Adherence to the EAT-lancet diet and incident depression and anxiety.

High-quality diets have been increasingly acknowledged as a promising candidate to counter the growing prevalence of mental health disorders. This study aims to investigate the prospective associations of adhering to the EAT-Lancet reference diet with incident depression, anxiety and their co-occurrence in 180,446 UK Biobank participants. Degrees of adherence to the EAT-Lancet diet were translated into three different diet scores. Over 11.62 years of follow-up, participants in the highest adherence group of the Knuppel EAT-Lancet index showed lower risks of depression (hazard ratio: 0.806, 95% CI: 0.730-0.890), anxiety (0.818, 0.751-0.892) and their co-occurrence (0.756, 0.624-0.914), compared to the lowest adherence group. The corresponding hazard ratios (95% CIs) were 0.711 (0.627-0.806), 0.765 (0.687-0.852) and 0.659 (0.516-0.841) for the Stubbendorff EAT-Lancet index, and 0.844 (0.768-0.928), 0.825 (0.759-0.896) and 0.818 (0.682-0.981) for the Kesse-Guyot EAT-Lancet diet index. Our findings suggest that higher adherence to the EAT-Lancet diet is associated with lower risks of incident depression, anxiety and their co-occurrence.

Increased serine synthesis in cumulus cells of young infertile women with diminished ovarian reserve.

STUDY QUESTION: What are the differences in gene expression of cumulus cells (CCs) between young women with diminished ovarian reserve (DOR) and those of similar age with normal ovarian reserve (NOR)? SUMMARY ANSWER: Gene expression and metabolome profiling analysis demonstrate that the de novo serine synthesis pathway (SSP) is increased in the CCs of young women with DOR. WHAT IS KNOWN ALREADY: The incidence of DOR has risen, tending to present at younger ages. Its mechanisms and aetiologies are still poorly understood. Abnormal metabolism is present in luteinized CCs of patients with DOR. Previous studies have revealed that mitochondrial dysfunction and impaired oxidative phosphorylation in CCs are related to DOR in women of advanced age. The pathogenic mechanisms likely differ between young women with DOR and cases associated with advanced maternal age. Several studies have examined amino acid metabolism in the follicle, with a focus on embryo development, but less information is available about CCs. The physiological significance of de novo serine synthesis in follicles and oocytes remains largely unknown. STUDY DESIGN, SIZE, DURATION: CC samples were obtained from 107 young infertile women (age <38 years) undergoing ICSI, from July 2017 to June 2019, including 54 patients with DOR and 53 patients with NOR. PARTICIPANTS/MATERIALS, SETTING, METHODS: Oocyte development data were analysed retrospectively. Comprehensive genome-wide transcriptomics of CCs was performed. Differentially expressed genes (DEGs) were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to categorize the functions of the DEGs and identify significantly enriched pathways. The transcript and protein levels of key enzymes involved in serine synthesis were verified in additional samples using quantitative real-time PCR (qRT-PCR) (n = 10) and capillary western blotting (n = 36). Targeted metabolomics of amino acids in CC extracts was performed by ultrahigh-performance liquid MS (UHPLC-MS/MS). MAIN RESULTS AND THE ROLE OF CHANCE: The number of oocytes (2.4 ± 2.2 versus 12.1 ± 5.3) and metaphase II oocytes (2.1 ± 2.0 versus 9.9 ± 4.9) retrieved was significantly decreased in the DOR versus the NOR group, respectively (P < 0.0001). The rates of fertilization (80.7% versus 78.8%), viable embryos (73.7% versus 72.5%), and high-quality embryos (42.8% versus 49.0%) did not differ between the DOR and NOR groups, respectively (P > 0.05). A total of 95 DEGs were found by transcriptome sequencing. GO and KEGG analyses demonstrated that the DEGs were linked to amino acid metabolism and suggested significantly higher activity of the de novo SSP in the CCs of young women with DOR. Further qRT-PCR and capillary western blotting revealed that key enzymes (PHGDH, PSAT1, PSPH, and SHMT2) involved in de novo serine synthesis were upregulated, and UHPLC-MS/MS analysis showed increases in serine and glycine (a downstream product of serine) levels in the CCs of young patients with DOR. Our data clearly demonstrate that the de novo SSP, which diverts 3-phosphoglycerate from glycolysis to serine synthesis, was upregulated in young DOR CCs. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Regarding the reproductive capacity of young patients DOR, the pregnancy outcomes were not analysed. The sample size was limited, and only women undergoing ICSI were examined since this was a prerequisite for the acquisition of CCs, which may cause selection bias. The exact mechanisms by which the SSP in CCs regulates ovarian reserve still require further study. WIDER IMPLICATIONS OF THE FINDINGS: Our research presents new evidence that alterations of the SSP in CCs of young infertile women are associated with DOR. We believe this is a significant contribution to the field, which should be key for understanding the cause and mechanisms of ovarian hypofunction in young women. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by grants from the Ministry of Science and Technology of China (2018YFC1005001) and National Natural Science Foundation of China (31601197). There were no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Effect of advanced paternal age on reproductive outcomes in IVF cycles of non-male-factor infertility: a retrospective cohort study.

