[Effect of UVRAG Gene on Ferroptosis Induced by Sorafenib in K562 Cells].

OBJECTIVE: To explore the effect of UV radiation resistance-associated gene (UVRAG) on ferroptosis induced by sorafenib in leukemia K562 cells. METHODS: K562 cells were treated with 0, 0.625, 1.25, 2.5, 5, 10, and 20 µmol/L sorafenib for 24 or 48 hours, and the cell viability was detected by CCK-8 assay. Flow cytometry technology was used to detect the changes of reactive oxygen species (ROS) in K562 cells treated with 0, 5, and 10 µmol/L sorafenib for 24 hours. Western blot was used to detect the protein expression of GPX4 in K562 cells treated with 0, 5, and 10 µmol/L sorafenib and pretreatment with ferroptosis inhibitor. A recombinant lentiviral vector was used to construct UVRAG overexpression cell line in K562 cells. qPCR and Western blot were used to verify UVRAG gene overexpression, and Western blot detected the effect of UVRAG on the protein expression of GPX4 and HMGB1 after treatment with sorafenib. RESULTS: Different concentrations of sorafenib could significantly inhibit the proliferation of K562 cells, and the cell viability gradually decreased with the increase of concentration (r 24 h=-0.9841, r 48 h=-0.9970). The level of ROS was increased (When the concentration was 10 µmol/L, P <0.001), while the expression of GPX4 protein was decreased in the process of 0, 5, 10 µmol/L sorafenib-induced K562 cell death (P <0.05), and the decrease in GPX4 protein could be partially reversed by pretreatment with ferroptosis inhibitor (P <0.05). Compared with NC group and NC-Sorafenib group, the expression of GPX4 protein was significantly decreased (both P <0.05), while HMGB1 protein was significantly increased (both P <0.05). CONCLUSION: Sorafenib can induce ferroptosis in K562 cells, and this process can be promoted by UVRAG.

Ceria Nanoparticle Systems Alleviate Degenerative Changes in Mouse Postovulatory Aging Oocytes by Reducing Oxidative Stress and Improving Mitochondrial Functions.

Postovulatory aging oocytes usually feature diminished potential for fertilization and poor embryonic development due to enhanced oxidative damage to the subcellular organelles and macromolecules, which stands as a formidable obstacle in assisted reproductive technologies (ART). Here, we developed lipoic acid (LA) and polyethylene glycol (PEG)-modified CeO2 nanoparticles (LA-PEG-CeNPs) with biocompatibility, enzyme-like autocatalytic activity, and free radical scavenging capacity. We further investigated the LA-PEG-CeNPs effect in mouse postovulatory oocytes during in vitro aging. The results showed that LA-PEG-CeNPs dramatically reduced the accumulation of ROS in aging oocytes, improving mitochondrial dysfunction; they also down-regulated the pro-apoptotic activity by rectifying cellular caspase-3, cleaved caspase-3, and Bcl-2 levels. Consistently, this nanoenzyme prominently alleviated the proportion of abnormalities in spindle structure, chromosome alignment, microtubule stability, and filamentous actin (F-actin) distribution in aging oocytes, furthermore decreased oocyte fragmentation, and improved its ability of fertilization and development to blastocyst. Taken together, our finding suggests that LA-PEG-CeNPs can alleviate oxidative stress damage on oocyte quality during postovulatory aging, implying their potential value for clinical practice in assisted reproduction.

Mortality Risk Factors Among People Living with HIV Receiving Second-line Antiretroviral Therapy in Rural China.

