Irisin alleviated the reproductive endocrinal disorders of PCOS mice accompanied by changes in gut microbiota and metabolomic characteristics.

Introduction: Folliculogenesis and oligo/anovulation are common pathophysiological characteristics in polycystic ovary syndrome (PCOS) patients, and it is also accompanied by gut microbiota dysbiosis. It is known that physical activity has beneficial effects on improving metabolism and promoting ovulation and menstrual cycle disorder in PCOS patients, and it can also modulate the gastrointestinal microbiota in human beings. However, the mechanism remains vague. Irisin, a novel myokine, plays a positive role in the mediating effects of physical activity. Methods: Mice were randomly divided into the control group, PCOS group and PCOS+irisin group. PCOS model was induced by dehydroepiandrosterone (DHEA) and high-fat diet (HFD). The PCOS+irisin group was given irisin 400µg/kg intraperitoneal injection every other day for 21 days. The serum sex hormones were measured by radioimmunoassay. Hematoxylin and Eosin (H&E) Staining and immunohistochemistry (IHC) were conducted on ovarian tissue. The feces microbiota and metabolomic characteristics were collected by 16S rRNA gene sequencing and liquid chromatography-mass spectrometry (LC-MS). Results: In this study, we demonstrated that irisin supplementation alleviated reproductive endocrine disorders of PCOS mice, including estrous cycle disturbance, ovarian polycystic degeneration, and hyperandrogenemia. Irisin also improved the PCOS follicles dysplasia and ovulation disorders, while it had no significant effect on the quality of oocytes. Moreover, irisin could mitigate the decreased bacteria of Odoribacter and the increased bacteria of Eisenbergiella and Dubosiella in PCOS mice model. Moreover, irisin could alleviate the increased fecal metabolites: Methallenestril and PS (22:5(4Z,7Z,10Z,13Z,16Z)/ LTE4). Conclusion: These results suggest that irisin may alleviate the status of PCOS mice model by modulating androgen-induced gut microbiota dysbiosis and fecal metabolites. Hence, our study provided evidence that irisin may be considered as a promising strategy for the treatment of PCOS.

Rationalization design, soluble expression and PEG modification of highly active recombinant human-porcine uricase mutant protein.

Uric acid is the end product of purine metabolism in humans due to inactivation of the uricase determined by the mutated uricase gene. Uricase catalyzes the conversion of uric acid into water-soluble allantoin that is easily excreted by the kidneys. Hyperuricemia occurs when the serum concentration of uric acid exceeds its solubility (7 mg/dL). However, modifications to improve the uricase activity is under development for treating the hyperuricemia. Here we designed 7 types of human-porcine chimeric uricase by multiple sequence comparisons and targeted mutagenesis. An optimal human-porcine chimeric uricase mutant (uricase-10) with both high activity (6.33 U/mg) and high homology (91.45 %) was determined by enzyme activity measurement. The engineering uricase was further modified with PEGylation to improve the stability of recombinant protein drugs and reduce immunogenicity, uricase-10 could be more suitable for the treatment of gout and hyperuricemia theoretically.

The influence of embryo stage on obstetric complications and perinatal outcomes following programmed compared to natural frozen-thawed embryo transfer cycles: a systematic review and meta-analysis.

Objective: To investigate the effect of embryo stage at the time of transfer on obstetric and perinatal outcomes in programmed frozen-thawed embryo transfer (FET) versus natural FET cycles. Design: Systematic review and meta-analysis. Setting: Not applicable. Patients: Women with programmed frozen-thawed embryo transfer (FET) and natural FET. Interventions: The PubMed, MEDLINE, and EMBASE databases and the Cochrane Central Register of Controlled Trials (CCRT) were searched from 1983 to October 2022. Twenty-three observational studies were included. Primary outcome measure: The primary outcomes were hypertensive disorders of pregnancy (HDPs), gestational hypertension and preeclampsia (PE). The secondary outcomes were gestational diabetes mellitus (GDM), placenta previa, postpartum haemorrhage (PPH), placental abruption, preterm premature rupture of membranes (PPROM), large for gestational age (LGA), small for gestational age (SGA), macrosomia, and preterm delivery (PTD). Results: The risk of HDP (14 studies, odds ratio (OR) 2.17; 95% confidence interval (CI) 1.95-2.41; P<0.00001; I2 = 43%), gestational hypertension (11 studies, OR 1.38; 95% CI 1.15-1.66; P=0.0006; I2 = 19%), PE (12 studies, OR 2.09; 95% CI 1.88-2.32; P<0.00001; I2 = 0%), GDM (20 studies, OR 1.09; 95% CI 1.02-1.17; P=0.02; I2 = 8%), LGA (18 studies, OR 1.11; 95% CI 1.07-1.15; P<0.00001; I2 = 46%), macrosomia (12 studies, OR 1.15; 95% CI 1.07-1.24; P=0.0002; I2 = 31%), PTD (22 studies, OR 1.21; 95% CI 1.15-1.27; P<0.00001; I2 = 49%), placenta previa (17 studies, OR 1.2; 95% CI 1.02-1.41; P=0.03; I2 = 11%), PPROM (9 studies, OR 1.19; 95% CI 1.02-1.39; P=0.02; I2 = 40%), and PPH (12 studies, OR 2.27; 95% CI 2.02-2.55; P <0.00001; I2 = 55%) were increased in programmed FET cycles versus natural FET cycles with overall embryo transfer. Blastocyst transfer had a higher risk of HDP (6 studies, OR 2.48; 95% CI 2.12-2.91; P<0.00001; I2 = 39%), gestational hypertension (5 studies, OR 1.87; 95% CI 1.27-2.75; P=0.002; I2 = 25%), PE (6 studies, OR 2.23; 95% CI 1.93-2.56; P<0.00001; I2 = 0%), GDM (10 studies, OR 1.13; 95% CI 1.04-1.23; P=0.005; I2 = 39%), LGA (6 studies, OR 1.14; 95% CI 1.07-1.21; P<0.0001; I2 = 9%), macrosomia (4 studies, OR 1.15; 95% CI 1.05-1.26; P<0.002; I2 = 68%), PTD (9 studies, OR 1.43; 95% CI 1.31-1.57; P<0.00001; I2 = 22%), PPH (6 studies, OR 1.92; 95% CI 1.46-2.51; P<0.00001; I2 = 55%), and PPROM (4 studies, OR 1.45; 95% CI 1.14-1.83; P=0.002; I2 = 46%) in programmed FET cycles than in natural FET cycles. Cleavage-stage embryo transfers revealed no difference in HDPs (1 study, OR 0.81; 95% CI 0.32-2.02; P=0.65; I2 not applicable), gestational hypertension (2 studies, OR 0.85; 95% CI 0.48-1.51; P=0.59; I2 = 0%), PE (1 study, OR 1.19; 95% CI 0.58-2.42; P=0.64; I2not applicable), GDM (3 study, OR 0.79; 95% CI 0.52-1.20; P=0.27; I2 = 21%), LGA (1 study, OR 1.15; 95% CI 0.62-2.11; P=0.66; I2not applicable), macrosomia (1 study, OR 1.22; 95% CI 0.54-2.77; P=0.64; I2 not applicable), PTD (2 studies, OR 1.05; 95% CI 0.74-1.49; P=0.79; I2 = 0%), PPH (1 study, OR 1.49; 95% CI 0.85-2.62; P=0.17; I2not applicable), or PPROM (2 studies, OR 0.74; 95% CI 0.46-1.21; P=0.23; I2 = 0%) between programmed FET cycles and natural FET cycles. Conclusions: The risks of HDPs, gestational hypertension, PE, GDM, LGA, macrosomia, SGA, PTD, placenta previa, PPROM, and PPH were increased in programmed FET cycles versus natural FET cycles with overall embryo transfer and blastocyst transfer, but the risks were not clear for cleavage-stage embryo transfer.

Effects of vitamin D supplementation on ovulation and pregnancy in women with polycystic ovary syndrome: a systematic review and meta-analysis.

