ABSTRACT
BACKGROUND: Androgens and androgen receptor (AR) are critical regulators of the masculinization process in male sexual development. The absence of a functioning AR results in the development of the androgen insensitivity syndrome (AIS), a rare disorder of sexual development (DSD) characterized by the external genitalia feminization, gynecomastia, and impaired spermatogenesis. OBJECTIVE: To determine the AR gene mutations associated with male DSD in four unrelated Vietnamese patients. METHODS: To detect the disease-causing mutations, whole exome sequencing (WES) was performed on four patients diagnosed with AIS. Sanger sequencing was then used for validation of the identified mutations. Finally, 12 web-based tools, three-dimensional protein modeling software, and the guidelines issued by the American College of Medical Genetics and Genomics were used to assess the potential pathogenicity of these mutations. RESULTS: Four distinct novel mutations, namely c.1834T > A (p.Cys612Ser), c.2122 C > G (p.Leu708Val), c.2630T > G (p.Phe877Cys), and c.2641 C > A (p.Leu881Met) in the AR gene, were identified in four AIS patients using WES. The in silico analysis results revealed that the Cys612, Leu708, Phe877, and Leu881 sites are important for an appropriate response to androgens of the AR, and mutation at these sites can have adverse effects on the AR functions, androgen-AR interaction, and AR signaling pathway. CONCLUSIONS: WES and in silico analyses strongly suggested that four novel AR mutations are pathogenic and have led to the development of AIS in the four Vietnamese patients under consideration.
Subject(s)
Androgen-Insensitivity Syndrome , Humans , Male , Androgen-Insensitivity Syndrome/genetics , Androgen-Insensitivity Syndrome/diagnosis , Androgen-Insensitivity Syndrome/metabolism , Androgens , Receptors, Androgen/genetics , Receptors, Androgen/metabolism , Southeast Asian People , MutationABSTRACT
Chemical investigation of the marine-derived fungal isolate Penicillium sp. SF-5497 resulted in the isolation of two new preaustinoid-related meroterpenoids, named preaustinoid A6 (1) and preaustinoid A7 (2), along with three known metabolites (3-5). Their structures were elucidated by extensive spectroscopic analyses, such as 1D and 2D NMR and MS data. Among these, compounds 1 and 3 inhibited PTP1B activity in a dose-dependent manner, with IC50 values of 17.6 and 58.4 µM, respectively. Furthermore, kinetic analyses indicated that compound 1 inhibited PTP1B in a noncompetitive manner, with the Ki value of 17.0 µM.
Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Penicillium/chemistry , Protein Tyrosine Phosphatase, Non-Receptor Type 1/antagonists & inhibitors , Terpenes/chemistry , Terpenes/pharmacology , Dose-Response Relationship, Drug , Humans , Models, Molecular , Molecular StructureABSTRACT
Five new secondary metabolites, modiolides D-G (1-4) and 1-(2,5-dihydroxyphenyl)-3-methoxy-butan-1-one (8), one new natural product, 1-(2,5-dihydroxyphenyl)-3-hydroxybutan-1-one (7), along with three known compounds, modiolides A (5) and B (6), and 1-(2,5-dihydroxyphenyl)-2-buten-1-one (9) were isolated from a fermentation culture of the marine endophytic fungus Paraconiothyrium sp. VK-13. Their chemical structures were elucidated by the NMR and MS spectroscopic analysis as well as the modified Mosher's method. Compounds 7 and 9 inhibited the overproduction of proinflammatory mediators NO and PGE2 in LPS-stimulated RAW264.7 cells, with IC50 values ranging from 3.9 to 12.5 µM. The inhibitory effects of 7 and 9 on the release of NO and PGE2 were correlated with their significant suppression of iNOS and COX-2 protein expression, respectively. Furthermore, both compounds 7 and 9 inhibited the mRNA expression of proinflammatory cytokines, including TNF-α, IL-1ß, IL-6, and IL-12, with IC50 values in a range of 2.4-12.5 µM.
