Establishment and validation of a nomogram model for predicting ovulation in the PCOS women.

BACKGROUND: The mechanisms underlying ovulatory dysfunction in PCOS remain debatable. This study aimed to identify the factors affecting ovulation among PCOS patients based on a large sample-sized randomized control trial. METHODS: Data were obtained from a multi-centered randomized clinical trial, the PCOSAct, which was conducted between 2011 and 2015. Univariate and multivariate analysis using binary logistic regression were used to construct a prediction model and nomogram. The accuracy of the model was assessed using receiver operating characteristic (ROC) curves and calibration curves. RESULTS: The predictive variables included in the training dataset model were luteinizing hormone (LH), free testosterone, body mass index (BMI), period times per year, and clomiphene treatment. The ROC curve for the model in the training dataset was 0.81 (95% CI [0.77, 0.85]), while in the validation dataset, it was 0.7801 (95% CI [0.72, 0.84]). The model showed good discrimination in both the training and validation datasets. Decision curve analysis demonstrated that the nomogram designed for ovulation had clinical utility and superior discriminative ability for predicting ovulation. CONCLUSIONS: The nomogram composed of LH, free testosterone, BMI, period times per year and the application of clomiphene may predict the ovulation among PCOS patients.

Magnetic propelled hydrogel microrobots for actively enhancing the efficiency of lycorine hydrochloride to suppress colorectal cancer.

Research and development in the field of micro/nano-robots have made significant progress in the past, especially in the field of clinical medicine, where further research may lead to many revolutionary achievements. Through the research and experiment of microrobots, a controllable drug delivery system will be realized, which will solve many problems in drug treatment. In this work, we design and study the ability of magnetic-driven hydrogel microrobots to carry Lycorine hydrochloride (LH) to inhibit colorectal cancer (CRC) cells. We have successfully designed a magnetic field driven, biocompatible drug carrying hydrogel microsphere robot with Fe3O4 particles inside, which can achieve magnetic field response, and confirmed that it can transport drug through fluorescence microscope. We have successfully demonstrated the motion mode of hydrogel microrobots driven by a rotating external magnetic field. This driving method allows the microrobots to move in a precise and controllable manner, providing tremendous potential for their use in various applications. Finally, we selected drug LH and loaded it into the hydrogel microrobot for a series of experiments. LH significantly inhibited CRC cells proliferation in a dose- and time-dependent manner. LH inhibited the proliferation, mobility of CRC cells and induced apoptosis. This delivery system can significantly improve the therapeutic effect of drugs on tumors.

Is elevated baseline SHBG associated with increased ovulation?

Sexual hormone binding globulin (SHBG) is associated with the endocrine and reproductive systems. We aimed to investigate the role of SHBG in the reproductive process. Therefore, we conducted a secondary analysis of the PCOSAct (Polycystic Ovary Syndrome and Acupuncture Clinical Trial) study, which involved 21 sites in China and a total of 1000 women with PCOS. Out of these, 954 women with SHBG were included in the analysis. Through multivariate analysis of ovulation predictors, we found that age, BMI, estradiol, testosterone, and SHBG all showed a positive predictive value for ovulation (p = 0.0211, 0.0011, 0.0211, 0.0029, 0.0434, respectively). However, the LH to FSH ratio had a negative predictive value (p = 0.0539). Higher quartiles of SHBG were associated with a higher rate of ovulation, and per quartile increased was statistically significant (HR = 1.138, 95%CI [1.054,1.229]). The association remained significant even after adjusting for testosterone (HR = 1.263, 95%CI [1.059, 1.507]). On the other hand, quartiles of testosterone and estradiol did not exhibit any significant tendency toward ovulation. SHBG demonstrated predictive ability for ovulation, conception, pregnancy, and live birth (p < 0.05), and this correlation remained significant after adjusting intervention. Kaplan-Meier curves illustrated that increased levels of SHBG were a factor in high rates of ovulation, conception, and pregnancy. In comparison to other sexual hormones, a higher baseline level of SHBG was related to increased ovulation.

Acupuncture improves the emotion domain and lipid profiles in women with polycystic ovarian syndrome: a secondary analysis of a randomized clinical trial.

