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DNA double-strand breaks (DSBs) are functionally linked to genomic instability in spermatocytes and to male infertility. The heavy metal cadmium (Cd) is known to induce DNA damage in spermatocytes by unknown mechanisms. Here, we showed that Cd ions impaired the canonical non-homologous end-joining (NHEJ) repair pathway, but not the homologous recombination (HR) repair pathway, through stimulation of Ser2056 and Thr2609 phosphorylation of DNA-PKcs at DSB sites. Hyper-phosphorylation of DNA-PKcs led to its premature dissociation from DNA ends and the Ku complex, preventing recruitment of processing enzymes and further ligation of DNA ends. Specifically, this cascade was initiated by the loss of PP5 phosphatase activity, which results from the dissociation of PP5 from its activating ions (Mn), that is antagonized by Cd ions through a competitive mechanism. In accordance, in a mouse model Cd-induced genomic instability and consequential male reproductive dysfunction were effectively reversed by a high dosage of Mn ions. Together, our findings corroborate a protein phosphorylation-mediated genomic instability pathway in spermatocytes that is triggered by exchange of heavy metal ions.

The aim of this study was to determine the impact of glycyrrhizin, an inhibitor of high mobility group box 1, on glucose metabolic disorders and ovarian dysfunction in mice with polycystic ovary syndrome. We generated a polycystic ovary syndrome mouse model by using dehydroepiandrosterone plus high-fat diet. Glycyrrhizin (100 mg/kg) was intraperitoneally injected into the polycystic ovary syndrome mice and the effects on body weight, glucose tolerance, insulin sensitivity, estrous cycle, hormone profiles, ovarian pathology, glucolipid metabolism, and some molecular mechanisms were investigated. Increased number of cystic follicles, hormonal disorders, impaired glucose tolerance, and decreased insulin sensitivity in the polycystic ovary syndrome mice were reverted by glycyrrhizin. The increased high mobility group box 1 levels in the serum and ovarian tissues of the polycystic ovary syndrome mice were also reduced by glycyrrhizin. Furthermore, increased expressions of toll-like receptor 9, myeloid differentiation factor 88, and nuclear factor kappa B as well as reduced expressions of insulin receptor, phosphorylated protein kinase B, and glucose transporter type 4 were restored by glycyrrhizin in the polycystic ovary syndrome mice. Glycyrrhizin could suppress the polycystic ovary syndrome-induced upregulation of high mobility group box 1, several inflammatory marker genes, and the toll-like receptor 9/myeloid differentiation factor 88/nuclear factor kappa B pathways, while inhibiting the insulin receptor/phosphorylated protein kinase B/glucose transporter type 4 pathways. Hence, glycyrrhizin is a promising therapeutic agent against polycystic ovary syndrome.

Decidualization of uterine stromal cells plays an important role in the establishment of normal pregnancy. Previous studies have demonstrated that Acyl-CoA binding protein (Acbp) is critical to cellular proliferation, differentiation, mitochondrial functions, and autophagy. The characterization and physiological function of Acbp during decidualization remain largely unknown. In the present study, we conducted the expression profile of Acbp in the endometrium of early pregnant mice. With the occurrence of decidualization, the expression of Acbp gradually increased. Similarly, Acbp expression was also strongly expressed in decidualized cells following artificial decidualization, both in vivo and in vitro. We applied the mice pseudopregnancy model to reveal that the expression of Acbp in the endometrium of early pregnant mice was not induced by embryonic signaling. Moreover, P4 significantly upregulated the expression of Acbp, whereas E2 appeared to have no regulating effect on Acbp expression in uterine stromal cells. Concurrently, we found that interfering with Acbp attenuated decidualization, and that might due to mitochondrial dysfunctions and the inhibition of fatty acid oxidation. The level of autophagy was increased after knocking down Acbp. During induced decidualization, the expression of ACBP was decreased with the treatment of rapamycin (an autophagy inducer), while increased with the addition of Chloroquine (an autophagy inhibitor). Our work suggests that Acbp plays an essential role in the proliferation and differentiation of stromal cells during decidualization through regulating mitochondrial functions, fatty acid oxidation, and autophagy.