Objective: To evaluate the effect of vitamin D supplementation on pregnancy and ovulation in patients with polycystic ovary syndrome. Method: We searched Pubmed, Medline (via Ovid, 1974 to 2020), EMBASE (via Ovid, 1974 to 2020), Cochrane Central Register of Controlled Trials (via Ovid), Web of Science, CNKI, WangFang and the Vip database from inception until April 2021. Two researchers independently screened articles, collected data and evaluated the quality, with Review manager 5.3 for meta-analysis. Results: Totally 20 randomized controlled studies with 1961 subjects were included. Meta analysis showed that pregnancy rate [RR=1.44 (1.28, 1.62), p<0.00,001], ovulation rate [RR=1.42 (1.14, 1.78), p=0.002] and matured oocytes rate [RR=1.08 (1.03, 1.13), p=0.002] of vitamin D supplementation group were significantly higher than those of control group. Meanwhile, early miscarriage rate [RR=0.44 (0.30, 0.66), p<0.00,001], androgen level [MD=-2.31 (-3.51, -1.11), p=0.0002], luteinizing hormone [MD=-1.47 (-2.57, -0.36), p=0.009], follicle stimulating hormone [MD=-0.15 (-0.24, -0.05), p=0.002], and premature delivery rate [RR=0.38, 95% CI (0.21, 0.70), p=0.002] were declined significantly than the controls. However, only one article suggested that the progesterone [MD=6.52 (4.52, 8.52), p<0.05] in the vitamin D intervention group was increased. There was no notable difference in the biochemical pregnancy rate [RR=0.95 (0.55, 1.63), p=0.84], gestational hypertension rate [RR=0.40, 95% CI (0.15, 1.11), p=0.08], gestational diabetes mellitus rate [RR=0.27, 95% CI (0.05, 1.39), p=0.11], fertilization rate [RR=1.05 (1.00, 1.10), p=0.04], cleavage rate [RR=1.03 (0.99, 1.06), p=0.17], high-quality embryo rate [RR=1.08 (0.98, 1.20), p=0.10], endometrial thickness [MD=0.10], 77 (-0.23, 1.77), p=0.13], estrogen level [MD=-0.34 (-1.55, 0.87), p=0.59], LH/FSH [MD=-0.14, 95% CI (-0.48, 0.20), p=1.00] and anti-Mullerian hormone [MD=-0.22 (-0.65, 0.21), p=0.32]. Conclusion: Vitamin D supplementation contribute to the higher pregnancy and ovulation rates, and lower androgen, LH, FSH and early miscarriage rates in women with PCOS, regardless of the use of ovulation induction drugs or assisted reproductive technologies. However, no significant improvement was observed in fertilization rate or cleavage rate. Due to the limitation in quality of involved studies, more high-quality RCTs are needed for further validation. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO, identifier CRD42021250284.

Is time-restricted eating (8/16) beneficial for body weight and metabolism of obese and overweight adults? A systematic review and meta-analysis of randomized controlled trials.

Time-restricted eating (TRE) is a new therapeutic strategy for the management of weight loss and dysmetabolic diseases. At present, TRE (8/16, 8 h eating:16 h fasting) is the most common form of TRE. Therefore, this meta-analysis included randomized controlled trials (RCTs) on TRE (8/16) in overweight and obese adults to determine its impact on body weight and metabolism. Articles reviewed from PubMed, Ovid MEDLINE, Embase, and Cochrane Central Register for the relevant RCTs that compared TRE (8/16) to non-TRE in overweight and obese adults. Eight RCTs were included in this meta-analysis. Participants following TRE (8/16) showed significant body weight reduction (mean difference [MD]: -1.48 kg, 95% confidence interval [CI]: -2.53 to -0.44) and fat mass reduction (MD: -1.09 kg, 95% CI: -1.55 to -0.63). There was no significant difference in lean mass change with TRE intervention (MD: -0.48 kg, 95% CI: -1.02 to 0.05, p = .08, I 2 = 41%). The energy restriction and early TRE (eTRE) subgroups resulted in greater weight loss. TRE (8/16) showed beneficial effects on the homeostatic model assessment of insulin resistance (HOMA-IR, MD: -0.32, 95% CI: -0.59 to -0.06), but had no significant effect on other parameters of glucose metabolism and lipid profiles. In conclusion, TRE (8/16), especially eTRE, or in combination with caloric intake restriction, is a potential therapeutic strategy for weight control in overweight and obese adults. TRE (8/16) also reduced HOMA-IR; therefore, it may have a positive effect on glucose metabolism.

Effects on the intestinal morphology, inflammatory response and microflora in piglets challenged with enterotoxigenic Escherichia coli K88.

