Identification and Potential Clinical Utility of Common Genetic Variants in Gestational Diabetes among Chinese Pregnant Women.

Background: The genetic basis for hyperglycaemia in pregnancy remain unclear. This study aimed to uncover the genetic determinants of gestational diabetes mellitus (GDM) and investigate their applications. Methods: We performed a meta-analysis of genome-wide association studies (GWAS) for GDM in Chinese women (464 cases and 1,217 controls), followed by de novo replications in an independent Chinese cohort (564 cases and 572 controls) and in silico replication in European (12,332 cases and 131,109 controls) and multi-ethnic populations (5,485 cases and 347,856 controls). A polygenic risk score (PRS) was derived based on the identified variants. Results: Using the genome-wide scan and candidate gene approaches, we identified four susceptibility loci for GDM. These included three previously reported loci for GDM and type 2 diabetes mellitus (T2DM) at MTNR1B (rs7945617, odds ratio [OR], 1.64; 95% confidence interval [CI],1.38 to 1.96]), CDKAL1 (rs7754840, OR, 1.33; 95% CI, 1.13 to 1.58), and INS-IGF2-KCNQ1 (rs2237897, OR, 1.48; 95% CI, 1.23 to 1.79), as well as a novel genome-wide significant locus near TBR1-SLC4A10 (rs117781972, OR, 2.05; 95% CI, 1.61 to 2.62; Pmeta=7.6×10-9), which has not been previously reported in GWAS for T2DM or glycaemic traits. Moreover, we found that women with a high PRS (top quintile) had over threefold (95% CI, 2.30 to 4.09; Pmeta=3.1×10-14) and 71% (95% CI, 1.08 to 2.71; P=0.0220) higher risk for GDM and abnormal glucose tolerance post-pregnancy, respectively, compared to other individuals. Conclusion: Our results indicate that the genetic architecture of glucose metabolism exhibits both similarities and differences between the pregnant and non-pregnant states. Integrating genetic information can facilitate identification of pregnant women at a higher risk of developing GDM or later diabetes.

Microbiota-targeted interventions and clinical implications for maternal-offspring health: An umbrella review of systematic reviews and meta-analyses of randomised controlled trials.

Background: Microbes in the human body are the determinants of life-long health and disease. Microbiome acquisition starts in utero and matures during early childhood through breastfeeding. However, maternal gut dysbiosis affects the maternal-offspring microbiome interplay. Lines of evidence on dysbiosis-targeted interventions and their effect on maternal-offspring health and gut microbiome are inconsistent and inconclusive. Therefore, this study summarised studies to identify the most common microbiota-targeted intervention during pregnancy and lactation and to comprehensively evaluate its effects on maternal and offspring health. Methods: This umbrella review was conducted by systematically searching databases such as PubMed and the Web of Science from inception to 2 September 2023. The quality was assessed using the Assessment of Multiple Systematic Reviews-2 checklist. The Grading of Recommendations Assessment, Development, and Evaluation was used for grading the strength and certainty of the studies. The overlap of primary studies was quantified by the corrected covered area score. Results: A total of 17 systematic reviews and meta-analyses with 219 randomised controlled trials, 39 113 mothers, and 20 915 infants were included in this study. About 88% of studies had moderate and above certainty of evidence. Probiotics were the most common and effective interventions at reducing gestational diabetes risk (fasting blood glucose with the mean difference (MD) = -2.92, -0.05; I2 = 45, 98.97), fasting serum insulin (MD = -2.3, -2.06; I2 = 45, 77), glycated haemoglobin (Hb A1c) = -0.16; I2 = 0.00)), Homeostatic Model Assessment of insulin resistance (HOMA-IR) (MD = -20.55, -0.16; I2 = 0.00, 72.00), and lipid metabolism (MD = -5.47, 0.98; I2 = 0.00, 90.65). It was also effective in preventing and treating mastitis (risk ratio (RR) = 0.49; I2 = 2.00), relieving anxiety symptoms (MD = -0.99, 0.01; I2 = 0.00, 70.00), depression in lactation (MD = -0.46, -0.22; I2 = 0.00, 74.00) and reducing recto-vaginal bacterial colonisation (odds ratio (OR) = 0.62; I2 = 4.80), and with no adverse events. It also effectively remodelled the infant gut microbiome (MD = 0.89; I2 = 95.01) and prevented infant allergies. However, studies on pregnancy outcomes and preeclampsia incidences are limited. Conclusions: Our findings from high-quality studies identify that probiotics are the most common microbiome interventions during pregnancy and lactation. Probiotics have a strong impact on maternal and offspring health through maintaining gut microbiome homeostasis. However, further studies are needed on the effect of microbiota-targeted interventions on maternal cardiometabolic health, pregnancy, and neonatal outcomes. Registration: This umbrella review was registered with PROSPERO, CRD42023437098.

