TNKS1BP1 mediates AECII senescence and radiation induced lung injury through suppressing EEF2 degradation.

BACKGROUND: Although recent studies provide mechanistic understanding to the pathogenesis of radiation induced lung injury (RILI), rare therapeutics show definitive promise for treating this disease. Type II alveolar epithelial cells (AECII) injury in various manner results in an inflammation response to initiate RILI. RESULTS: Here, we reported that radiation (IR) up-regulated the TNKS1BP1, causing progressive accumulation of the cellular senescence by up-regulating EEF2 in AECII and lung tissue of RILI mice. Senescent AECII induced Senescence-Associated Secretory Phenotype (SASP), consequently activating fibroblasts and macrophages to promote RILI development. In response to IR, elevated TNKS1BP1 interacted with and decreased CNOT4 to suppress EEF2 degradation. Ectopic expression of EEF2 accelerated AECII senescence. Using a model system of TNKS1BP1 knockout (KO) mice, we demonstrated that TNKS1BP1 KO prevents IR-induced lung tissue senescence and RILI. CONCLUSIONS: Notably, this study suggested that a regulatory mechanism of the TNKS1BP1/CNOT4/EEF2 axis in AECII senescence may be a potential strategy for RILI.

Low-dose ionizing radiation-induced RET/PTC1 rearrangement via the non-homologous end joining pathway to drive thyroid cancer.

Thyroid cancer incidence increases worldwide annually, primarily due to factors such as ionizing radiation (IR), iodine intake, and genetics. Papillary carcinoma of the thyroid (PTC) accounts for about 80% of thyroid cancer cases. RET/PTC1 (coiled-coil domain containing 6 [CCDC6]-rearranged during transfection) rearrangement is a distinctive feature in over 70% of thyroid cancers who exposed to low doses of IR in Chernobyl and Hiroshima‒Nagasaki atomic bombings. This study aims to elucidate mechanism between RET/PTC1 rearrangement and IR in PTC. N-thy-ori-3-1 cells were subjected to varying doses of IR (2/1/0.5/0.2/0.1/0.05 Gy) of IR at different days, and result showed low-dose IR-induced RET/PTC1 rearrangement in a dose-dependent manner. RET/PTC1 has been observed to promote PTC both in vivo and in vitro. To delineate the role of different DNA repair pathways, SCR7, RI-1, and Olaparib were employed to inhibit non-homologous end joining (NHEJ), homologous recombination (HR), and microhomology-mediated end joining (MMEJ), respectively. Notably, inhibiting NHEJ enhanced HR repair efficiency and reduced IR-induced RET/PTC1 rearrangement. Conversely, inhibiting HR increased NHEJ repair efficiency and subsequent RET/PTC1 rearrangement. The MMEJ did not show a markable role in this progress. Additionally, inhibiting DNA-dependent protein kinase catalytic subunit (DNA-PKcs) decreased the efficiency of NHEJ and thus reduced IR-induced RET/PTC1 rearrangement. To conclude, the data suggest that NHEJ, rather than HR or MMEJ, is the critical cause of IR-induced RET/PTC1 rearrangement. Targeting DNA-PKcs to inhibit the NHEJ has emerged as a promising therapeutic strategy for addressing IR-induced RET/PTC1 rearrangement in PTC.

Effects of exposure to multiple metallic elements in the first trimester of pregnancy on the risk of preterm birth.

Exposure to certain heavy metals has been demonstrated to be associated with a higher risk of preterm birth (PTB). However, studies focused on the effects of other metal mixtures were limited. A nested case‒control study enrolling 94 PTB cases and 282 controls was conducted. Metallic elements were detected in maternal plasma collected in the first trimester using inductively coupled plasma‒mass spectrometry. The effect of maternal exposure on the risk of PTB was investigated using logistic regression, least absolute shrinkage and selection operator, restricted cubic spline (RCS), quantile g computation (QGC) and Bayesian kernel machine regression (BKMR). Vanadium (V) and arsenic (As) were positively associated with PTB risk in the logistic model, and V remains positively associated in the multi-exposure logistic model. QGC analysis determined V (69.42%) and nickel (Ni) (70.30%) as the maximum positive and negative contributors to the PTB risk, respectively. BKMR models further demonstrated a positive relationship between the exposure levels of the mixtures and PTB risk, and V was identified as the most important independent variable among the elements. RCS analysis showed an inverted U-shape effect of V and gestational age, and plasma V more than 2.18 µg/L was considered a risk factor for shortened gestation length. Exposure to metallic elements mixtures consisting of V, As, cobalt, Ni, chromium and manganese in the first trimester was associated with an increased risk of PTB, and V was considered the most important factor in the mixtures in promoting the incidence of PTB.