Enterotoxigenic Escherichia coli (ETEC) is an important cause of diarrhea in piglets, which leads to great economic losses. In this study, the ternary crossbred weaned piglets were orally administered with 1.5 × 1011 CFU ETEC K88 for three days. The results showed the ratio of villus length to crypt depth decreased in the duodenum and ileum after ETEC K88 infection. The expression of tight junction proteins ZO-1 in the jejunum and ileum, occludin in the jejunum and colon, and claudin-1 in the colon were down-regulated. The expression of IL-8 in the duodenum and jejunum, IL-13 in the colon, and TNF-α in the jejunum and colon were up-regulated. The expression of pBD1 in the colon, pBD2 in the jejunum, and pBD3 in the duodenum increased after infection. Meanwhile, the expression of TLR4, p38 MAPK and NF-κB p65 increased in all intestinal segments. Moreover, the expression of IL-8 in superficial cervical lymph nodes (SCLN), TNF-α in mesenteric lymph nodes (MLN), and IL-13 in inguinal lymph nodes (ILN) and MLN were up-regulated. The expression of pBD1 and pBD2 in SCLN and MLN, and pBD3 in SCLN were up-regulated. Acidobacteria and Proteobacteria were the most abundant phyla in both groups by analysis of intestinal microflora using 16 s rRNA sequencing, and the relative abundances of bacteria were found to be changed by Metastats software and LEfSe analysis. Our results indicated that cytokines and pBDs had different roles in different intestinal segments or different lymph nodes against ETEC K88, and gut microbiota was influenced after infection.

The influence of perinatal maternal exposure to dibutyl phthalate on glucolipid metabolism in adult female offspring.

BACKGROUND: Maternal exposure to dibutyl phthalate (DBP) may result in obesity in female offspring. However, the underlying mechanisms remain elusive. MATERIALS AND METHODS: Sprague-Dawley rats were intraperitoneally injected with different doses of DBP and corn oil from gestational day 7 until the end of lactation. The weights, visceral fat percentage, serum lipid, insulin and glucose, protein levels of PI3K signal pathway in muscle were detected in F1 female offspring. RESULTS: Although the birth weight of F1 female offspring was not different among groups, the weights were heavier in DBP groups from postnatal day 7 to adult (P < 0.001). The visceral adipose percentage in adult female offspring was increased by perinatal exposure to DBP (P < 0.001). Decreased serum level of triglyceride (P = 0.001) in F1 female offspring was found in DBP group as compared to control, especially in medium and high DBP. However, none difference was found for fasting glucose, prolactin, HOMA-IR, fasting insulin, total cholesterol, adiponectin. Different protein levels of GPR30 were observed in muscle of female offspring among four groups (P = 0.016). The protein level of AKT seemed higher in DBP group but without statistical significance (P = 0.05). None difference was observed for the protein levels of PI3K, p-AKT, pAKT/AKT, PTEN, GLUT4, InsR, IRS. CONCLUSION: Maternal perinatal exposure to DBP might induce obesity and accumulation of visceral adipose tissue for the adult female offspring. Serum glucolipid and local signal transduction of PTEN/PI3K/AKT pathway in muscle were not adversely affected by perinatal exposure to DBP for adult female offspring.

Transcriptome Analysis Reveals the Multiple Functions of pBD2 in IPEC-J2 Cells against E. coli.

Defensins play an important role in fighting bacteria, and are a good candidate for bactericidal agents. However, the function and mechanism of defensins in regulating host responses against bacteria is unclear. In this study, transcriptome analysis was used to study the comprehensive functions of pBD2 in IPEC-J2 cells against E. coli. In total, 230 differentially expressed genes (DEGs) were identified in IPEC-J2 cells between the control and E. coli groups, and were found by KEGG analysis to be involved in many signaling pathways related to immunity. Furthermore, 812 DEGs were observed between E. coli and E. coli +pBD2 groups, involved in the ribosome, oxidative phosphorylation, and certain disease pathways. Among these, 94 overlapping DEGs were in the two DEG groups, and 85 DEGs were reverse expression, which is involved in microRNA in cancer, while PTEN and CDC6 were key genes according to PPI net analysis. The results of qRT-PCR verified those of RNA-seq. The results indicated that pBD2 plays an important role against E. coli by acting on the genes related to immune response, cell cycle, ribosomes, oxidative phosphorylation, etc. The results provide new insights into the potential function and mechanism of pBD2 against E. coli. Meanwhile, this study provides a certain theoretical basis for research and the development of novel peptide drugs.

Systematic Review and Meta-analysis: Changes of Gut Microbiota before and after Menopause.