BACKGROUND: Second-line antiretroviral therapy (ART) was introduced in Henan Province in 2009. The number of people living with human immunodeficiency virus (HIV) starting this therapy is increasing. OBJECTIVE: This study aimed to investigate the survival and factors affecting mortality among this group. METHODS: We conducted a retrospective cohort study of people living with HIV (PLHIV) who switched to second-line ART between May 1, 2010, and May 1, 2016, using the Kaplan-Meier method and Cox proportional hazards models. RESULTS: We followed 3,331 PLHIV for 26,988 person-years, of whom 508 (15.3%) died. The mortality rate was 1.88/100 person-years. After adjusting for confounding factors, we found being a woman (hazard ratio (HR), 0.66; 95% confidence interval (CI) 0.55-0.79), > 50 years old (HR, 2.69; 95% CI, 2.03-3.56), single/widowed (HR, 1.26; 95% CI, 1.04-1.52), having > 6 years of education (HR, 0.78; 95% CI, 0.65-0.94), Chinese medicine (HR, 0.75; 95% CI, 0.52-0.96), liver injury (HR, 1.58; 95% CI, 1.19-2.10), and CD4+ T cell count <200 cells/µl (HR, 1.94; 95% CI, 1.47-2.55), or 200-350 cells/µl (HR, 1.37; 95% CI, 1.03-1.82) were associated with mortality risk. CONCLUSIONS: We found lower mortality among PLHIV who switched to second-line ART than most previous studies. The limitations of a retrospective cohort may, therefore, have biased the data, and prospective studies are needed to confirm the results. Moreover, Chinese medicine combined with second-line ART shows potential as a treatment for HIV.

[Effect of Silencing UVRAG on Mitophagy in Leukemia Cells K562].

OBJECTIVE: To explore the effect of UVRAG on mitophagy in leukemia cells K562. METHODS: K562 cells were induced with different concentrations of mitophagy inducer carbonylcyanide-m-chlorophenylhydrazone (CCCP) for 6, 12 and 24 hours, and the cell viability was detected by the CCK-8 assay. K562 cells were divided into NC, UVRAG-siRNA, UVRAG-siRNA+CCCP, and CCCP group, while Western blot was used to detect the expression of UVRAG protein. Flow cytometry was used to detect the changes in reactive oxygen species (ROS) and mitochondrial structural integrity. The expressions of autophagy related proteins P62 and LC3-Ⅱ/LC3-Ⅰ were detected by Western blot. RESULTS: Compared with NC group, the expression of UVRAG protein in UVRAG -siRNA group significantly decreased (P<0.01). Compared with CCCP group, in UVRAG -siRNA+CCCP group ROS, mitochondrial structure damage, and the expression of LC3-Ⅱ/LC3-Ⅰ decreased significantly (P<0.05, P<0.05, P<0.01), while the expression of P62 protein increased (P<0.05). Compared with NC group, the differences in the expressions of P62 and LC3-Ⅱ/LC3-Ⅰ protein, ROS, and mitochondrial structural integrity in UVRAG -siRNA group were not obvious (P>0.05). CONCLUSION: Under the treatment of CCCP, silencing UVRAG can inhibit mitophagy in K562 cells.

The potent role of Src kinase-regulating glucose metabolism in cancer.

Src kinase is a membrane-related nonreceptor tyrosine kinase that plays an essential role in cell growth, division, migration, and survival signaling pathways. In addition, it regulates glucose metabolism in cancer cells through different mechanisms, such as directly regulating glucose metabolism related enzymes and glucose transporters or indirectly regulating transcription factors and signal transduction pathways. In this review, we clarify the role of Src kinase in regulating glucose metabolism in cancer cells, and partially explain the pathogenesis of malignant tumors. We also discuss that further understanding and study of the role of Src kinase in glucose metabolism will provide a potential therapeutic window for cancer treatment.

Advances in the study of HLA class Ib in maternal-fetal immune tolerance.

The HLA class Ib molecule is an alloantigen that causes transplant rejection on behalf of individual human and plays an important role in maternal-fetal immune tolerance. Early studies on HLA class Ib focused on the mechanism of HLA-G-induced immune escape, but in recent years, studies on the mechanism of HLA-G have deepened and gradually explored the mechanism of HLA-E and HLA-F, which are also HLA class Ib molecules. In the maternal-fetal interface, trophoblast cells express HLA class Ib molecules to protect the fetus from maternal immune cells by binding to inhibitory receptors of decidual immune cells (DICs) and shifting Th1/Th2 balance toward Th2 bias. Further studies on the molecular mechanism of HLA class Ib molecules provide a reference for its application in the field of clinical assisted reproduction.