Advanced paternal age has been overlooked, and its effect on fertility remains controversial. Previous studies have focused mainly on intracytoplasmic sperm injection (ICSI) cycles in men with oligozoospermia. However, few studies have reported on men with semen parameters within reference ranges. Therefore, we conducted a retrospective cohort study analyzing the reproductive outcomes of couples with non-male-factor infertility undergoing in vitro fertilization (IVF) cycles. In total, 381 cycles included were subgrouped according to paternal age (<35-year-old, 35-39-year-old, or ≥40-year-old), and maternal age was limited to under 35 years. Data on embryo quality and clinical outcomes were analyzed. The results showed that fertilization and high-quality embryo rates were not significantly different (all P > 0.05). The pregnancy rate was not significantly different in the 35-39-year-old group (42.0%; P > 0.05), but was significantly lower in the ≥40-year-old group (26.1%; P < 0.05) than that in the <35-year-old group (40.3%). Similarly, the implantation rate significantly decreased in the ≥40-year-old group (18.8%) compared with that in the <35-year-old group (31.1%) and 35-39-year-old group (30.0%) (both P < 0.05). The live birth rate (30.6%, 21.7%, and 19.6%) was not significantly different across the paternal age subgroups (<35-year-old, 35-39-year-old, and ≥40-year-old, respectively; all P > 0.05), but showed a declining trend. The miscarriage rate significantly increased in the 35-39-year-old group (44.8%) compared with that in the <35-year-old group (21.0%; P < 0.05). No abnormality in newborn birth weight was found. The results indicated that paternal age over 40 years is a key risk factor that influences the assisted reproductive technology success rate even with good semen parameters, although it has no impact on embryo development.

Mitochondrial dysfunction in cumulus cells is related to decreased reproductive capacity in advanced-age women.

OBJECTIVE: To reveal the relationship between mitochondrial function in cumulus cells (CCs) and the aging-related decline in ovarian function and reproductive capacity. DESIGN: Retrospective and transcriptome analysis of human tissue. SETTING: University hospital. PATIENT(S): A total of 186 infertile women with normal weight and no other diseases, including 86 young women (aged <38 years) with normal ovarian reserve and 100 advanced-age women (aged ≥38 years) with diminished ovarian reserve. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Embryo development data were analyzed. The mitochondrial ultrastructure of CCs was observed by transmission electron microscopy. Mitochondrial activity was detected by immunofluorescence. The per-CC mitochondrial deoxyribonucleic acid copy numbers and cellular adenosine triphosphate levels were quantified. Unbiased comprehensive genome-wide transcriptomics was performed. The functions of all annotated genes and biologic pathways were analyzed by the Kyoto Encyclopedia of Genes and Genomes. RESULT(S): Advanced-age women with diminished ovarian function had significantly fewer retrieved oocytes and lower embryo quality. The normal mitochondrial rate in CCs was significantly lower. In addition to mitochondrial morphology and structural changes, the fluorescence intensity of Fluo-3/AM was significantly higher, and that of MitoTracker was lower than that of young women with normal ovarian reserve, suggesting that age negatively affects the mitochondrial activity of CCs. The per-CC mitochondrial deoxyribonucleic acid copy number and adenosine triphosphate levels significantly decreased in the advanced-age group. The Kyoto Encyclopedia of Genes and Genomes analysis showed that differentially expressed genes were significantly enriched in the oxidative phosphorylation pathway. Additionally, most mitochondrially encoded genes related to oxidative phosphorylation were significantly down-regulated in the advanced-age group. CONCLUSION(S): We present current evidence that mitochondrial dysfunction in CCs may play a key role in the age-related decline in ovarian function and reproductive capacity.

Long Noncoding RNA HUPCOS Promotes Follicular Fluid Androgen Excess in PCOS Patients via Aromatase Inhibition.