Zishen Qingre Lishi Huayu Recipe May Ameliorate the Symptoms of PCOS Model Rats via Alleviating Systemic and Ovarian Inflammation.

BACKGROUND: Zishen Qingre Lishi Huayu recipe (ZQLHR) has shown significant therapeutic effects in treating sex hormone levels and follicular developmental disorders in patients with polycystic ovary syndrome (PCOS). However, little is known about the potential mechanisms of its treatment. METHODS: Dehydroepiandrosterone and a high-fat diet induced the PCOS model rat. The serum of rats was collected to detect the levels of sex hormones and inflammatory cytokines by enzyme-linked immunosorbent assay, and the ovaries were collected for ovarian histopathology and qPCR assay to detect the levels of inflammatory cytokines in ovarian tissues. Granulosa cells (GCs) were collected for western blot assay to detect of IL-1ß, IL-6R, and LOX protein expression levels. RESULTS: ZQLHR could reduce body weight, regulate estrous cycles, and improve serum sex hormone levels, follicular development, and insulin resistance (IR) in PCOS model rats. In addition, ZQLHR treatment improved the levels of inflammatory cytokines in serum and ovary, and regulated the protein expression of IL-6R, IL-1ß, and LOX in GCs of PCOS model rats. The results showed that the HOMA-IR index increased with the increasing levels of IL-6, IL-1ß, and CRP, and decreased with the increased IL-10. CONCLUSION: This study reveals that the treatment of endocrine disorders and ovulation disorders in PCOS with ZQLHR may be closely related to the improvement of systemic and ovarian inflammation in PCOS patients, as well as the inhibition of IL-6R, IL-1ß, and LOX expression in GCs, which reemphasizes the role of reducing chronic inflammatory states in the treatment of PCOS. Moreover, this study reemphasizes the correlation between multiple inflammatory mediators and IR.

Proteomics approach to discovering non-invasive diagnostic biomarkers and understanding the pathogenesis of endometriosis: a systematic review and meta-analysis.

BACKGROUND: Endometriosis is one of the most common gynaecological diseases, yet it lacks efficient biomarkers for early detection and unravels disease mechanisms. Proteomic profiling has revealed diverse patterns of protein changes in various clinical samples. Integrating and systematically analysing proteomics data can facilitate the development of biomarkers, expediting diagnosis and providing insights for potential clinical and therapeutic applications. Hence, this systematic review and meta-analysis aimed to explore potential non-invasive diagnostic biomarkers in various biological samples and therapeutic targets for endometriosis. METHODS: Online databases, including Scopus, PubMed, Web of Science, MEDLINE, Embase via Ovid, and Google Scholar, were searched using MeSH terms. Two independent authors screened the articles, extracted the data, and assessed the methodological quality of the included studies. GO and KEGG analyses were performed to identify the pathways that were significantly enriched. Protein­protein interaction and hub gene selection analyses were also conducted to identify biomarker networks for endometriosis. RESULTS: Twenty-six observational studies with a total of 2,486 participants were included. A total of 644 differentially expressed proteins (180 upregulated and 464 downregulated) were identified from 9 studies. Proteins in peripheral blood exhibited a sensitivity and specificity of 38-100% and 59-99%, respectively, for detecting endometriosis, while proteins in urine had a sensitivity of 58-91% and specificity of 76-93%. Alpha-1-antitrypsin, albumin, and vitamin D binding proteins were significantly DEPs in both serum and urine. Complement C3 is commonly expressed in serum, menstrual blood, and cervical mucus. Additionally, S100-A8 is commonly expressed in both menstrual blood and cervical mucus. Haptoglobin is commonly detected in both serum and plasma, whereas cathepsin G is found in urine, serum, and plasma. GO and KEGG enrichment analyses revealed that proteoglycans in cancer pathways, which regulate cell-to-cell interactions, modulate the extracellular matrix, and promote the proliferation and invasion of endometrial cells, are commonly enriched in serum and urine. CONCLUSION: This comprehensive study revealed potential proteomes that were significantly differentially expressed in women with endometriosis utilizing various non-invasive clinical samples. Exploring common differentially expressed proteins in various biological samples provides insights into the diagnosis and pathophysiology of endometriosis, as well as potential clinical and therapeutic applications.

