Comprehensive Analysis of PANoptosis-Related Gene Signature of Ulcerative Colitis.

Accumulating evidence shows that the abnormal increase in the mortality of intestinal epithelial cells (IECs) caused by apoptosis, pyroptosis, and necroptosis is closely related to the function of mucous membrane immunity and barrier function in patients with ulcerative colitis (UC). As a procedural death path that integrates the above-mentioned many deaths, the role of PANoptosis in UC has not been clarified. This study aims to explore the characterization of PANoptosis patterns and determine the potential biomarkers and therapeutic targets. We constructed a PANoptosis gene set and revealed significant activation of PANoptosis in UC patients based on multiple transcriptome profiles of intestinal mucosal biopsies from the GEO database. Comprehensive bioinformatics analysis revealed five key genes (ZBP1, AIM2, CASP1/8, IRF1) of PANoptosome with good diagnostic value and were highly correlated with an increase in pro-inflammatory immune cells and factors. In addition, we established a reliable ceRNA regulatory network of PANoptosis and predicted three potential small-molecule drugs sharing calcium channel blockers that were identified, among which flunarizine exhibited the highest correlation with a high binding affinity to the targets. Finally, we used the DSS-induced colitis model to validate our findings. This study identifies key genes of PANoptosis associated with UC development and hypothesizes that IRF1 as a TF promotes PANoptosome multicomponent expression, activates PANoptosis, and then induces IECs excessive death.

Embryo morphologic quality in relation to the metabolic and cognitive development of singletons conceived by in vitro fertilization and intracytoplasmic sperm injection: a matched cohort study.

BACKGROUND: Embryos with higher morphologic quality grading may have a greater potential to achieve clinical pregnancy that leads to a live birth regardless of the type of cleavage-stage embryos or blastocysts. Few studies have investigated the impacts of embryo grading on the long-term health of the offspring. OBJECTIVE: This pilot study aimed to examine the associations between embryo morphologic quality and the physical, metabolic, and cognitive development of singletons conceived by in vitro fertilization and intracytoplasmic sperm injection at preschool age. STUDY DESIGN: This matched cohort study included singletons born to infertile couples who underwent fresh cleavage-stage embryo transfer cycles with good- or poor-quality embryos from 2014 to 2016 at the reproductive center of the Women's Hospital, School of Medicine, Zhejiang University. A total of 144 children, aged 4 to 6 years, participated in the follow-up assessment from 2020 to 2021, and the response rate of poor-quality embryo offspring was 39%. Singletons in the good-quality embryo group were matched with singletons in the poor-quality embryo group at a 2:1 ratio according to the fertilization method and the children's age (±1 year). We measured the offspring's height, weight, body mass index, blood pressure, thyroid hormone levels, and metabolic indicators. Neurodevelopmental assessments were performed using the Chinese version of the Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition, and the Adaptive Behavior Assessment System, Second Edition. We also collected data from the medical records. A linear regression model was used to analyze the association between embryo morphologic quality and offspring health outcomes. RESULTS: A total of 48 singletons conceived with poor-quality embryo transfer and 96 matched singletons conceived with good-quality embryo transfer were included in the final analysis. Age, sex, height, weight, body mass index, blood pressure, thyroid function, and metabolic indicators were comparable between the 2 groups. After adjustment for potential risk factors by linear regression model 1 and model 2, poor-quality embryo offspring exhibited a tendency toward higher free thyroxine levels than offspring of good-quality embryo transfers (beta, 0.22; 95% confidence interval, 0.09-0.90; beta, 0.22; 95% confidence interval, 0.09-0.91, respectively), but this difference was not clinically significant. Regarding neurodevelopmental assessments, there was no difference in the full-scale intelligence quotient based on the Wechsler Preschool and Primary Scale of Intelligence (109.96±12.42 vs 109.60±14.46; P=.88) or the general adaptive index based on the Adaptive Behavior Assessment System (108.26±11.70 vs 108.08±13.44; P=.94) between the 2 groups. The subindices of the 2 tests were also comparable. These findings remained after linear regression analysis. CONCLUSION: At 4 to 6 years of age, singletons born from poor-quality embryo transfers have comparable metabolic and cognitive development as those born from good-quality embryo transfers using fresh cleavage-stage embryos. The results of this pilot study indicate that poor-quality embryos that can survive implantation and end in live birth are likely to have a developmental potential comparable to that of good-quality embryos.

A clinical prediction model to estimate the risk for coarctation of the aorta: From fetal to newborn life.

AIM: A prenatal diagnosis of coarctation of the aorta (CoA) is challenging. This study aimed to develop a coarctation probability model incorporating prenatal cardiac sonographic markers to estimate the probability of an antenatal diagnosis of CoA. METHODS: We reviewed 89 fetuses as an investigation cohort with prenatal suspicion for CoA and categorized them into three subgroups: severe CoA: symptomatic CoA and surgery within the first 3 months; mild CoA: surgery within 4 months to 1 year (29); and false-positive CoA: not requiring surgery (45). Logistic regression was used to create a multiparametric model, and a validation cohort of 86 fetuses with suspected CoA was used to validate the model. RESULTS: The prediction model had an optimal criterion >0.25 (sensitivity of 97.7%; specificity of 59.1%), and the area under the receiver operator curve was 0.85. The parameters and their cut-off values were as follows: left common carotid artery to left subclavian artery distance/distal transverse arch (LCCA-LSCA)/DT Index >1.77 (sensitivity 62%, specificity 88%, 95% confidence interval [CI]: 0.6-0.8), and z-score of AAo peak Doppler > -1.7 (sensitivity 77%, specificity 56%, 95% CI: 0.6-0.8). The risk assessment demonstrated that fetuses with a model probability >60% should have inpatient observation for a high risk of CoA, whereas fetuses with a model probability <15% should not undergo clinical follow-up. CONCLUSION: The probability model performs well in predicting CoA outcomes postnatally and can also improve the accuracy of risk assessment. The objectivity of its parameters may allow its implementation in multicenter studies of fetal cardiology.

Peripheral inflammation triggering central anxiety through the hippocampal glutamate metabolized receptor 1.

AIMS: This study aimed to investigate the relationship between ulcerative colitis (UC) and anxiety and explore its central mechanisms using colitis mice. METHODS: Anxiety-like behavior was assessed in mice induced by 3% dextran sodium sulfate (DSS) using the elevated plus maze and open-field test. The spatial transcriptome of the hippocampus was analyzed to assess the distribution of excitatory and inhibitory synapses, and Toll-like receptor 4 (TLR4) inhibitor TAK-242 (10 mg/kg) and AAV virus interference were used to examine the role of peripheral inflammation and central molecules such as Glutamate Receptor Metabotropic 1 (GRM1) in mediating anxiety behavior in colitis mice. RESULTS: DSS-induced colitis increased anxiety-like behaviors, which was reduced by TAK-242. