ABSTRACT
Background: Gestational diabetes mellitus (GDM), a transient disease, may lead to short- or long-term adverse influences on maternal and fetal health. Therefore, its potential functions, mechanisms and related molecular biomarkers must be comprehended for the control, diagnosis and treatment of GDM. Methods: The differentially expressed genes (DEGs) were identified using GSE49524 and GSE87295 associated with GDM from the Gene Expression Omnibus database, followed by function enrichment analysis, protein-protein interactions network construction, hub DEGs mining, diagnostic value evaluation and immune infiltration analysis. Finally, hub DEGs, the strongest related to immune infiltration, were screened as immune-related biomarkers. Results: A hundred and seven DEGs were identified between patients with GDM and healthy individuals. Six hub genes with high diagnostic values, including ALDH1A1, BMP4, EFNB2, MME, PLAUR and SLIT2, were identified. Among these, two immune-related genes (PLAUR and SLIT2) with the highest absolute correlation coefficient were considered immune-related biomarkers in GDM. Conclusion: Our study provides a comprehensive analysis of GDM, which would provide a foundation for the development of diagnosis and treatment of GDM.
Subject(s)
Diabetes, Gestational , Humans , Female , Pregnancy , Diabetes, Gestational/diagnosis , Diabetes, Gestational/genetics , Genes, Regulator , Biomarkers , Computational Biology , Databases, FactualABSTRACT
Neuregulin-4 (Nrg4) and melatonin play vital roles in endocrine diseases. However, there is little discussion about the function and potential mechanism of Nrg4 and melatonin in prolactin (PRL) regulation. The human normal pituitary data from Gene Expression Profiling Interactive Analysis (GEPIA) database was used to explore the correlation between NRG4 and PRL. The expression and correlation of NRG4 and PRL were determined by Immunofluorescence staining (IF) and human normal pituitary tissue microarray. Western Blot (WB) was used to detect the expression of PRL, p-ErbB2/3/4, ErbB2/3/4, p-Erk1/2, Erk1/2, p-Akt and Akt in PRL-secreting pituitary GH3 and RC-4B/C cells treated by Nrg4, Nrg4-small interfering RNA, Erk1/2 inhibitor FR180204 and melatonin. The expression of NRG4 was significantly positively correlated with that of PRL in the GEPIA database and normal human pituitary tissues. Nrg4 significantly increased the expression and secretion of PRL and p-Erk1/2 expression in GH3 cells and RC-4B/C cells. Inhibition of Nrg4 significantly inhibited PRL expression. The increased levels of p-Erk1/2 and PRL induced by Nrg4 were abolished significantly in response to FR180204 in GH3 and RC-4B/C cells. Additionally, Melatonin promotes the expression of Nrg4, p-ErbB4, p-Erk1/2, and PRL and can further promote the expression of p-Erk1/2 and PRL in combination with Nrg4. Further investigation into the function of Nrg4 and melatonin on PRL expression and secretion may provide new clues to advance the clinical control of prolactinomas and hyperprolactinemia.
Subject(s)
MAP Kinase Signaling System , Melatonin , Neuregulins , Prolactin , Receptor, ErbB-4 , Melatonin/pharmacology , Humans , Prolactin/metabolism , Receptor, ErbB-4/metabolism , Receptor, ErbB-4/genetics , Neuregulins/metabolism , Neuregulins/genetics , MAP Kinase Signaling System/drug effects , Pituitary Gland/metabolism , Pituitary Gland/cytology , Animals , RatsABSTRACT
A series of N-phenylarylformamide derivatives (PAFAs) with anti-wild-type HIV-1 activity (EC(50) values) ranging from 0.3 nM to 5.1 nM and therapeutic index (TI) ranging from 10 616 to 271 000 were identified as novel non-nucleoside reverse transcriptase inhibitors. Among them, compound 13g (EC(50) = 0.30 nM, TI = 184 578), 13l (EC(50) = 0.37 nM, TI = 212 819), 13m (EC(50) = 0.32 nM, TI = 260 617) and 13r (EC(50) = 0.27 nM, TI = 271 000) displayed the highest activity against this type virus nearly as potent as lead compound GW678248. Moreover, all of them were also active to inhibit the double mutant strain A(17) (K103N + Y181C) with EC(50) values of 0.29 µM, 0.14 µM, 0.10 µM and 0.27 µM, respectively. In particular, compound 13m, which showed broad-spectrum anti-HIV activity, was also effective to inhibit the HIV-2 ROD replication within 4.37 µM concentration.
