Antioxidants and Fertility in Women with Ovarian Aging: A Systematic Review and Meta-Analysis.

Ovarian aging is a major factor for female subfertility. Multiple antioxidants have been applied in different clinical scenarios, but their effects on fertility in women with ovarian aging are still unclear. To address this, a meta-analysis was performed to evaluate the effectiveness and safety of antioxidants on fertility in women with ovarian aging. A total of 20 randomized clinical trials with 2617 participants were included. The results showed that use of antioxidants not only significantly increased the number of retrieved oocytes and high-quality embryo rates but also reduced the dose of gonadotropin, contributing to higher clinical pregnancy rates. According to the subgroup analysis of different dose settings, better effects were more pronounced with lower doses; in terms of antioxidant types, coenzyme Q10 (CoQ10) tended to be more effective than melatonin, myo-inositol, and vitamins. When compared with placebo or no treatment, CoQ10 showed more advantages, whereas small improvements were observed with other drugs. In addition, based on subgroup analysis of CoQ10, the optimal treatment regimen of CoQ10 for improving pregnancy rate was 30 mg/d for 3 mo before the controlled ovarian stimulation cycle, and women with diminished ovarian reserve clearly benefited from CoQ10 treatment, especially those aged <35 y. Our study suggests that antioxidant consumption is an effective and safe complementary therapy for women with ovarian aging. Appropriate antioxidant treatment should be offered at a low dose according to the patient's age and ovarian reserve. This study was registered at PROSPERO as CRD42022359529.

Membrane-bound transcription factor LRRC4 inhibits glioblastoma cell motility.

Membrane-bound transcription factors (MTFs) have been observed in many types of organisms, such as plants, animals and microorganisms. However, the routes of MTF nuclear translocation are not well understood. Here, we reported that LRRC4 is a novel MTF that translocates to the nucleus as a full-length protein via endoplasmic reticulum-Golgi transport, which is different from the previously described nuclear entry mechanism. A ChIP-seq assay showed that LRRC4 target genes were mainly involved in cell motility. We confirmed that LRRC4 bound to the enhancer element of the RAP1GAP gene to activate its transcription and inhibited glioblastoma cell movement by affecting cell contraction and polarization. Furthermore, atomic force microscopy (AFM) confirmed that LRRC4 or RAP1GAP altered cellular biophysical properties, such as the surface morphology, adhesion force and cell stiffness. Thus, we propose that LRRC4 is an MTF with a novel route of nuclear translocation. Our observations demonstrate that LRRC4-null glioblastoma led to disordered RAP1GAP gene expression, which increased cellular movement. Re-expression of LRRC4 enabled it to suppress tumors, and this is a potential for targeted treatment in glioblastoma.

The effectiveness and safety of Chinese herbal medicine in infertile women with luteal phase deficiency: a systematic review and meta-analysis.

BACKGROUND: Chinese herbal medicine (CHM) has been reported to treat infertile women with luteal phase deficiency (LPD) in some clinical studies, however, the efficacy and safety of CHM for LPD are still under controversy. Here, we aim to evaluate the efficacy and safety of CHM using meta-analysis, and further compare it with conventional Western therapies (CWT) to elucidate the improvement in progestin and clinical pregnancy rates. METHODS: Eight randomized controlled trials (RCTs) involving 465 women were included in our systematic review; these RCTs compared CHM with CWT in treating LPD in infertile women. The methodological quality of the included RCTs was assessed according to the Cochrane risk-of-bias assessment criteria. The data were analyzed by Review Manager 5.3 software. We estimated the risk ratio (RR) for dichotomous data and calculated the mean difference for continuous data. RESULTS: In contrast to CWT, CHM was superior in improving clinical pregnancy rates (RR 0.19; 95% CI: 0.11-0.27; P<0.001), increasing progesterone levels in the luteal phase [mean difference (MD) 2.28; 95% CI: 1.91-2.64; P<0.001] and luteal phase estrogen (MD 9.88; 95% CI: 4.53-15.24; P=0.0003), reducing traditional Chinese medicine (TCM) syndrome scores (MD -3.06; 95% CI: -3.95 to -2.17; P<0.001), and the incidence of adverse reactions (RR 0.12; 95% CI: 0.02-0.70; P=0.02). CONCLUSIONS: Evidence from eight small studies suggested that CHM has a therapeutic effect on infertile women with luteal insufficiency. We indicated that CHM may improve the level of progesterone and estradiol in the luteal phase, and the clinical pregnancy rate, with few side effects based on the current studies. However, given the relatively small number of included studies, further studies about the higher quality of study designs, larger population and the underlying mechanism are required to elucidate the role of CHM in LPD treatment.