Objective: This study aims to evaluate the effect of acupuncture on the emotion domain and metabolic parameters of Chinese women with polycystic ovarian syndrome (PCOS) by secondary analysis of a randomized clinical trial, conducted from 6 July 2012 to 7 October 2015. Method: In this study, we investigated the effects of acupuncture (458 patients) and sham acupuncture (468 patients) on metabolic parameters, serum ions, and all quality-of-life scale scores related to PCOS. The quality of life of patients was evaluated using five relevant scales, operated by the research assistant, namely, PCOSQ, SF-36, and ChiQOL, as well as Zung-SAS and Zung-SDS. Metabolic parameters and serum ions were measured. Results: A reduction in acne score, AN, Hcy, and LDL-C, and an increase in the level of lipoprotein α, Apo A1, and Apo A1/Apo B were observed in the acupuncture group after 4 months' intervention after adjusting clomiphene and reproductive outcome (p< 0.05). An increase in SF-36 total scores, RP and RE scores, ChiQOL total scores, and emotion domain scores was observed in the acupuncture group after 4 months' intervention, while PF and HT scores were decreased (adjusted p< 0.05). Those same changes were observed in sham acupuncture. Meanwhile, the serum levels of Ca, K, and Cl were elevated in the acupuncture group after the interventions (adjusted p< 0.005). There were no significant differences in HOMA-IR, MetS, FPG, FINS, HDL-C, TG, Apo B, and level of serum P, Mg, and Na. Also, no changes in BP, GH, VT, SF, physical form domain, and spirit domain were observed after treatment. Conclusion: Acupuncture can improve not only the emotional changes in SF-36 scores and ChiQOL scores, but also lipid metabolism, implying that it may have a correlation between emotional change and lipid metabolism. Furthermore, acupuncture can also regulate the changes of serum Ca, K, and Cl. Clinical trial registration: ClinicalTrials.gov, identifier NCT01573858.

Exercise-induced irisin improves follicular dysfunction by inhibiting IRE1α-TXNIP/ROS-NLRP3 pathway in PCOS.

BACKGROUND: Excessive production of androgen drives oxidative stress (OS) and inflammasome activation in ovarian granulosa cells (GCs). Therefore, the induced follicular developmental disorder is the major cause of infertility in women with polycystic ovary syndrome (PCOS). Exercise-induced upregulation of irisin is capable of regulating metabolism by reducing OS and inflammation. Exercise has been shown to alleviate a range of PCOS symptoms, including maintaining a normal menstrual cycle, in several clinical trials. METHODS: Female Sprague-Dawley (SD) rats and primary ovarian cells were treated with two different androgens, dehydroepiandrosterone (DHEA) and dihydrotestosterone (DHT), to simulate a hyperandrogenic environment, followed by eight weeks of exercise training and irisin intervention. The levels of reactive oxygen species (ROS), tissue inflammation and fibrosis were examined using hematoxylin and eosin (H&E) staining, western blot, quantitative real-time PCR (qRT-PCR), dichlorofluorescein diacetate (DCF-DA) probe detection, immunofluorescence staining, immunohistochemistry, and Sirius red staining. RESULTS: Exercise for eight weeks improved polycystic ovarian morphology and decreased the levels of inflammation, OS, and fibrosis in PCOS rats. Hyperandrogen increased ROS production in ovarian cells by inducing endoplasmic reticulum stress (ERS) and activating the inositol-requiring enzyme 1α (IRE1α)-thioredoxin-interacting protein (TXNIP)/ROS-NOD-like receptor family pyrin domain containing 3 (NLRP3) signaling pathway, further enhancing the levels of inflammation. Irisin suppressed the expression of IRE1α and its downstream targets, thus improving the ovarian dysfunction of PCOS rats induced by hyperandrogen. CONCLUSION: Exercise can alleviate various phenotypes of PCOS rats induced by DHEA, and its therapeutic effect may be mediated by secreting beneficial myokines. IRE1α may be an important target of irisin for reducing OS and inflammation, thereby improving ovarian fibrosis.

Exosomal circRNAs as promising liquid biopsy biomarkers for glioma.

Liquid biopsy strategies enable the noninvasive detection of changes in the levels of circulating biomarkers in body fluid samples, providing an opportunity to diagnose, dynamically monitor, and treat a range of diseases, including cancers. Glioma is among the most common forms of intracranial malignancy, and affected patients exhibit poor prognostic outcomes. As such, diagnosing and treating this disease in its early stages is critical for optimal patient outcomes. Exosomal circular RNAs (circRNAs) are involved in both the onset and progression of glioma. Both the roles of exosomes and methods for their detection have received much attention in recent years and the detection of exosomal circRNAs by liquid biopsy has significant potential for monitoring dynamic changes in glioma. The present review provides an overview of the circulating liquid biopsy biomarkers associated with this cancer type and the potential application of exosomal circRNAs as tools to guide the diagnosis, treatment, and prognostic evaluation of glioma patients during disease progression.