Abnormal endometrial decidualization is closely related to embryo implantation failure and other pregnancy complications. Steroidogenic factor-1 (SF-1), which is also known as nuclear receptor subfamily 5 group A member 1, is a transcriptional activator that is involved in sexual differentiation and formation of the primary steroidogenic tissues. Its regulatory role in mouse and human endometrial decidualization remains unclear. In normal pregnant mice models, the expression of SF-1 was detected by immunohistochemistry and Western blot analysis. In normal pregnant mice, the expression of SF-1 at the implantation site is higher than that in the inter-implantation site. In the artificial decidualization in vivo and in vitro models, the expression of SF-1 increased with the deepening of decidualization. The high expression of SF-1 could promote the decidualization of endometrial stromal cells (ESCs). Based on the detection results of bisulfite sequencing PCR (BSP), the methylation of the CpG island in the SF-1 promoter region decreased after the decidualization of mouse endometrium. The interference of DNA methyltransferase (DNMT) expression promoted the expression of SF-1. The methylation inhibitor 5-aza resulted in the decrease in DNMTs, increase in SF-1 expression, and decidualization of ESCs. With the decidualization of the endometrium, the expression of SF-1 increased, whereas the DNA methylation of the SF-1 promoter decreased. The decrease in DNMTs resulted in increased SF-1 expression and promoted the decidualization of the endometrium. This study provides clues for the diagnosis and treatment of embryo implantation failure associated with abnormal decidualization.

Problem Natural killer (NK) cells from the peripheral blood and spleen represent the source from which various tissues replenish their immune cell populations. Hyperandrogenism and high interleukin-2 (IL-2) levels are factors present in polycystic ovary syndrome (PCOS). These factors and metformin, one of the commonest medications used in treating PCOS, may have an impact on NK cells. However, this is presently unknown. Here, we aimed to assess the distribution of peripheral blood and splenic NK cells and their CD2 and CD94 expression patterns in a PCOS mouse model and test whether metformin could reverse these effects. Method of study Four mouse groups were designed as follows (n = 15/group): control, PCOS, PCOS plus vehicle, PCOS plus metformin. Dehydroepiandrosterone and a high-fat diet were administered to induce the PCOS mouse model. Flow cytometry was used to analyze the expressions of CD2 and CD94 on peripheral blood and splenic NK cells. Results PCOS mice had a low surface-density of CD2 on peripheral blood NK cells and a decreased percentage of CD2+ splenic NK cells. Metformin administration did not significantly influence these changes; however, it reduced the splenic NK cell counts. Conclusions Our findings proved the association of PCOS with an altered expression of CD2 on peripheral blood and splenic NK cells and that of metformin with a lowered splenic NK cell reserve in PCOS conditions. These findings could further unlock key mechanisms in PCOS pathophysiology and in the mechanism of action of metformin, towards improving PCOS management.

Preeclampsia is a pregnancy complication which threatens the survival of mothers and fetuses. It originates from abnormal placentation, especially insufficient fusion of the cytotrophoblast cells to form the syncytiotrophoblast. In this study, we found that THBS1, a matricellular protein that mediates cell-to-cell and cell-to-matrix interactions, is downregulated during the fusion of primary cytotrophoblast and BeWo cells, but upregulated in the placenta of pregnancies complicated by preeclampsia. Also, THBS1 was observed to interact with CD36, a membrane signal receptor and activator of the cAMP signaling pathway, to regulate the fusion of cytotrophoblast cells. Overexpression of THBS1 inhibited the cAMP signaling pathway and reduced the BeWo cells fusion ratio, while the effects of THBS1 were abolished by a CD36-blocking antibody. Our results suggest that THBS1 signals through a CD36-mediated cAMP pathway to regulate syncytialization of the cytotrophoblast cells, and that its upregulation impairs placental formation to cause preeclampsia. Thus, THBS1 can serve as a therapeutic target regarding the mitigation of abnormal syncytialization and preeclampsia.

Introduction: Though human beings look similar in their general anatomical appearances but during the investigation of a particular structure in detail, it is surprising how frequently we meet one sort or another type of variation. Literature reports that accurate dimensions of CBD are debatable. Therefore, determination of a spontaneous abnormality or atypical variation is important and reference range plays a significant role to classify the normal or abnormal duct. Materials and Methods: A total of thirty (30) cadavers were dissected at MGM Medical College Mumbai, India from Jan 2012 to March 2013 for anatomical features of the common bile duct-like their size, variations in the course and termination. Results: The length of the common bile duct varies 35.19 mm to 62.43 mm with Mean ± SD 46.92 ± 7.91 mm and diameter varied between 3.65 mm to 10.31 mm with mean value 6.50 ± 1.77. The correlation between length and diameter of common bile duct is statistically insignificant (p = 0.243) Conclusion: We established a reference range for the CBD length and diameter. Thus, the exact knowledge of the anatomy of the common bile duct is significant for successful hepato-biliary surgery and biliary pathology.