Administration of growth hormone improves endometrial function in women undergoing in vitro fertilization: a systematic review and meta-analysis.

BACKGROUND: The positive effects of growth hormone (GH) on IVF are often attributed to improvements in oocyte and embryo quality. While emerging evidence emphasizes GH-induced improvements in the endometrium, these results are controversial. OBJECTIVE AND RATIONALE: This meta-analysis aimed to evaluate whether GH administration improved endometrial function and reproductive outcomes during IVF cycles and to thus guide clinical practice. SEARCH METHODS: A literature search in the Cochrane Central Register of Controlled Trials, PubMed and Embase was performed through to 30 November 2021, without language restrictions. Randomized controlled trials (RCTs) evaluating the effects of GH on IVF outcomes were included. Risk of bias and quality of evidence (QoE) were assessed according to the Cochrane Collaboration's tool and the Grading of Recommendations Assessment, Development and Evaluation system. Odds ratios (ORs) and mean differences (MDs) with 95% confidence intervals (CIs) were assessed by random-effects models. OUTCOMES: A total of 25 trials with 2424 women were included. Seventeen RCTs with poor responders (n = 1723) showed that GH administration significantly increased endometrial thickness (EMT) (MD = 0.38, 95% CI: 0.18-0.59; moderate QoE), which contributed to an improved live birth rate (OR = 1.67, 95% CI: 1.13-2.49; very low QoE) and clinical pregnancy rate (CPR) (OR = 1.97, 95% CI: 1.43-2.72; low QoE). Subgroup analyses showed a dose- and time-dependent relationship between GH cotreatment and IVF outcomes; the optimal recommendation for improving CPR was consistent with that for EMT, rather than for oocytes and embryos. Hence, GH might improve fertility via effects on the endometrium. Administration of GH daily from the follicular phase of previous cycle until the hCG trigger with < 5 IU/day led to a thicker endometrium and a greater chance of becoming pregnant, while 5-10 IU/day or administration from the luteal phase of the previous cycle until the hCG trigger resulted in higher oocyte and embryo quality. Poor responders might benefit from cotreatment with the GnRH agonist long protocol more than other stimulation protocols. Pooled data from four trials (n = 354) on women with a thin endometrium indicated that improved endometrial function might be critical for improving reproductive outcomes during GH treatment, as no improvements in embryo quality were found. GH administration not only increased EMT (MD = 1.48, 95% CI: 1.21-1.75; moderate QoE) but also promoted endometrial morphology (OR = 2.67, 95% CI: 1.36-5.23; low QoE) and perfusion (OR = 5.84, 95% CI: 1.30-26.17; low QoE), thereby improving the CPR (OR = 2.71, 95% CI: 1.69-4.34; P < 0.0001; low QoE). There was insufficient evidence to reach a conclusion regarding the effects of GH in normal responders (n = 80). Due to obvious improvements in the CPR, women with a thin endometrium might be the most appropriate population to benefit from GH administration. WIDER IMPLICATIONS: Improving endometrial function might be another vital mechanism by which GH improves IVF outcomes. Optimal treatment should be offered to the target population according to their personal conditions and needs. The QoE was moderate to very low, due to limited sample sizes and methodological problems; thus, the results should be interpreted with caution. More rigorous RCTs with large sample sizes are needed to confirm the effects and determine optimal GH protocols.

Dietary Modification for Reproductive Health in Women With Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis.

