ABSTRACT
The complex pathogenesis of Alzheimer's disease (AD) has become a major obstacle in its treatment. An effective approach is to develop multifunctional agents that simultaneously target multiple pathological processes. Here, a series of diosgenin-indole compounds were designed, synthesized and evaluated for their neuroprotective effects against H2O2 (hydrogen peroxide), 6-OHDA (6-hydroxydopamine) and Aß (beta amyloid) damages. Preliminary structure-activities relationship revealed that the introduction of indole fragment and electron-donating group at C-5 on ring indole could be beneficial for neuroprotective activities. Results indicated that compound 5b was the most promising candidate against cellular damage induced by H2O2 (52.9 ± 1.9%), 6-OHDA (38.4 ± 2.4%) and Aß1-42 (54.4 ± 2.7%). Molecular docking study suggested the affinity for 5b bound to Aß1-42 was -40.59 kcal/mol, which revealed the strong binding affinity of 5b to Aß1-42. The predicted values of brain/blood partition coefficient (-0.733) and polar surface area (85.118 Å2) indicated the favorable abilities of BBB permeation and absorption of 5b. In addition, 5b significantly decreased ROS (reactive oxygen species) production induced by H2O2. In the following in vivo experiment, 5b obviously attenuated memory and learning impairments of Aß-injected mice. In summary, compound 5b could be considered as a promising dual-functional neuroprotective agent against AD.
Subject(s)
Diosgenin/chemistry , Drug Design , Indoles/chemistry , Neuroprotective Agents/chemical synthesis , Alzheimer Disease/drug therapy , Amyloid beta-Peptides/chemistry , Amyloid beta-Peptides/metabolism , Amyloid beta-Peptides/pharmacology , Animals , Binding Sites , Blood-Brain Barrier/drug effects , Blood-Brain Barrier/metabolism , Cell Survival/drug effects , Disease Models, Animal , Humans , Hydrogen Peroxide/pharmacology , Male , Maze Learning/drug effects , Mice , Mice, Inbred ICR , Molecular Docking Simulation , Neuroprotective Agents/therapeutic use , Peptide Fragments/chemistry , Peptide Fragments/metabolism , Peptide Fragments/pharmacology , Reactive Oxygen Species/metabolism , Structure-Activity RelationshipABSTRACT
In order to produce an effective and multi-targeted clinical drug that could prevent progressive neurodegeneration, a series of diosgenin carbamate derivatives were designed, synthesized and tested for their anti-inflammatory, antioxidant and anti-Aß activities. The results demonstrated that compound M15 was the most promising derivative against inflammatory (NO inhibition 22.7 ± 2.2%,10 µM) and cellular damage induced by H2O2 (SH-SY5Y cell protection = 75.3 ± 3.4%, 10 µM) or Aß (astrocytes protection = 70.2 ± 6.5%, 10 µM). Molecular docking studies revealed the strong binding affinity of M15 to the active site of nNOS, Aß42 and pro-inflammatory proteins. Western blot demonstrated that M15 decreased IL-1ß, IL-6 and TNF-α level, which may contribute to its anti-inflammatory effects. In addition, M15 maintained mitochondrial function as well as cell viability through reducing H2O2-induced ROS production. The results indicated that oral administration of M15 attenuated memory deficits and played a neuroprotective effect on subcutaneous (s.c.) D-gal aging mice. In summary, M15 could be considered as a potential multifunctional neuroprotective agent due to the effects of anti-inflammatory, antioxidant and anti-Aß activities.
Subject(s)
Alzheimer Disease/drug therapy , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Carbamates/pharmacology , Diosgenin/pharmacology , Drug Design , Neuroprotective Agents/pharmacology , Aging/drug effects , Aging/metabolism , Alzheimer Disease/metabolism , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Astrocytes/drug effects , Astrocytes/metabolism , Carbamates/chemical synthesis , Carbamates/chemistry , Cell Line, Tumor , Cell Survival/drug effects , Diosgenin/chemical synthesis , Diosgenin/chemistry , Dose-Response Relationship, Drug , Galactose/administration & dosage , Galactose/pharmacology , Humans , Inflammation/drug therapy , Inflammation/metabolism , Male , Mice , Mice, Inbred ICR , Molecular Structure , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/chemistry , Oxidative Stress/drug effects , Protein Aggregates/drug effects , Structure-Activity RelationshipABSTRACT
Objective@#To explore the correlation between blood pressure and urinary phthalandione, MMP, MEP, MnBP, MiBP, PAEs.@*Methods@#Three schools were selected from Shenzhen, China for the present study. A total of 765 firstgrade students of Han ethnicity were recruited voluntarily from the selected schools during September 2016 to June 2017. They were divided into normal blood pressure (BP) group (lower than P90 group) and high BP group (BP≥P90). Linear and Logistic regression models were used to analyze the relationships between blood pressure and urine phthalate metabolite levels.@*Results@#Urinary MMP and MnBP in students of high BP group were significantly higher than that of students in normal BP group(t=13.12, 3.97, P<0.05). Linear regression models showed that Z score increased when MMP and MnBP levels increased(P<0.05). Logistic regression model suggested that the risk of high BP increased with the increment of MMP level adjusting creatinine, sex, age and BMI(OR=1.47, P<0.05). There was no statistical significance in the differences after adjusting many factors including family income and education level of parents(P>0.05).@*Conclusion@#Urinary phthalate metabolite levels are positively associated with blood pressure in first-grade children.
ABSTRACT
BACKGROUND & OBJECTIVE: Nucleotide excision repair is an important pathway for cellular DNA damage repair. The drug resistance of tumor cell is often companied with the enhanced expression of DNA repair genes. Down-regulation of DNA repair capacity by antisense strategy can increase the drug sensitivity of tumor cells. The aim of this study was to construct the eukaryotic expression plasmid pcDNA-XPB/AS (XPB: xeroderma pigmentosum B) and to investigate the function of XPB gene and its roles in chemotherapeutic drug sensitivity in lung cancer A549 cell. METHODS: The XPB cDNA (69-520 bp) fragment amplified by reverse transcription polymerase chain reaction (RT-PCR) was inserted into pcDNA3.1/His plasmid with an inverted orientation. The recombinant plasmid was transiently transfected into A549 cells. The Adriamycin-induced DNA damage was compared between the transfected and the untransfected cells by single cell gel electrophoresis assay (SCGE). The cellular sensitivity to Adriamycin of the transfected and the untransfected cells was determined by MTT assay. RESULTS: The successful construction of antisense plasmid was proved by restriction map and sequence analysis. RT-PCR results showed that the XPB mRNA expression was inhibited in transfected A549 cells. SCGE showed that the cellular damage repair ability induced by 4.0 microg/ml Adriamycin was suppressed in transfected cells. MTT assay showed the sensitivity of the transfected cells to Adriamycin was different from the untransfected cells but without statistical meaning. CONCLUSION: The antisense plasmid constructed by the authors can down-regulate the expression of XPB mRNA in the transfected cells and inhibit the cellular DNA damage repair ability, providing a basis to further study the gene function of XPB.