The Suzuki-Miyaura cross-coupling reaction is an effective process for C-C bond formation in organic synthesis. Herein, we report a NiO nanodot-decorated Pd/SiC catalyst, synthesized by atomic layer deposition, which shows high photocatalytic activity for the Suzuki-Miyaura coupling of both aryl bromides and chlorides with phenylboronic acid at 30 °C in air. The Mott-Schottky contact in SiC/Pd enhances the rapid transfer of the photogenerated electrons from SiC to Pd nanoparticles. Moreover, the energy different between the highest occupied molecular orbital of the ultrafine NiO nanodots and the Fermi level of Pd forces a spontaneous electron transfer from NiO to Pd. As a result, the concentrated electrons in the Pd nanoparticles can facilitate the cleavage of C-Br or C-Cl bonds, which normally requires rather high temperatures in thermal processes. The holes left on the SiC support can assist the cleavage of the C-B bond.

Background: Obesity is associated with many adverse effects on female fertility. Obese women are more likely to have ovulatory dysfunction due to dysregulation of the hypothalamic-pituitary-ovarian axis. However, ovarian function in obese women during early pregnancy still needs further assessment. Methods: Obesity was induced in C57BL6/J mice using high-fat diets (HFD) for 12 weeks; In vitro high-fat model was established with KGN cells treated with Oleate acid and Palmitic acid. Ovarian morphology of obese mice in early pregnancy was assessed by Hematoxylin and Eosin staining and its function was assessed using ELISA, Western blotting and Immunohistochemistry. The Oil Red O staining and Transmission electron microscopy were used to detect fatty acid accumulation and specific markers relating to ovarian functional mechanism were assessed by Real time PCR, Western blotting, Lactate detection, ATP detection, Biochemical analyses and ELISA.Results: The results of this study showed that during early pregnancy, the number of corpus luteum, serum estradiol and progesterone levels, and the expression of genes CYP19A1, CYP11A1 and StAR, which are related to steroid biosynthesis, were significantly increased in HFD female mice. HFD-fed mice also showed a significant increase in ovarian lipid accumulation on day 7 of pregnancy. Genes involved in fatty acid synthesis (Acsl4 and Elovl5) and fatty acid uptake and transport (Slc27a4), together with the β-oxidation rate-limiting enzyme (Cpt1a) were significantly upregulated in HFD-fed mice. Specifically, there was abnormal elevation of ATP level and aberrant expression of tricarboxylic acid cycle (TCA) and electron transport chain related genes in the ovary of HFD pregnant mice. Treatment of KGN cells with etomoxir targeting β-oxidation of fatty acid, showed decrease tricarboxylic acid cycle and electron transport chain. The elevated ATP level and the increased estradiol and progesterone levels were reversed. Conclusions: This study indicated that during early pregnancy, high-fat diet and induced-obesity increased fatty acid β-oxidation, which in turn increase the tricarboxylic acid cycle and the electron transport chain, and consequently increases ATP production and ovarian dysfunction.

Endometriosis is defined as a hormone-dependent benign inflammatory disease of the female reproductive system...

Objective: This study explored the association between an Alu I polymorphism at position 1,377 of the calcitonin receptor (CTR) gene and endemic fluorosis. Subjects and Methods: A case-control study of 321 participants was conducted in regions with high fluorosis rates (Wushan and Fengjie counties) and those without high fluorosis rates (Yubei Qu county; termed nonfluorosis areas) in Chongqing, China. The participants were divided into three groups: the fluorosis group (FG) from areas with high fluoride exposure (121), the nonfluorosis group (NFG) from areas with high fluoride exposure (130), and a control group (CG) from areas with no excessive fluoride exposure (70). An Alu I polymorphism in the CTR gene was genotyped using polymerase chain reaction-restriction fragment length polymorphism analysis. Results: The genotype distributions within each group were as follows: CC 60.33% (73/121), CT 30.58% (37/121) and TT 9.09% (11/121) for the FG; CC 74.62% (97/130), CT 21.54% (28/130) and TT 3.85% (5/130) for the NFG, and CC 68.57% (48/70), CT 31.43% (22/70) and TT 0% (0/70) for the CG. Significant differences in Alu I genotypes were observed among the groups (χ2 = 12.317, υ = 4, p = 0.015). Allele frequencies of CTR genotypes differed significantly among the groups (χ2 = 8.859, υ = 2, p = 0.012): C 75.62% (183/242) and T 24.38% (59/242) for the FG, C 85.38% (222/260) and T 14.62% (38/260) for the NFG, and C 84.29% (118/140) and T 15.71% (22/140) for the CG. Conclusion: An association between fluorosis and the Alu I polymorphism in the CTR gene was observed in fluoride-exposed populations.

