| 1. |
- Feng, Ruizhi, et al.
(author)
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Mutations in TUBB8 and Human Oocyte Meiotic Arrest.
- 2016
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In: The New England journal of medicine. - 1533-4406. ; 374:3, s. 223-232
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Journal article (peer-reviewed)abstract
- Background Human reproduction depends on the fusion of a mature oocyte with a sperm cell to form a fertilized egg. The genetic events that lead to the arrest of human oocyte maturation are unknown. Methods We sequenced the exomes of five members of a four-generation family, three of whom had infertility due to oocyte meiosis I arrest. We performed Sanger sequencing of a candidate gene, TUBB8, in DNA samples from these members, additional family members, and members of 23 other affected families. The expression of TUBB8 and all other β-tubulin isotypes was assessed in human oocytes, early embryos, sperm cells, and several somatic tissues by means of a quantitative reverse-transcriptase-polymerase-chain-reaction assay. We evaluated the effect of the TUBB8 mutations on the assembly of the heterodimer consisting of one α-tubulin polypeptide and one β-tubulin polypeptide (α/β-tubulin heterodimer) in vitro, on microtubule architecture in HeLa cells, on microtubule dynamics in yeast cells, and on spindle assembly in mouse and human oocytes. Results We identified seven mutations in the primate-specific gene TUBB8 that were responsible for oocyte meiosis I arrest in 7 of the 24 families. TUBB8 expression is unique to oocytes and the early embryo, in which this gene accounts for almost all the expressed β-tubulin. The mutations affect chaperone-dependent folding and assembly of the α/β-tubulin heterodimer, disrupt microtubule behavior on expression in cultured cells, alter microtubule dynamics in vivo, and cause catastrophic spindle-assembly defects and maturation arrest on expression in mouse and human oocytes. Conclusions TUBB8 mutations have dominant-negative effects that disrupt microtubule behavior and oocyte meiotic spindle assembly and maturation, causing female infertility. (Funded by the National Basic Research Program of China and others.).
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| 2. |
- Feng, Ruizhi, et al.
(author)
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MiRNA-320 in the human follicular fluid is associated with embryo quality in vivo and affects mouse embryonic development in vitro.
- 2015
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In: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 5
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Journal article (peer-reviewed)abstract
- Previous work from our laboratory demonstrated the existence of miRNAs in human follicular fluid. In the current study, we have sought to identify miRNAs that might affect oocyte/embryo quality in patients undergoing intracytoplasmic sperm injection and to investigate their roles in in vitro fertilization outcomes in mouse oocytes. 53 samples were classified as Group 1 (high quality) if the day-3 embryos had seven and more cells or as Group 2 (low quality) if the embryos had six and fewer cells. TaqMan Human microRNAs cards and qRT-PCR were performed to verify differently expressed miRNAs. The function of the corresponding miRNA was investigated in mouse oocytes by injecting them with miRNA-inhibitor oligonucleotides. We found that hsa-miR-320a and hsa-miR-197 had significantly higher expression levels in the Group 1 follicular fluids than in Group 2 (p = 0.0073 and p = 0.008, respectively). Knockdown of mmu-miR-320 in mouse oocytes strongly decreased the proportions of MII oocytes that developed into two-cell and blastocyst stage embryos (p = 0.0048 and p = 0.0069, respectively). Wnt signaling pathway components had abnormal expression level in miR-320 inhibitor-injected oocytes. This study provides the first evidence that miRNAs in human follicular fluid are indicative of and can influence embryo quality.
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| 3. |
- Sun, Xiaoxi
(author)
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Effects of mifepristone on the human endometrium and the fallopian tube during the luteal phase
- 2005
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Doctoral thesis (other academic/artistic)abstract
- Mifepristone given postovulatory has been shown effective for contraception, but the precise mechanism of action is still poorly understood. A better understanding of the mechanisms of action of mifepristone, when used for contraception, is important for further development and optimizing the regimen of use. To study the effects of mifepristone during the luteal phase, a single dose of 200mg mifepristone was administered on day LH+2. Endometrial biopsies were obtained on day LH+6 to LH+8 (the expected time for endometrial receptivity and implantation) and the fallopian tube on day LH+4 to LH+6 (approximately the time when the embryo is still in the fallopian tube). Immunohistochemistry, RT-PCR and Western blot were used for analysis of the endometrium and the fallopian tube samples. After treatment with mifepristone, progesterone receptor isoform B (PR-B) concentrations increased in glandular cells of the endometrium and in epithelial and stromal cells in the fallopian tube. In the endometrium endothelial nitric oxide synthase (eNOS) expression was attenuated in the glandular epithelium, in contrast to endothelial eNOS, which was not changed. The expression of insulin-like growth factor binding protein-1 (IGFBP-1) was significantly increased in the glandular epithelial cells. The staining intensity of heparin-binding epidermal growth factor-like growth factor (HB-EGF) was not affected by mifepristone. Treatment with mifepristone increased the immunostaining of HB-EGF receptor HER1 in the epithelium and the stroma in the endometrium, while the opposite was seen in the luminal epithelium of the fallopian tube. The immunostaining of HB-EGF receptor HER4 increased in the epithelial cells of the endometrium, while a decrease was seen in the stroma of the fallopian tube. In conclusion these results indicate that mifepristone administered immediately after ovulation has pronounced effects on the endometrium at the expected time of endometrial receptivity. These changes may contribute to cause defective endometrial receptivity and altered intraluminal milieu. The effect on the fallopian tube may also be of importance for the contraceptive effect of mifepristone.