CONTEXT: Androgen excess is a key feature of polycystic ovary syndrome (PCOS), but the underlying molecular mechanism remains unclear. OBJECTIVE: To determine the role and mechanism of novel long noncoding RNA (lncRNA) highly up-regulated in PCOS (HUPCOS) in the androgen excess of PCOS patients. DESIGN: The lncRNA expression profile in granulosa cells derived from PCOS and non-PCOS women were analyzed by using microarray assay. Human granulosa cell line KGN was used for mechanism investigation. SETTING: This was a university-based study. PATIENTS: Thirty-eight PCOS and 38 control patients were recruited: 8 PCOS and 8 control samples used for microarray discovery, the remaining 30 PCOS cases and 30 controls for quantitative RT-PCR validation. MAIN OUTCOME MEASURES: The aberrant expression lncRNA profile of PCOS patients was measured using microarray. The relationship of HUPCOS and follicular fluid testosterone was measured. Aromatase expression were analyzed after HUPCOS downregulation. HUPCOS interaction protein was confirmed by RNA pull-down. RESULTS: The significantly elevated lncRNA in PCOS granulosa cells was named HUPCOS, which was positively correlated with follicular fluid testosterone of PCOS patients. HUPCOS downregulation increased aromatase expression and promoted conversion of androgen to estrogen. RNA-binding protein with multiple splicing (RBPMS) was the most likely protein that combined with HUPCOS. CONCLUSIONS: Our findings suggested that HUPCOS mediated androgen excess in follicular fluid of PCOS patients by suppressing aromatase expression via interaction with RBPMS.

Laser-assisted hatching and clinical outcomes in frozen-thawed cleavage-embryo transfers of patients with previous repeated failure.

Assisted hatching (AH) is initially developed to provide an artificial manipulation of the zona pellucida (ZP) to help embryos hatch and improve the capacity of the embryos to implant. However, these effects remain unclear and controversial because of variation in patient characteristics, and it is critical to ascertain the indications for AH and to identify those patients who might benefit from AH. Here, this study aimed to assess the effect of laser-assisted zona thinning hatching technology (LAH) during the frozen-thawed D3 embryos on pregnancy outcomes in patients with previous repeated failures in vitro fertilization-embryo transfer (IVF-ET). To the best of our knowledge, these relationships have not been previously investigated. A retrospective cohort analysis was carried out. Infertility patients with previous repeated failure who underwent assisted reproductive therapy at our in vitro fertilization (IVF) center from May 2014 to May 2016 were enrolled. A total of 415 cleavage FET cycles (225 in the LAH group and 190 in the control group) were analyzed. Clinical outcomes including clinical pregnancy, implantation, live birth, miscarriage, and multiple gestation rates after transfer were compared between the LAH and control groups. The clinical pregnancy (49.3% versus 38.9%) and implantation rates (31.2% versus 24.6%) were significantly higher for the LAH group than the control group (P < 0.05). The live birth (44.8% versus 35.8%), multiple pregnancy (32.4% versus 31.0%), preterm birth (22.8% versus 17.1%), miscarriage (7.2% versus 5.4%), and ectopic rates (1.9% versus 0%) did not differ significantly between the two groups (P > 0.05). This study showed that LAH via zona pellucida (ZP) thinning significantly improves clinical outcomes, particularly clinical pregnancy and implantation rates, associated with FET cycles among patients with previous repeated failure.

Molecular regulation of ovarian cancer cell invasion.

The molecular mechanism underlying ovarian cancer invasiveness and metastasis remains unclear. Since significant downregulation in microRNA 200 (miRNA200) family (miR200a, miR200b, and miR200c) has been reported in the invasive ovarian cancer cells, here, we used two human ovarian cancer cell lines, OVCAR3 and SKOV3, to study the molecular basis of miR200, matrix metalloproteinase 3 (MMP3) activation, and cancer invasiveness. We found that overexpression of either miR200 family member in OVCAR3 or SKOV3 cells significantly inhibited production and secretion of MMP3 and cancer invasiveness. Moreover, forced MMP3 expression abolished miR200-induced inhibition of ovarian cancer cell invasiveness, suggesting that miR200 family inhibited ovarian cell invasiveness via downregulating MMP3. Furthermore, ZEB1, a major target of miR200, was inhibited by miR200 overexpression. Forced ZEB1 expression abolished miR200-induced inhibition of ovarian cancer cell invasiveness, suggesting that ZEB1 is a direct target of miR200 for inhibiting ovarian cell invasiveness. Finally, phosphorylated SMAD3 (pSMAD3), a major partner of ZEB1, was efficiently inhibited by miR200, which could be restored by forced expression of ZEB1, but not by forced expression of MMP3, suggesting that ZEB1/pSMAD3 is signaling cascade upstream of MMP3 in this model. Taken together, our data suggest that miR200 family inhibited ovarian cancer cell invasiveness and metastasis by downregulating MMP3, possibly through ZEB1/pSMAD3.