Preventive effect of prenatal maternal oral probiotic supplementation on neonatal jaundice (POPS Study): A protocol for the randomised double-blind placebo-controlled clinical trial.

INTRODUCTION: Neonatal jaundice is a common and life-threatening health problem in neonates due to overaccumulation of circulating unconjugated bilirubin. Gut flora has a potential influence on bilirubin metabolism. The infant gut microbiome is commonly copied from the maternal gut. During pregnancy, due to changes in dietary habits, hormones and body weight, maternal gut dysbiosis is common, which can be stabilised by probiotics supplementation. However, whether probiotic supplements can reach the baby through the mother and reduce the incidence of neonatal jaundice has not been studied yet. Therefore, we aim to evaluate the effect of prenatal maternal probiotic supplementation on the incidence of neonatal jaundice. METHODS AND ANALYSIS: This is a randomised double-blind placebo-controlled clinical trial among 94 pregnant women (47 in each group) in a tertiary hospital in Hong Kong. Voluntary eligible participants will be recruited between 28 and 35 weeks of gestation. Computer-generated randomisation and allocation to either the intervention or control group will be carried out. Participants will take either one sachet of Vivomixx (450 billion colony-forming units per sachet) or a placebo per day until 1 week post partum. Neither the study participants nor researchers will know the randomisation and allocation. The intervention will be initiated at 36 weeks of gestation. Neonatal bilirubin level will be measured to determine the primary outcome (hyperbilirubinaemia) while the metagenomic microbiome profile of breast milk and maternal and infant stool samples as well as pregnancy outcomes will be secondary outcomes. Binary logistic and linear regressions will be carried out to assess the association of the microbiome data with different clinical outcomes. ETHICS AND DISSEMINATION: Ethics approval is obtained from the Joint CUHK-NTEC Clinical Research Ethics Committee, Hong Kong (CREC Ref: 2023.100-T). Findings will be published in peer-reviewed journals and presented at international conferences. TRIAL REGISTRATION NUMBER: NCT06087874.

Lycopene Protects against Atrazine-Induced Kidney STING-Dependent PANoptosis through Stabilizing mtDNA via Interaction with Sam50/PHB1.

Atrazine (ATR) is a widely used herbicide worldwide that can cause kidney damage in humans and animals by accumulation in water and soil. Lycopene (LYC), a carotenoid with numerous biological activities, plays an important role in kidney protection due to its potent antioxidant and anti-inflammatory effects. The current study sought to investigate the role of interactions between mtDNA and the cGAS-STING signaling pathway in LYC mitigating PANoptosis and inflammation in kidneys induced by ATR exposure. In our research, 350 mice were orally administered LYC (5 mg/kg BW/day) and ATR (50 or 200 mg/kg BW/day) for 21 days. Our results reveal that ATR exposure induces a decrease in mtDNA stability, resulting in the release of mtDNA into the cytoplasm through the mPTP pore and the BAX pore and the mobilization of the cGAS-STING pathway, thereby inducing renal PANoptosis and inflammation. LYC can inhibit the above changes caused by ATR. In conclusion, LYC inhibited ATR exposure-induced histopathological changes, renal PANoptosis, and inflammation by inhibiting the cGAS-STING pathway. Our results demonstrate the positive role of LYC in ATR-induced renal injury and provide a new therapeutic target for treating renal diseases in the clinic.

Establishment of an Experimental Mouse Model of Endometrioma to Study its Related Infertility.