Objective: Diet has been reported as the first-line management of polycystic ovary syndrome (PCOS). However, the relationship between diet and fertility in PCOS is still controversial. This meta-analysis aimed to evaluate whether diet could promote reproductive health in women with PCOS while providing evidence-based nutrition advice for clinical practice. Methods: Seven databases, including Cochrane Central Register of Controlled Trials, PubMed, Embase, Web of Science, and some Chinese database, were searched up to January 31, 2021. Randomized controlled trials evaluating the effects of diet in women with PCOS were included. Based on a preregistered protocol (PROSPERO CRD42019140454), the systematic review was performed following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Two reviewers made study selection, data extraction and bias assessment independently. Risk ratios and mean difference with 95% confidence intervals were assessed by a random-effects model. Statistical heterogeneity within comparisons was evaluated by Cochran's Q test and quantified by the I-squared (I2 ) statistic. Results: Twenty RCTs with 1113 participants were included. Results showed diet significantly related to improved fertility outcomes (increasing clinical pregnancy, ovulation and menstrual regularity rate; reducing miscarriage rate), reproductive endocrine [increasing sex hormone-binding globulin (SHBG); decreasing Anti-Müllerian Hormone (AMH), free androgen index (FAI), total testosterone (T)] and clinical hyperandrogenism (hirsutism assessed by Ferriman-Gallwey score) in PCOS. Specifically, subgroup analyses indicated low-carbohydrate diets were superior in optimizing reproductive outcomes and calorie restriction was critical in ameliorating hyperandrogenism. Additionally, the positive effects were associated with the treatment duration. The longer the duration, the greater the improvement was. Conclusion: Overall, diet is an effective intervention for improving fertility health, thus professional and dynamic dietary advice should be offered to all PCOS patients, based on the changeable circumstances, personal needs and expectations of the individuals.

Effect of Diet on Insulin Resistance in Polycystic Ovary Syndrome.

OBJECTIVE: The effect of diet on insulin resistance (IR) in polycystic ovary syndrome (PCOS) is controversial. Thus, we conducted this systematic review and meta-analysis to evaluate whether diet could reduce IR in women with PCOS while providing optimal and precise nutrition advice for clinical practice. DESIGN: The search was conducted in 8 databases through June 30, 2019. The systematic review was performed following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. A random-effects model was adopted to calculate the overall effects. RESULTS: A total of 19 trials (1193 participants) were included. The analysis showed that diet was significantly related to improvements in IR and body composition (eg, homeostasis model assessment of insulin resistance, fasting insulin, fasting plasma glucose, body mass index [BMI], weight, and waist circumference) in PCOS patients. The Dietary Approaches to Stop Hypertension diet and calorie-restricted diets might be the optimal choices for reducing IR and improving body composition, respectively, in the PCOS population. Additionally, the effects were associated with the course of treatment. The longer the duration, the greater the improvement was. Compared with metformin, diet was also advantageous for weight loss (including BMI and weight) and had the same effects on insulin regulation. CONCLUSION: Overall, our findings suggest that diet is an effective, acceptable and safe intervention for relieving IR, and professional dietary advice should be offered to all PCOS patients.

Increasing thermal stability of glutamate decarboxylase from Escherichia. coli by site-directed saturation mutagenesis and its application in GABA production.

Gamma-amino butyric acid (GABA) is an important bio-product used in pharmaceuticals, functional foods, and a precursor of the biodegradable plastic polyamide 4 (Nylon 4). Glutamate decarboxylase B (GadB) from Escherichia. coli is a highly active biocatalyst that can convert l-glutamate to GABA. However, its practical application is limited by the poor thermostability and only active under acidic conditions of GadB. In this study, we performed site-directed saturation mutagenesis of the N-terminal residues of GadB from Escherichia coli to improve its thermostability. A triple mutant (M6, Gln5Ile/Val6Asp/Thr7Gln) showed higher thermostability, with a 5.6 times (560%) increase in half-life value at 45 °C, 8.7 °C rise in melting temperature (Tm) and a 14.3 °C rise in the temperature at which 50% of the initial activity remained after 15 min incubation (T1550), compared to wild-type enzyme. Protein 3D structure analysis showed that the induced new hydrogen bonds in the same polypeptide chain or between polypeptide chains in E. coli GadB homo-hexamer may be responsible for the improved thermostability. Increased thermostability contributed to increased GABA conversion ability. After 12 h conversion of 3 mol/L l-glutamate, GABA produced and mole conversion rate catalyzed by M6 whole cells was 297 g/L and 95%, respectively, while those by wild-type GAD was 273.5 g/L and 86.2%, respectively.