HSP90AB1 as the Druggable Target of Maggot Extract Reverses Cisplatin Resistance in Ovarian Cancer.

Cisplatin resistance is a crucial factor affecting ovarian cancer patient's survival rate, but the primary mechanism underlying cisplatin resistance in ovarian cancer remains unclear, and this prevents the optimal use of cisplatin therapy. Maggot extract (ME) is used in traditional Chinese medicine for patients with comas and patients with gastric cancer when combined with other drug treatments. In this study, we investigated whether ME enhances the sensitivity of ovarian cancer cells to cisplatin. Two ovarian cancer cells-A2780/CDDP and SKOV3/CDDP-were treated with cisplatin and ME in vitro. SKOV3/CDDP cells that stably expressed luciferase were subcutaneously or intraperitoneally injected into BALB/c nude mice to establish a xenograft model, and this was followed by ME/cisplatin treatment. In the presence of cisplatin, ME treatment effectively suppressed the growth and metastasis of cisplatin-resistant ovarian cancer in vivo and in vitro. RNA-sequencing data showed that HSP90AB1 and IGF1R were markedly increased in A2780/CDDP cells. ME treatment markedly decreased the expression of HSP90AB1 and IGF1R, thereby increasing the expression of the proapoptotic proteins p-p53, BAX, and p-H2AX, while the opposite effects were observed for the antiapoptotic protein BCL2. Inhibition of HSP90 ATPase was more beneficial against ovarian cancer in the presence of ME treatment. In turn, HSP90AB1 overexpression effectively inhibited the effect of ME in promoting the increased expression of apoptotic proteins and DNA damage response proteins in SKOV3/CDDP cells. Inhibition of cisplatin-induced apoptosis and DNA damage by HSP90AB1 overexpression confers chemoresistance in ovarian cancer. ME can enhance the sensitivity of ovarian cancer cells to cisplatin toxicity by inhibiting HSP90AB1/IGF1R interactions, and this might represent a novel target for overcoming cisplatin resistance in ovarian cancer chemotherapy.

Integrative multi-omics analysis depicts the methylome and hydroxymethylome in recurrent bladder cancers and identifies biomarkers for predicting PD-L1 expression.

BACKGROUND: Urinary bladder cancer (UBC) is a common malignancy of the urinary tract; however, the mechanism underlying its high recurrence and responses to immunotherapy remains unclear, making clinical outcome predictions difficult. Epigenetic alterations, especially DNA methylation, play important roles in bladder cancer development and are increasingly being investigated as biomarkers for diagnostic or prognostic predictions. However, little is known about hydroxymethylation since previous studies based on bisulfite-sequencing approaches could not differentiate between 5mC and 5hmC signals, resulting in entangled methylation results. METHODS: Tissue samples of bladder cancer patients who underwent laparoscopic radical cystectomy (LRC), partial cystectomy (PC), or transurethral resection of bladder tumor (TURBT) were collected. We utilized a multi-omics approach to analyze both primary and recurrent bladder cancer samples. By integrating various techniques including RNA sequencing, oxidative reduced-representation bisulfite sequencing (oxRRBS), reduced-representation bisulfite sequencing (RRBS), and whole exome sequencing, a comprehensive analysis of the genome, transcriptome, methylome, and hydroxymethylome landscape of these cancers was possible. RESULTS: By whole exome sequencing, we identified driver mutations involved in the development of UBC, including those in FGFR3, KDMTA, and KDMT2C. However, few of these driver mutations were associated with the down-regulation of programmed death-ligand 1 (PD-L1) or recurrence in UBC. By integrating RRBS and oxRRBS data, we identified fatty acid oxidation-related genes significantly enriched in 5hmC-associated transcription alterations in recurrent bladder cancers. We also observed a series of 5mC hypo differentially methylated regions (DMRs) in the gene body of NFATC1, which is highly involved in T-cell immune responses in bladder cancer samples with high expression of PD-L1. Since 5mC and 5hmC alternations are globally anti-correlated, RRBS-seq-based markers that combine the 5mC and 5hmC signals, attenuate cancer-related signals, and therefore, are not optimal as clinical biomarkers. CONCLUSIONS: By multi-omics profiling of UBC samples, we showed that epigenetic alternations are more involved compared to genetic mutations in the PD-L1 regulation and recurrence of UBC. As proof of principle, we demonstrated that the combined measurement of 5mC and 5hmC levels by the bisulfite-based method compromises the prediction accuracy of epigenetic biomarkers.

