Distinct molecular targets of ProEGCG from EGCG and superior inhibition of angiogenesis signaling pathways for treatment of endometriosis

Endometriosis is a common chronic gynecological disease with endometrial cell implantation outside the uterus.Angiogenesis is a major pathophysiology in endometriosis.Our previous studies have demonstrated that the prodrug of epigallocatechin gallate(ProEGCG)exhibits superior anti-endometriotic and anti-angiogenic effects compared to epigallocatechin gallate(EGCG).However,their direct binding targets and underlying mechanisms for the differential effects remain unknown.In this study,we demonstrated that oral ProEGCG can be effective in preventing and treating endometriosis.Additionally,1D and 2D Proteome Integral Solubility Alteration assay-based chemical proteomics identified metadherin(MTDH)and PX domain containing serine/threonine kinase-like(PXK)as novel binding targets of EGCG and ProEGCG,respectively.Computational simulation and BioLayer interferometry were used to confirm their binding affinity.Our results showed that MTDH-EGCG inhibited protein kinase B(Akt)-mediated angiogenesis,while PXK-ProEGCG inhibited epidermal growth factor(EGF)-mediated angiogenesis via the EGF/hypoxia-inducible factor(HIF-1a)/vascular endothelial growth factor(VEGF)pathway.In vitro and in vivo knockdown assays and microvascular network imaging further confirmed the involvement of these signaling pathways.Moreover,our study demonstrated that ProEGCG has superior therapeutic effects than EGCG by targeting distinct signal transduction pathways and may act as a novel antiangiogenic therapy for endometriosis.

Comparison of Transvaginal Ultrasound, Saline Infusion Sonohysterography versus Diagnostic Hysteroscopy in Evaluation of Endometrial Cavity Pathology amongst Women with Abnormal Uterine Bleeding in Low Resource Setting

Introduction: Hysteroscopy is currently the gold-standard protocol for evaluating patients with abnormal uterine bleeding (AUB). Unfortunately, though accurate, its adoption in low-resource countries such as in Africa is limited due to lack of equipment and qualified personnel. As such, there is a need for an alternative diagnostic procedure that is as accurate as hysteroscopy, but also affordable, easy to administer, and acceptable by women with endometrial pathologies. Transvaginal Sonography (TVS) and Saline Infusion Sonohysterography (SIS) are proposed. However, their diagnostic accuracy versus hysteroscopy has not been determined in low resource setting. Objective: To compare the diagnostic efficacy of TVS and SIS versus diagnostic hysteroscopy in evaluation of endometrial pathology among pre-menopausal and post-menopausal women and to determine the etiology of AUB amongst these women. Methodology: A prospective cohort study was done at a hospital in Nairobi, Kenya between May and September 2019. Forty patients with AUB were recruited using consecutive sampling, and women who consented were recruited. The etiology of AUB was recorded. All participants underwent TVS, SIS and Diagnostic Hysteroscopy (DH) evaluation in the first half of the menstrual cycle and the findings recorded on a patient’s information sheet. The sociodemographic and bleeding characteristics of patients and the outcomes of TVS, SIS, and DH evaluations were also recorded and the data was analysed using version 5 of the Software for Statistics and Data Science (STATA). Summary statistics on the etiology of AUB were presented and the sensitivity of TVS and SIS versus DH as the gold-standard evaluated using two by two tables and the ROC curve. Results: The mean age of participants was 38.1 ± 8.8 years, range of 25 - 71 years. Heavy Menstrual Bleeding (HMB) was reported in 70.0% of participants, while about 12.0%, 7.5%, and 7.5% had post-menopausal bleeding, amenorrhea, and hypomenorrhea. The incidence of submucosal fibroids and endometrial polyps was 17.5% and 15.0% via TVS, 47.5% and 20.0% via SIS and 52.5% and 20% via DH respectively. The overall sensitivity, specificity, Positive Predictive Value (PPV), Positive Predictive Value (NPV), and diagnostic accuracy of SIS were 92.1%, 83.3%, 96.9%, 62.5%, and 90.0% while TVS was 38.2%, 100%, 100%, 22.2%, and 47.5%. The sensitivity, specificity, PPV, and NPV of TVS in diagnosis of endometrial polyp were 75.0%, 100%, 100%, and 94.0%. SIS did better with a sensitivity, specificity, PPV, and NPV of 100%, 100%, 100%, and 100%. Conclusion: Our data suggests SIS had a higher diagnostic accuracy than TVS and showcased a comparable diagnostic accuracy to hysteroscopy. SIS is more suitable safe alternative technique for investigating AUB in pre/post-menopausal women in low resource setting where hysteroscopy is unavailable or unaffordable.