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| 4. |
- Sun, Zhendong, et al.
(author)
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Butylated hydroxyanisole isomers induce distinct adipogenesis in 3T3-L1 cells
- 2019
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In: Journal of Hazardous Materials. - : Elsevier. - 0304-3894 .- 1873-3336. ; 379
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Journal article (peer-reviewed)abstract
- Butylated hydroxyanisole (BHA) isomers, as the widely used anthropogenic antioxidants in food, have been revealed to induce endocrine disrupting effects, while the mechanism how BHA isomers regulate the lipogenic differentiation remains to be elucidated. Using 3T3-L1 differentiation model, the effects of BHA isomers, including 2-tert-butyl-4-hydroxyanisole (2-BHA), 3-tert-butyl-4-hydroxyanisole (3-BHA) and their mixture (BHA), on adipogenesis were tested. The results showed that 3-BHA and BHA promoted adipocyte differentiation and enhanced the cellular lipid accumulation through the regulation of the transcriptional and protein levels of the adipogenetic biomarkers, while 2-BHA had no effect. The effective window for 3-BHA induced lipogenesis was the first four days during 3T3-L1 differentiation. BHA isomers showed no binding affinities for peroxisome proliferator activated receptor gamma (PPAR gamma). Instead, the upstream of PPAR gamma signaling pathway, i.e. the phosphorylation of cAMP-response element binding protein (CREB), upregulation of CAAT/enhancer-binding proteins beta (C/EBP beta) and elevated cell proliferation during postconfluent mitosis stage were induced by 3-BHA exposure. Altogether, this study revealed the adipogenic effect of 3-BHA through interference with the upstream events of the PPAR gamma signaling pathway. The authorized usage of BHA as food additives and its occurrence in human sera can potentially contribute to the incidence of obesity, which is of high concern.
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| 5. |
- Sun, Zhendong, et al.
(author)
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Perturbation of 3-tert-butyl-4-hydroxyanisole in adipogenesis of male mice with normal and high fat diets
- 2020
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In: Science of the Total Environment. - : Elsevier. - 0048-9697 .- 1879-1026. ; 703
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Journal article (peer-reviewed)abstract
- As one of the widely used anthropogenic food additives, 3-tert-butyl-4-hydroxyanisole (3-BHA) has been found to perturb adipogenesis in vitro and induce lipid accumulation in some strains of oleaginous microalgae. The impact of this chemical on adipocyte development and lipid metabolism in mammals remains to be elucidated. In this study, we performed 18-week oral administration of 3-BHA to male C57BL/6J mice with normal diet (ND) or high-fat diet (HFD) and investigated its impacts on adipogenesis and lipid accumulation in vivo. The results indicated that long-term exposure to 3-BHA impacted the mouse body weight gain, white adipose tissue accumulation, and plasma lipids through transcriptional regulation of adipogenesis, lipid metabolism, and adipocyte endocrine function, while glucose metabolism and insulin sensitivity remained unaffected. HFD-fed mice responded to 3-BHA stimulation differently from ND-fed animals, suggesting potential risks for the human burden of 3-BHA in lean and obese subjects. The findings herein validate 3-BHA as an environmental obesogen, and more caution is recommended for its authorized use as a food antioxidant against lipid rancidity.
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| 6. |
- Wang, Anqi, et al.
(author)
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Characterizing prostate cancer risk through multi-ancestry genome-wide discovery of 187 novel risk variants
- 2023
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In: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 55:12, s. 2065-2074
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Journal article (peer-reviewed)abstract
- The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P = 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups.
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| 7. |
- Zhang, Shunming, et al.
(author)
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Added sugar intake and its forms and sources in relation to risk of non-alcoholic fatty liver disease : results from the Tianjin Chronic Low-grade Systemic Inflammation and Health cohort study
- 2023
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In: British Journal of Nutrition. - 1475-2662. ; 129:12, s. 2094-2101
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Journal article (peer-reviewed)abstract
- It has been suggested that added sugar intake is associated with non-alcoholic fatty liver disease (NAFLD). However, previous studies only focused on sugar-sweetened beverages; the evidence for associations with total added sugars and their sources is scarce. This study aimed to examine the associations of total added sugars, their physical forms (liquid vs. solid), and food sources with risk of NAFLD among adults in Tianjin, China. We used data from 15,538 participants, free of NAFLD, other liver diseases, cardiovascular disease, cancer, or diabetes at baseline (2013-2018 years). Added sugar intake was estimated from a validated 100-item food frequency questionnaire. NAFLD was diagnosed by ultrasonography after exclusion of other causes of liver diseases. Multivariable Cox proportional hazards models were fitted to calculate hazards ratios (HRs) and corresponding 95% confidence intervals (CIs) for NAFLD risk with added sugar intake. During a median follow-up of 4.2 years, 3,476 incident NAFLD cases were documented. After adjusting for age, sex, body mass index and its change from baseline to follow-up, lifestyle factors, personal and family medical history, and overall diet quality, the multivariable HRs (95% CIs) of NAFLD risk were 1.18 (1.06, 1.32) for total added sugars, 1.20 (1.08, 1.33) for liquid added sugars, and 0.96 (0.86, 1.07) for solid added sugars when comparing the highest quartiles of intake with the lowest quartiles of intake. In this prospective cohort of Chinese adults, higher intakes of total added sugars and liquid added sugars, but not solid added sugars, were associated with a higher risk of NAFLD.
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