Molybdenum-Modified Titanium Dioxide Nanotube Arrays as an Efficient Electrode for the Electroreduction of Nitrate to Ammonia.

Electrochemical nitrate reduction (NO3-RR) has been recognized as a promising strategy for sustainable ammonia (NH3) production due to its environmental friendliness and economical nature. However, the NO3-RR reaction involves an eight-electron coupled proton transfer process with many by-products and low Faraday efficiency. In this work, a molybdenum oxide (MoOx)-decorated titanium dioxide nanotube on Ti foil (Mo/TiO2) was prepared by means of an electrodeposition and calcination process. The structure of MoOx can be controlled by regulating the concentration of molybdate during the electrodeposition process, which can further influence the electron transfer from Ti to Mo atoms, and enhance the binding energy of intermediate species in NO3-RR. The optimized Mo/TiO2-M with more Mo(IV) sites exhibited a better activity for NO3-RR. The Mo/TiO2-M electrode delivered a NH3 yield of 5.18 mg h-1 cm-2 at -1.7 V vs. Ag/AgCl, and exhibited a Faraday efficiency of 88.05% at -1.4 V vs. Ag/AgCl. In addition, the cycling test demonstrated that the Mo/TiO2-M electrode possessed a good stability. This work not only provides an attractive electrode material, but also offers new insights into the rational design of catalysts for NO3-RR.

DNA-PKcs/AKT1 inhibits epithelial-mesenchymal transition during radiation-induced pulmonary fibrosis by inducing ubiquitination and degradation of Twist1.

INTRODUCTION: Radiation-induced pulmonary fibrosis (RIPF) is a chronic, progressive, irreversible lung interstitial disease that develops after radiotherapy. Although several previous studies have focused on the mechanism of epithelial-mesenchymal transition (EMT) in lung epithelial cells, the essential factors involved in this process remain poorly understood. The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) exhibits strong repair capacity when cells undergo radiation-induced damage; whether DNA-PKcs regulates EMT during RIPF remains unclear. OBJECTIVES: To investigate the role and molecular mechanism of DNA-PKcs in RIPF and provide an important theoretical basis for utilising DNA-PKcs-targeted drugs for preventing RIPF. METHODS: DNA-PKcs knockout (DPK-/-) mice were generated via the Cas9/sgRNA technique and subjected to whole chest ionizing radiation (IR) at a 20 Gy dose. Before whole chest IR, the mice were intragastrically administered the DNA-PKcs-targeted drug VND3207. Lung tissues were collected at 1 and 5 months after IR. RESULTS: The expression of DNA-PKcs is low in pulmonary fibrosis (PF) patients. DNA-PKcs deficiency significantly exacerbated RIPF by promoting EMT in lung epithelial cells. Mechanistically, DNA-PKcs deletion by shRNA or inhibitor NU7441 maintained the protein stability of Twist1. Furthermore, AKT1 mediated the interaction between DNA-PKcs and Twist1. High Twist1 expression and EMT-associated changes caused by DNA-PKcs deletion were blocked by insulin-like growth factor-1 (IGF-1), an AKT1 agonist. The radioprotective drug VND3207 prevented IR-induced EMT and alleviated RIPF in mice by stimulating the kinase activity of DNA-PKcs. CONCLUSION: Our study clarified the critical role and mechanism of DNA-PKcs in RIPF and showed that it could be a potential target for preventing RIPF.

Pre-eclamptic foetal programming predisposes offspring to hepatic steatosis via DNA methylation.