Objective: To systematically evaluate the differences in intestinal flora before and after menopause. To provide a possible mechanism for perimenopausal syndrome and provide a basis for probiotics as adjuvant therapy. Methods: MEDLINE, EMBASE, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL), CNKI, Wanfang, and VIP databases were searched. The included studies were case-control studies. Results: Three case-control studies were included, with a total of 156 people. At the phylum level, there were no differences between premenopausal and postmenopausal women. At the genus level, the relative abundances of A. odoratum and B. cholerae were higher in postmenopausal women than in premenopausal women, with no differences among other genera. The Shannon diversity index increased after menopause, but no differences were found. Only one study found a positive association of estradiol with Gammaproteobacteria and Myxococcales and a negative association with Prevotellaceae. Conclusions: On the basis of previous studies, it was found that there was no significant difference at the phylum level between postmenopausal women and premenopausal women, but Odoribacter and Bilophila increased at the genus level in postmenopausal women. The class of Gammaproteobacteria may be positively correlated with estradiol. Limited by the number of included studies, more high-quality clinical studies are needed for validation.

Effects of metformin on pregnancy outcome, metabolic profile, and sex hormone levels in women with polycystic ovary syndrome and their offspring: a systematic review and meta-analysis.

Background: Researches of the efficacy and safety of metformin on long-term pregnancy outcomes remains conflicted. We performed an updated systematic review and meta-analysis to systematically investigate the effect of metformin treatment on pregnancy outcome, metabolic profile, and sex hormone characteristics in women with polycystic ovary syndrome (PCOS) and their offspring. Methods: The PubMed, Embase, and Cochrane Library databases were searched from inception to July 10, 2021 with the keywords "metformin", "PCOS", and "pregnancy". Randomized controlled studies reported pregnant related outcomes after metformin intervention among PCOS women were included, while abstracts and reviews were excluded. Two authors independently identified trials, extracted data and assessed risk of bias with Cochrane Reviewer's Handbook 5.0. Random effects models were used to evaluate the pooled risk ratios (RR) and 95% confidence intervals (95% CI) of pregnancy outcome, metabolic profile, and sex hormone levels. Results: Eighteen studies were included. The majority of trials were in medium methodological quality. In terms of pregnancy complications among women with PCOS, metformin treatment was associated with a significantly reduced risk of preterm delivery (RR =0.37, 95% CI: 0.23-0.61), pregnancy-induced hypertension (PIH) and preeclampsia (RR =0.45, 95% CI: 0.24-0.83) and macrosomia (RR =0.26, 95% CI: 0.11-0.64). In terms of offspring, metformin significantly associated with larger head circumference (MD =0.29, 95% CI: 0.13-0.45) and higher long-term body mass index (BMI) measures (MD =0.37, 95% CI: 0.17-0.56). In terms of metabolic profile and sex hormone characteristics, a significant decrease in homeostatic model assessment for insulin resistance (HOMA2-IR) scores was found in mothers (MD =-0.32, 95% CI: -0.63 to -0.02), whereas a significant increase of sex hormone binding globulin (SHBG) levels was detected in offspring (MD =0.33, 95% CI: 0.01-0.65). Discussion: Although the relative low quality of randomized controlled trials (RCTs) and limited results made it difficult to draw a definite conclusion, our study showed that metformin treatment during pregnancy can reduce the risk of pregnancy complications but may have impacts on increasing SHBG levels and long-term BMI in offspring.

Recombinant porcine beta defensin 2 alleviates inflammatory responses induced by Escherichia coli in IPEC-J2 cells.

pBD2 is one of the porcine beta defensins with broad antimicrobial activity, and plays an important role in immune regulation. However, the activities and mechanisms of pBD2 regulating host resistance to Escherichia coli infection are unclear. In this study, the immunomodulatory activity and mechanisms of recombinant pBD2 against Escherichia coli infection were explored in IPEC-J2 cells. Recombinant pBD2 had no obvious effect on the growth of cells below 80 µg/mL, however, it reduced the number of E. coli adhering to cells. Furthermore, pBD2 restored the abnormal expression of ZO-1 and occludin in cells challenged with E. coli. pBD2 treatment also reduced cell apoptosis and decreased the expression of the apoptosis-related genes Cox-2 and Caspase-3, and decreased the expression of the pro-inflammatory IL-6, IL-8, IL-1α and TNF-α, and Cxcl2 and Ccl20. pBD2 also reduced the expression of TAK1, and inhibited the phosphorylation of NF-κB p65 following E. coli infection. In addition, pBD2 was localized in the cytoplasm. Collectively, pBD2 appeared to penetrate cells and alleviate inflammatory responses via the TAK1-NF-κB signaling pathway. Our results revealed the immunomodulatory activity of recombinant pBD2 against E. coli and provided insights into the molecular mechanisms that protected cells from E. coli infection.