Protective effects of electroacupuncture on polycystic ovary syndrome in rats: Down-regulating Alas2 to inhibit apoptosis, oxidative stress, and mitochondrial dysfunction in ovarian granulosa cells.

Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder affecting women at reproductive age. The therapeutic effect of electroacupuncture (EA) on PCOS has been revealed, while the anti-PCOS mechanisms of EA have not been fully explored. In this study, PCOS were induced in rats by daily injection with dehydroepiandrosterone (DHEA) for 20 days and EA treatment was performed for 5 weeks. The mRNA expression profiles in ovarian tissues from control, PCOS, and EA-treated rats were examined by high-throughput mRNA sequencing. 5'-aminolevulinate synthase 2 (Alas2), a vital rate-limiting enzyme of the heme synthesis pathway, was selected to be further studied. PCOS led to the upregulation of Alas2 mRNA, whereas EA treatment restored this change. In vitro, primary ovarian granulosa cells (GCs) were challenged with H2O2 to mimic the oxidative stress (OS) state in PCOS. H2O2 induced apoptosis, OS, mitochondrial dysfunction, as well as Alas2 overexpression in GCs, while lentivirus-mediated Alas2 knockdown evidently restrained the above impairments. In summary, this study highlights the crucial role of Alas2 in cell apoptosis, OS, and mitochondrial dysfunction of PCOS GCs and provides potential therapeutic candidates for further investigation on PCOS treatment.

Thymoma-associated autoimmune encephalitis: Analysis of factors determining prognosis.

INTRODUCTION: Autoimmune encephalitis (AE) is a heterogeneous group of inflammatory central nervous system disorders caused by a misdirected immune response against self-antigens expressed in the central nervous system. The thymus is a central organ in the immune system and thymic tumors are thought to be possible initiators of many neurological disorders. Recently, there is growing evidence that thymomas are associated with autoimmune encephalitis. AIMS: Our study initially explored the characteristics of patients with autoimmune encephalitis combined with thymoma. METHODS: We used patient data from January 1, 2011 to October 1, 2021 from the PubMed, Web of Science, Ovid, and CNKI platforms to analyze overall demographics, frequency of symptoms and associations, and treatment prognosis outcomes. RESULTS: A total of 68 patients were included. There were 39 female cases (57.4%). The mean age was 50 years (IQR 40-66 years). All had acute and subacute onset. The clinical manifestations were mostly cognitive changes (70.6%), mental disorders (57.4%), and epilepsy (50.0%). The most common neuronal antibody was alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA). Magnetic resonance imaging (MRI) abnormalities were present in 81.0% of patients, mostly in the hippocampus, temporal lobe, and some in cortical and subcortical areas. Abnormalities in the electroencephalogram (EEG) in 69.8% of patients. Treatment involved immunotherapy and thymoma treatment, with 79.7% of patients improving after treatment. While 20.3% of patients had a poor prognosis. Further, 14.8% of patients relapsed. Mental disorders, autonomic dysfunction, sleep disturbances, anti-Ma2, and thymoma untreated were more frequent in patients with poor prognosis. CONCLUSION: Thymoma-associated autoimmune encephalitis is a unique disease entity. Long-term follow-up of chest CT findings is recommended for patients with autoimmune encephalitis.

Exosomal circTUBGCP4 promotes vascular endothelial cell tipping and colorectal cancer metastasis by activating Akt signaling pathway.