Endometrioma (OMA), a subtype of endometriosis characterized by the formation of endometriotic cysts in the ovaries, affects 17-44% of individuals diagnosed with endometriosis. Women with OMA often experience compromised fertility, yet the exact mechanisms underlying OMA-associated infertility remain unclear. Notably, existing animal models simulate superficial peritoneal endometriosis (SUP) and deep infiltrating endometriosis (DIE), leaving a notable gap in research focused on OMA. In response to the gap of knowledge, this paper introduces a pioneering OMA-simulating mouse model and provides a comprehensive description of the techniques and procedures employed in the model. With a high success rate of 83% and ovarian lesion specificity, this model holds significant promise for advancing our understanding of OMA, particularly in the context of infertility. It offers a valuable platform for conducting targeted research into OMA-associated fertility challenges, potentially paving the way for improved diagnostic and therapeutic strategies in the field of reproductive medicine.

The Nrf2/ARE pathway as a potential target to ameliorate atrazine-induced endocrine disruption in granulosa cells.

Atrazine (ATR) is widely used worldwide as a commercial herbicide, Diaminochlorotriazine (DACT) is the main metabolite of ATR in the organism. Both of them disrupt the production of steroids and induce abnormal reproductive development. The granulosa cells (GCs) are important for growth and reproduction of animals. However, the toxicity of ATR on the GCs of birds is not well clarified. To evaluate the effect of the environmental pollutant ATR on bird GCs. The quail GCs were allotted into 7 groups, C (The medium of M199), A20 (20 µM ATR), A100 (100 µM ATR), A250 (250 µM ATR), D20 (20 µM DACT), D100 (100 µM DACT) and D200 (200 µM DACT). The results demonstrated that ATR reduced the viability of GCs, disrupted mitochondrial structure (including mitochondrial cristae fragmentation and the mitochondrial morphology disappearance) and decreased mitochondrial membrane potential. Meanwhile, ATR interfered with the expression of key factors in the steroid synthesis pathway, inducing the secretion of the sex hormones E2 and P in GCs. which in turn induced apoptosis. Furthermore, the Nrf2/ARE pathway as a potential target to ameliorate ATR-induced endocrine disruption in GCs for proper reproductive functions. Our research provides a new perspective for understanding the effects of ATR on reproductive functions in birds.

Thrombospondin-1 Regulates Trophoblast Necroptosis via NEDD4-Mediated Ubiquitination of TAK1 in Preeclampsia.

Preeclampsia (PE) is considered as a disease of placental origin. However, the specific mechanism of placental abnormalities remains elusive. This study identified thrombospondin-1 (THBS1) is downregulated in preeclamptic placentae and negatively correlated with blood pressure. Functional studies show that THBS1 knockdown inhibits proliferation, migration, and invasion and increases the cycle arrest and apoptosis rate of HTR8/SVneo cells. Importantly, THBS1 silencing induces necroptosis in HTR8/SVneo cells, accompanied by the release of damage-associated molecular patterns (DAMPs). Necroptosis inhibitors necrostatin-1 and GSK'872 restore the trophoblast survival while pan-caspase inhibitor Z-VAD-FMK has no effect. Mechanistically, the results show that THBS1 interacts with transforming growth factor B-activated kinase 1 (TAK1), which is a central modulator of necroptosis quiescence and affects its stability. Moreover, THBS1 silencing up-regulates the expression of neuronal precursor cell-expressed developmentally down-regulated 4 (NEDD4), which acts as an E3 ligase of TAK1 and catalyzes K48-linked ubiquitination of TAK1 in HTR8/SVneo cells. Besides, THBS1 attenuates PE phenotypes and improves the placental necroptosis in vivo. Taken together, the down-regulation of THBS1 destabilizes TAK1 by activating NEDD4-mediated, K48-linked TAK1 ubiquitination and promotes necroptosis and DAMPs release in trophoblast cells, thus participating in the pathogenesis of PE.

Cycasin derivative: a potential embryotoxic component of Atractylodes macrocephala rhizome for limb malformation.