Different regimens of menopausal hormone therapy for improving sleep quality: a systematic review and meta-analysis.

IMPORTANCE: Long-term sleep disturbances in menopausal women are closely related to cardiovascular disorders, metabolic disorders, and cognitive impairment. At present, hormone therapy (HT) is a standard treatment for menopausal symptoms. However, it remains unclear whether HT can improve sleep quality. OBJECTIVE: We did a systematic review and meta-analysis to assess the effects of different HT regimens on menopausal sleep quality. EVIDENCE REVIEW: We systematically searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, PsycINFO, CINAHL, and Web of Science for randomized controlled trials of menopausal HT on sleep disturbances up to June 14,2021. Information about ongoing and unpublished trials was collected by searching WHOICTRP and ClinicalTrials.gov. Our primary outcome was sleep quality with objective measurements. We estimated the standardized mean difference (SMD) using random-effects models. FINDINGS: We identified a total of 3,059 studies and finally included 15 studies in the meta-analysis. Compared with placebo, HT improved self-reported sleep outcomes (SMD = -0.13; 95% CI, -0.18 to -0.08, P  < 0.00001 and I2 = 41%), but not sleep parameters measured by polysomnography. Subgroup analyses according to the regimen of HT showed that 17ß-estradiol (17ß-E2) (SMD = -0.34; 95% CI, -0.51 to -0.17, P  < 0.0001, and I2 = 0%) and conjugated equine estrogens (SMD = -0.10; 95% CI, -0.12 to -0.07, P  < 0.00001, and I2 = 0%) improved sleep quality. Moreover, transdermal administration (SMD = -0.35; 95% CI, -0.64 to -0.06, and P  = 0.02) was more beneficial than oral (SMD = -0.10; 95% CI, -0.14 to -0.07, and P  < 0.00001). In addition, the combination of estrogen and progesterone had a positive effect on sleep disturbance (SMD = -0.10; 95% CI, -0.13 to -0.07, P  < 0.00001, and I2 = 0%), while estrogen monotherapy did not. The results showed that estrogen/micronized progesterone (SMD = -0.22; 95% CI, -0.37 to -0.06, P = 0.007, and I2 = 0%) and estrogen/medroxyprogesterone acetate (SMD = -0.10; 95% CI, -0.13 to -0.07, P  < 0.00001, and I2 = 0%) could alleviate sleep disturbance. CONCLUSIONS AND RELEVANCE: HT has a beneficial effect on sleep disturbance to some extent, and the formulations and routes of administration of hormonal agents influence the effect size.

Maternal Perinatal Exposure to Dibutyl Phthalate Promotes Ovarian Dysfunction in Adult Female Offspring via Downregulation of TGF-ß2 and TGF-ß3.

Maternal exposure to dibutyl phthalate (DBP) may result in ovarian dysfunction in female offspring. However, the underlying mechanisms remain elusive. Pregnant Sprague-Dawley rats were intraperitoneally injected with different doses of DBP, estradiol, and corn oil from gestational day 7 until the end of lactation. The reproductive characteristics, mRNA, and protein expression of ovaries for the adult female offspring were compared. KGN cells were cultured in vitro with DBP, estrogen receptor antagonist, or ALK-5 inhibitor. Genes, proteins, estradiol, and progesterone expressed by KGN, cell proliferation, and apoptosis were measured respectively. Maternal perinatal exposure to DBP induced prolonged estrous period, increased secondary follicles, significant decreased mRNA, and protein levels of TGF-ß2, TGF-ß3, and TGF-ßRII in ovaries of the adult female offspring, but none difference for serum levels of sex hormones, ovarian TGF-ß1, and estrogen receptor. The mRNA levels of LHR, FSHR, and CYP19a in ovaries were also decreased. DBP might decrease the mRNA of TGF-ß2, TGF-ß3, and TGF-ßR II of KGN. DBP can inhibit the mRNA of CYP19 at 24 h, which might be blocked by the estrogen receptor antagonist, whose effects were attenuated at 48 h. DBP combined with FSH might time-dependently regulate the gene expression of TGF-ßR II, inhibitory at 24 h, but stimulative at 48 h, which could be blocked by the ALK5 inhibitor. However, the protein expressed by KGN was not influenced by DBP. DBP stimulated the proliferation of KGN at 24 h, which could be blocked by estrogen receptor antagonist, but attenuated at 48 h. The progesterone in culture medium secreted by KGN was decreased by DBP at 24 h. Maternal perinatal exposure to DBP induced decreased gene expression of TGF-ß signaling and functional proteins in ovaries of the adult female offspring. Molecular cross-talk between estrogen receptor and TGF-ß signaling pathway may play role in the mechanism of granulosa dysfunction induced by DBP.