OBJECTIVES: Gamete and embryo-foetal origins of adult diseases hypothesis proposes that adulthood chronic disorders are associated with adverse foetal and early life traits. Our study aimed to characterise developmental changes and underlying mechanisms of metabolic disorders in offspring of pre-eclampsia (PE) programmed pregnancy. METHODS: Nω-Nitro-l-arginine methyl ester hydrochloride (L-NAME) induced pre-eclampsia-like C57BL/6J mouse model was used. Lipid profiling, histological morphology, indirect calorimetry, mRNA sequencing, and pyrosequencing were performed on PE offspring of both young and elderly ages. RESULTS: PE offspring exhibited increased postnatal weight gain, hepatic lipid accumulation, enlarged adipocytes, and impaired energy balance that continued to adulthood. Integrated RNA sequencing of foetal and 52-week-old livers revealed that the differentially expressed genes were mainly enriched in lipid metabolism, including glycerol-3-phosphate acyl-transferase 3 (Gpat3), a key enzyme for de novo synthesis of triglycerides (TG), and carnitine palmitoyltransferase-1a (Cpt1a), a key transmembrane enzyme that mediates fatty acid degradation. Pyrosequencing of livers from PE offspring identified hypomethylated and hypermethylated regions in Gpat3 and Cpt1a promoters, which were associated with upregulated and downregulated expressions of Gpat3 and Cpt1a, respectively. These epigenetic alterations are persistent and consistent from the foetal stage to adulthood in PE offspring. CONCLUSION: These findings suggest a methylation-mediated epigenetic mechanism for PE-induced intergenerational lipid accumulation, impaired energy balance and obesity in offspring, and indicate the potential benefits of early interventions in offspring exposed to maternal PE to reduce their susceptibility to metabolic disorder in their later life.

Metabolome implies increased fatty acid utilization and histone methylation in the follicles from hyperandrogenic PCOS women.

Well-balanced metabolism is essential for the high-quality of oocytes, and metabolic fluctuations of follicular microenvironment potentially encourage functional changes in follicle cells, ultimately impacting the developmental potential of oocytes. Here, the global metabolomic profiles of follicular fluid from PCOS women with ovarian hyperandrogenism and nonhyperandrogenism were depicted by untargeted metabolome and transcriptome. In parallel, functional methods were employed to evaluate the possible impact of dysregulated metabolites on oocyte and embryo development. Our findings demonstrated that PCOS women exhibited distinct metabolic features in follicles, such as the increase in fatty acid utilization and the downregulation in amino acid metabolism. And intrafollicular androgen levels were positively correlated with contents of multiple fatty acids, suggesting androgen as one of the contributing factors to the metabolic abnormalities in PCOS follicles. Moreover, we further demonstrated that elevated levels of α-linolenic acid and H3K27me3 could hinder oocyte maturation, fertilization, and early embryo development. Hopefully, our data serve as a broad resource on the metabolic abnormalities of PCOS follicles, and advances in the relevant knowledge will allow the identification of biomarkers that predict the progression of PCOS and its poor pregnancy outcomes.

Effect of transvaginal Lactobacillus supplementation on reversing lower genital tract dysbiosis and improving perinatal outcomes in PCOS patients after IVF-FET: a study protocol for a multicenter randomized controlled trial.

BACKGROUND: Significant lower genital tract (LGT) dysbiosis and an associated lower rate of clinical pregnancy after in vitro fertilization-frozen embryo transfer (IVF-FET) among polycystic ovary syndrome (PCOS) patients have been previously reported by our group. We aimed to assess whether transvaginal Lactobacillus supplementation can reverse LGT dysbiosis and further improve perinatal outcomes in PCOS patients after IVF-FET. METHODS/DESIGN: This is a protocol for a multicenter, open-label, randomized controlled trial in China. Women diagnosed with PCOS who are undergoing IVF-FET treatment will be recruited. Allocation to the intervention/control arms at a ratio of 1:1 will be executed by an electronic randomization system. Participants in the intervention arm will receive the live Lactobacillus capsule vaginally for 10 consecutive days before embryo transfer, while those in the control arm will receive standard individualized care. The primary outcomes will be the clinical pregnancy rate, implantation rate, and live birth rate. 16S rRNA sequencing and liquid chromatography-mass spectrometry will be conducted to evaluate the LGT microbiome and systemic metabonomics before and after the intervention. A sample of 260 participants will provide 95% power to detect a 20% increase in the rate of clinical pregnancy (α = 0.025, one-tailed test, 15% dropout rate). A total of 300 participants will be recruited. DISCUSSION: This is the first large and multicenter randomized controlled trial aimed at assessing the efficacy of transvaginal Lactobacillus supplementation on restoring the LGT microbiome and improving perinatal outcomes in PCOS patients after IVF-FET. This pragmatic trial is promising for increasing the rates of clinical pregnancy and live birth in PCOS patients after IVF-FET. ETHICS AND DISSEMINATION: Ethical review approval was obtained from the Medical Research Ethics Committees of the International Peace Maternity and Child Health Hospital of Shanghai Jiao Tong University (15 October 2020, GKLW 2020-29). To maximize dissemination, these findings will be reported in open access publications in journals with high impact, and oral and poster conference presentations will be performed. TRIAL REGISTRATION: ChiCTR ChiCTR2000036460. Registered on 13 September 2020, https://www.chictr.org.cn/showproj.html?proj=59549 .

