Ginsenoside Rb1 inhibits oxidative stress-induced ovarian granulosa cell injury through Akt-FoxO1 interaction

Ginsenoside Rb1 shows a strong antioxidant effect and has potential activation effects on Akt.The aim of the present study was to investigate the protective effect of Rb1 on age-related ovarian granulosa cell injury.Ovarian granulosa cells(GCs)were obtained from 50 young women(≤30 years)and 50 aged women(≥38 years)at an IVF center.Young and aged ICR mice were administered with or without Rb1(10 mg kg^(-1),i.p.)for 2 weeks.The protective effects of Rb1 were investigated and the role of Rb1 on the modulation of Akt-FoxO1 interaction was determined with immunofluorescence,Western blotting,immunoprecipitation,si RNA silencing and pharmacological inhibitor.Rb1 effectively decreased LDH and MDA,and reversed the apoptotic-related protein levels in h GL cells from old patients.Similar results were found in mice.In addition,the mitochondrial membrane potential was restored and the overaccumulation of ROS was reversed by Rb1.Rb1 preserved peroxide-impaired Akt activation,to some extent,by increasing phosphorylation at Ser473.Rb1 also facilitated p-Akt binding to FoxO1 and promoted the phosphorylation of FoxO1.Si RNA silencing of Akt,Akt inhibitor LY294002,and FoxO1 inhibitor AS1842856 attenuated the effects of Rb1.Ginsenoside Rb1 inhibits age-related GCs oxidative damage by activating Akt phosphorylation at Ser473 and by further interaction with FoxO1.

HPV-CCDC106 integration alters local chromosome architecture and hijacks an enhancer by three-dimensional genome structure remodeling in cervical cancer

Integration of human papillomavirus(HPV)DNA into the human genome is a reputed key driver of cervical cancer.However,the effects of HPV integration on chromatin structural organization and gene expression are largely unknown.We studied a cohort of 61 samples and identified an integration hot spot in the CCDC106 gene on chromosome 19.We then selected fresh cancer tissue that contained the unique integration loci at CCDC106 with no HPV episomal DNA and performed whole-genome,RNA,chromatin immunoprecipitation and high-throughput chromosome conformation capture(Hi-C)sequencing to identify the mechanisms of HPV integration in cervical carcinogenesis.Molecular analyses indicated that chromosome 19 exhibited significant genomic variation and differential expression densities,with correlation found between three-dimensional(3D)structural change and gene expression.Importantly,HPV integration divided one topologically associated domain(TAD)into two smaller TADs and hijacked an enhancer from PEG3 to CCDC106,with a decrease in PEG3 expression and an increase in CCDC106 expression.This expression dysregulation was further confirmed using 10 samples from our cohort,which exhibited the same HPV-CCDC106 integration.In summary,we found that HPV-CCDC106 integration altered local chromosome architecture and hijacked an enhancer via 3D genome structure remodeling.Thus,this study provides insight into the 3D structural mechanism underlying HPV integration in cervical carcinogenesis.

Amino acid variation analysis of surface spike glycoprotein at 614 in SARS-CoV-2 strains

As severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)continues to disperse globally with worrisome speed,identifying amino acid variations in the virus could help to understand the characteristics of it.Here,we studied 489 SARS-CoV-2 genomes obtained from 32 countries from the Nextstrain database and performed phylogenetic tree analysis by clade,country,and genotype of the surface spike glycoprotein(S protein)at site 614.We found that virus strains from China's Mainland were mostly distributed in Clade B and Clade undefined in the phylogenetic tree,with very few found in Clade A.In contrast,Clades A2(one case)and A2a(112 cases)predominantly contained strains from European regions.Moreover,Clades A2 and A2a differed significantly from those of China's Mainland in age of infected population(P Z 0.0071,mean age 40.24 to 46.66),although such differences did not exist between the US and China's Mainland.Further analysis demonstrated that the variation of the Sprotein at site 614(QHD43416.1:p.614D>G)was a characteristic of stains in Clades A2 and A2a.Importantly,this variation was predicted to have neutral or benign effects on the function of the S protein.In addition,global quality estimates and 3D protein structures tended to be different between the two S proteins.In summary,we identified different genomic epidemiology among SARS-CoV-2 strains in different clades,especially in an amino acid variation of the S protein at 614,revealing potential viral genome divergence in SARS-CoV-2 strains.

The role of extracellular matrix on unfavorable maternal-fetal interface:focusing on the function of collagen in human fertility

Extracellular matrix(ECM)is characterized as widespread,abundant,and pluripotent.Among ECM members,collagen is widely accepted as one of the most prominent components for its essential structural property that can provide a scaffold for other components of ECM and the rich biological functions,which has been extensively used in tissue engineering.Emerging evidence has shown that the balance of ECM degradation and remodeling is vital to regulations of maternal-fetal interface including menstrual cycling,decidualization,embryo implantation and pregnancy maintenance.Moreover,disorders in these events may eventually lead to failure of pregnancy.Although the improvement of assisted conception and embryo culture technologies bring hope to many infertile couples,some unfavorable outcomes,such as recurrent implantation failure(RIF),recurrent pregnancy loss(RPL)or recurrent miscarriage(RM),keep troubling the clinicians and patients.Recently,in vitro three-dimensional(3D)model mimicking the microenvironment of the maternal-fetal interface is developed to investigate the physiological and pathological conditions of conception and pregnancy.The progress of this technology is based on clarifying the role of ECM in the endometrium and the interaction between endometrium and conceptus.Focusing on collagen,the present review summarized the degradation and regulation of ECM and its role in normal menstruation,endometrium receptivity and unsatisfying events occurring in infertility treatments,as well as the application in therapeutic approaches to improve pregnancy outcomes.More investigations about ECM focusing on the maternal-fetal interface interaction with mesenchymal stem cells or local immunoregulation may inspire new thoughts and advancements in the clinical application of infertility treatments.