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Cancer cells with their distinct energy supply and metabolic patterns offer unique opportunities for targeted therapy development. This study presents pH/ROS dual-responsive enzyme-carrying nanoparticles for efficient starvation and oxidative therapy in cancer treatment. The nanoparticles, composed of zeolitic imidazolate framework-8 (ZIF-8), glucose oxidase (GOx), and hyaluronic acid (HA), were designed to leverage the unique metabolic characteristics of cancer cells. GOx was covalently modified onto HA to create HA-GOx, demonstrating enhanced enzymatic activity and thermal stability compared with free GOx. The nanoparticles ZIF@HAgel-GOx were then synthesized by adsorbing HA-GOx onto ZIF-8 and crosslinking with a ROS-sensitive crosslinker, acetone-[bis-(2-amino-ethyl)-dithioacetal] (TK). The enzymatic properties of ZIF@HAgel-GOx in solution and in cells were comparable to those of free GOx, and both could consume glucose to catalyze the reaction. The produced H2O2 could decrosslink the gel layer of ZIF@HAgel-GOx, and the produced gluconic acid could degrade the ZIF-8 core, eventually leading to the complete disassembly of ZIF@HAgel-GOx. Cytotoxicity assays revealed that GOx-carrying nanoparticles exhibited superior cytotoxicity to DOX carriers and could effectively eliminate cancer cells with minimal dosage. The findings provide a scientific rationale for the use of enzyme-based therapies in the treatment of various diseases. [ABSTRACT FROM AUTHOR]

This retrospective cohort study aimed to compare clinical outcomes following fresh or frozen embryo transfer (FET) in women with advanced reproductive age (ARA). Women aged 35–45 years who underwent their first autologous fresh or frozen cleavage stage embryo transfer cycle in the Centre for Assisted Reproduction of Shanghai First Maternity and Infant Hospital between January 2016 and December 2020 were included. The primary outcome was live birth after the first embryo transfer of the in vitro fertilization (IVF) cycle. Multiple covariates were used for propensity score matching (PSM) and generalized estimating equations were performed to examine the independent association between FET and live birth. Of the total 1453 patients, 327 patients had FET and 1126 patients had fresh ET. After the PSM procedure, 274 patients were included in each group. The live birth rate was 24.8% in the FET group and 25.2% in the fresh ET group (OR 0.98, 95% CI: 0.67–1.44, P = 0.92). Other pregnancy, perinatal and neonatal outcomes were all comparable between the two groups. This study showed that FET did not improve live birth and other clinical outcomes as compared with fresh embryo transfer in women with ARA who underwent their first IVF cycle. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Does ambient temperature exposure affect outcomes including clinical pregnancy and live birth in women undergoing IVF? SUMMARY ANSWER Both extreme cold and hot ambient temperatures were significantly associated with adverse pregnancy outcomes of IVF cycles. WHAT IS KNOWN ALREADY Heat exposure has been linked to adverse pregnancy outcomes worldwide. However, the effect of ambient temperature on infertile women undergoing IVF treatment is unclear. STUDY DESIGN, SIZE, DURATION A retrospective cohort study was conducted from a database of 3452 infertile women who underwent their first fresh or frozen embryo transfer in the Shanghai First Maternity and Infant Hospital from April 2016 to December 2020. PARTICIPANTS/MATERIALS, SETTING, METHODS Daily mean ambient temperature exposure for each patient was obtained based on their residential address. Temperature-stratified multiple logistic regression analysis was performed to investigate associations between temperature exposure and pregnancy outcomes after controlling for confounders. Vulnerable sub-groups were identified using forest plots. MAIN RESULTS AND THE ROLE OF CHANCE The clinical pregnancy rate and live birth rate were 45.7% and 37.1%, respectively. Regarding clinical pregnancy, a higher temperature during cold weather was significantly associated with a higher pregnancy rate in the period about 11 weeks before ovarian stimulation (adjusted odds ratio (aOR) = 1.102, 95% CI: 1.012–1.201). Regarding live birth, an increased temperature during cold weather was significantly related to a higher live birth rate in the period after confirmation of clinical pregnancy or biochemical pregnancy, with the aORs of 6.299 (95% CI: 3.949–10.047) or 10.486 (95% CI: 5.609–19.620), respectively. However, a higher temperature during hot weather was negatively associated with the live birth rate in the periods after confirmation of clinical pregnancy or biochemical pregnancy, with the aORs at 0.186 (95% CI: 0.121–0.285) or 0.302 (95% CI: 0.224–0.406), respectively. Moreover, the decline in live birth rates during cold and hot weather was accompanied by increased rates of early miscarriage (P  < 0.05). Stratified analyses identified susceptibility characteristics among the participants. LIMITATIONS, REASONS FOR CAUTION Climate monitoring data were used to represent individual temperature exposure levels according to the patient's residential address in the study. We were not able to obtain information of personal outdoor activity and use of indoor air conditioners in this retrospective study, which may affect actual temperature exposure. WIDER IMPLICATIONS OF THE FINDINGS This study highlights that the ambient temperature exposure should be taken into account during IVF treatment and afterwards. There is a need to be alert to extremes in cold and hot ambient temperatures, especially during the period of follicle development and pregnancy. With this knowledge, clinicians can scientifically determine the timing of IVF treatment and reinforce patients' awareness of self-protection to minimize adverse pregnancy outcomes associated with extreme temperatures. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by a grant from the Clinical Research Plan of Shanghai Hospital Development Center [SHDC2020CR4080], a grant from the Science and Technology Commission of Shanghai Municipality [19411960500], and two grants from the National Natural Science Foundation of China [81871213, 81671468]. B.W.M. is supported by a NHMRC Investigator grant (GNT1176437). B.W.M. reports consultancy for ObsEva, and research grants from Merck KGaA, Ferring and Guerbet. The other authors have no conflict of interest to declare. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