The impact of COVID-19 non-pharmaceutical interventions on HIV care continuum in China: An interrupted time series analysis.

Background: China implemented strict non-pharmaceutical interventions to contain COVID-19 at the early stage. We aimed to evaluate the impact of COVID-19 on HIV care continuum in China. Methods: Aggregated data on HIV care continuum between 1 January 2017 and 31 December 2020 were collected from centers for disease control and prevention at different levels and major infectious disease hospitals in various regions in China. We used interrupted time series analysis to characterize temporal trend in weekly numbers of HIV post-exposure prophylaxis (PEP) prescriptions, HIV tests, HIV diagnoses, median time intervals between HIV diagnosis and antiretroviral therapy (ART) initiation (time intervals, days), ART initiations, mean CD4+ T cell counts at ART initiation (CD4 counts, cells/µL), ART collections, and missed visits for ART collection, before and after the implementation of massive NPIs (23 January to 7 April 2020). We used Poisson segmented regression models to estimate the immediate and long-term impact of NPIs on these outcomes. Findings: A total of 16,780 PEP prescriptions, 1,101,686 HIV tests, 69,659 HIV diagnoses, 63,409 time intervals and ART initiations, 61,518 CD4 counts, 1,528,802 ART collections, and 6656 missed visits were recorded during the study period. The majority of outcomes occurred in males (55·3-87·4%), 21-50 year olds (51·7-90·5%), Southwestern China (38·2-82·0%) and heterosexual transmission (47·9-66·1%). NPIs was associated with 71·5% decrease in PEP prescriptions (IRR 0·285; 95% CI 0·192-0·423), 36·1% decrease in HIV tests (0·639, 0·497-0·822), 32·0% decrease in HIV diagnoses (0·680, 0·511-0·904), 59·3% increase in time intervals (1·593, 1·270-1·997) and 17·4% decrease in CD4 counts (0·826, 0·746-0·915) in the first week during NPIs. There was no marked change in the number of ART initiations, ART collections and missed visits during the NPIs. By the end of 2020, the number of HIV tests, HIV diagnoses, time intervals, ART initiations, and CD4 counts reached expected levels, but the number of PEP prescriptions (0·523, 0·394-0·696), ART collections (0·720, 0·595-0·872), and missed visits (0·137, 0·086-0·220) were still below expected levels. With the ease of restrictions, PEP prescriptions (slope change 1·024/week, 1·012-1·037), HIV tests (1·016/week, 1·008-1·026), and CD4 counts (1·005/week, 1·001-1·009) showed a significant increasing trend. Interpretation: HIV care continuum in China was affected by the COVID-19 NPIs at various levels. Preparedness and efforts to maintain the HIV care continuum during public health emergencies should leverage collaborations between stakeholders. Funding: Natural Science Foundation of China.

Effectors of Hyperlipidemia among HIV/AIDS patients with second-line antiretroviral therapy based on register data.

OBJECTIVE: In this study, we aimed to determine the prevalence and effectors of hyperlipidemia among people living with HIV/AIDS (PLWHA) and taking second-line antiretroviral therapy (ART) using registry data in central China. METHODS: We conducted a cross-sectional study and collected information of PLWHA on second-line ART during 2018 from two medical registries. Hyperlipidemia was defined according to the 2016 Chinese guidelines for the management of dyslipidemia in adults. Univariate and multivariate logistic regression analyses were performed to explore the influencing factors of hyperlipidemia. We calculated odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: A total of 2886 PLWHA taking second-line ART were included in this study, and 978 (33.9%) had hyperlipidemia. Female patients, those with hyperglycemia, and patients with CD4+ cell counts >500 cells/µL had a higher prevalence of hyperlipidemia with 37.0%, 49.0%, and 41.3%, respectively. Multivariate analysis showed that CD4+ cell count 350-500 cells/µL (OR=1.72, 95% CI: 1.26-2.38), CD4+ cell count >500 cells/µL (OR=2.49, 95% CI: 1.85-3.38), and FPG >6.2 mmol/L (OR=2.08, 95% CI:1.64-2.65) were risk factors for hyperlipidemia. Male sex (OR=0.72, 95% CI: 0.61-0.85) and Hb <110 g/L (OR=0.59, 95% CI: 0.45-0.76) were protective factors against hyperlipidemia. CONCLUSIONS: PLWHA on second-line ART had a higher prevalence of hyperlipidemia. Gender, CD4+ cell count, FPG, and hemoglobin were influencing factors of hyperlipidemia.