BACKGROUND: Exosome is crucial mediator and play an important role in tumor angiogenesis. Tip cell formation is a prerequisite for persistent tumor angiogenesis which causes tumor metastasis. However, the functions and underlying mechanisms of tumor cell-derived exosomes in angiogenesis and tip cell formation remain less understood. METHODS: Exosomes derived from serum of colorectal cancer (CRC) patients with metastasis/non-metastasis and CRC cells were isolated by ultracentrifugation. CircRNAs in these exosomes were analyzed by circRNA microarray. Then, exosomal circTUBGCP4 was identified and verified by quantitative real-time PCR (qRT-PCR) and in situ hybridization (ISH). Loss- and gain-of-function assays were performed to explore the effect of exosomal circTUBGCP4 on vascular endothelial cell tipping and colorectal cancer metastasis in vitro and in vivo. Mechanically, bioinformatics analysis, biotin-labeled circTUBGCP4/ miR-146b-3p RNA pulldown, RNA immunoprecipitation (RIP), and luciferase reporter assay were used to confirm the interaction among circTUBGCP4, miR-146b-3p, and PDK2. RESULTS: Here, we showed that exosomes derived from CRC cells enhanced vascular endothelial cell migration and tube formation via inducing filopodia formation and endothelial cell tipping. We further screened the upregulated circTUBGCP4 in serum of CRC patients with metastasis compared to non-metastasis. Silencing circTUBGCP4 expression in CRC cell-derived exosomes (CRC-CDEs) inhibited endothelial cell migration, tube formation, tip cell formation, and CRC metastasis. Overexpression of circTUBGCP4 had opposite results in vitro and in vivo. Mechanically, circTUBGCP4 upregulated PDK2 to activate Akt signaling pathway by sponging miR-146b-3p. Moreover, we found that miR-146b-3p could be a key regulator for vascular endothelial cell dysfunction. Exosomal circTUBGCP4 promoted tip cell formation and activated the Akt signaling pathway by inhibiting miR-146b-3p. CONCLUSIONS: Our results suggest that colorectal cancer cells generate exosomal circTUBGCP4, which causes vascular endothelial cell tipping to promote angiogenesis and tumor metastasis by activating Akt signaling pathway.

The efficacy and mechanism of acupuncture in the treatment of male infertility: A literature review.

Fertility, a social, cultural, and medical issue, has aroused public attention because of its potential to predict future health. In recent years, the incidence of male infertility has increased significantly, and various risk factors, such as congenital factors, acquired factors, and idiopathic factors, have led to this situation. Male infertility causes substantial psychological and social distress in patients. With the implementation of the two-child policy, male infertility has brought enormous psychological and social pressure and huge economic burden to patients and the healthcare system. This has attracted the attention of not only men of childbearing age but also many male experts. The conventional therapeutic approaches for treating male infertility, including drugs, varicocele surgery, intrauterine insemination, in vitro fertilization, and intracytoplasmic sperm injection, can restore fertility to a certain extent, but their efficacy is far from satisfactory, not to mention some adverse events. Therefore, acupuncture has been chosen by many men to treat their infertility and produced significant effects. In the present paper, the efficacy and mechanism of acupuncture in the treatment of male infertility were analyzed from different perspectives such as regulating hormone secretion, reducing inflammation, and improving semen parameters. The existing literature shows that acupuncture can effectively treat male infertility.

Maggot Extract Inhibits Cell Migration and Tumor Growth by Targeting HSP90AB1 in Ovarian Cancer.

Ovarian cancer is one of the most lethal gynecological malignancies, because of metastatic dissemination with poor late clinical therapy. Maggots have been used in traditional Chinese medicine, where they are also known as 'Wu Gu Chong'. Previous studies have indicated that maggot extract (ME) was beneficial for the treatment of gastric cancer when combined with other drugs, but the effect on anti-ovarian cancer and the underlying mechanism remains unclear. The aim of this study was to investigate the effects of ME on suppressing the proliferation and migration of ovarian cancer cells, and to clarify the underlying mechanism. In this research, Cell Counting Kit-8 (CCK-8), colony formation assay, and luciferase-positive cell quantification assay were employed to identify the inhibitory effects of ME on cell proliferation. Then, the pro-apoptosis and anti-metastasis effects of ME were explored by Western blot, dual annexin V-fluorescein isothiocyanate/propidium iodide (FITC/PI) assay, immunofluorescent staining, and wound-healing assay. We further established a xenograft model by subcutaneously or intraperitoneally injecting BALB/c nude mice with SKOV3 cells stably expressing luciferase, and the mice were treated with ME. The results showed that ME therapy effectively restrained the growth and metastasis of ovarian tumors in vivo. Furthermore, the mRNA levels of cancer factors including heat shock protein 90 alpha family class B member 1 (HSP90AB1), MYC, and insulin like growth factor 1 receptor (IGF1R) were analyzed by quantitative real-time PCR assay to explore the possible antitumor mechanisms of ME. Next, HSP90 ATPase activity was inhibited by geldanamycin in A2780, and the cell viability was shown to be dramatically reduced, decreasing further with the combination of ME and cisplatin. In turn, HSP90AB1 overexpression effectively inhibited the effect of ME in suppressing capability for cell viability and migration. In addition, HSP90AB1 overexpression limited the ability of ME to inhibit expression of MYC and IGF1R, while the opposite effect was observed for expression of pro-apoptosis protein caspase3 and BAX. Therefore, this study confirmed the potential roles and mechanisms of ME in inhibiting the growth and metastasis of ovarian tumors and promoting apoptosis of ovarian cancer cells by inhibiting overexpression of HSP90AB1.

