ABSTRACT
Aerogels are three-dimensional solid networks with incredibly low densities, high porosity, and large specific surface areas. These aerogels have both nanoscale and macroscopic interior structures. Combined with graphene, the aerogels show improved mechanical strength, electrical conductivity, surface area, and adsorption capacity, making them ideal for various biomedical applications. The graphene aerogel has a high drug-loading capacity due to its large surface area, and the porous structure enables controlled drug release over time. The presence of graphene makes it a suitable material for wound dressings, blood coagulation, and bilirubin adsorption. Additionally, graphene's conductivity can help in the electrical stimulation of cells for improved tissue regeneration, and it is also appropriate for biosensors. In this review, we discuss the preparation and advantages of graphene-based aerogels in wound dressings, drug delivery systems, bone regeneration, and biosensors.
ABSTRACT
SUMO-modification of nuclear proteins has profound effects on gene expression. However, non-toxic chemical tools that modulate sumoylation in cells are lacking. Here, to identify small molecule sumoylation inhibitors we developed a cell-based screen that focused on the well-sumoylated substrate, human Liver Receptor Homolog-1 (hLRH-1, NR5A2). Our primary gene-expression screen assayed two SUMO-sensitive transcripts, APOC3 and MUC1, that are upregulated by SUMO-less hLRH-1 or by siUBC9 knockdown, respectively. A polyphenol, tannic acid (TA) emerged as a potent sumoylation inhibitor in vitro (IC50 = 12.8 µM) and in cells. TA also increased hLRH-1 occupancy on SUMO-sensitive transcripts. Most significantly, when tested in humanized mouse primary hepatocytes, TA inhibits hLRH-1 sumoylation and induces SUMO-sensitive genes, thereby recapitulating the effects of expressing SUMO-less hLRH-1 in mouse liver. Our findings underscore the benefits of phenotypic screening for targeting post-translational modifications, and illustrate the potential utility of TA for probing the cellular consequences of sumoylation.
Subject(s)
Enzyme Inhibitors/isolation & purification , Enzyme Inhibitors/metabolism , Hepatocytes/drug effects , Receptors, Cytoplasmic and Nuclear/metabolism , Sumoylation/drug effects , Tannins/isolation & purification , Tannins/metabolism , Animals , Cells, Cultured , Drug Evaluation, Preclinical/methods , Gene Expression Profiling , Hepatocytes/enzymology , Humans , Inhibitory Concentration 50 , Mice , Mice, SCIDABSTRACT
Inactivation of the TCA cycle enzyme, fumarate hydratase (FH), drives a metabolic shift to aerobic glycolysis in FH-deficient kidney tumors and cell lines from patients with hereditary leiomyomatosis renal cell cancer (HLRCC), resulting in decreased levels of AMP-activated kinase (AMPK) and p53 tumor suppressor, and activation of the anabolic factors, acetyl-CoA carboxylase and ribosomal protein S6. Reduced AMPK levels lead to diminished expression of the DMT1 iron transporter, and the resulting cytosolic iron deficiency activates the iron regulatory proteins, IRP1 and IRP2, and increases expression of the hypoxia inducible factor HIF-1α, but not HIF-2α. Silencing of HIF-1α or activation of AMPK diminishes invasive activities, indicating that alterations of HIF-1α and AMPK contribute to the oncogenic growth of FH-deficient cells.
Subject(s)
AMP-Activated Protein Kinases/metabolism , Fumarate Hydratase/deficiency , Iron Deficiencies , Kidney Neoplasms/metabolism , Leiomyomatosis/congenital , Acetyl Coenzyme A/biosynthesis , Acetyl-CoA Carboxylase/biosynthesis , Acetyl-CoA Carboxylase/metabolism , Animals , Basic Helix-Loop-Helix Transcription Factors/biosynthesis , Cation Transport Proteins/biosynthesis , Cell Line, Tumor , Fumarate Hydratase/metabolism , Glycolysis/drug effects , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/biosynthesis , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Iron Regulatory Protein 1/biosynthesis , Iron Regulatory Protein 1/metabolism , Iron Regulatory Protein 2/biosynthesis , Iron Regulatory Protein 2/metabolism , Kidney Neoplasms/enzymology , Kidney Neoplasms/pathology , Leiomyomatosis/metabolism , Leiomyomatosis/pathology , Mice , NADP/biosynthesis , Neoplastic Syndromes, Hereditary , Ribose/biosynthesis , Ribosomal Protein S6/biosynthesis , Ribosomal Protein S6/metabolism , Skin Neoplasms , Thenoyltrifluoroacetone/pharmacology , Tumor Suppressor Protein p53/biosynthesis , Uterine NeoplasmsSubject(s)
Acetylene/analogs & derivatives , Benzene Derivatives/chemistry , Molybdenum/chemistry , Nanostructures/chemistry , Oxides/chemistry , Polymers/chemistry , Rotaxanes/chemistry , Acetylene/chemical synthesis , Acetylene/chemistry , Benzene Derivatives/chemical synthesis , Models, Molecular , Molecular Structure , Particle Size , Surface PropertiesABSTRACT
A new series of hematoporphyrin-platinum(II) conjugates was prepared by platination of the glutamate ligand tethered to hydrophilic hematoporphyrin derivatives, in which different numbers of ethylene oxide unit were introduced to modulate the hydrophobic/hydrophilic balance of the conjugates. The antitumor activity of the hematoporphyrin-platinum(II) conjugates was assayed in vitro and in vivo against the leukemia L1210 cell line. Among the complexes, compound 11 exhibited not only higher in vivo activity (T/C% = 192) than cisplatin (T/C% = 184) and carboplatin (T/C% = 168), but also elevated tumor-localizing effect (tumor/muscle ratio > 3).