Content analysis of breast milk substitutes marketing on Chinese e-commerce platforms.

China has the largest and fastest-growing breast milk substitutes (BMSs) market and a disproportionately low exclusive breastfeeding rate. Many BMS manufacturers have established Chinese e-commerce stores. This marketing is of concern as it is likely to undermine breastfeeding. This study aimed to identify: (1) the marketing themes and strategies used to promote BMSs on the Chinese BMSs e-commerce websites; (2) if and how digital BMSs marketing may deviate from the World Health Organization Code of Marketing of Breast Milk Substitutes (the Code) recommendations. Content analysis was conducted on the flagship websites of 10 BMSs companies on the Chinese e-commerce platform "TMall" in July 2019. The main landing page (n = 10) of the flagship TMall website and the product description page (n = 113) of all individual formulas (Stages 1-3) within each company's TMall website were examined. The content was analysed and coded using an iterative thematic analysis approach. Emphasis on Premiumization and Science & Nutrition was the most commonly used marketing approaches. A total of 27.4% of the product description pages sampled used images of infants (<12 months), 33.6% made favourable comparisons of BMSs to breast milk, and only 34.5% included probreastfeeding statements. Marketing strategies were often inconsistent with the Code, and companies used "creative" ways to target mothers, often circumventing the Code recommendations. Unsubstantiated information was commonplace and of concern, because the e-commerce platform provided easy opportunities for bulk purchases. National regulatory actions are urgently needed to monitor online BMS marketing and the undermining of breastfeeding in China.

Advanced paternal age increased metabolic risks in mice offspring.

OBJECTIVES: The Developmental Origins of Health and Disease Science indicate that chronic diseases in adulthood are associated with prenatal and early-life traits. Our study aimed to explore the metabolic phenotype of offspring from advanced paternal age (APA) and the inherited alterations in sperm. METHODS: 3-month-old (Young father, YF-F0) and 21-month-old male (Old Father, OF-F0) C57BL/6J mice were used to study paternal aging's effect on offspring. Blood glucose testing, lipid analysis, indirect calorimetry and RNA sequencing were performed. RESULTS: The characterized metabolic changes in OF-F1 male mice offspring were glucose intolerance, hepatic lipid accumulation, increased adipocytes and impaired energy balance that lasted until they were elderly. Gene expression in both 8-week-old and 52-week-old offspring livers significantly altered in lipid metabolism- and thermogenesis-related pathways. PPAR signaling pathway was activated in both young and elderly offspring livers as indicated by significant upregulation of Cyp7a1, Cyp8b1, Cyp4a10, Cyp4a31, Fabp2, and Scd1. These targeted genes were also confirmed to be increased in offspring adipocytes. Furthermore, when examined the differentially expressed genes in F0 and F1 sperm, upregulated pathways including cholesterol metabolism, type II diabetes mellitus and endocrine resistance were strongly related to the APA offspring phenotype. Importantly, approximately 46.7% of enriched pathways in the sperm of APA offspring were consistent with those of APA fathers. CONCLUSIONS: These findings added evidence of the connection between paternal gametes and alterations in progeny genome and raised the possibility that inherited alterations in sperm contribute to the intergenerational effects of paternal aging offspring's chronic metabolic risks.