Suboptimal immune recovery and associated factors among people living with HIV/AIDS on second-line antiretroviral therapy in central China: A retrospective cohort study.

The introduction and scale-up of antiretroviral therapy (ART) have contributed to significantly improved patients with acquired immune deficiency syndrome (AIDS) quality of life and prolongs their survival. This has occurred by suppressing viral replication and recovering the CD4 cell count. However, some patients do not normalize their CD4 cell count, despite suppression of the viral load (VL). Patients with suboptimal immune recovery (SIR), as defined by a VL < 400 copies/ml with a CD4 cell count of<200 cells/µl, after ART initiation, exhibit severe immune dysfunction and have a higher risk of AIDS and non-AIDS events. In recent years, People living with HIV/AIDS (PLWHA) with first-line ART failure began to gradually switch to second-line ART. This study aimed to examine the prevalence and factors affecting SIR among PLWHA who switch to second-line ART in rural China. A 1-year retrospective cohort study was conducted among PLWHA who switched to second-line ART between January 2009 and December 2018. All patients with a VL < 400 copies/ml after 1 year of second-line ART were included. SIR was defined as a CD4 cell count <200 cells/µl and a VL < 400 copies/ml after 1 year of second-line ART. The data collected from medical records were analyzed by univariate and multivariate analyses. A total of 5294 PLWHA met the inclusion criteria, 24 died, and 1152 were lost to follow-up after 1 year of second-line ART. Among 4118 PLWHA who were followed up, 3039 with a VL < 400 copies/ml had their data analyzed, and the prevalence of SIR was 13.1%. The patients' mean age at recruitment was 47.6 ± 8.1 years and 45.3% were men. A total of 30.7% of patients were HIV-positive for >8 years and 88.2% were receiving ART before starting second-line ART for >3 years. The mean CD4 cell count was 354.8 ± 238.2 cells/µl. A multivariable analysis showed that male sex, single status (unmarried or divorced), and a low CD4 cell count were risk factors for SIR among PLWHA with second-line ART. The prevalence of SIR among PLWHA who switched to second-line ART in this retrospective cohort study is lower than that in most other studies. Several factors associated with SIR include male sex, marital status, and CD4 cell count levels in PLWHA.

Comparison of bromocriptine and hydroxyethyl starch in the prevention of ovarian hyperstimulation syndrome.

OBJECTIVE: To evaluate the effectiveness of bromocriptine for prevention of ovarian hyperstimulation syndrome (OHSS). METHODS: The retrospective study included women at risk of OHSS who were receiving gonadotropin-releasing hormone antagonist protocols, including 52 women given 2.5 mg bromocriptine by rectal insertion, 52 women given 500 ml intravenous hydroxyethyl starch (HES), and 40 women who received no intervention. Treatments were administered daily for 5 days beginning on the day of oocyte retrieval. Baseline information and data related to OHSS were compared. RESULTS: No significant differences were found among groups in estradiol concentration on the day of trigger or in number of retrieved oocytes. Incidence of mild OHSS was not significantly different among groups, respectively 13.5%, 15.4%, and 17.5% (P > 0.05). The incidence of moderate to severe OHSS was significantly lower in the bromocriptine and HES groups compared with the control group, respectively 7.7%, 5.8%, and 22.5% (P < 0.05). D-dimer levels were significantly lower in the bromocriptine and HES groups compared with the control group on Day 5 after oocyte retrieval (P < 0.05). No differences in liver or renal function were found in the three groups. CONCLUSION: Bromocriptine was apparently as effective as intravenous HES in patients with high risk of OHSS.