Encapsulation and release of water-insoluble drugs has been a challenge. In this paper, a pH/glutathione (GSH) dual-responsive self-assembly based on graphene oxide (GO) was designed and fabricated for the effective delivery of the anti-cancer drug, quercetin (QU). The pH-sensitive poly(2-(diisopropylamino ethylmethacrylate) (PDPA) was synthesized and grafted onto GOvia a disulfide bond (GO–PDPA). Then, the hydrophobic QU was loaded onto GO–PDPA followed by coating with chitosan (CHI) to obtain a biological medium-stable GO-based self-assembly (GO–PDPA–CHI). Dynamic light scattering (DLS), field emission scanning electron microscopy (FESEM) and X-ray photoelectron spectroscopy (XPS) were used to investigate their size and zeta-potential, morphology, and chemical structures. The coating of chitosan on GO–PDPA not only increased the pH sensitivity of the carrier but also reduced its drug leakage from 60% to 40% at a pH of 7.4. Drug release experiments also showed that under the stimulus of pH and GSH, the drug cumulative release amount was over 75%. The dual-sensitive GO-based self-assembly exhibits great potential as a drug carrier for hydrophobic drugs in cancer therapy. [ABSTRACT FROM AUTHOR]

Increasing evidence suggests that in vitro fertilization (IVF) may be associated with an increased risk of developing obesity and metabolic diseases later in life in the offspring. Notably, the addition of melatonin to culture medium may improve embryo development and prevent cardiovascular dysfunction in IVF adult mice. This study aimed to determine if melatonin supplementation in the culture medium can reverse impaired glucose metabolism in IVF mice offspring and the underlying mechanisms. Blastocysts used for transfer were generated by natural mating (control group) or IVF with or without melatonin (10−6 M) supplementation (mIVF and IVF group, respectively) in clinical‐grade culture media. Here, we first report that IVF decreased hepatic expression of Fbxl7, which was associated with impaired glucose metabolism in mice offspring. Melatonin addition reversed the phenotype by up‐regulating the expression of hepatic Fbxl7. In vitro experiments showed that Fbxl7 enhanced the insulin signaling pathway by degrading RhoA through ubiquitination and was up‐regulated by transcription factor Foxa2. Specific knockout of Fbxl7 in the liver of adult mice, through tail intravenous injection of recombinant adeno‐associated virus, impaired glucose tolerance, while overexpression of hepatic Fbxl7 significantly improved glucose tolerance in adult IVF mice. Thus, the data suggest that Fbxl7 plays an important role in maintaining glucose metabolism of mice, and melatonin supplementation in the culture medium may rescue the long‐term risk of metabolic diseases in IVF offspring. [ABSTRACT FROM AUTHOR]

