Latest ArticlesSoluble resistance-related calcium-binding protein, SORCIN, is a 22 kDa calcium binding protein with "penta-EF hand", which participates in the regulation of intracellular calcium homeostasis in cells. SORCIN is highly expressed in many tissues such as hearts and brains. It is overexpressed in some of cancer tissues as well. Recently, a large amount of clinical data showed that SORCIN was closely related to drug resistance in cancer. Meanwhile, basic research found that SORCIN participates in the formation of multidrug resistance (MDR) and is related to severity and poor prognosis of tumors. Moreover, it may also regulate MDR induced by ATP-binding cassette transporters. Therefore, SORCIN is expected to become a new target for diagnosis and treatment of MDR. The present review summarizes recent progress in SORCIN study and its effect on MDR.
Mycobacterial membrane protein large 3 (MmpL3) belongs to the resistance, nodulation and division (RND) superfamily whose role in mycobacteria is transporting trehalosemonomycolate (TMM). The inhibition of MmpL3 influences the formation of cell wall of mycobacteria. In the past few years, several whole cell-based screenings of compound libraries by different research groups has brought by a number of diverse chemical scaffolds active against Mycobacterium tuberculosis (Mtb). The aim of this review is to provide the recent advances in discovery of MmpL3 inhibitors with a special focus on the structure-activity relationship (SAR). Besides, this review will provide the information of target identification and the modes of action of the MmpL3 inhibitors.
Ellipticine is an alkaloid isolated from natural product with cytotoxicity, which has antitumor and anti-aids activity. Since it was first identified in 1959, a great deal of effort has been devoted to the development of various approaches for synthesis of ellipticine. This review provides a summary for synthesis approaches of ellipticine from different starting materials. The antitumor mechanism and structure-activity relationship are also discussed.
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 effects of cordycepin on proliferation and invasion of pancreatic cancer stem cells (Pan CSC) and its mechanisms, MTT assay was used to investigate the effect of cordycepin on proliferation of Pan CSC. Inverted microscope was used to observe the morphologic change of cells. Propidium iodide staining methods was employed to observe the cell apoptosis. Cell scratch method was used to detect the ability of migration of Pan CSC in each group. RT-PCR and Western blot were used to determine the expression of apoptosis gene and epithelial-mesenchymal transitions (EMT) gene. The growth of Pan CSC was inhibited by cordycepin in a dose-and time-dependent manner, with IC50 107.364 and 48.472 μmol·L-1 at 24 and 48 h, respectively. Moreover, the cell migration was inhibited at the same time. RT-PCR and Western blot results showed that cordycepin decreased the expression of Bcl-2 and activated pro-apoptotic gene levels such as Bax, p53, caspase-3. Furthermore, cordycepin reduced the expression of EMT genes by up-regulation of E-cadherin and down-regulation of N-cadherin. Cordycepin has the ability to inhibit Pan CSC proliferation and invasion by activating p53 pathway as well as suppressing the EMT. This study provides a new basis for inhibition of pancreatic cancer stem cells in the treatment of pancreatic cancer.
The study was designed to explore the effects and the underlying mechanism of ginsenoside Rg1 on corticosterone (CORT)-induced astrocytes injury. The primary hippocampal and prefrontal cortical astrocytes from rats were cultured and purified. CORT was used to stimulate stress condition. Western blot was used to detect the effects of ginsenoside Rg1 on the phosphorylation of Cx43. Cell Counting Kit (CCK8) was used to detect the effects of ginsenoside Rg1 on astrocytes viability. The roles of ginsenoside Rg1 was reversed by protein kinase inhibitors in the change of astrocytes morphology. Our results showed that ginsenoside Rg1 reversed the phosphorylation of Cx43 induced by CORT; ginsenoside Rg1 significantly upregulated the cell viability of astrocytes against CORT; the role of ginsenoside Rg1 was obviously inhibited by Src protein kinase inhibitors PP2 and Akt protein kinase inhibitors BAY1125976 in prefrontal cortical astrocytes; in hippocampal astrocytes, Src protein kinase inhibitor PP2, p38 protein kinase inhibitor SB203580, Akt protein kinase inhibitor BAY1125976 significantly inhibited the cell protective effects of ginsenoside Rg1. In conclusion, ginsenoside Rg1 improved the activity of Cx43 gap junctions in astrocytes exposed to CORT; ginsenoside Rg1 protected astrocytes against that CORT activated the Src, p38 and Akt signaling pathways, and the mechanism was different in prefrontal cortical and hippocampal astrocytes.
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.
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.
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.
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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