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1.
Pharmazie ; 76(9): 422-427, 2021 09 01.
Article in English | MEDLINE | ID: mdl-34481532

ABSTRACT

MicroRNAs are emerging as important endogenous regulators of gene function and they are playing an important role in the occurrence and development of cancer. They are also regarded as robust biomarkers of cancer diagnosis and prognosis. Hepatocellular carcinoma (HCC) is a common and complex human malignancy with high mortality and morbidity in the world. MicroRNA-122 (miR-122) is a liver-specific microRNA and is closely associated with HCC metastasis, which makes miR-122 a promising target for drug design and development. In this study, we performed a cell-based screening method for discovering miR-122 activators and found that oleanolic acid (OA), a natural pentacyclic triterpene, specifically increased miR-122 expression in a concentration-dependent manner. Two HCC cell lines (HepG2 and Sk-hep-1 cells) were used to evaluate the effect of OA on cell migration and invasion abilities. The results indicated that OA attenuated the migration and invasion abilities of HCC cells by upregulating miR-122 expression. In addition, OA increased the expression of E-cadherin and decreased the expression of ß-catenin, N-cadherin and vimentin. After knocking down miR-122 with miR-122 inhibitor, we found that the effect of OA on these epithelial-to-mesenchymal transition (EMT) related molecules was significantly weakened, indicating OA exhibited anti-EMT effect by increasing the expression of miR-122. These finding may help to better understand the molecular mechanism of OA's anti-metastasis activity.


Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , MicroRNAs , Oleanolic Acid , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/metabolism , Cell Line, Tumor , Cell Movement/genetics , Epithelial-Mesenchymal Transition/genetics , Gene Expression Regulation, Neoplastic , Hep G2 Cells , Humans , Liver Neoplasms/drug therapy , Liver Neoplasms/genetics , Liver Neoplasms/metabolism , MicroRNAs/metabolism , Oleanolic Acid/pharmacology
2.
Virus Res ; 298: 198404, 2021 06.
Article in English | MEDLINE | ID: mdl-33775754

ABSTRACT

MicroRNAs are emerging as critical endogenous regulators of gene function. Aberrant regulation of microRNAs is associated with various human diseases, most importantly cancer. MicroRNA-122 (miR-122), a liver-specific microRNA, has been implicated in the control of hepatitis C virus (HCV) RNA replication and its response to interferon (IFN) in human hepatoma cells. Here, we report that daidzein, a naturally occurring plant isoflavone, inhibits HCV replication and enhances the antiviral effect of IFN-α on HCV therapy by decreasing microRNA-122 levels in vitro without significantly affecting cell growth. Moreover, daidzein was found to inhibit the expression of miR-122 and miR-21 by down-regulating the expression of TRBP, indicating that daidzein is possibly a general inhibitor of the miRNA pathway. Thus, daidzein provides new insights for drug discovery and HCV prevention.


Subject(s)
Hepatitis C , Isoflavones , MicroRNAs , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Hepacivirus/physiology , Hepatitis C/genetics , Humans , Interferon-alpha/metabolism , Isoflavones/metabolism , Isoflavones/pharmacology , MicroRNAs/genetics , MicroRNAs/metabolism , Virus Replication
3.
Biomed Pharmacother ; 131: 110663, 2020 Nov.
Article in English | MEDLINE | ID: mdl-32858501

ABSTRACT

The glyoxalase system is a ubiquitous enzymatic network which plays important roles in biological life. It consists of glyoxalase 1 (GLO1), glyoxalase 2 (GLO2), and reduced glutathione (GSH), which perform an essential metabolic function in cells by detoxifying methylglyoxal (MG) and other endogenous harmful metabolites into non-toxic d-lactate. MG and MG-derived advanced glycation endproducts (AGEs) are associated with various diseases, such as diabetes, cardiovascular disease, neurodegenerative disorders and cancer, and GLO1 is a key rate-limiting enzyme in the anti-glycation defense. The abnormal activity and expression of GLO1 in various diseases make this enzyme a promising target for drug design and development. This review focuses on the regulatory mechanism of GLO1 in diverse pathogenic conditions with a thorough discussion of GLO1 regulators since their discovery, including GLO1 activators and inhibitors. The different classes, chemical structure and structure-activity relationship are embraced. Moreover, assays for the discovery of small molecule regulators of the glyoxalase system are also introduced in this article. Compared with spectrophotometer-based assay, microplate-based assay is a more simple, rapid and quantitative high-throughput method. This review will be useful to design novel and potent GLO1 regulators and hopefully provide a convenient reference for researchers.