Objective: The rhizome of Atractylodes macrocephala Koidz. (Asteraceae), called Atractylodes macrocephala rhizome (AMR) and known by its traditional name Bai Zhu, is a prominent Chinese herbal medicine employed for preventing miscarriage. However, our previous study revealed that high dosages of AMR administered during pregnancy could cause embryotoxicity but the specific embryotoxic components and their underlying mechanisms remain unclear. This study aimed to screen and identify the potential embryotoxic components of AMR. Methods: The AMR extracts and sub-fractions were analyzed by thin layer chromatography and subsequently screened by in vitro mouse limb bud micromass and mouse whole embryo culture bioassays. The embryotoxic fractions from AMR were further evaluated in vivo using a pregnant mouse model. The structures of the potential embryotoxic components were analyzed using matrix-assisted laser desorption/ionization tandem time-of-flight mass spectrometry (MALDI-TOF/TOF-MS). Results: In vitro and in vivo bioassays revealed that AMR glycoside-enriched sub-fractions (AMR-A-IIa and AMR-A-IIb) exhibited potential embryotoxicity. These sub-fractions, when administered to pregnant animals, increased the incidence of stillbirth and congenital limb malformations. MS spectrometry analysis identified cycasin derivatives in both sub-fractions, suggesting their possible role in the observed limb malformations. However, further experiments are necessary to validate this hypothesis and to elucidate the underlying mechanisms. Conclusions: Our study provides significant scientific evidence on the pharmacotoxicity of AMR, which is important for the safe clinical application of commonly used Chinese herbal medicines during pregnancy.

Aspirin versus metformin in pregnancies at high risk of preterm pre-eclampsia in China (AVERT): protocol for a multicentre, double-blind, 3-arm randomised controlled trial.

INTRODUCTION: Pre-eclampsia (PE) affects about 5% of Chinese pregnant women and is a major cause of maternal and perinatal morbidity and mortality. The first trimester screening model developed by the Fetal Medicine Foundation, which uses the Bayes theorem to combine maternal characteristics and medical history together with measurements of biomarkers, has been proven to be effective and has superior screening performance to that of the traditional risk factor-based approach for the prediction of PE. Prophylactic use of low-dose aspirin in women at risk for PE has resulted in a lower incidence of preterm-PE. However, there is no consensus on the preferred aspirin dosage for the prevention of preterm-PE. Evidence has also suggested that metformin has the potential benefit in preventing PE in pregnant women who are at high risk of the disorder. METHOD AND ANALYSIS: We present a protocol (V.2.0, date 17 March 2022) for the AVERT trial, which is a multicentre, double-blinded, 3-arm randomised controlled trial (RCT) that uses an effective PE screening programme to explore the optimal dosage of aspirin and the role of metformin for the prevention of PE among high-risk pregnant women in China. We intend to recruit 66 000 singleton pregnancies without treatment of low-dose aspirin and metformin at 11-13 weeks' gestation and all eligible women attending for their first trimester routine scan will be invited to undergo screening for preterm-PE by the combination of maternal factors, mean arterial pressure and placental growth factor. Women found to be at high risk of developing preterm-PE will be invited to take part in the RCT. This study will compare the incidence of preterm-PE with delivery at <37 weeks' gestation, as the primary outcome, of three different interventional groups: (1) aspirin 75 mg daily, (2) aspirin 150 mg daily and (3) aspirin 75 mg with metformin 1.5 g daily. 957 participants per treatment group are required to detect a significant difference of 59% in the reduction of the incidence of preterm-PE with 80% power and type I error of 5%. Pregnancy and neonatal outcomes will be collected and analysed. ETHICS AND DISSEMINATION: Ethical approval for the study was obtained from the Joint Chinese University of Hong Kong-New Territories East Cluster Clinical Research Ethics Committee (CREC Ref. No. 2021.406) in Hong Kong and the Ethics Committee of each participating hospital in Mainland China. The study is registered at ClinicalTrials.gov. The results of the AVERT trial will be disseminated at international academic conferences and published in high-impact factor journals. TRIAL REGISTRATION NUMBER: NCT05580523.

Cryptochrome 1 regulates ovarian granulosa cell senescence through NCOA4-mediated ferritinophagy.