Subject(s)
Anti-HIV Agents/pharmacology , Formamides/pharmacology , HIV Reverse Transcriptase/antagonists & inhibitors , HIV-1/drug effects , HIV-2/drug effects , Reverse Transcriptase Inhibitors/pharmacology , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/chemistry , Dose-Response Relationship, Drug , Formamides/chemical synthesis , Formamides/chemistry , HIV Reverse Transcriptase/metabolism , Microbial Sensitivity Tests , Models, Molecular , Molecular Dynamics Simulation , Molecular Structure , Reverse Transcriptase Inhibitors/chemical synthesis , Reverse Transcriptase Inhibitors/chemistry , Structure-Activity RelationshipABSTRACT
A series of 18 cycloalkyl arylpyrimidines (CAPYs) were designed from lead compounds diarylpyrimidines (DAPYs), synthesized and evaluated for in vitro anti-HIV activity. Among them, the compound 1p displayed potent anti-HIV-1 activity against WT HIV-1 with an EC(50) value of 0.055 µM and a selectivity index (SI) >7290. The preliminary structure-activity relationship (SAR) of this new series of compounds was also investigated, which enriched the SAR of diarylpyrimidines (DAPYs).
Subject(s)
Anti-HIV Agents/chemistry , HIV Reverse Transcriptase/antagonists & inhibitors , HIV-1/enzymology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Reverse Transcriptase Inhibitors/chemistry , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacology , HIV Reverse Transcriptase/genetics , HIV Reverse Transcriptase/metabolism , Humans , Models, Molecular , Pyrimidines/chemical synthesis , Reverse Transcriptase Inhibitors/chemical synthesis , Reverse Transcriptase Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
A novel series of benzophenone derivatives with B-ring substituted by naphthyl ring has been synthesized and evaluated as non-nucleoside HIV-1 reverse transcriptase inhibitors. Most of these compounds showed good to moderate activity against wild-type HIV-1 and mutated viruses. In particular, the analogue 10i demonstrated the most potent activity against wild-type HIV-1 with an EC50 value of 4.8 nM, and with a high selectivity index up to 10347.9, it also proved to be active against the HIV-1 double mutant strain A17 (K103N+Y181C) with an EC50 value of 2.1 µM. In addition, the molecular modeling study was used to explore the major interactions between the potent inhibitors with the HIV-1 RT. The investigation of the structure-activity relationships may serve as an important lead for the further optimization.
Subject(s)
Anti-HIV Agents/pharmacology , Benzophenones/pharmacology , HIV Infections/drug therapy , HIV Reverse Transcriptase/antagonists & inhibitors , HIV-1/drug effects , Reverse Transcriptase Inhibitors/pharmacology , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/chemistry , Benzophenones/chemical synthesis , Benzophenones/chemistry , HIV Infections/enzymology , HIV Infections/genetics , HIV Reverse Transcriptase/metabolism , HIV-1/enzymology , HIV-1/genetics , Humans , Models, Molecular , Mutation , Reverse Transcriptase Inhibitors/chemical synthesis , Reverse Transcriptase Inhibitors/chemistry , Structure-Activity RelationshipABSTRACT
A series of (±)-benzhydrol derivatives featuring the essential sulfonamide group at the para position on the C-ring were synthesized and evaluated for the potential anti-HIV activity in C8166 cells. Most of these analogues demonstrated low concentration inhibitory activity with EC(50) values less than 1 µM against the wild-type HIV-1. In particular, compound 7h was identified as the highest active inhibitor of wild-type HIV-1 with an EC(50) value of 0.12 µM and selectivity index value of 312.73. Furthermore, some of them also exhibited moderate activity against the double mutant strain A(17) (K103N+Y181C) with EC(50) values lower than 5 µM. In addition, the binding modes with RT and the preliminary structure-activity relationships of these derivatives were also explored for further chemical modifications.
Subject(s)
Anti-HIV Agents/chemical synthesis , Drug Design , HIV Reverse Transcriptase/antagonists & inhibitors , Molecular Targeted Therapy , Reverse Transcriptase Inhibitors/chemical synthesis , Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , Benzhydryl Compounds/chemistry , Benzhydryl Compounds/pharmacology , Cell Line , Drug Evaluation, Preclinical , HIV-1 , Humans , Models, Molecular , Reverse Transcriptase Inhibitors/chemistry , Reverse Transcriptase Inhibitors/pharmacology , Structure-Activity Relationship , Sulfonamides/chemistryABSTRACT
An efficient and highly stereoselective total synthesis of d-biotin has been achieved starting from cis-1,3-dibenzyl-2-imidazolidone-4,5-dicarboxylic acid (2) with an overall yield of 33%. Polymer-supported oxazaborolidine-catalyzed asymmetric reduction of meso-cyclic imide 4 constitutes the key synthetic step in introducing stereogenic centers into the d-biotin molecule.