Therapeutic effect and safety of curcumin in women with PCOS: A systematic review and meta-analysis.

Background: Polycystic ovary syndrome (PCOS) is a multi-factorial heterogeneous syndrome that has both adverse reproductive and metabolic implications for affected women and its management is a challenging clinical problem. Curcumin, as a phenolic compound with potent anti-inflammatory and antioxidant properties exerting positive effects on the lipid profile and insulin resistance, appears to be a valuable treatment regimen for patients with PCOS. Objective: This study aimed to evaluate the efficacy and safety of curcumin in the treatment of PCOS. Methods: Chinese databases (Chinese National Knowledge Infrastructure, China Biology Medicine Databases, VIP database, Wanfang Database, and Chinese Clinical Trial Registry) and English databases (PubMed, Web of Science, Embase, Cochrane Library, Scopus and Clinical trials) were thoroughly investigated through screening randomized controlled trials on curcumin in PCOS published from the date of inception to May 2022. Standardized data search and abstraction were conducted following the preferred reporting items for systematic reviews and meta-analysis (PRISMA) statement. Quantitative and qualitative analyses were performed. Heterogeneity was assessed using I2 statistics. Results: A total of 447 patients from seven randomized controlled trials were included in the meta-analysis. Results showed that the ingestion of curcumin decreased body mass index (WMD -0.267, 95% CI -0.450 to -0.084, P = 0.004, I2 = 0.0%), fasting plasma glucose (WMD -3.618, 95% CI -5.165 to -2.071, P < 0.001, I2 = 20.4%), insulin (WMD -1.834, 95% CI -2.701 to -0.968, P < 0.001, I2 = 8.4%), homeostatic model assessment for insulin resistance (WMD -0.565, 95% CI -0.779 to -0.351, P < 0.001, I2 = 0.0%), total cholesterol (WMD -15.591, 95% CI -27.908 to -3.273, P = 0.013, I2 = 68.9%), C-reactive protein (WMD -0.785, 95% CI -1.553 to -0.017, P = 0.045, I2 = 23.9%), and increased the quantitative insulin sensitivity check index (WMD 0.011, 95% CI 0.005 to 0.017, P = 0.001, I2 = 39.6%). As for safety, the treatment group did not cause significant adverse reactions than that in the control group. Conclusion: In light of presented findings, curcumin has beneficial effects on serum markers of inflammation, weight loss and glucose and lipid metabolism in patients with PCOS. The incidence of adverse reactions does not increase with the application of curcumin. However, a larger, more definitive study is needed to further investigate these results. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42022332394.

Association between preconception serum lipid concentrations and treatment outcomes in women with PCOS who underwent ovulation induction.

RESEARCH QUESTION: What is the association between preconception serum lipid concentrations and reproductive outcomes after ovulation induction in women with polycystic ovary syndrome (PCOS)? DESIGN: A secondary analysis of a randomized controlled trial with 1000 PCOS women undergoing ovulation induction with clomiphene with or without acupuncture. Preconception serum total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides, apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB) were measured. Outcomes were ovulation, conception, pregnancy, live birth and miscarriage. Logistic regression was used to calculate odds ratios (OR) with 95% confidence intervals (CI). RESULTS: In total, 780 women ovulated; 320 women achieved conception, 218 had a clinical pregnancy, 205 had a live birth and 115 had a miscarriage. Serum lipid concentrations per one unit increment were independently associated with reproductive outcomes after controlling for confounders. Increasing LDL-C (OR 0.79, 95% CI 0.63-0.99) was independently associated with a lower chance of ovulation. Increasing total cholesterol (OR 0.76, 95% CI 0.62-0.92), LDL-C (OR 0.73, 95% CI 0.57-0.93), triglycerides (OR 0.74, 95% CI 0.58-0.95) and ApoB (OR 0.34, 95% CI 0.16-0.74) were independently associated with a lower chance of clinical pregnancy. Increased total cholesterol (OR 0.78, 95% CI 0.64-0.96), LDL-C (OR 0.77, 95% CI 0.60-0.99), triglycerides (OR 0.76, 95% CI 0.59-0.96) and ApoB (OR 0.39, 95% CI 0.18-0.86) were independently associated with a lower chance of live birth. Furthermore, increased total cholesterol (OR 1.43, 95% CI 1.06-1.93), LDL-C (OR 1.51, 95% CI 1.04-2.19) and ApoB (OR 3.82, 95% CI 1.17-12.41) were independently associated with a higher chance of miscarriage. CONCLUSIONS: Increased serum lipids were negatively associated with the reproductive outcomes of PCOS women undergoing ovulation induction with clomiphene with or without acupuncture.

