Latest ArticlesWith the increasing drug resistance of bacteria, especially Gram-negative bacteria, the infection of drug-resistant bacteria has become one of the most challengeable clinical problems. The siderophore-antibiotic conjugates based on the "Trojan horse" strategy can penetrate the extracellular membrane of Gram-negative bacteria by active transport, and they are expected to become a powerful weapon for clinical anti-infection treatment. This review describes the drug design strategies of siderophore-antibiotic conjugates reported in recent years, and focuses on the use of different types of antibiotics in this strategy.
The development of mass spectrometry and proteomics significantly advanced our understanding of post-translational methylation of proteins. In recent years, a large number of proteins containing the methylation recognition domain have been identified. Protein methylation mainly occurs on lysine and arginine residues. Both lysine and arginine have three different methylation states. Lysine can be mono-methylated, di-methylated, and tri-methylated, while the arginine residue can be modified as mono-methylation, symmetrical di-methylation, and asymmetrical di-methylation. Methylation recognition domains can accurately identify lysine or arginine with different state of methylation, transfer methylation signals, and perform functions in a variety of cellular processes, including gene expression regulation, RNA splicing and translation, cell cycle regulation, etc. In recent years, researchers have found that the abnormalities of these recognition proteins are also closely related to the genesis and development of tumors. Therefore, these methylation recognition proteins were considered as potential drug targets for small molecule intervention. In this review, we summarized the researches on the recognition domains of protein methylation as well as their inhibitors, hoping to provide the basis for further drug development in this field.
Clearance reflects the speed of extraction and elimination of drug molecules from systemic circulation. Reducing the clearance of compounds using structure modification strategy could lead to good pharmacokinetic and pharmacodynamic properties. Herein, the concept of clearance, as well as several prediction methods of in vivo clearance are introduced. The strategies of reducing drug clearance are reviewed. These methods include reducing hepatic metabolic clearance through reducing lipophilicity, blocking metabolic site, scaffold modification and increasing steric hindrance; reducing biliary or renal excretion clearance through increasing lipophilicity, reducing polar surface area and bioisosterism. In addition, the influence of spatial configuration on drug clearance is also summarized.
Polymeric micelles have become a potential drug carrier. However, some single-copolymer micelles often have some performance defects, such as low drug loading, poor stability and weak response to microenvironment. Mixed micelles self-assembled from two or more dissimilar macromolecular polymers provides a direct and convenient approach to improve drug delivery. This paper attempts to review the internal force, preparation and characterization, performance advantages and biological activity of mixed polymer micelles, aims to show the advantages of polymer mixed micelles, analyzes the problems and shortcomings, and hopes to provide reference for the development of anti-tumor nano-micelles.
Glycosylation abnormalities are common in all stages of tumor development, and sialic acid (SA) modified polysaccharides have been found highly expressed on many different types of tumor cells. These highly sialylated tumor cells promote the formation of tumor immunosuppressive environment and help tumor cells gain metastatic potential by interacting with SA binding receptors Siglecs/selectins expressed on peripheral immune cells or endothelial cells. Related theoretical studies have promoted the development of tumor therapeutic strategies by targeting SA-binding receptors, mainly including specific antibodies trastuzumab (Mylotarg) or polysaccharides that block the interaction between Siglecs/selectins and its ligands, as well as nano-based drug delivery systems modified with SA and its derivatives. This article reviews the specific mechanisms of how SA-binding receptor Siglecs/selectins-mediated interactions contribute to tumor development and metastasis, and tumor therapeutic strategies by targeting SA-binding receptors, as well as makes a rational evaluation and reflection on these therapeutic strategies.
We aimed to explore the involvement of Fas-associated death domain protein (FADD) in the inhibitory effects of etoposide (VP16) on the proliferation, migration, and apoptosis of A549 non-small cell lung cancer (NSCLC) cells. FADD knockout (KO) and control A549 cells were constructed using the CRISPR/Cas9 system. The cell counting kit-8 (CCK-8) assay, the scratch wounding assay, and the Annexin V/PI staining-based flow cytometry were used to assess the effect of FADD KO on viability, migration, and apoptosis of A549 cells with or without the presence of etoposide, respectively. The expression pattern of several proteins involved in proliferation[raf proto-oncogene serine/threonine-protein kinase (c-Raf) and extracellular signal-regulated kinase of phosphorylation (p-ERK)], apoptosis[B-cell lymphoma 2 (BCL2), cleaved cysteinyl aspartate specific proteinase 3 (cleaved-caspase-3), and cleaved-caspase-9] and migration[matrix metalloproteinase 2 (MMP2)] was detected by Western blot. We found that FADD KO attenuated proliferation and migration of A549 cells. Consistently, we demonstrated that FADD KO enhanced etoposide-mediated inhibition of proliferation and migration in A549 cells. We further demonstrated that FADD KO obviously enhanced etoposide-mediated apoptosis in A549 cells. For mechanism exploration, we found that etoposide sensitivity enhanced by FADD KO may be partly explained by reduced expression of c-Raf, p-ERK, MMP2, and increased cleavage of caspase-3 and -9. Combined with the Kaplan-Meier (KM) survival curve analysis obtained from the GEPIA database, it is preliminarily judged that patients with high FADD gene levels in lung adenocarcinoma have a poor prognosis. Our study suggests that FADD can be used as a potential biomarker for the treatment of lung adenocarcinoma, providing a personalized treatment plan for the treatment of lung adenocarcinoma.