Subject(s)
Antineoplastic Agents/chemical synthesis , Hematoporphyrins/pharmacokinetics , Organoplatinum Compounds/pharmacokinetics , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacokinetics , Cell Line, Tumor , Cell Survival/drug effects , Glutamic Acid/chemistry , Hematoporphyrins/administration & dosage , Hematoporphyrins/chemistry , Hydrophobic and Hydrophilic Interactions , Inhibitory Concentration 50 , Leukemia/drug therapy , Mice , Organoplatinum Compounds/administration & dosage , Organoplatinum Compounds/chemical synthesis , Structure-Activity Relationship , Tissue Distribution , Treatment OutcomeABSTRACT
The trans-(+/-)-1,2-diaminocyclohexaneplatinum(II) complexes of multidentate L-glutamate (Glu) and L-aspartate (Asp) were prepared and their antitumor activity was examined in relation with their coordination modes. All these complexes were obtained as a mixture of (O,O')- and (O,N)-chelate isomers due to rapid isomerization of the initially formed (O,O')-isomer to the thermodynamically more stable (O,N)-isomer. The (O,O')/(O,N)-isomeric mixture with the mole ratio of 80/20 exhibited excellent antitumor activity while the pure (O,N)-isomer was only marginally active. Therefore, in order to prevent the linkage isomerization of the active (O,O')-isomer to the inactive (O,N)-isomer, we have designed N-substituted amino dicarboxylic acids as a leaving group and prepared a new series of complexes, [Pt(dach)(RGlu)] and [Pt(dach)(RAsp)] (dach=trans-(+/-)-1,2-diaminocyclohexane; R=acetyl (Ac), propionyl (Pro), pivaloyl (Piv), carbobenzyloxy (Cbz) or phthaloyl (Phth)) and characterized by means of elemental analyses, and 1H NMR, 195Pt NMR and IR spectroscopies. The N-substituted amino dicarboxylate ligands were found to coordinate to platinum(II) ion through only the (O,O')-chelation mode, and their Pt(II) complexes were chemically stable in aqueous solution. The present Pt(II) complexes of N-substituted amino dicarboxylic acids showed excellent antitumor activity against both murine leukemia L1210 and human tumor cells. Especially, the highly hydrophobic N-phthaloylglutamate complex, [Pt(dach)(PhthGlu)], exhibited an outstanding in vitro activity (IC50=2.22 microM) on the human stomach cancer cells which are not responsive to cisplatin and carboplatin.
Subject(s)
Amino Acids, Dicarboxylic/chemistry , Amino Acids, Dicarboxylic/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Organoplatinum Compounds/chemistry , Organoplatinum Compounds/pharmacology , Amino Acids, Dicarboxylic/chemical synthesis , Animals , Antineoplastic Agents/chemical synthesis , Cell Line, Tumor , Drug Screening Assays, Antitumor , Humans , Hydrophobic and Hydrophilic Interactions , Inhibitory Concentration 50 , Isomerism , Leukemia L1210/drug therapy , Organoplatinum Compounds/chemical synthesisABSTRACT
A new series of platinum(II) complexes of pegylated hematoporphyrin derivatives with controlled hydrophobic/hydrophilic balance were synthesized by introducing different kinds of poly(ethylene glycol) and amine ligands to the porphyrin ring. The antitumor activity of the porphyrin-platinum(II) conjugates was assayed in vitro and in vivo against leukemia L1210 cell line and various human tumor cell lines. The present complexes exhibited high antitumor activity and improved water solubility as well as considerable lipophilicity. In particular, complex 16 showed not only higher in vivo activity (T/C%=258) than cisplatin (T/C%=184) and carboplatin (T/C%=168), but also excellent solubility in water and organic solvent. The antitumor activity of complex 20 was superior to that of carboplatin against all human tumor cell lines tested. Moreover, some amphiphilic complexes (7 and 12) exhibited elevated tumor-localizing effect (tumor/muscle ratio>2).
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Hematoporphyrins/chemistry , Hematoporphyrins/pharmacology , Organoplatinum Compounds/chemistry , Organoplatinum Compounds/pharmacology , Animals , Antineoplastic Agents/pharmacokinetics , Carboplatin/pharmacology , Cell Line, Tumor , Hematoporphyrins/chemical synthesis , Hematoporphyrins/pharmacokinetics , Humans , Hydrophobic and Hydrophilic Interactions , Leukemia L1210/drug therapy , Male , Mice , Mice, Inbred C57BL , Organoplatinum Compounds/chemical synthesis , Organoplatinum Compounds/pharmacokinetics , Solubility , Tissue DistributionABSTRACT
New balls please! Reaction of Cu(BF4 )2 with [(dach)PtII ] (dach=trans (±)-1,2-diaminocyclohexane) and bis(ethylthio)methylenepropanedioate (BETMP) gave [{(dach)Pt(BETMP)}2 Cu(BF4 )2 ] (1; shown schematically). Dimerization of 1 in methanol leads to the first inorganic "tennis ball" 2 [Eq. (1)]. A BF4- ion is encapsulated in the cavity of 2.