Association of Estrogen Receptor Genes Polymorphisms With Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis Based on Observational Studies.

Purpose: Controversial results existed in amounts of studies investigating the authentic association of estrogen receptor genes (ESR1 and ESR2) polymorphisms with the occurrence and progression of polycystic ovary syndrome (PCOS). The inconsistency might result from different loci, sample sizes, and ethnicities. To find the potential correlations between ESR1/ESR2 polymorphisms and PCOS risk, we conducted the first systematic review and meta-analysis to comprehensively summarize current studies in a large combined population. Methods: Eligible studies were retrieved from PubMed, MEDLINE, EMBASE, Cochrane Library, CBM, CNKI, WANFANG, and VIP up to February 28, 2021. The quality of studies was assessed using the Newcastle-Ottawa Scale (NOS) scoring system. Odds ratios (ORs) and 95% confidence intervals (95%CIs) were calculated to synthesize data in five genetic models. Subgroup analyses were conducted by ethnicity. Heterogeneity and publication bias were also assessed. The protocol was registered in PROSPERO under the number CRD42021239200. Results: A total of 8 studies involving 1,522 PCOS patients and 4,198 controls were included. No evidence demonstrated the association of ESR1 rs2234693 (OR=1.07 95%CI 0.98-1.18), ESR1 rs9340799 (OR=0.99 95%CI 0.69-1.43), or ESR2 rs4986938 (OR=1.06 95%CI 0.81-1.38) polymorphisms and PCOS risk in five genetic models. According to stratified subgroup analyses, ethnicity was considered the major source of heterogeneity. No publication bias was found in eligible studies. Conclusion: The present meta-analysis found no significant associations between the variants of ESR1 rs2234693, ESR1 rs9340799, ESR2 rs4936938, and individual PCOS susceptibility, even if ethnicity was taken into account. Systematic Review Registration: The protocol was registered in PROSPERO (available from https://www.crd.york.ac.uk/PROSPERO) with the ID number CRD42021239200.

Elevated peripheral absolute monocyte count related to clinicopathological features and poor prognosis in solid tumors: Systematic review, meta-analysis, and meta-regression.

BACKGROUND: Absolute monocyte count (AMC) is often used to be assessed in cancer follow-up, which has regained interest as a potential prognostic indicator in many solid tumors, though not consistently or comprehensively. In the present study, we set out to perform a comprehensive meta-analysis of all available data regarding the prognostic significance of AMC in solid tumors. We also evaluated the association between AMC and clinical features in solid tumors. METHODS: A hazard ratio (HR) and corresponding 95% confidence interval (CI) or a p value (p) from eligible studies were extracted and subsequently pooled analyzed. Subgroup analyses and meta-regression analyses were conducted according to the confounders of included studies. In addition, the relationships between AMC and clinical characteristics were also explored in the meta-analysis. RESULTS: Overall, ninety-three articles comprising 104 studies with 32229 patients were finally included. The results showed that elevated AMC was associated with worse overall survival (OS) (HR = 1.615; 95% CI: 1.475-1.768; p < 0.001), disease-free survival (DFS) (HR:1.488; 95% CI: 1.357-1.633; p < 0.001), progressive-free survival (PFS) (HR: 1.533; 95% CI: 1.342-1.751; p < 0.001) and cancer-specific survival (CSS) (HR: 1.585; 95% CI: 1.253-2.006; p < 0.001) in non-hematological tumors. Subgroup analyses according to each confounder further proved the consistent prognostic value of AMC in solid tumor outcomes. Moreover, elevated AMC was more likely to be observed in male group and patients with smoking history, and associated with longer tumor length and advanced T stage. CONCLUSION: In short, the meta-analysis found that elevated AMC might indicate poor long-term outcomes in non-hematologic cancers, thus AMC may be a valuable marker in the prognosis for patients with solid tumors.

Pyrolyzed fabrication of N/P co-doped biochars from (NH4)3PO4-pretreated coffee shells and appraisement for remedying aqueous Cr(VI) contaminants.