Subject(s)
Biological Products/metabolism , Biological Products/therapeutic use , Lactoylglutathione Lyase/metabolism , Pyruvaldehyde/metabolism , Animals , Biological Products/pharmacology , Cardiovascular Diseases/drug therapy , Cardiovascular Diseases/metabolism , Drug Evaluation, Preclinical/methods , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Glycosylation/drug effects , Humans , Lactoylglutathione Lyase/antagonists & inhibitors , Neoplasms/drug therapy , Neoplasms/metabolism , Pyruvaldehyde/antagonists & inhibitors
4.
Bioorg Med Chem ; 28(4): 115243, 2020 02 15.
Article in English | MEDLINE | ID: mdl-31879183

ABSTRACT

Glyoxalase I (GLO1) is a homodimeric Zn2+-metalloenzyme that catalyses the transformation of methylglyoxal (MG) to d-lacate through the intermediate S-d-lactoylglutathione. Growing evidence indicates that GLO1 has been identified as a potential target for the treatment cancer and other diseases. Various inhibitors of GLO1 have been discovered or developed over the past several decades including natural or natural product-based inhibitors, GSH-based inhibitors, non-GSH-based inhibitors, etc. The aim of this review is to summarize recent achievements of concerning discovery, design strategies, as well as pharmacological aspects of GLO1 inhibitors with the target of promoting their development toward clinical application.


Subject(s)
Biological Products/pharmacology , Drug Development , Enzyme Inhibitors/pharmacology , Lactoylglutathione Lyase/antagonists & inhibitors , Biological Products/chemical synthesis , Biological Products/chemistry , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Lactoylglutathione Lyase/metabolism , Molecular Structure
5.
Chem Pharm Bull (Tokyo) ; 65(5): 455-460, 2017 May 01.
Article in English | MEDLINE | ID: mdl-28320998

ABSTRACT

Several glutathione derivatives bearing the S-(N-aryl-N-hydroxycarbamoyl) or S-(C-aryl-N-hydroxycarbamoyl) moieties (10, 10', 13-15) were synthesized, characterized, and their human glyoxalase I (hGLO1) inhibitory activity was evaluated. Compound 10 was proved to be the effective hGLO1 inhibitor with a Ki value of 1.0 nM and the inhibition effect of compound 10 on hGLO1 was nearly ten-fold higher than that of the strongest inhibitor 2 (Ki=10.0 nM) which has been reported in the field of glutathione-type hGLO1 inhibitors. Its diethyl ester prodrug 10' was able to penetrate cell membrane and had good inhibitory effect on the growth of NCI-H522 cell xenograft tumor model.


Subject(s)
Drug Design , Esters/chemical synthesis , Glutathione/chemical synthesis , Lactoylglutathione Lyase/antagonists & inhibitors , Animals , Biological Assay , Cell Line, Tumor , Enzyme Activation/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Esters/chemistry , Esters/pharmacology , Glutathione/chemistry , Glutathione/pharmacology , Humans , Mice , Models, Biological , Molecular Structure , Tumor Burden/drug effects
6.
Virus Res ; 227: 231-239, 2017 01 02.
Article in English | MEDLINE | ID: mdl-27777077

ABSTRACT

Interferon stimulated (sensitive) genes (ISGs) are the effector molecules downstream of type I/III interferon (IFN) signaling pathways in host innate immunity. ISG12a can be induced by IFN-α. Although ISG12a has been reported to inhibit the replication of HCV, the exact mechanism remains to be determined. In this study, we investigated the possible mechanisms of ISG12a anti- HCV property by exploring the production of type I IFN and the activation of Janus kinase/signal transducer and activator of transcription (Jak/STAT) signaling pathway, apoptosis and autophagy in Huh7.5.1 cells transiently transfected with ISG12a over-expression plasmid. Interestingly, we found that ISG12a inhibited HCV replication in both Con1b replicon and the HCV JFH1-based cell culture system and potentiated the anti-HCV activity of IFN-α. ISG12a promoted the production of IFN α/ß and activated the type I IFN signaling pathway as shown by increased p-STAT1 level, higher Interferon sensitive response element (ISRE) activity and up-regulated ISG levels. However, ISG12a over-expression did not affect cell autophagy and apoptosis. Data from our current study collectively indicated that ISG12a inhibited HCV replication and potentiated the anti-HCV activity of IFN-α possibly through induced production of type I IFNs and activation of Jak/STAT signaling pathway independent of autophagy and cell apoptosis.