Age-associated decreases in follicle number and oocyte quality result in a decline in female fertility, which is associated with increased infertility. Granulosa cells play a major role in oocyte development and maturation both in vivo and in vitro. However, it is unclear whether a reduction in cryptochrome 1 (Cry1) expression contributes to granulosa cell senescence, and further exploration is needed to understand the underlying mechanisms. In this study, we investigated the role of Cry1, a core component of the molecular circadian clock, in the regulation of senescence in ovarian granulosa cells. Western blotting and qRT-PCR showed that Cry1 expression was downregulated in aged human ovarian granulosa cells and was correlated with age and anti-Müllerian hormone (AMH) levels. RNA-seq analysis suggested that ferritinophagy was increased after Cry1 knockdown in KGN cells. MDA, iron, and reactive oxygen species (ROS) assays were used to detect cellular ferritinophagy levels. Ferroptosis inhibitors, iron chelators, autophagy inhibitors, and nuclear receptor coactivator 4 (NCOA4) knockdown alleviated KGN cell senescence induced by Cry1 knockdown. Immunofluorescence, immunoprecipitation, and ubiquitination assays indicated that Cry1 affected NCOA4 ubiquitination and degradation through HERC2, thereby affecting NCOA4-mediated ferritinophagy and causing granulosa cell senescence. KL201, a Cry1 stabilizer, enhanced ovarian function in naturally aged mice by reducing ferritinophagy. Our study reveals the potential mechanisms of action of Cry1 during ovarian aging and provides new insights for the clinical treatment of age-related fertility decline.

Isolation of myeloid-derived suppressor cells (MDSC) from endometriotic mice model and their immunomodulatory functions.

Endometriosis is a chronic, painful disease whose etiology remains unknown. The development of novel therapies and diagnostic tools for endometriosis has been limited due in part to challenges in studying the disease. Recently, a few reports have shown that immunosuppressive cells, such as myeloid-derived suppressor cell (MDSC), may promote the progression of endometriosis. MDSCs are a heterogeneous group of myeloid cells with potent immunosuppressive and angiogenic properties. Here, in this chapter, we provide a detailed protocol to phenotype MDSC as well as to isolate and assess the functionality from the peritoneal cavity of a mouse model of surgically induced endometriosis. Importantly, the current mouse model has been widely used to study how the immune system, hormones, and environmental factors affect endometriosis as well as the effects of endometriosis on fertility and pain.

Amelioration of Functional, Metabolic, and Morphological Deterioration in the Retina following Retinal Detachment by Green Tea Extract.

Retinal detachment (RD) can result in the loss of photoreceptors that cause vision impairment and potential blindness. This study explores the protective effects of the oral administration of green tea extract (GTE) in a rat model of RD. Various doses of GTE or epigallocatechin gallate (EGCG), the most active ingredient in green tea catechins, were administered to Sprague Dawley (SD) rats with experimentally induced retinal detachment. The rats received sub-retinal injections of hyaluronic acid (0.1%) to induce RD and were given different doses of GTE and EGCG twice daily for three days. Notably, a low dose of GTE (142.9 mg/kg) caused significantly higher signal amplitudes in electroretinograms (ERGs) compared to higher GTE doses and any doses of EGCG. After administration of a low dose of GTE, the outer nuclear layer thickness, following normalization, of the detached retina reduced to 82.4 ± 8.2% (Mean ± SEM, p < 0.05) of the thickness by RD treatment. This thickness was similar to non-RD conditions, at 83.5 ± 4.7% (Mean ± SEM) of the thickness following RD treatment. In addition, the number of TUNEL-positive cells decreased from 76.7 ± 7.4 to 4.7 ± 1.02 (Mean ± SEM, p < 0.0001). This reduction was associated with the inhibition of apoptosis through decreased sphingomyelin levels and mitigation of oxidative stress shown by a lowered protein carbonyl level, which may involve suppression of HIF-1α pathways. Furthermore, GTE showed anti-inflammatory effects by reducing inflammatory cytokines and increasing resolving cytokines. In conclusion, low-dose GTE, but not EGCG, significantly alleviated RD-induced apoptosis, oxidative stress, inflammation, and energy insufficiency within a short period and without affecting energy metabolism. These findings suggest the potential of low-dose GTE as a protective agent for the retina in RD.