In this study, an agricultural residue-derived biochar was fabricated by pyrolyzing coffee shells using (NH4)3PO4 pretreatment. The influence of pyrolysis temperature on the structure and properties of biochars was investigated. The elemental analysis, spectroscopic and textural studies showed that the biochars were endued sufficient N and P co-doping and large specific surface area by (NH4)3PO4-pretreatment. The appraisement for remedying aqueous Cr(VI) contaminants demonstrated that the N/P co-doped biochars offered high efficiencies above 95% for aqueous Cr(VI) removal. The mechanism investigation displayed that the adsorption and reduction of Cr(VI) were boosted by the synergistic effect between the hierarchical pore structure and the groups related to oxygen, nitrogen and phosphorus. Moreover, the biochar can be readily regenerated by HCl solution soaking for reuses several times. This work should permit for providing a convenient utilization of coffee shell agricultural residues, and the coffee shell-derived biochars supplied potential for remedying Cr(VI) in effluents.

Variation of Laparoscopic Ovarian Drilling for Clomiphene Citrate-resistant Patients with Polycystic Ovary Syndrome and Infertility: A Meta-analysis.

OBJECTIVE: To evaluate novel surgical variations of laparoscopic ovarian drilling (LOD) and compare with standard bilateral LOD. DATA SOURCES: Electronic databases were searched, including Cochrane database, CENTRAL, Ovid MEDLINE, Embase, PsycINFO, PubMed, Virtual Health Library, OpenSIGLE, ClinicalTrials.gov, ISRCTN, and The Chinese Clinical Trial Register in February 2019. METHODS OF STUDY SELECTION: Randomized controlled trials (RCTs) evaluating LOD for patients with clomiphene citrate-resistant polycystic ovary syndrome and infertility and reporting reproductive outcomes, surgical complications, serum indexes, menses resumption, and ultrasound results were included. Quality and risk of bias were evaluated by 2 authors, respectively. TABULATION, INTEGRATION, AND RESULTS: A total of 20 RCTs with 1615 patients were included. Evaluation of the quality of evidence for each study was based on each study's limitations of 5 outcome domains described by the Grading of Recommendations, Assessment, Development, and Evaluation and found to be moderate to very low. Live births were only reported by 4 studies. Unilateral LOD did not differ with bilateral LOD in reproductive outcomes, such as pregnancy (p = .11, I2 = 75%), ovulation (p = .08, I2 = 0%), miscarriage (p = .61), and menstruation resumption (p = .06). There was insufficient evidence regarding efficacy and safety of novel methods of LOD, such as transvaginal hydrolaparoscopy (1 RCT) and micro-LOD (3 RCTs). Evidence regarding the suitable number of ovarian punctures, duration of drilling, and antimüllerian hormone or antral follicle numbers following LOD were inconclusive. CONCLUSION: Unilateral LOD seems to be suitable replacement for conventional bilateral LOD for clomiphene citrate-resistant polycystic ovary syndrome, although more studies involving long-term reproductive efficacy, adverse events, and varying forms of LOD are warranted.

Repurposing sertraline sensitizes non-small cell lung cancer cells to erlotinib by inducing autophagy.

Lung cancer patients treated with tyrosine kinase inhibitors (TKIs) often develop resistance. More effective and safe therapeutic agents are urgently needed to overcome TKI resistance. Here, we propose a medical genetics-based approach to identify indications for over 1,000 US Food and Drug Administration-approved (FDA-approved) drugs with high accuracy. We identified a potentially novel indication for an approved antidepressant drug, sertraline, for the treatment of non-small cell lung cancer (NSCLC). We found that sertraline inhibits the viability of NSCLC cells and shows a synergy with erlotinib. Specifically, the cotreatment of sertraline and erlotinib effectively promotes autophagic flux in cells, as indicated by LC3-II accumulation and autolysosome formation. Mechanistic studies further reveal that dual treatment of sertraline and erlotinib reciprocally regulates the AMPK/mTOR pathway in NSCLC cells. The blockade of AMPK activation decreases the anticancer efficacy of either sertraline alone or the combination. Efficacy of this combination regimen is decreased by pharmacological inhibition of autophagy or genetic knockdown of ATG5 or Beclin 1. Importantly, our results suggest that sertraline and erlotinib combination suppress tumor growth and prolong mouse survival in an orthotopic NSCLC mouse model (P = 0.0005). In summary, our medical genetics-based approach facilitates discovery of new anticancer indications for FDA-approved drugs for the treatment of NSCLC.