We analyzed the main chemical constituents of Huangqi decoction by HPLC coupled with diode array and evaporative light scattering detectors (HPLC-DAD-ELSD). The study on the mechanism of Huangqi decoction was based on network pharmacology and included multi-components, multi-targets, and multi-pathways in the treatment of non-alcoholic fatty liver disease (NAFLD). The chemical "fingerprints" of 15 batches of Huangqi decoction were established. Network pharmacology was used to screen and analyze the targets and pathways of the components of Huangqi decoction, and a "component-target-pathway" network was constructed to predict the mechanism of Huangqi decoction for the treatment of NAFLD. HPLC analysis of Huangqi decoction revealed 27 common peaks and the main chemical constituents were identified. Gene ontology (GO) analysis and Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis revealed that glycyrrhetinic acid, isoliquiritigenin, glycyrrhizic acid, astragaloside Ⅳ, liquiritigenin, and astragaloside Ⅰ, the main active components of Huangqi decoction, may act on RAC-alpha serine/threonine-protein kinase (AKT1), interleukin-6 (IL-6), vascular endothelial cell growth factor A (VEGFA), mitogen-activated protein kinase 8 (MAPK8), and signal transducer and activator of transcription 3 (STAT3), and may regulate pathways involving phosphatidylinositol-3-kinases (PI3K)/protein kinase B (AKT), insulin resistance, hypoxia inducible factor-1 (HIF-1), tumor necrosis factor (TNF), among others. A decrease in insulin resistance, a reduction of inflammation, and anti-oxidative stress-related effects may be the mechanism of Huangqi decoction for the treatment of NAFLD.
To provide new ideas for further research and treatment of nonalcoholic fatty liver fibrosis, we used bioinformatics technology to search the gene microarray data related to this disease and identified differentially expressed genes and potential therapeutic drugs. Gene Expression Omnibus (GEO) was used to search the entry of "nonalcoholic fatty liver fibrosis"; the GSE109345 microarray data was downloaded, the differentially expressed genes in the control group and the fibrosis model group were screened with the BioJupie analysis platform, and GO function, KEGG pathway, protein-protein interaction (PPI) network analysis and visualization were conducted for the differentially expressed genes. Finally, through the Connectivity Map (CMap) data platform, compounds with potential efficacy on nonalcoholic fatty liver fibrosis were predicted. A total of 109 differentially expressed genes were screened, including 70 up-regulated genes and 39 down-regulated genes. Functional analysis showed that differentially expressed genes were mainly involved in protein kinase B signal transduction, extracellular domain function, small molecule binding and other functions; pathway analysis showed that these genes participated in retinol metabolism, steroid hormone synthesis, and arachidonic acid metabolism; PPI network analysis showed that metallopeptidase inhibitor 1 (TIMP1), chemokine (C-C motif) ligand 2 (CCL2), recombinant signal regulatory protein beta 1 (SIRPB1), and cytochrome P450 (CYP) were the main genes related to nonalcoholic fatty liver fibrosis. CMap analysis showed that pioglitazone, midodrine, arecoline and other compounds had potential efficacy in nonalcoholic fatty liver fibrosis. Thus, by screening for differentially expressed genes, related genes and potential therapeutic compounds effective in the treatment of non-alcoholic fatty liver fibrosis can be identified, as well as new ideas and approaches for the clinical treatment of non-alcoholic fatty liver fibrosis.
Twenty compounds were isolated and purified from the fresh roots of Huaizhong NO.1 Rehmannia glutinosa by various chromatographic techniques such as Toyopreal HW-40C, Sephadex LH-20, silica gel and semi-preparative HPLC. Their structures were identified by analysis of physicochemical properties and spectral data, and determined as 3-methyl-2-(hydroxymethyl)-4H-pyrone-4-one (1), 3-amino-2-pyridine ethanol (2), (5'S)-2-oxo-N-phenylpyrrolidine-3-carboxamide (3), L-pyroglutamic acid methyl ester (4), indazole (5), uridine (6), adenosine (7), rehmanalkaloid C (8), 1-(3-ethylphenyl)-1, 2-ethanediol (9), (3-ethylphenyl)-1, 2-ethanediol (10), 2-hydroxymethylphenyl-1-O-β-D-glucopyranoside (11), mussaenoside (12), 11-methylforsythide (13), 7-deoxygardoside (14), 1-O-α-L-rhamnopyranosyl(1→6)-β-D-glucopyranoside (15), 6-deoxy-D-mannono-1, 4-lactone (16), monoethylfumarate (17), daphneresinol (18), dihydroquercetin (19), rhamnopyranosyl vaniloyl (20). Compound 1 is a new compound, named as 3-methyl-2-(hydroxymethyl)-4H-pyrone-4-one, compounds 2 and 3 are new natural products, and compounds 4, 5, 9-11, 13, 14 and 16-19 are isolated from Rehmannia for the first time.
In this study, 9 aztreonam prodrug compounds were designed and synthesized, and their metabolic stability in plasmas of different species (rat, mouse, dog, monkey and human) were evaluated. Species differences were observed in aztreonam carboxylates's sensitivity to the plasma esterases among different species, and the hydrolysis rates of aztreonam carboxylates in rodent plasmas were much higher than in non-rodent plasmas. Moreover, the hydrolysis rates of aztreonam carboxylates might be positively correlated with the ClogP values in human plasma. These results provide useful guidance for the further development of monocyclic β lactam prodrugs.
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