RNA methylation-mediated LINC01559 suppresses colorectal cancer progression by regulating the miR-106b-5p/PTEN axis.

Long noncoding RNAs (lncRNAs) regulate multiple biological effects in cancers. Recently, RNA methylation has been found to modify not only coding RNAs but also some noncoding RNAs. How RNA methylation affects lncRNAs to affect colorectal cancer (CRC) progression remains elusive. The expression of LINC01559 was explored through RNA sequencing, quantitative real-time PCR (qRT-PCR) and in situ hybridization (ISH). The preliminary exploration of its function was performed using Western blotting (WB) and immunohistochemistry (IHC). Functional experiments in vitro and in vivo were conducted to explore the biological functions of LINC01559 in CRC. The LINC01559/miR-106-5p/PTEN axis was verified through fluorescence in situ hybridization (FISH), luciferase assays, and rescue experiments. RIP-sequencing, m6A RNA immunoprecipitation (MeRIP) assays and bioinformatic analysis were conducted to determine the upstream mechanism of LINC01559. The results showed that LINC01559 was downregulated in CRC compared with normal controls. Lower expression of LINC01559 in CRC patients predicted a poor prognosis. In addition, PTEN was found to be positively correlated with LINC01559, and miR-106b-5p could be the link between LINC01559 and PTEN. Then, silencing LINC01559 restored the malignant phenotype of CRC cells, while cotransfection of miR-106b-5p inhibitor neutralized this effect. Mechanistically, we found abundant m6A modification sites on LINC01559. Then, we uncovered these sites as potential targets of METTL3 through experiments in vivo. The results revealed a negative functional regulation of the LINC01559/miR-106b-5p/PTEN axis in CRC progression and explored a new mechanism of METTL3-mediated m6A modification on LINC01559. These results elucidate a novel potential therapeutic target for CRC treatment.

Effect of Low-Frequency Electro-Acupuncture in Unmarried Women With Polycystic Ovary Syndrome: A Randomized Controlled Study.

Objectives: We aimed to evaluate the effect of low-frequency electro-acupuncture (EA) in unmarried women with polycystic ovary syndrome (PCOS). Design: A total of 54 women with PCOS were randomly assigned to either the acupuncture group (n=27) or the sham acupuncture group (control, n=27) for a total of 32 treatments over 16 weeks. In the acupuncture group 26 patients and in the control group 20 patients completed the trial. Outcome Measures: Main measures were androgen levels including 17-α-hydroxyprogesterone (17-α-OHP), androstenedione (A2), testosterone (T) and dehydroepiandrosterone (DHEA) at 0, 24 and 48 hours after stimulation with a dose of human chorionic gonadotropin (HCG). Other measures included body mass index, waist-to-hip ratio, sex hormone levels, etc. Results: After treatment, there was no significant difference in the main measures between the 2 groups (P > .05), except for the DHEA level at 0 h of HCG stimulation (P = .024) and acne score (P < .05). Comparison within the acupuncture group found that 17-α-OHP and A2 levels at 0 h and DHEA levels at 24 h of HCG stimulation after treatment were significantly decreased (P < .05), whereas T levels at 24 h were significantly increased (P < .05). Comparison within the control group showed 17-α-OHP level at 0 h and 17-α-OHP and A2 and DHEA levels at 24 h after treatment were significantly lower (P < .05). In addition, weight, BMI, HCG and Ferriman-Gallwey score in the acupuncture group and LH/FSH ratio was significantly reduced in the control group. Conclusion: Traditional EA is slightly more effective than sham acupuncture in reducing DHEA secretion and the acne score. Meanwhile, sham acupuncture is not completely ineffective. The specific mechanism of the two may be different.