[The comorbid mechanism of vestibular migraine and persistent postural-perceptual dizziness].

Vestibular migraine and persistent postural-perceptual dizziness both involve the vestibular system and are similar in clinical manifestations. After acute attack of vestibular migraine, it can gradually evolve into persistent posture-perceptual dizziness; persistent posture-perceptual dizziness caused by various factors can be combined with symptoms similar to vestibular migraine. Studies have shown that abnormal multi-sensory signal integration, abnormal neurotransmitters and genetic factors may be the co-disease mechanism of the two.

A mathematical model to predict the probability of a successful pregnancy.

AIM: To develop a scoring system for the prediction of a successful pregnancy. METHODS: Data were collected prospectively from women diagnosed with pregnancy from January 1, 2015, to December 31, 2018. Pregnant days, hormone levels, and gestational sac diameters were recorded. Relationships among the pregnancy days, hormones, and gestational sac were analyzed by Spearman correlation analysis. A scoring system was established and stratified by the 5th, 50th, and 95th percentile of hormone levels and gestational sac diameters on different pregnancy days. Pregnancy outcomes were predicted by the scores using quadratic polynomial regression analyses. A portable desktop analyzer was developed and the performance was evaluated by receiver operating characteristic (ROC) curve. RESULTS: In 273 successful pregnancy cases, the length of gestational days was significantly correlated to beta-human chorionic gonadotropin (ß-hCG) (r = 0.74, p < 0.001) and E2 (r = 0.79, p < 0.001) levels, and the size of the gestational sac (r = 0.88, p < 0.001). Meanwhile, the size of gestational sac was positively correlated with ß-hCG (r = 0.93, p < 0.001) and E2 (r = 0.55, p < 0.001). For 273 delivery and 103 miscarriage cases included in this study, our scoring-based prediction model rendered an area under the ROC curve (AUC) of 0.86 with the sensitivity of 78.31% and the specificity of 80.83%. CONCLUSIONS: We successfully developed a scoring-based analyzer to evaluate the viability of embryos at different gestation stages and to predict the probability of a successful delivery, which would provide a reference for clinicians in postpregnancy management.

Effects of Chinese Medicine on the Survival of AIDS Patients Administered Second-Line ART in Rural Areas of China: A Retrospective Cohort Study Based on Real-World Data.

OBJECTIVES: Chinese medicine (CM) improves the symptoms of patients with acquired immune deficiency syndrome (AIDS) and prolongs their survival. This real-world study aimed to evaluate the effects of CM on the survival of AIDS patients administered second-line antiretroviral therapy (ART). METHODS: We conducted a retrospective cohort study of the medical records of patients with AIDS who switched to second-line ART between January 2009 and December 2014. Patients were divided into ART and CM + ART groups. Propensity score matching (PSM) was performed to correct for biases between groups. Kaplan-Meier analysis and the log-rank test were used to compare survival rates, and Cox regression models were employed to identify factors significantly associated with survival. RESULTS: The study population (n = 4180) was comprised of the CM + ART group (n = 855) and the ART group (n = 3325). After 1 : 2 PSM, 855 patients in the CM + ART group and 1699 in the ART group were selected for analysis. Patients in the CM + ART group were followed for 4246.8 person-years, and the mortality rate was 2.12/100 person-years. Patients in the ART group were followed for 8381.2 person-years, and the mortality rate was 2.91/100 person-years. Cox regression model analysis revealed that patients in the CM + ART group survived significantly longer than those in the ART group (hazard ratio: 0.73 and 95% confidence interval: 0.57-0.93). Gender, age, symptoms, CD4 cell counts, and viral loads were independently associated with the survival of AIDS patients treated with second-line ART. CONCLUSIONS: CM significantly improved the survival rate of AIDS patients treated with second-line ART.