生育和不育男性精液维生素B_(12)、叶酸、活性氧和精子质量的比较

为了探讨精液维生素 B1 2 (VB1 2 )、叶酸和活性氧 (ROS)对精子质量和生殖功能的影响。收集成年男性不育者 44名 (不育组 )和经证实配偶已怀孕的健康成年男性 176名 (生育组 )的精液 ,根据 WHO推荐方法检测精子质量指标 ,并测定精液 VB1 2 、叶酸和 ROS水平。结果显示二组 VB1 2 和叶酸没有显著性差异 (P>0 .0 5 ) ,不育组 ROS和形态异常精子都显著高于生育组 (P<0 .0 1) ,ROS与精子形态异常呈正相关 (P<0 .0 1) ,VB1 2 和叶酸与 ROS均呈负相关 (P<0 .0 1)。结论认为精液 ROS升高 ,可能促使精子形态异常 ,从而影响男性生殖功能。

Biology and pathology of the uterine micro environ merit and its natural killer cells

Tissues are the new frontier of discoveries in immunology.Cells of the immune system are an integral part of tissue physiology and immunity.Determining how immune cells inhabit,housekeep,and defend gut,lung,brain,liver,uterus,and other organs helps revealing the intimate details of tissue physiology and may offer new therapeutic targets to treat pathologies.The uterine microenvironment modulates the development and function of innate lymphoid cells[ILC,largely represented by natural killer(NK)cells],macrophages,T cells,and dendritic cells.These immune cells,in turn,contribute to tissue homeostasis.Regulated by ovarian hormones,the human uterine mucosa(endometrium)undergoes ~400 monthly cycles of breakdown and regeneration from menarche to menopause,with its fibroblasts,glands,blood vessels,and immune cells remodeling the tissue into the transient decidua.Even more transformative changes occur upon blastocyst implantation.Before the placenta is formed,the endometrial glands feed the embryo by histiotrophic nutrition while the uterine spiral arteries are stripped of their endothelial layer and smooth muscle actin.This arterial remodeling is carried out by invading fetal trophoblast and maternal immune cells,chiefly uterine NK(uNK)cells,which also assist fetal growth.The tran sformed arteries no Ion ger resp ond to mater nal stimuli and meet the increasi ng dema nds of the growing fetus.This review focuses on how the everchanging uterine microenvironment affects uNK cells and how uNK cells regulate homeostasis of the decidua,placenta development,and fetal growth.Determining these pathways will help understand the causes of major pregnancy complications.

Transdermal delivery of interleukin-12 gene targeting dendritic cells enhances the anti-tumour effect of programmed cell death protein 1 monoclonal antibody

Recent studies have suggested that the anti-tumour effect of the programmed cell death protein 1 monoclonal antibody(aPD-1)depends on the expression of interleukin-12(IL-12)by dendritic cells(DCs).Since DCs are abundant in skin tissues,transdermal delivery of IL-12 targeting DCs may significantly improve the anti-tumour effect of aPD-1.In this study,a novel mannosylated chitosan(MC)-modified ethosome(Eth-MC)was obtained through electrostatic adsorption.The Eth-MC loaded with plasmid containing the IL-12 gene(pIL-12@Eth-MC)stimulated DCs to express mature-related molecular markers such as CD86,CD80,and major histocompatibility complex-II in a targeted manner.The pIL-12@Eth-MC was then mixed with polyvinyl pyrrolidone solution to make microspheres using the electrospray technique,and sprayed onto the surface of electrospun silk fibroin-polyvinyl alcohol nanofibres to obtain a PVP-pIL-12@Eth-MC/silk fibroin-polyvinyl alcohol composite nanofibrous patch(termed a transcutaneous immunization(TCI)patch).The TCI patch showed a good performance on transdermal drug release.Animal experiments on melanoma-bearing mice showed that topical application of the TCI patches promoted the expression of IL-12 and inhibited the growth of tumour.Furthermore,combined application of the TCI patch and aPD-1 showed a stronger anti-tumour effect than aPD-1 monotherapy.The combination therapy significantly promoted the expression of IL-12,interferon-γand tumour necrosis factor-α,the infiltration of CD4+and CD8+T cells into tumour tissues,and thus promoted the apoptosis of tumour cells.The present study provides a convenient and non-invasive strategy for improving the efficacy of immune checkpoint inhibitor therapy.This study was approved by the Institutional Animal Care and Use Committee at Donghua University(approval No.DHUEC-NSFC-2020-11)on March 31,2020.

Why the Silent Pandemic of Stillbirths Following COVID-19?

The world is in the midst of a major health crisis as coronavirus disease 2019(COVID-19)continues to spread at an alarming rate and claim an ever-increasing number of lives.Some countries are experiencing their fifth or sixth waves of COVID-19 transmission,with no end to this situation in the foreseeable future.1 The COVID-19 pandemic has affected every segment of the population.The effects of COVID-19 on pregnant women and adolescents as well as geriatric,child,and even mental health have been reported.2s However,there have been few studies of the im.pact on the health and wellbeing of the unborn fetus.While direct effects on abortion,preterm delivery,premature rupture of membranes,preeclampsia,and fetal growth restriction have been described,4 indirect effects on fetal health are less evident but far more disturbing and damaging.

Comparative efficacy of ChatGPT 3.5,ChatGPT 4,and other large language models in gynecology and infertility research

Dear Editor,As experts in gynecology and infertility research,we have witnessed the rapid advancement of artificial intelligence(Al)technologies,particularly language models,which have greatly improved their capabilities.In this communication,we aim to compare the proficiency of advanced language models,such as Chat Generative Pre-Trained Transformer(ChatGPT)3.5,ChatGPT 4,and others,in relation to our field.