Background: Early cumulus cell removal combined with early rescue intracytoplasmic sperm injection (ICSI) has been widely practiced in many in vitro fertilization (IVF) centers in China in order to avoid total fertilization failure. However, uncertainty remains whether the pregnancy and neonatal outcomes are associated with early cumulus cell removal. Objectives: To investigate if early cumulus cell removal alone after 4 hours co-incubation of gametes (4 h group), has detrimental effect on the pregnancy and neonatal outcomes in patients undergoing IVF, through a comparison with conventional cumulus cell removal after 20 hours of insemination (20 h group). Methods: This retrospective cohort study included 1784 patients who underwent their first fresh cleavage stage embryo transfer at the Centre for Assisted Reproduction of Shanghai First Maternity and Infant Hospital from June 2016 to December 2018 (4 h group, n=570; 20 h group, n=1214). A logistic regression analysis was performed to examine the independent association between early cumulus cell removal and pregnancy outcomes after adjustment for potential confounders. The neonatal outcomes between the two groups were compared. Results: When compared with the 20 h group, the 4 h group had similar pregnancy outcomes, including rates for biochemical pregnancy, clinical pregnancy, ongoing pregnancy, miscarriage, ectopic pregnancy, multiple pregnancy, live birth. There were 1073 infants delivered after embryo transfer (4 h group, n=337; 20 h group, n=736). Outcomes in both groups were similar for both singleton and twin gestations, including preterm birth rate and very preterm birth rate, mean birth weight, mean gestational age, sex ratio at birth and rate of congenital birth defects. In addition, findings pertaining to singleton gestations were also similar in the two groups for Z-scores (gestational age- and sex-adjusted birth weight), rates of small for gestational age, very small for gestational age, large for gestational age and very large for gestational age infants. Conclusions: In this study early cumulus cell removal alone was not associated with adverse pregnancy and neonatal outcomes. From this perspective, early cumulus cell removal to assess for a potential early rescue ICSI is therefore considered to be a safe option in patients undergoing IVF. [ABSTRACT FROM AUTHOR]

Conception via assisted reproductive technology (ART) increases the risk of type 2 diabetes and cardiovascular disease in adulthood. Underlying differences between ART-conceived and in-vivo-conceived embryos that contribute to this increased risk are, however, not known. This study examined the developmental characteristics of mouse blastocysts derived from ART- compared with in-vivo-conceived embryos. To determine the effect of ovarian stimulation versus IVF versus in-vitro embryo culture on phenotype, six distinct groups of blastocysts were generated. Female mice were naturally cycling or treated with high or mild doses of gonadotrophin, followed by natural mating or IVF under clinical conditions. Embryo morphokinetics were assessed by continuous time-lapse monitoring. Cell lineage allocation to the inner cell mass (Oct4+) or trophectoderm (Cdx2+) was determined by immunohistochemistry, and mitochondrial DNA (mtDNA) copy number was measured by quantitative PCR. Ovarian stimulation increased embryo number but reduced the percentage of blastocysts. Morphokinetic analysis showed that gonadotrophin treatment led to advanced development (P < 0.05) due to earlier post-pronuclear breakdown. The blastocyst rate was reduced in IVF embryos compared with those fertilized in vivo before culture (P < 0.001). Morphokinetics showed that embryo development was slower in all the IVF groups (P < <0.05), due to a delay from the 3-cell stage. A reduced total and trophectoderm cell number was observed in all groups of cultured blastocysts compared with naturally conceived blastocysts (P < 0.01). Gonadotrophin treatment did not affect the blastocyst mtDNA copy number; however, IVF embryos exhibited reduced mtDNA copy number compared with naturally conceived embryos. Ovarian stimulation, IVF and in-vitro culture differentially impair blastocyst developmental kinetics, differentiation and mtDNA copy number. [ABSTRACT FROM AUTHOR]

Summary Selenoprotein P (SeP) is secreted primarily by the liver and postulated to cause insulin resistance. The aim of this study was to measure plasma SeP in individuals who are lean ( N = 29) or overweight/obese ( N = 34), and examine relationships between circulating SeP, SEPP1 (SeP, plasma 1) expression in subcutaneous adipose tissue, and markers of insulin resistance. SeP was higher in individuals who were overweight/obese ( P < 0.001), and associated with insulin resistance by HOMA-IR and by clamp, but not independently of BMI. SEPP1 mRNA was correlated negatively with BMI, suggesting there may be tissue specific regulation. This study suggests that obesity, rather than insulin resistance, is central to the increase in SeP. [ABSTRACT FROM AUTHOR]

