AIM:To investigate the contribution of ABCB4 mutations to pediatric idiopathic gallstone disease and the potential of hormonal contraceptives to prompt clinical manifestations of multidrug resistance protein 3 ***:Mut...
详细信息
AIM:To investigate the contribution of ABCB4 mutations to pediatric idiopathic gallstone disease and the potential of hormonal contraceptives to prompt clinical manifestations of multidrug resistance protein 3 ***:Mutational analysis of ABCB4,screening for copy number variations by multiplex ligation-dependent probe amplification,genotyping for low expression allele c.1331T>C of ABCB11 and genotyping for variation c.55G>C in ABCG8 previously associated with cholesterol gallstones in adults was performed in 35 pediatric subjects with idiopathic gallstones who fulfilled the clinical criteria for low phospholipid-associated cholelithiasis syndrome(LPAC,OMIM#600803)and in 5young females with suspected LPAC and their families(5 probands,15 additional family members).The probands came to medical attention for contraceptiveassociated intrahepatic ***:A possibly pathogenic variant of ABCB4was found only in one of the 35 pediatric subjects with idiopathic cholesterol gallstones whereas 15 members of the studied 5 LPAC kindreds were confirmed and another one was highly suspected to carry predictably pathogenic mutations in *** these 16,however,none developed gallstones in *** 5index patients,all young females carrying at least one pathogenic mutation in one allele of ABCB4,manifestation of LPAC as intrahepatic cholestasis with elevated serum activity of gamma-glutamyltransferase was induced by hormonal *** ABCB11c.1331T>C and ABCG8 c.55G>C were not significantly overrepresented in the 35 examined patients with suspect ***:Clinical criteria for LPAC syndrome caused by mutations in ABCB4 cannot be applied topediatric patients with idiopathic *** immaturity even prevents manifestation of LPAC.
Background: The histone code is an established epigenetic regulator of early embryonic development in *** lysine residue K9 of histone H3(H3 K9) is a prime target of SIRT1, a member of NAD+-dependent histone deacetyla...
详细信息
Background: The histone code is an established epigenetic regulator of early embryonic development in *** lysine residue K9 of histone H3(H3 K9) is a prime target of SIRT1, a member of NAD+-dependent histone deacetylase family of enzymes targeting both histone and non-histone substrates. At present, little is known about SIRT1-modulation of H3 K9 in zygotic pronuclei and its association with the success of preimplantation embryo development. Therefore, we evaluated the effect of SIRT1 activity on H3 K9 methylation and acetylation in porcine zygotes and the significance of H3 K9 modifications for early embryonic ***: Our results show that SIRT1 activators resveratrol and BML-278 increased H3 K9 methylation and suppressed H3 K9 acetylation in both the paternal and maternal pronucleus. Inversely, SIRT1 inhibitors nicotinamide and sirtinol suppressed methylation and increased acetylation of pronuclear H3 K9. Evaluation of early embryonic development confirmed positive effect of selective SIRT1 activation on blastocyst formation rate(5.2 ± 2.9% versus 32.9 ± 8.1% in vehicle control and BML-278 group, respectively; P ≤ 0.05). Stimulation of SIRT1 activity coincided with fluorometric signal intensity of ooplasmic ubiquitin ligase MDM2, a known substrate of SIRT1 and known limiting factor of epigenome ***: We conclude that SIRT1 modulates zygotic histone code, obviously through direct deacetylation and via non-histone targets resulting in increased H3 K9 me3. These changes in zygotes lead to more successful pre-implantation embryonic development and, indeed, the specific SIRT1 activation due to BML-278 is beneficial for in vitro embryo production and blastocyst achievement.
Background: SIRT1 histone deacetylase acts on many epigenetic and non-epigenetic targets. It is thought that SIRT1 is involved in oocyte maturation;therefore, the importance of the ooplasmic SIRT1 pool for the further...
详细信息
Background: SIRT1 histone deacetylase acts on many epigenetic and non-epigenetic targets. It is thought that SIRT1 is involved in oocyte maturation;therefore, the importance of the ooplasmic SIRT1 pool for the further fate of mature oocytes has been strongly suggested. We hypothesised that SIRT1 plays the role of a signalling molecule in mature oocytes through selected epigenetic and non-epigenetic ***: We observed SIRT1 re-localisation in mature oocytes and its association with spindle *** mature oocytes, SIRT1 distribution shows a spindle-like pattern, and spindle-specific SIRT1 action decreasesα-tubulin acetylation. Based on the observation of the histone code in immature and mature oocytes, we suggest that SIRT1 is mostly predestined for an epigenetic mode of action in the germinal vesicles(GVs) of immature oocytes. Accordingly, BML-278-driven trimethylation of lysine K9 in histone H3 in mature oocytes is considered to be a result of GV epigenetic ***: Taken together, our observations point out the dual spatiotemporal SIRT1 action in oocytes,which can be readily switched from the epigenetic to non-epigenetic mode of action depending on the progress of meiosis.
暂无评论