Association of homocysteine with IVF/ICSI outcomes stratified by MTHFR C677T polymorphisms: a prospective cohort study.

RESEARCH QUESTION: What is the association between homocysteine (Hcy) and IVF/intracytoplasmic sperm injection (ICSI) outcomes, stratified by methylenetetrahydrofolate reductase (MTHFR) C677T polymorphisms? DESIGN: This prospective cohort study recruited 1011 infertile women undergoing IVF/ICSI treatment for the first time at the International Peace Maternity and Child Health Hospital between June 2015 and March 2018. RESULTS: The concentration of total serum Hcy was significantly negatively associated with clinical pregnancy and implantation rate. When adjusted for maternal and paternal age and educational level, maternal body mass index, and FSH and oestradiol concentrations, logistic regression analysis showed that women with higher Hcy had a higher risk of unsuccessful pregnancy. After stratification by MTHFR C677T polymorphisms and adjustment for confounding factors, a higher risk of unsuccessful pregnancy and a significantly lower implantation rate only existed in women with higher Hcy concentration in the MTHFR C677T TT genotype. There was no significant association between Hcy concentrations and other ovarian stimulation outcomes (oocytes retrieved, metaphase II stage oocytes, fertilization rate, cleavage rate, high-quality embryo rate) or neonatal outcomes (preterm birth, gestational age at delivery, Caesarean section, birthweight, small for gestational age, large for gestational age or birth defects). CONCLUSIONS: Hcy is highly negatively associated with clinical pregnancy and implantation rate during the first IVF/ICSI cycle, especially in women carrying the MTHFR C677T TT genotype. Other factors with impacts on reproductive outcomes, such as stage of embryo transferred, other factors involved in folate metabolism, preimplantation genetic testing, etc., should be taken into account in further research.

Comorbidities and Quality of Life in Women Undergoing First Surgery for Endometriosis: Differences Between Chinese and Italian Population.

An observational cross-sectional study was conducted in a group (n = 371) of fertile age women with endometriosis, by administering a structured questionnaire, in order to evaluate the incidence of gynecological and systemic comorbidities and the impact on quality of life (QoL) in two different groups of Italian and Chinese patients affected by endometriosis. Chinese (n = 175) and Italian (n = 196) women were compared regarding systemic (inflammatory, autoimmune, and mental) and gynecological comorbidities, pain symptoms, and QoL, by using the Short Form 12 (SF-12). Italian patients resulted younger at the diagnosis and suffered more frequently from severe pain than Chinese ones. Deep infiltrating endometriosis (DIE) and mixed phenotypes were more frequent in Italian patients, whereas ovarian (OMA) and superficial endometriosis (SUP) were more common in the Chinese. The Italian group showed more systemic comorbidities, and those disorder were already present before the diagnosis of endometriosis. Furthermore, the Italian group showed lower SF-12 physical and mental scores, suggesting a worse health-related QoL in Italian endometriotic patients. A number of differences has been observed between Italian and Chinese women with endometriosis in terms of comorbidities and QoL, which may be related to the ethnicity, the different health system organization and the social and cultural background.

Long-term hormonal treatment reduces repetitive surgery for endometriosis recurrence.

RESEARCH QUESTION: How effective is medical hormonal treatment in preventing endometriosis recurrence and in improving women's clinical symptoms and quality of life? DESIGN: This observational cross-sectional study evaluated the effects of hormonal medical treatment (progestins, gonadotrophin-releasing hormone analogues or continuous oral contraceptives) on endometriosis recurrence, current clinical symptoms and quality of life in three groups of patients: Group A (n = 34), no hormonal treatment either before or after the first endometriosis surgery; Group B (n = 76), on hormonal treatment after the first endometriosis surgery; and Group C (n = 75), on hormonal treatment both before and after the first endometriosis surgery. RESULTS: Group C patients were characterized by a lower rate of endometriosis reoperation (P = 0.011) and a lower rate of dysmenorrhoea (P = 0.006). Women who experienced repetitive endometriosis surgery showed worse physical (P = 0.004) and mental (P = 0.012) status than those who received a single surgery, independent of the treatment. CONCLUSION: Hormonal treatments represent a valid cornerstone of endometriosis management and may be useful as an alternative to surgery, but also before surgery, to plan better, and after surgery in order to reduce the risk of recurrence. Medical counselling is very helpful in choosing the correct and individualized endometriosis treatment. In fact, the gold standard for modern endometriosis management is the individualized approach and surgery should be considered, depending on the clinical situation and a patient's symptoms.