Suppression of uterine and placental ferroptosis by N-acetylcysteine in a rat model of polycystic ovary syndrome.

The mechanisms that link hyperandrogenism and insulin (INS) resistance (HAIR) to the increased miscarriage rate in women with polycystic ovary syndrome (PCOS) remain elusive. Previous studies demonstrate that increased uterine and placental ferroptosis is associated with oxidative stress-induced fetal loss in a pre-clinical PCOS-like rat model. Here, we investigated the efficacy and molecular mechanism of action of the antioxidant N-acetylcysteine (NAC) in reversing gravid uterine and placental ferroptosis in pregnant rats exposed to 5α-dihydrotestosterone (DHT) and INS. Molecular and histological analyses showed that NAC attenuated DHT and INS-induced uterine ferroptosis, including dose-dependent increases in anti-ferroptosis gene content. Changes in other molecular factors after NAC treatment were also observed in the placenta exposed to DHT and INS, such as increased glutathione peroxidase 4 protein level. Furthermore, increased apoptosis-inducing factor mitochondria-associated 2 mRNA expression was seen in the placenta but not in the uterus. Additionally, NAC was not sufficient to rescue DHT + INS-induced mitochondria-morphological abnormalities in the uterus, whereas the same treatment partially reversed such abnormalities in the placenta. Finally, we demonstrated that NAC selectively normalized uterine leukemia inhibitory factor, osteopontin/secreted phosphoprotein 1, progesterone receptor, homeobox A11 mRNA expression and placental estrogen-related receptor beta and trophoblast-specific protein alpha mRNA expression. Collectively, our data provide insight into how NAC exerts beneficial effects on differentially attenuating gravid uterine and placental ferroptosis in a PCOS-like rat model with fetal loss. These results indicate that exogenous administration of NAC represents a potential therapeutic strategy in the treatment of HAIR-induced uterine and placental dysfunction.

m6A Modification in Non-Coding RNA: The Role in Cancer Drug Resistance.

Cancer drug resistance has always been a major difficulty in cancer therapy. In the face of drug pressure, resistant cancer cells show complex molecular mechanisms including epigenetic changes to maintain survival. Studies prove that cancer cells exhibit abnormal m6A modification after acquiring drug resistance. m6A modification in the target RNA including non-coding RNA can be a controller to determine the fate and metabolism of RNA by regulating their stability, subcellular localization, or translation. In particular, m6A-modified non-coding RNA plays multiple roles in multiple drug-resistant cancer cells, which can be a target for cancer drug resistance. Here, we provide an overview of the complex regulatory mechanisms of m6A-modified non-coding RNA in cancer drug resistance, and we discuss its potential value and challenges in clinical applications.

Associations of Serum Magnesium With Insulin Resistance and Testosterone in Women With Polycystic Ovary Syndrome.

Objective: This article aimed to investigate whether serum magnesium is associated with insulin resistance index and testosterone level in women with polycystic ovary syndrome (PCOS). Materials and Methods: Overall 1000 women with PCOS were enrolled in a randomized controlled trial and a cross-sectional analysis of the association of serum magnesium with glucose metabolism markers and testosterone was performed. Serum magnesium, glucose metabolism markers and testosterone were measured. Insulin resistance was evaluated by homeostatic model assessment of insulin resistance (HOMA-IR) and quantitative insulin-sensitivity check index (QUICKI). Multivariable linear regression and logistic regression models were used to estimate the association between serum magnesium, insulin resistance and testosterone. Results: In comparative analyses, women with higher quartile of serum magnesium had significantly lower fasting glucose, HOMA-IR and testosterone. Multiple linear regression showed serum magnesium was independently negatively associated with insulin, glucose, HOMA-IR, testosterone and positively associated with QUICKI (P for trend <0.05) after adjusting confounding covariates. Logistic regression showed serum magnesium in quartile 1 and 2 were independently associated with insulin resistance status (Quartile 1: OR: 2.15, 95%CI: 1.35-3.40, P = 0.001; Quartile 2: OR: 1.90, 95%CI: 1.20-3.02, P = 0.006), while quartile 1 was marginally associated with hyperandrogenemia status (Quartile 1: OR: 1.45, 95%CI: 0.99-2.11, P = 0.055) after adjusting confounding covariates. Conclusion: The current findings suggest that lower serum magnesium was associated with aggravated insulin resistance and higher testosterone levels among women with PCOS.