ABSTRACT
Depression is a serious and potentially life-threatening mental illness. Recently, the role of sirtuin 1 (SIRT1) in chronic unpredictable mild stress (CUMS) management has been examined. The present study explored and clarified whether microRNA (miR)-135b-5p could play a role in depression by regulating the expression of SIRT1. SIRT1 was identified as the target gene of miR-135b-5p using TargetScan and the dual luciferase reporter assay. In addition, the expression levels of SIRT1 were significantly reduced in mouse peripheral blood and hippocampal tissue samples, while the expression of miR-135b-5p exhibited the opposite effects. Subsequently, the effects of miR-135b-5p inhibition were investigated in mice with depression. The results indicated that the miR-135b-5p inhibitor significantly increased the weight loss induced by CUMS compared with the model group, while reducing the expression levels of miR-135b-5p and further alleviating the depression-like behavior induced by CUMS. Concomitantly, the results indicated that the miR-135b-5p inhibitor inhibited CUMS-induced hippocampal cell apoptosis and significantly reduced the expression levels of cleaved caspase-3 and the ratio of cleaved caspase-3/caspase-3. Moreover, the miR-135b-5p inhibitor significantly reduced the CUMS-induced increase of the inflammatory factors IL-1ß, IL-6 and TNF-α in the hippocampal mouse samples, while significantly increasing the expression levels of SIRT1. Finally, the results demonstrated that all the effects of the miR-135b-5p inhibitor on CUMS-induced mice were significantly reversed by SIRT1 silencing. In conclusion, the present study indicated that the miR-135b-5p/SIRT1 pathway was a key mediator of antidepressant effects induced in depressed mice. Therefore, it could be considered a potential therapeutic target for the treatment of CUMS-induced depression.
Subject(s)
MicroRNAs , Sirtuin 1 , Animals , Antidepressive Agents/pharmacology , Apoptosis , Down-Regulation , Mice , MicroRNAs/genetics , Sirtuin 1/genetics , Sirtuin 1/metabolismABSTRACT
A highly efficient and practical Pd(II)/Cu(OAc)2-catalyst system of Saegusa oxidation, which converts enol ethers to the corresponding enals with a number of diverse substrates at extremely low catalyst loadings (500 mol ppm) under ligand-free and aqueous conditions, is described. Its synthetic utility was demonstrated by large-scale applications of the catalyst system to important nature molecules. This work allows Saegusa oxidation to become a highly practical approach to preparing enals and also suggests new insight into the Pd(II)/Cu(II)-catalyst system for dehydrogenation of carbonyl compounds and decreasing Pd-catalyst loadings.
ABSTRACT
A novel series of polyhalobenzonitrile quinazolin-4(3H)-one derivatives were synthesized and characterized by NMR, IR, MS, and HRMS spectra. All of the newly prepared compounds were screened for antimicrobial activities against four strains of bacteria (Gram-positive bacterial: Staphylococcus aureus and Bacillus cereus; Gram-negative bacterial: Escherichia coli and Pseudomonas aeruginosa) and one strain of fungi (Candida albicans). Among the synthesized compounds, 5-(dimethylamino)-8-(2,4,5-trichloro-isophthalonitrile) quinazolin-4(3H)-one (7k) exhibited significant activity towards Gram-positive bacterial, Gram-negative bacterial, and the fungi strains. The MIC (0.8-3.3µg/mL) and MBC (2.6-7.8µg/mL) for this compound were close to those of nofloxacin, chlorothalonil, and fluconazole, making it the most potent antimicrobial agents in the series.
Subject(s)
Anti-Infective Agents/chemistry , Anti-Infective Agents/pharmacology , Bacteria/drug effects , Candida albicans/drug effects , Quinazolines/chemistry , Quinazolines/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Anti-Infective Agents/chemical synthesis , Antifungal Agents/chemical synthesis , Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Bacterial Infections/drug therapy , Candidiasis/drug therapy , Humans , Microbial Sensitivity Tests , Quinazolines/chemical synthesisABSTRACT
Previously it was found that 4-hydroxybenzaldehyde is a competitive inhibitor of GABA transaminase. Here 3-chloro-1-(4-hydroxyphenyl)propan-1-one (9), a 4-hydroxybenzaldehyde analogue, was found to inactivate potently the enzyme in a time-dependent manner. alpha-Ketoglutarate prevented the enzyme from inactivation, suggesting that the inactivation occurs in its active site. Several experiments indicated that the inactivation is irreversible. This study provides a novel strategy for the design of more effective inhibitors.
Subject(s)
4-Aminobutyrate Transaminase/antagonists & inhibitors , 4-Aminobutyrate Transaminase/chemistry , Chemistry, Pharmaceutical/methods , Enzyme Inhibitors/pharmacology , Ketoglutaric Acids/chemistry , Propiophenones/chemistry , Catalytic Domain , Dose-Response Relationship, Drug , Drug Design , Enzyme Activation , Enzyme Inhibitors/chemical synthesis , Humans , Kinetics , Models, Chemical , Propiophenones/chemical synthesisABSTRACT
In the present review, English literature on the pharmacological effects of Gastrodia elata was summarized. The literature mainly reported the effects of G. elata on central nervous system, including anticonvulsant, neuroprotection, improvement on learning and memory, and so on. These pharmacological effects were closely associated with its phenolic components.
Subject(s)
Drugs, Chinese Herbal/pharmacology , Gastrodia/chemistry , Animals , Central Nervous System/drug effects , Humans , Memory/drug effectsABSTRACT
Previous study showed that 4-hydroxybenzaldehyde is a competitive inhibitor of GABA transaminase. As a result, 4-acryloylphenol was synthesized as a 4-hydroxybenzaldehyde analogue, and shown to inactivate potently the enzyme in a time-dependent manner. The inactivation was protected by alpha-ketoglutarate, indicating that it occurs at the active site of the enzyme. Beta-mercaptoethanol also prevented the enzyme from inactivation. The possible mechanism involving a Michael addition was proposed to rationalize the inactivation.
Subject(s)
4-Aminobutyrate Transaminase/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Phenols/chemical synthesis , Phenols/pharmacology , Benzaldehydes/chemistry , Binding Sites , Ketoglutaric Acids/pharmacology , Mercaptoethanol/pharmacology , Structure-Activity Relationship , Time FactorsABSTRACT
4-Hydroxybenzaldehyde (HBA) derivatives were examined as inhibitors for GABA transaminase (GABA-T) and succinic semialdehyde dehydrogenase (SSADH). Investigation of structure-activity relation revealed that a carbonyl group or an amino group as well as a hydroxy group at the para position of the benzene ring are important for both enzymes' inhibition. HBA was shown to give competitive inhibition of GABA-T with respect to alpha-ketoglutarate and competitive inhibition of SSADH. 4-Hydroxybenzylamine (HBM) also showed the competitive inhibition on GABA-T with respect to GABA. In conclusion, the inhibitory effects of HBA and HBM on both enzymes could result from the similarity between both molecules and the two enzymes' substrates in structure, as well as the conjugative effect of the benzene ring. This suggested that the presence of the benzene ring may be accepted by the active site of both enzymes, HBA and HBM may be considered as lead compounds to design novel GABA-T inhibitors.