AQP7 mediates post-menopausal lipogenesis in adipocytes through FSH-induced transcriptional crosstalk with AP-1 sites.

RESEARCH QUESTION: Fat accumulation is present in most post-menopausal women, but the underlying mechanism remains unclear. Aquaporin 7 (AQP7) is the most important glycerol channel facilitating glycerol efflux in adipocytes. High circulating FSH in post-menopausal women may play an independent role in regulation of the lipogenic effect of AQP7 in adipocytes. This study explored the role of AQP7 in the pathophysiology of post-menopausal lipogenesis mediated by high concentrations of circulating FSH. DESIGN: Primary adipocytes from post-menopausal and childbearing women were analysed. An in-vivo post-menopausal animal model was established. AQP7 expression, lipid accumulation and glycerol concentration in adipocytes were measured. Luciferase reporter assay and chromatin immunoprecipitation were performed to identify transcriptional crosstalk in AQP7 promoter. RESULTS: It was found that FSH down-regulated AQP7 expression and glycerol efflux function in mature adipocytes of post-menopausal women and ovariectomized (OVX) mice. In vitro, FSH inhibited lipid accumulation in primary cultured mature adipocytes in a dose-dependent manner and the mechanism was down-regulating AQP7 expression via a FSH receptor pathway. The effect of FSH on AQP7 in adipocytes was through activation of cAMP response element-binding (CREB) protein, which could bind to activator protein-1 (AP-1) sites in the AQP7 promoter, and therefore inhibited the transcriptional activation elicited by c-Jun. CONCLUSIONS: Down-regulation of AQP7 by FSH mediated post-menopausal lipogenesis, and the role of FSH was based on binding competition for AP-1 sites between CREB and c-Jun.

Epigenetics of Estrogen and Progesterone Receptors in Endometriosis.

Endometriosis is an estrogen-dependent inflammatory gynecological disease. Increased estrogen activity and progesterone resistance are the main hormonal substrate of this disease and are associated with inflammatory response and debilitating symptoms, including pain and infertility. Estrogens and progesterone act via their specific nuclear receptors. The regulation of receptor expression by epigenetics maybe a critical factor for endometriosis. The present review aims to discuss the epigenetic mechanisms related to the expression of estrogen receptors (ERs) and progesterone receptors (PRs) in patients with endometriosis, including two classic epigenetic mechanisms: DNA methylation and histone modification, and, other non-classic mechanisms: miRNAs and lncRNA. Several in vitro and in vivo studies support the key role of epigenetics in the regulation of the expression of ERs and PRs, which may provide new molecules and targets for the diagnosis and treatment of endometriosis.

Flavone protects HBE cells from DNA double-strand breaks caused by PM2.5.

Ambient air particulate matter 2.5 (PM2.5) contains many harmful components that can enter the circulatory system and produce reactive oxygen species (ROS) in body. Oxidative stress and DNA damage induced by ROS may affect any cellular macromolecule and lead to DNA double-strand breaks (DSBs). Flavonoids, widely distributed in some herbs and berries, have been proved having anti-oxidative or anti-cancer efficacy. In this study, we investigated whether Flavone, a kind of flavonoids, can protect human bronchial epithelial cells (HBE) from DSBs caused by PM2.5 and how this function is probably implemented. We found that cells exposed to PM2.5 obviously induced viability inhibition, DNA damage and part of apoptosis. However, Flavone treatment prior to PM2.5 apparently improved cell viability, and mitigated the formation of 8-hydroxy-2-deoxyguanosine, the expression of DNA damage-relative protein and cell apoptosis. Our studies demonstrated that PM2.5 induced oxidative DSBs while Flavone ameliorated the DNA damage and increased cell viability probably through influencing DNA repair mechanism of cells.