An efficient approach for integrin targeting cRGDfK conjugate synthesis has been developed by using a new protected cyclopentapeptide, cR(NO2)GD(Bn)fK(Fmoc), as the key intermediate. cR(NO2)GD(Bn)fK(Fmoc) was conveniently prepared in high yield. The Fmoc group of this cyclopentapeptide was selectively removed under mild conditions which makes it an ideal intermediate for cRGDfK conjugate synthesis as was well demonstrated in this paper by the synthesis of cRGDfK chlorambucil conjugate.

An efficient approach for integrin-targeting cRGDfK conjugate synthesis has been developed using a new protected cyclopentapeptide, cR(NO2)GD(Bn)fK(Fmoc), as the key intermediate. cR(NO2)GD(Bn)fK(Fmoc) was conveniently prepared in high yield. The Fmoc group of this cyclopentapeptide was selectively removed under mild conditions which makes it an ideal intermediate for cRGDfK conjugate synthesis as was well demonstrated in this paper by the synthesis of cRGDfK chlorambucil conjugate.

The ‘fetal origin hypothesis’ suggests that metabolic diseases are directly related to poor nutritional status in early life. Thus, a high birth weight (HBW) may pose a lower risk than normal birth weight. Overweight and overnutrition are among the most widely recognized risk factors of metabolic diseases. To explore the possible effects of HBW on blood pressure and hypertension, a systematic review was performed. The PubMed and Embase databases were searched for relevant studies. The outcomes included systolic blood pressure (SBP), diastolic blood pressure (DBP) and hypertension. We included all of the studies that assessed the differences in outcomes for children aged >1 year between those born with normal birth weight (birth weight between 2500 and 4000 g or between the 10th and 90th percentiles for their gestational age) and those born with HBW (birth weight⩾4000 g or ⩾90th percentile for their gestational age). The outcomes were analyzed descriptively and by conducting a meta-analysis. Thirty-one studies satisfied the inclusion criteria. The mean difference in blood pressure and the relative risk of hypertension between individuals with HBW and individuals with normal birth weight was inversely associated with age. SBP and DBP, as well as the prevalence of hypertension, were higher in younger children with HBW but lower in older adults with HBW compared with individuals with normal birth weight. The findings suggested that an individual with HBW is prone to hypertension and higher blood pressure during childhood. However, a ‘catch-down’ effect in the elevation of blood pressure is observed in subjects with HBW as they grow older. Thus, older individuals with HBW are less susceptible to hypertension than those with normal birth weight.

The centromere is responsible for the correct inheritance of eukaryotic chromosomes during cell division. Centromere protein B (CENP‑B) and its 17 base pair binding site (CENP‑B box), which appears at regular intervals in centromeric α-satellite DNA (α-satDNA), are important for the assembly of the centromere components. Therefore, it is conceivable that CENP-B box mutations may induce errors in cell division. However, the association between the deoxynucleotide alterations of the CENP‑B box and the extra chromosome 21 (Chr21) present in patients with Down syndrome (DS) remains to be elucidated. The mutational spectrum of the α‑satDNA, including 4 functional CENP‑B boxes in Chr21 from 127 DS and 100 healthy children were analyzed by direct sequencing. The de novo occurrences of mutations within CENP‑B boxes in patients with DS were excluded. The prevalence of 6 novel mutations (g.661delC, g.1035_1036insA, g.1076_1077insC, g.670T>G, g.1239A>T, g.1343T>C) and 3 single nucleotide polymorphisms (g.727C/T, g.863A/C, g.1264C/G) were not significantly different between DS and controls (P>0.05). However, g.525C/G (P=0.01), g.601T/C (P=0.00000002), g.1279A/G (P=0.002), g.1294C/T (P=0.0006) and g.1302 G/T (P=0.004) were significantly associated with the prevalence of DS (P

Angelmarin, a naturally occurring coumarin, exhibited highly anti-austerity potency towards human pancreatic carcinoma cell line PANC-1. In this paper, an efficient and eco-friendly synthesis of angelmarin and its analogs from columbianetin has been developed via a ZnO mediated esterification and a Wittig reaction.