Background/Aims: The secretions of liver-derived cytokines angiopoietin-like 6, insulin-like growth factor 1, selenoprotein-P and C-reactive protein and adipokines, adiponectin and monocyte chemoattractant protein-1 are altered in obese individuals, and they directly induce insulin resistance in both cellular and animal models. This study is aimed at examining the effects of acute overnutrition on these cytokines in healthy individuals, and identifying association with markers of insulin resistance. Methods: Thirty-one young healthy individuals (10 men, body mass index (BMI) 22.4 ± 2.7; 21 women, BMI 23.3 ± 4.9) were enrolled for the study. Metabolic assessments were done 3 days after an energy balanced diet (30% fat) and 3 days of a high-fat overfeeding diet (+1,250 kcal/day, 45% fat), and the assessments included thefasting body weight and blood samples to analyze the selected cytokines and evaluate the insulin sensitivity by a hyperinsulinemic euglycemic clamp (80 mU/m²/min). Results: Three days of overfeeding increased the body weight, fasting glucose and insulin, and thus the homeostasis model assessment of insulin resistance. However, there were no changes in peripheral insulin sensitivity, or in the circulating cytokines assessed. Conclusions: The hepatokines and adipokines assessed were not acutely sensitive to overnutrition in healthy individuals, despite increases in markers of hepatic insulin resistance. [ABSTRACT FROM AUTHOR]

Individuals conceived by in vitro fertilization (IVF) may be at increased risk of cardio-metabolic disorders. We recently reported that IVF conceived male mice displayed impaired glucose metabolism at normal and high body weights. In this study, we examined glucose metabolism in mature female C57BL/6J mice that were conceived by natural conception (NC), by ovarian stimulation (OS) or by IVF following chow or high-fat diet (HFD) for 8 weeks. By design, litter size was comparable between groups, but interestingly the birth weight of IVF and OS females was lower than NC females (p≤0.001). Mature IVF female mice displayed increased fasting glucose as compared to NC and OS mice, irrespective of diet. Mature IVF and OS mice were also more susceptible to the metabolic consequences of high fat diet as compared with NC females, with impaired glucose tolerance (p≤0.01), whereas peripheral insulin resistance and increased hepatic expression of gluconeogenic genes Ppargc1α, Pck1 and G6pc was observed in IVF mice only (p<0.05). This study suggests that ovarian stimulation alone and IVF program distinct metabolic effects in females, but that high fat diet may be required to unmask these effects. This study adds to the growing body of literature that assisted reproduction procedures may increase the risk of developing type 2 diabetes in an obesity prone environment. [ABSTRACT FROM AUTHOR]

Assisted reproductive technology has been widely applied in the treatment of human infertility. However, accumulating evidence indicates that in vitro fertilization (IVF) is associated with a low pregnancy rate, placental defects, and metabolic diseases in offspring. Here, we find that IVF manipulation notably disrupts extraembryonic tissue-specific gene expression, and 334 epiblast (Epi)-specific genes and 24 Epi-specific transcription factors are abnormally expressed in extraembryonic ectoderm (ExE) of IVF embryos at embryonic day 7.5. Combined histone modification analysis reveals that aberrant H3K4me3 modification at the Epi active promoters results in increased expression of these genes in ExE. Importantly, we demonstrate that knockdown of the H3K4me3-recruited regulator Kmt2e , which is highly expressed in IVF embryos, greatly improves the development of IVF embryos and reduces abnormal gene expression in ExE. Our study therefore identifies that abnormal H3K4me3 modification in extraembryonic tissue is a major cause of implantation failure and abnormal placental development of IVF embryos. [Display omitted] • IVF affects implantation, extraembryonic ectoderm (ExE), and placental development • IVF disrupts extraembryonic tissue-specific gene expression in ExE • Aberrant H3K4me3 in ExE causes gene expression and developmental defects • Kmt2e knockdown improves the development of IVF embryos Bai et al. show that IVF manipulation disrupts extraembryonic ectoderm (ExE) gene expression and placental development. Aberrant histone H3K4me3 in ExE is an important cause for embryo implantation failure and extraembryonic developmental abnormalities. Kmt2e knockdown improves the development of IVF embryos and reduces abnormal gene expression in ExE. [ABSTRACT FROM AUTHOR]