Effect of antiretroviral therapy initiation time and baseline CD4+ cell counts on AIDS-related mortality among former plasma donors in China: a 21-year retrospective cohort study.

BACKGROUND: The conventional survival analysis model on HIV/AIDS prognosis is the Cox proportional hazard model, which deals with only one event type, death, regardless of the cause. Few studies have used a competing risk model to evaluate the predictors of AIDS-related mortality. OBJECTIVE: To estimate the influence of antiretroviral therapy (ART) initiation time and baseline CD4+ cell counts on acquired immunodeficiency syndrome (AIDS)-related death among former plasma donors. METHODS: A retrospective cohort study was conducted involving 11,905 human immunodeficiency virus (HIV) or AIDS patients in a high-risk area of Henan province in China between 1995 and 2016. Demographic and clinical data were collected. Sub-distribution hazard ratios (sHRs) for AIDS-related mortality with baseline CD4+ cell counts and ART initiation time were determined using a competing risk model. RESULTS: Patients who initiated ART within 90 days of HIV/AIDS diagnosis (sHR: 0.24, 95% CI: 0.22-0.27) or had baseline CD4+ counts of >500 cells/µL (sHR: 0.23, 95% CI: 0.19-0.28) were associated with lower AIDS-related mortality risk. Patients with ART initiation time >1 year but CD4+ counts >350 cells/µL (sHR: 4.42, 95% CI: 3.30-5.91) had a higher AIDS-related mortality risk than those with ART initiation time >90 days but CD4+ counts ≤350 cells/µL (sHR: 4.33, 95% CI: 3.58-5.23). CONCLUSIONS: Our results demonstrate that patients with high CD4+ cell counts and late ART had a 9% higher risk of AIDS-related death than those with low CD4+ cell counts and early ART. This study confirms the great significance of immediate ART initiation among former plasma donor HIV patients in China.

[Potential targets of Euodiae Fructus in treatment of insomnia based on network pharmacology].

The acupoint application of Euodiae Fructus at Yongquan(KI1) can significantly improve the sleep quality of patients with insomnia with berberine as the main effective component for the efficacy. Nineteen active compounds and 203 drug targets were screened out from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP). After comparison with GeneCards and Online Mendelian Inheritance in Man(OMIM), 24 common genes of diseases and drugs were obtained. STRING 11.0 was used to construct a protein-protein interaction(PPI) network of the overlapping genes, and Matthews correlation coefficient(MCC) was employed to screen the core genes, which were then subjected to enrichment analysis with gene ontology(GO) and Kyoto encyclopedia of genes and genomes(KEGG). The results revealed that the main compounds of Euodiae Fructus, such as berberine and rutaecarpine, participated in the biological processes(such as neurotransmitter receptor activity) by regulating C-reactive protein(CRP), estrogen receptor 1(ESR1), 5-hydroxytryptamine(5-HT) receptor, and interleukin-6(IL-6) to exert sedative, anxiolytic, and antidepressant effects. Sixty 4-week-old SPF mice were randomly divided into a control group, a model group, a positive drug(diazepam tablets) group, and low-, medium-, and high-dose berberine groups. Medication with corresponding drugs was performed for one week. The results demonstrated that berberine was potent in reducing the activities and standing times of mice, down-regulating the levels of CRP and IL-6 mRNA in the hypothalamus, and up-regulating the expression of 5-HT(P<0.01); however, no significant effect on ESR1 was observed. The network of Euodiae Fructus in treating insomnia was constructed by network pharmacology and verified by tests. The findings indicated that the therapeutic efficacy of Euodiae Fructus in treating insomnia was achieved by participating in multiple biological processes, such as neurotransmitter receptor activity, which provided a scientific basis for its clinical application.

Effect of Traditional Chinese Medicine Therapy on the Trend in CD4+ T-Cell Counts among Patients with HIV/AIDS Treated with Antiretroviral Therapy: A Retrospective Cohort Study.