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.

Interplay of Ferroptosis and Cuproptosis in Cancer: Dissecting Metal-Driven Mechanisms for Therapeutic Potentials.

Iron (Fe) and copper (Cu), essential transition metals, play pivotal roles in various cellular processes critical to cancer biology, including cell proliferation, mitochondrial respiration, distant metastases, and oxidative stress. The emergence of ferroptosis and cuproptosis as distinct forms of non-apoptotic cell death has heightened their significance, particularly in connection with these metal ions. While initially studied separately, recent evidence underscores the interdependence of ferroptosis and cuproptosis. Studies reveal a link between mitochondrial copper accumulation and ferroptosis induction. This interconnected relationship presents a promising strategy, especially for addressing refractory cancers marked by drug tolerance. Harnessing the toxicity of iron and copper in clinical settings becomes crucial. Simultaneous targeting of ferroptosis and cuproptosis, exemplified by the combination of sorafenib and elesclomol-Cu, represents an intriguing approach. Strategies targeting mitochondria further enhance the precision of these approaches, providing hope for improving treatment outcomes of drug-resistant cancers. Moreover, the combination of iron chelators and copper-lowering agents with established therapeutic modalities exhibits a synergy that holds promise for the augmentation of anti-tumor efficacy in various malignancies. This review elaborates on the complex interplay between ferroptosis and cuproptosis, including their underlying mechanisms, and explores their potential as druggable targets in both cancer research and clinical settings.

Antiviral Effects and Mechanisms of Green Tea Catechins on Influenza: A Perception on Combating Symptoms from COVID-19.

Over the centuries, influenza and its associated epidemics have been a serious public health problem. Although vaccination and medications (such as neuraminidase inhibitors) are the mainstay of pharmacological approaches to prevent and treat influenza, however, frequent mutations in the influenza genome often result in treatment failure and resistance to standard medications which limit their effectiveness. In recent years, green tea catechins have been evaluated as potential anti-influenza agents. Herein, in this review, we highlighted the effects and mechanisms underlying the inhibitory effects of epigallocatechin 3-gallate (EGCG), the most abundant ingredient in green tea, against different influenza viral infections, and their clinical benefits toward prevention and treatment. In addition, as the severe acute respiratory syndrome coronavirus 2 (SARSCoV- 2) causes the outbreak of COVID-19 pandemic, our review also delineates the current perspective on SARS-CoV-2 and future insights as to the potential application of EGCG on suppressing the flu-like symptoms caused by COVID-19.

The Association of Prenatal Vitamin D Status With Pregnancy and Neonatal Outcomes.

Context: Vitamin D inadequacy is globally prevalent among pregnant women; however, its impact on pregnancy remains inconclusive. Objective: This study aims to explore the associations of maternal and umbilical cord serum 25-hydroxyvitamin D (25(OH)D) levels with pregnancy and neonatal outcomes. Method: We used archived serum samples from the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study participants in the Hong Kong center and assayed maternal 25(OH)D levels at midgestation and umbilical cord 25(OH)D at birth using liquid chromatography-tandem mass spectroscopy. Data regarding pregnancy and perinatal outcomes were extracted from the HAPO study dataset and the hospital computerized medical system. Results: Only 247 (16.4%) mothers and 66 (5.0%) neonates met the criteria for vitamin D sufficiency (ie, 25(OH)D ≥ 75 nmol/L). The ratio of umbilical cord to maternal vitamin D levels was positively associated with maternal age and ambient solar radiation at the month of delivery, while negatively associated with maternal serum total 25(OH)D at midgestation (all P < .001). Umbilical cord serum 25(OH)D was independently associated with a lower primary cesarean section rate (OR 0.990, 95% CI 0.982-0.999; P = .032). There were no associations of maternal and umbilical cord 25(OH)D levels with other adverse pregnancy and neonatal outcomes. Conclusion: Placental vitamin D transfer was found to be higher with a lower maternal vitamin D level, older maternal age, and higher ambient solar radiation at the time of the delivery. The protective effect of sufficient vitamin D in a cesarean section will require further studies.