young control (28 PD), old control (50 PD), and old+SAL (50 PD with SAL), RNA from three groups was used for miRNA microarray analysis. In late PD cells, 43 miRNAs were found significantly changed relatively to those in young cells, and 58 miRNAs were regulated by SAL. The miRNAs including hsa-let-7c, hsa-let-7e and hsa-mir-3620 were significantly down-regulated in late PD cells which could be reversed by SAL treatment. However, hsa-mir-411, hsa-mir-24-2-5p and hsa-mir-485-3p exhibited an opposite trend. Gene Ontology and Pathway analysis revealed that target genes were significantly enriched in 31 GO and 11 pathways. The microarray data was further validated with qRT-PCR. This research provides new clues regarding the underlying mechanisms of SAL on cellular senescence through miRNAs regulation.
This study was aimed to construct a "drug-target-pathway" network of Xuebijing injection for sepsis treatment in an effort to explore the "multi-components, multi-targets, multi-pathways" mechanism based on "system-system" research mode. Active ingredients of Xuebijing injection were used to predict the potential targets according to reversed pharmacophore matching method. The pathway information was acquired from DAVID and KEGG database. The Cytoscape software was used to construct the "ingredient-target-pathway" network of Xuebijing injection for sepsis treatment. The results showed that 21 major active ingredients of Xuebijing injection regulated 550 targets (HRAS, GSK3B, BTK, AK, et al) and affected 10 inflammation and immune-related pathways, such as B cell receptor signaling pathway, VEGF signaling pathway, natural killer cell mediated cytotoxicity, Toll-like receptor signaling pathway. The sepsis therapeutic effect of Xuebijing injection reflected the action features of traditional Chinese medicine as multi-ingredients, multi-targets, multi-pathways. This research clarifies the material basis of Xuebijing injection for anti-inflammation and immunoregulation, providing a scientific basis for elucidation the mechanism of Xuebijing injection in the treatment of sepsis.
Plumbagin (Plumbago zeylanica L.) has a wide spectrum of anticancer activity with a relatively lower toxicity. The molecular mechanisms of proliferation inhibition and apoptosis induction by plumbagin on esophageal squamous carcinoma cell lines may be important for the structure modification and clinical application of plumbagin. After treatment of KYSE-30, KYSE-70 and KYSE-140 cells with 0-20 μmol·L-1 of plumbagin for 24, 48, 72 h, CCK8 was used to examine the proliferation, Annexin V and PI immunofluorescence staining for apoptosis, real-time PCR and Western blot for FoxM1 mRNA and protein expression, dual-luciferase reporter gene assay for the transcriptional activity of FoxM1, respectively. In addition, the relationship between anti-tumor effect of plumbagin and FoxM1 was investigated in vivo. Plumbagin significantly inhibited proliferation and induced apoptosis of esophageal squamous carcinoma cell in vitro and in vivo. Moreover, plumbagin down-regulated the expression of FoxM1 through suppression of its gene transcription. Our findings suggest that plumbagin may inhibit the proliferation of esophageal squamous carcinoma cell in vivo and in vitro through down-regulating the expression of FoxM1.
The aim of this research is to investigate the inhibitory effects of calpain inhibitors (ALLN and calpain inhibitor Ⅳ) on mammary epithelial-mesenchymal transition (EMT) of MCF-10A cells induced by fibronectin (FN). After FN treatment of MCF-10A cells for 48 h, cell migration and invasion were determined by scratch repair assay and matrigel coated transwell assay, respectively. Vimentin, E-cadherin, snail and calpain-2 protein expression were measured by Western blot. The results suggest that FN induced morphological changes in MCF-10A cells, significantly increased the migration and invasion abilities of MCF-10A cells, upregulated the expression of calpain-2, vimentin and snail, and downregulated the expression of E-cadherin. All such changes by FN were reversed with ALLN and calpain inhibitor Ⅳ. In conclusion, the upregulation of calpain-2 was involved in FN-induced EMT of MCF-10A mammary epithelial cells, which may be inhibited by ALLN and calpain inhibitor Ⅳ.
Tianlongtongxin (TLTX) formula is composed of six Chinese herbs including Rhodiola rosea L., Salviae Miltiorrhizae Radix et Rhizoma, Chuanxiong Rhizoma and so on. It has been mainly used in the treatment of chest-Bi syndrome in the clinics. To investigate the material foundation and provide reference for clinical dosage regimen, the pharmacokinetics of seven components in the rat plasma were studied after oral administration of TLTX. A high sensitive method was established to determine the seven active components from TLTX in rat plasma based on the LC-MS/MS technique. The method met the requirements of preclinical pharmacokinetic study, through the investigation of linearity, specificity, recovery, accuracy, precision and stability. After administration of TLTX at 4.5 g·kg-1 dose, all of the components were detectable in the plasma after 5 min. The concentration peaks were observed at 0.11-4.67 h respectively after administration with great difference in levels. The AUC of salidroside was significantly higher than other components, suggesting it as a main active component in TLTX formula. The observations provide scientific evidence for the rationality of salidroside as monarch drug in the formula.
Eighteen novel levofloxacin-thiadiazole HDACi conjugates were designed and synthesized from levofloxacin. The chemical structures of all conjugates were confirmed by 1H NMR, 13C NMR and HR-MS spectra. The inhibitory activities of new conjugates were evaluated in an assay with a HDACs reagent kit, and their anti-tumor activities were tested in CCK-8 assay. The results showed that these new conjugates displayed potent inhibitory activity against HDACs, and the hydroxamate conjugates exhibited more potent activity than carboxylic acid and benzamide derivatives. Specifically, conjugate 5d exhibited the most potent anti-HDAC1 (IC50=0.031±0.011 μmol·L-1) and HDAC6 (IC50=0.019±0.006 μmol·L-1) activities, which was more potent than SAHA. Molecular docking studies suggest that the hydroxamate group of conjugate 5d was deeply inserted into the active site to interact with the residues in coordination with the zinc ion. Additionally, the thiadiazole group of conjugate 5d also engaged in hydrogen bonding with F679 in HDAC6, which had been linked to the selectivity of the HDAC isoforms. Moreover, these conjugates displayed significant antiproliferative effects on SW620, MGC-803, PC-3, NCIH460, MCF-7 and HepG2 cells, in particular, conjugate 5d showed the greatest potency against MGC-803 (IC50=0.7±0.05 μmol·L-1), NCIH460 (IC50=2.3±0.421 μmol·L-1), MCF-7 (IC50=1.6±0.56 μmol·L-1) and HepG2 (IC50=3.9±0.26 μmol·L-1), which was >3-fold more potent than SAHA. Additionally, all conjugates were nontoxic to health GES-1 cells, while SAHA showed some toxicity.
HSP90 is widely expressed in cells with the main function in assisting the maturation of other proteins that are called clients. Many clients play critical roles in the occurrence and development of cancer. Inhibition of HSP90 can lead to degradation of the oncogenic proteins, and result in potent anti-cancer effects. HSP90-HOP interaction is critical for the chaperone function of HSP90, thereby disruption of the HSP90-HOP interaction is a novel strategy in the inhibition of HSP90. Based on the technology of homogeneous time-resolved fluorescence (HTRF), we developed a new assay for the identification of new inhibitors of HSP90-HOP interaction. This method was evaluated in the study of the HSP90-HOP inhibition activity of the pentapeptide MEEVD from HSP90 C-terminal and its derivatives. This study can provide a basis for the screening and discovery of novel HSP90-HOP disruptors.
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