Retinal Vascular Imaging Application in Women’s Reproductive Health:Clinical Implications and Future Directions

Over the past two decades,population-based studies employing semiautomatic computer-assisted programs have uncovered associations between retinal microvascular features and various systemic conditions.As the recognition of retinal imaging in cardiometabolic health grows,there is increasing evidence supporting its application in women’s health,particularly during the reproductive age.This review aims to summarize the indications of retinal imaging in women’s health and intergenerational health,where suboptimal retinal imaging has been found to mirror pathological systemic changes,such as suboptimal hemodynamic circulation,inflammation,endothelial dysfunction,oxidative stress,and hypoxia in vivo.Findings from Singapore Growing Up in Singapore Towards Healthy Outcomes and Singapore Preconception Study of Long-Term Maternal and Child Outcomes cohorts have reported serial changes in retinal conventional microvascular features(e.g.,retinal arteriolar narrowing,retinal venular widening)and retinal geometric microvascular features(e.g.,sparse fractal dimension,enlarged branching angle,and increased curvature tortuosity)during the preconception and antenatal phases.These morphological abnormalities were found to be related to female fertility,maternal antenatal health conditions,postnatal maternal cardiometabolic health,and intergenerational health in the fetus.Given the compelling evidence of the ability to detect microvascular changes through noninvasive methods at an early stage,retinal imaging holds the potential to facilitate timely interventions,mitigate the progression of complications,and prevent adverse pregnancy outcomes.Looking ahead,the convergence of artificial intelligence and advanced imaging techniques heralds a promising era in women’s health research and clinical practice.

Laparoscopic metroplasty for bicorporeal uterus: surgical techniques and outcomes

The incidence of congenital uterine anomalies(CUA)appears to be higher than previously thought owing to improved diagnostic imaging modalities.[1]A recent systematic review has estimated the prevalence to be 5.5%in the unselected population,8.0%in infertile women,and 13.3%in those with a history of miscarriage.The commonest anomaly across all populations appear to be the septate variety(ie,canalization defects)followed by the bicornuate variety(ie,fusion defects).[2]Another meta-analysis has shown that several adverse reproductive outcomes associated with CUA,such as increased miscarriage rates,increased preterm delivery rates,and increased perinatal mortality rates.[3]

Free bisphenol A(BPA),BPA-Glucuronide(BPA-G),and total BPA concentrations in maternal serum and urine during pregnancy and umbilical cord blood at delivery

While adult exposure to total bisphenol A(BPA)has been well documented,developmental exposure to BPA and fetal exposure to the bioactive form(free BPA)remains poorly defined.Therefore,pregnant women(n?199)between 28 and 35 weeks of pregnancy were invited to participate in this study.Maternal serum free of hemolysis(n?189)and urine(n?112)were collected at third trimester and delivery along with umbilical cord blood(UCB)at delivery.Free BPA,BPA mono-glucuronide(BPA-G)and total BPA concentrations were measured using gas chromatography coupled with tandem mass spectrometry.Circulating concentrations of free BPA were quantifiable above the method detection limit(MDL?0.026 ng/mL)in approximately 34%of serum samples in the third trimester and 21%of samples at delivery whereas BPA-G and total BPA were quantified in 43 and 70%of third trimester and delivery samples,respectively.The geometric mean of free BPA,BPA-G and total BPA concentrations in maternal serum during the third trimester and at delivery were 0.62 ng/L and<MDL,0.09 and 0.28 ng/mL,and 0.24 and 0.31 ng/mL,respectively.Geometric mean urinary concentrations of free BPA,BPA-G,and total BPA(MDL?0.027 ng/mL)in the third trimester and delivery samples were 0.07 and 0.06 ng/mL,0.36 and 0.09 ng/mL,and 0.36 and 0.09 ng/mL,respectively.In the UCB,the geometric means for free BPA,BPA-G,and total BPA concentrations were 0.05,0.08 and 0.10 ng/mL,respectively.Our results suggest that,in our study population,free BPA concentrations were low compared to other Canadian cohorts.

Variations in killer-cell immunoglobulin-like receptor and human leukocyte antigen genes and immunity to malaria

Malaria is one of the deadliest infectious diseases in the world. Immune responses to Plasmodium falciparum malaria vary among individuals and between populations. Human genetic variation in immune system genes is likely to play a role in this heterogeneity. Natural killer (NK) cells produce inflammatory cytokines in response to malaria infection, kill intraerythrocytic Plasmodium falciparum parasites by cytolysis, and participate in the initiation and development of adaptive immune responses to plasmodial infection. These functions are modulated by interactions between killer-cell immunoglobulin-like receptors (KIRs) and human leukocyte antigens (HLAs). Therefore, variations in KIR and HLA genes can have a direct impact on NK cell functions. Understanding the role of KIRs and HLAs in immunity to malaria can help to better characterize antimalarial immune responses. In this review, we summarize the different KIRs and HLAs associated with immunity to malaria thus far.