This retrospective cohort study was conducted to explore the effect of traditional Chinese medicine (TCM) therapy on the long-term trends in CD4+ T-cell count among patients with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) who were treated with combined antiretroviral therapy (cART) over a 14-year period. A total of 721 individuals were treated with cART alone (cART group), and 307 individuals were treated with both cART and TCM (TCM + cART group). Among all enrolled patients with HIV/AIDS, 99.5% were farmers, 71.1% had more than 6 years of education, and 96.8% were infected with HIV via a paid blood donation. For those patients with HIV/AIDS who had a baseline CD4+ T-cell count of <350 cells/mL, the CD4+ T-cell count tended to increase to approximately 350 cells/mL more rapidly in the TCM + cART group than in the cART group, but when the baseline CD4+ T-cell count was ≥350 cells/mL, there was no difference between the cART and TCM + cART groups. For other patients with HIV/AIDS who had a baseline CD4+ T-cell count of 350-500 cells/mL, the CD4+ T-cell counts tended to increase slightly, but there was no difference between the two groups. For patients with HIV/AIDS who had a baseline CD4+ T-cell count of ≥500 cells/mL, the CD4+ T-cell counts tended to be maintained at a particular level, with no difference between the two groups. The results show that the effect of TCM on the CD4+ T-cell counts of patients with HIV/AIDS is related to the CD4+ T-cell level at the time of initial treatment. TCM can increase the CD4+ T-cell count among patients with HIV/AIDS who have a baseline CD4+ T-cell count of <350 cells/mL. Sex and age have a slight influence on the therapeutic effect of TCM.

Follicular Metabolites-Assisted Clinical Evaluation of IVF/ICSI Outcomes.

As infertility became a significant public health problem, assisted reproductive technologies (ARTs) were introduced. However, the fertilization rate of in vitro fertilization (IVF) per cycle varied, and patients needed to repeat IVF or change to intracytoplasmic sperm injection (ICSI). Here, 75 couples suffering from female fallopian tubal blockage (tubal group) and 42 spouses beset by male abnormal sperm status (dysspermia group) were recruited. We comprehensively explored the relationship among couples' clinical factors, follicular metabolites, and IVF/ICSI stepwise outcomes. IVF/ICSI outcomes were affected by follicular metabolites and physical status in both women and men, regardless of which side infertility came from. Particularly, in the tubal group, the energy supporting pathways-glycolysis and pyruvate metabolism-were most essential in follicles, and IVF/ICSI outcomes were also related to sperm parameters. However, in the dysspermia group, in addition to sperm conditions, oocyte quality acted as a compensation for poor sperm quality, for which aminoacyl-tRNA biosynthesis and the related supporting metabolism were critical in the follicular environment, and ultimately played a decisive role in IVF/ICSI outcomes. The respective logistic regression models in combination with selective male sperm parameters, estradiol (E2), follicular alanine, glutamine, glycoprotein, lipid, and acetic acid, were constructed to predict IVF or ICSI outcomes. No matter which sex infertility comes from, factors from both men and women should be considered. The current study provides a feasible option for pre-IVF evaluation, as well as guidance for follow-up clinical intervention to improve IVF/ICSI success rates.

The effects of multiple controlled ovarian hyperstimulation over a 2-year period on ovarian reserve and reactivity: a retrospective clinical study.