It is well known that maternal folate deficiency results in adverse pregnancy outcomes. In addition to aspects in embryonic development, maternal uterine receptivity and the decidualization of stromal cells is also very important for a successful pregnancy. In this study, we focused on endometrium decidualization and investigated whether apoptosis, which is essential for decidualization, was impaired. Flow cytometry and TUNEL detection revealed that apoptosis of mouse endometrium decidual cells was suppressed in the dietary folate-deficient group on Days 7 and 8 of pregnancy (Day 1 = vaginal plug) when decidua regression is initiated. The endometrium decidual tissue of the folate deficiency group expressed less Bax compared to the normal diet group while they had nearly equal expression of Bcl2 protein. Further examination revealed that the mitochondrial transmembrane potential (ΔΨm) decreased, and the fluorescence of diffuse cytoplasmic cytochrome c protein was detected using laser confocal microscopy in normal decidual cells. However, no corresponding changes were observed in the folate-deficient group. Western blotting analyses confirmed that more cytochrome c was released from mitochondria in normal decidual cells. Taken together, these results demonstrated that folate deficiency could inhibit apoptosis of decidual cells via the mitochondrial apoptosis pathway, thereby restraining decidualization of the endometrium and further impairing pregnancy.

To study the relationship between chemical elements in soil and whole blood, and fluorosis induced by coal-fired pollution, ecological and case–control studies were carried out. We determined the concentrations of 11 chemical elements and pH values in soil in two fluorosis-affected counties in Chongqing, China, and analyzed the correlation between these values and prevalence of dental fluorosis. Ni, I, F, Hg, and pH values positively correlated with fluorosis prevalence (P < 0.05); these soil parameters may be related to coal-fired pollution fluorosis. Cu, Zn, Ca, Mg, and Fe concentrations in whole blood, and fluoride levels in urine of residents in epidemic and non-epidemic areas were determined. Cu, Zn, Mg, and Fe levels of the children in the case group were lower than those of the children in the external control group; urine fluoride level in the children in the case group was higher than that of the children in the internal and external control groups (P < 0.05). The levels of Mg, Fe, and urine fluoride were higher in the case adult group than in the internal adult control group (P < 0.05). Anti-fluoride elements were deficient in endemic areas.

Trisomy 21 is a chromosomal condition caused by the presence of all or part of an extra 21st chromosome. There has been limited research into the DNA methylation status of CpG islands (CGIs) in trisomy 21, therefore, exploring the DNA methylation status of CGIs in 21q is essential for the development of a series of potential epigenetic biomarkers for prenatal screening of trisomy 21. First, DNA sequences of CGIs in 21q from the USCS database were obtained and 149 sequences and 148 pairs of primers in the BGI YH database were aligned. All 300 cases were analyzed by a heavy methyl-polymerase chain reaction (HM-PCR) assay and a comparison of the DNA methylation status of CGIs was made between trisomy 21 and the control. The HM-PCR assay results did not show a difference in the DNA methylation status between individuals with trisomy 21 and the control. In total, there were 11 CGIs that showed various DNA methylation statuses between Japanese and Chinese patients. Subsequently, bisulfite genomic sequencing found variations in the methylation status of CpG dinucleotides in CGIs (nos. 14, 75, 109, 134 and 146) between trisomy 21 and the control. The different DNA methylation status of CpG dinucleotides in CGIs may be a potential epigenetic marker for diagnosing trisomy 21. No difference was identified in the DNA methylation status of 21q CGIs among Chinese individuals with trisomy 21 and the control. The homogeneity of the DNA methylation status of 21q CGIs in Chinese patients indicates that DNA methylation is likely to be an epigenetic marker distinguishing ethnicities.

Tubeimoside-1 (TBMS1) extracted from Bolbostemma paniculatum (Maxim), is a traditional Chinese herb with anticancer potential. It induces apoptosis in a number of human carcinoma cell lines, but the mechanism has remained unclear. In the present study, we investigated the pro-apoptotic activity of TBMS1 against SKOV-3 cell lines and the underlying mechanisms. Treatment with TBMS1 resulted in dose- and time-dependent inhibition of proliferation, led to arrest in phase G2/M of the cell cycle and increased the levels of intracellular Ca²⁺. Furthermore, TBMS1 up-regulated the levels of the glucose-regulated protein 78/immunoglobuin heavy chain binding protein (GRP78/Bip), C/EBP homologous protein (CHOP), Bax, and cleaved caspase-3 and down-regulated the levels of Bcl-2. It was shown to be linked to activation of the extracellular signal-regulated kinase (ERK) 1 and 2 signal transduction pathway. A decrease in Bcl-2/Bax ratio with increased expression of caspase-3, and intracellular Ca²⁺ provide compelling evidence that TBMS1-induced apoptosis is mediated by the mitochondrial pathway. The results of the present study suggest that TBMS1 has immense potential in cancer prevention and therapy based on its antiproliferative and apoptosis inducing effects.