• Design of microgel with double security function. • pH/redox/US multi-controllable drug release of microgel. • Achievement of quick and complete drug release. In this paper, the multi-responsive core-shell microgels were prepared for constructing a double-locked drug delivery system. The pH- sensitive poly(2-(diisopropylamino ethylmethacry-late)-block-poly(ethyleneimine) diblock copolymers (PDPA-b-PEI) were synthesized and used to prepare micelles through their self-assembly in neutral solution. Redox-responsive gel shells were formed by Michael addition of primary amine group of branched PEI using disulfide as a cross-linker, which was specifically cleaved by glutathione (GSH). Anticancer drug doxorubicin DOX and perfluorohexane (PFH) could be encapsulated in the core of microgel. The DOX was released sustainably only under the condition of pH and GSH were both right. For example, under neutral condition with GSH, DOX could not release swimmingly due to the core of microgels was in hydrophobic state and wrapped the DOX firmly, although the gel shells were collapsed by GSH. When exposed to ultrasound, the drug released abruptly and achieved a complete release instantly. Moreover, it was found that the structure of the microgels was not destroyed after the ultrasound stimulus but had undergone an expansion-recovery process. Finally, it was demonstrated that the microgel had a "double security" effect, ensuring the low drug leakage during the normal blood circulation and efficient drug release under the pH/redox/ultrasound stimulus. The multi-responsive microgels designed here, which combines the usage of both endogenous and exogenous stimuli, has the advantages of low side-effect, high spatiotemporal controllability and complete release. [ABSTRACT FROM AUTHOR]

• Ambient NO 2 exposure was associated with lower rates of pregnancy in IVF patients. • Exposure to PM 10 increased the risk of lower rate of live birth in IVF patients. • Subjects underwent single embryo transfer might be more vulnerable to air pollutants • IVF patients aged< 32 yrs were at the risk of lower live birth when exposure to PM 10 The effects of ambient air pollutants on adverse pregnancy outcomes have been reported. However, studies about air pollutants exposure and pregnancy outcomes in patients undergoing IVF were limited and inconclusive. To date Shanghai has been the only city in China to implement a compulsory single embryo transfer policy for all patients undergoing their first embryo transfer procedure effective from January 2019. We aimed to investigate the associations between exposure to ambient air pollutants and biochemical pregnancy and live births, and to identify potential vulnerability characteristics of patients undergoing IVF in Shanghai, China. A retrospective cohort study was conducted on 2766 infertile patients aged ≤ 45 years who underwent first fresh or frozen-thawed cleavage stage embryo transfer in the Shanghai First Maternity and Infant Hospital during April 2016 and December 2019. Daily average ambient levels of six air pollutants (PM 2.5 , PM 10 , NO 2 , SO 2 , CO and O 3 max-8h) were obtained from fixed air monitors located in closest proximity to patients' residences. The cumulative average level was calculated during three different exposure periods (period1: three months before oocyte retrieval to serum hCG test; period 2: from serum hCG test to live birth outcome; period 3: from three months before oocyte retrieval to live birth). Multiple logistic regression model was performed to investigate associations between exposure to ambient air pollutants and pregnancy outcomes. Stratified analyses were conducted to explore the potential effects modifier. The biochemical pregnancy rate and live birth rate were 54.2% and 36.4%, respectively. The ambient NO 2 exposure was significantly associated with a 14% lower pregnancy rate during period 1 (aOR = 0.86, 95%CI: 0.75–0.99). The ambient PM 10 was related to significantly increased risk of lowering live birth rate among the patients during period 3 [aOR = 0.88(0.79–0.99)]. Stratified analysis showed that ambient PM 10 was also significantly associated with a reduced pregnancy rate (aOR = 0.82, 95% CI: 0.69–0.97) in patients who underwent single embryo transfer during period 1. Subjects who underwent single embryo transfer also had a decreased likelihood of a live birth when exposed to ambient SO 2 and O 3 during period 3 [aOR = 0.74(0.57–0.95), and 0.92 (0.83–0.98), respectively]. Moreover, O 3 exposure was associated with decreased live birth rates in patients living in non-urban areas. Sensitivity analyses indicated robust negative association between PM 10 exposure and live birth outcomes. Our study suggested that exposure to ambient air pollutants, in particular NO 2 and PM 10 , was associated with an increased risk of lower rates of pregnancy and live birth respectively in patients undergoing IVF. Stratified analyses indicated that ambient SO 2 and O 3 levels were related to adverse pregnancy outcomes in some subgroups of IVF patients in this study. Notably, patients who underwent single embryo transfer were more susceptible to ambient air pollution exposure. Thus, prospective cohort studies are needed to investigate the underlying mechanisms and the susceptibility windows for women undergoing IVF treatment. [ABSTRACT FROM AUTHOR]