BACKGROUND: To evaluate the effects of controlled ovarian hyperstimulation (COH) on ovarian reserve function during in vitro fertilization and embryo transfer (IVF-ET). METHODS: From August 2018 to August 2020, the medical records of patients who received IVF-ET in the Department of Reproductive Medicine, Beijing Gynaecology and Obstetrics Hospital, Capital Medical University were analyzed retrospectively. Among them, 372 patients received 2 cycles of COH, 54 patients received 3 cycles, and 13 patients received 4 cycles. The levels of follicle-stimulating hormone (FSH), the number of antral follicles, levels of anti-Müllerian hormone (AMH), the total amount of gonadotropin (GN), the time of ovulation induction, the number of eggs obtained, the number of available embryos, and the number of high-quality embryos cycles were compared in different treatment. RESULTS: The age of female patients did not significantly affect the levels of AMH or FSH during menstruation, nor the number of antral follicles before ovulation induction (P>0.05). However, with an increase in age, an increase in the number of controlled COH cycles was observed. In patients who underwent 2 COH cycles, the number of high-quality embryos in the second cycle increased significantly compared to the first cycle (P<0.05). However, there were no significant differences in the ovulation induction time, the number of eggs, the GN dosage, and the number of available embryos (P>0.05). In patients with 3 treatment cycles, the GN dose used in the third cycle was significantly lower than that used in the first cycle (P<0.05). There were no significant differences in the ovulation induction time, the number of eggs obtained, and the quality of embryos (P>0.05). In patients with 4 treatment cycles, significant differences were observed in the ovulation induction time between the first and the fourth controlled COH cycle (P<0.05). However, no significant differences were detected in GN dosage, ovulation induction time, the number of eggs obtained, the number of available embryos, and the quality of embryos (P>0.05). CONCLUSIONS: Ovarian reserve function was not significantly affected in patients with up to 4 ovarian stimulation cycles.

Oestrogen induces epithelial-mesenchymal transition in endometriosis via circ_0004712/miR-148a-3p sponge function.

Endometriosis is a common, chronic gynaecologic disease affecting up to 10% of women in their reproductive age and leading to pain and infertility. Oestrogen (E2 )-induced epithelial-mesenchymal transition (EMT) process has been considered as a key factor of endometriosis development. Recently, the dysregulated circular RNAs (circRNAs) have been discovered in endometriosis tissues. However, the molecular mechanism of circRNAs on the E2 -induced EMT process in endometriosis is still unknown. Here, we demonstrated that circ_0004712 up-regulated by E2 treatment in endometrial epithelial cells. Knock-down the expression of circ_0004712 significantly suppressed E2 -induced cell migration activity. Meanwhile, we identified miR-148a-3p as a potential target miRNA of circ_0004712. Inhibited the expression of miR-148a-3p could recovered the effect of circ_0004712 knock-down in E2 -treated endometrial epithelial. Furthermore, Western blot assay showed that E2 treatment could increase the expression and activity of ß-catenin, snail and N-cadherin and reduce the expression of E-cadherin. The expression and activity of ß-catenin pathway were recovered by circ_0004712 knock-down or miR-148a-3p overexpression. Altogether, the results demonstrate that circ_0004712/miR-148a-3p plays an important role in E2 -induced EMT process in the development of endometriosis, and the molecular mechanism may be associated with the ß-catenin pathway. This work highlighted the importance of circRNAs in the development of endometriosis and provide a new biomarker for diagnosis and therapies.

LncRNA SNHG4 promotes the increased growth of endometrial tissue outside the uterine cavity via regulating c-Met mediated by miR-148a-3p.

Long noncoding RNAs (lncRNAs) modulate endometriosis. The current study investigated the mechanisms and effects of SNHG4 on endometriosis. The qRT-PCR was conducted to examine the miR-148a-3p and SNHG4 expressions in endometriosis tissues. The 5-ethynyl-2'-deoxyuridine incorporation assay and 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide assay were used to measure the rate of cell proliferation. The association between miR-148a-3p, SNHG4 and c-Met was confirmed via bioinformatical approach and luciferase reporter gene assay. Also, the function of SNHG4 on the growth of endometriotic lesions was investigated in vivo. The SNHG4 expression was considerably upregulated in endometriosis tissues, whereas the level of miR-148a-3p expression was reduced. In addition, SNHG4 can be considered as ceRNAs that bind miR-148a-3p and rise the proliferation activity of HESCs by downregulating miR-148a-3p. Furthermore, silencing SNHG4 could downregulate the c-Met level by enhancing miR-148a-3p expression, and finally inhibiting endometriosis development in vivo. LncRNA SNHG4 promotes the increased growth of endometrial tissue outside the uterine cavity via regulating c-Met mediated by miR-148a-3p, which may be used as diagnostic biomarker as well as molecular target in the treatment of endometriosis.