Subject(s)
Hepacivirus/physiology , Interferon-alpha/metabolism , Janus Kinases/metabolism , Membrane Proteins/metabolism , STAT Transcription Factors/metabolism , Signal Transduction , Virus Replication , Apoptosis/genetics , Autophagy/genetics , Cell Line , Cells, Cultured , Gene Expression , Hepatitis C/genetics , Hepatitis C/metabolism , Hepatitis C/virology , Humans , Interferon Type I/biosynthesis , Interferon-beta/metabolism , Membrane Proteins/genetics , Signal Transduction/drug effects
7.
Bioorg Med Chem Lett ; 25(21): 4724-4727, 2015 Nov 01.
Article in English | MEDLINE | ID: mdl-26320622

ABSTRACT

The zinc metalloenzyme glyoxalase I (GlxI) catalyzes the glutathione-dependent inactivation of cytotoxic methylglyoxal. Two competitive bivalent GlxI inhibitors, polyBHG2-62 (Ki=1.0 nM) and polyBHG2-54 (Ki=0.3 nM), were synthesized based on the transition-state analog S-(N-bromophenyl-N-hydroxycarbamoyl) glutathione (BHG). The most effective inhibitor, polyBHG2-54, is the first subnanomolar inhibitor of GlxI, and is over 50-fold more potent than BHG itself.


Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Lactoylglutathione Lyase/antagonists & inhibitors , Lactoylglutathione Lyase/metabolism , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/metabolism , Humans , Molecular Structure , Structure-Activity Relationship
8.
Bioconjug Chem ; 16(3): 598-607, 2005.
Article in English | MEDLINE | ID: mdl-15898727

ABSTRACT

The incorporation of anticancer prodrugs into polyacrylamide conjugates has been shown to improve tumor targeting via the so-called "enhanced permeability and retention" effect. This strategy has now been expanded to include two different classes of glutathione (GSH)-activated antitumor agents prepared by radical polymerization of N-(2-hydroxypropyl)methacrylamide (HPMA) with 2-methacryloyloxy-methyl-2-cyclohexenone (7) and/or with S-(N-4-chlorophenyl-N-hydroxycarbamoyl-thioethyl)methacrylamide (8), followed by treatment with 3-chloroperoxybenzoic acid, to give the HPMA copolymers of 7 and the 8-sulfoxide, respectively. In aqueous-buffered solution at pH 6.5, GSH reacts rapidly with poly-HPMA-8-sulfoxide (k approximately 2.3 mM(-1) min(-1)) to give S-(N-4-chlorophenyl-N-hydroxycarbamoyl)glutathione (1), a tight-binding transition state analogue inhibitor of the antitumor target enzyme glyoxalase I (K(i) = 46 nM), or with poly-HPMA-7 (k approximately 0.02 mM(-1) min(-1)) to give the electrophilic antitumor agent 3-glutathio-2-methylenecyclohexenone (4). Indeed, B16 melanotic melanoma in culture is inhibited by poly-HPMA-8-sulfoxide and by poly-HPMA-7 with IC(50) values of 168 +/- 8 and 284 +/- 5 microM, respectively. These values are significantly greater than those of the unpolymerized prodrugs suggesting that the cytotoxicity of the polymer prodrugs might be limited by slow cellular uptake via pinocytosis. This prodrug strategy should be applicable to a range of different GSH-based antitumor agents.


Subject(s)
Acrylamides/chemistry , Alkylating Agents/chemical synthesis , Antineoplastic Agents/chemical synthesis , DNA/metabolism , Glutathione/chemistry , Lactoylglutathione Lyase/antagonists & inhibitors , Polymers/chemistry , Alkylating Agents/blood , Alkylating Agents/chemistry , Alkylating Agents/pharmacology , Animals , Antineoplastic Agents/blood , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Chromatography, High Pressure Liquid , Endocytosis , Humans , Kinetics , Mice , Molecular Structure , Spectrum Analysis
9.
Org Lett ; 5(25): 4855-8, 2003 Dec 11.
Article in English | MEDLINE | ID: mdl-14653691

ABSTRACT

A new class of competitive inhibitors of homodimeric human glyoxalase I has been created by cross-linking two molecules of the transition-state analogue S-(N-4-chlorophenyl-N-hydroxycarbamoyl)glutathione (CHG) through their gamma-glutamyl-NH(2) groups with poly-beta-alanyl tethers of differing length: [CHG(beta-ala)n](2) suberate diamide (n = 1-7). The strongest inhibitors of this antitumor target enzyme likely bind simultaneously to the active site on each subunit to give K(i) values as small as 0.96 nM (n = 6). [structure: see text]


Subject(s)
Antineoplastic Agents/chemistry , Enzyme Inhibitors/chemistry , Glutathione/analogs & derivatives , Glutathione/chemistry , Lactoylglutathione Lyase/antagonists & inhibitors , Animals , Antineoplastic Agents/pharmacology , Binding Sites/drug effects , Binding, Competitive/drug effects , Enzyme Inhibitors/pharmacology , Glutathione/pharmacology , Humans , Lactoylglutathione Lyase/chemistry , Models, Molecular , Molecular Structure , Thiolester Hydrolases/antagonists & inhibitors
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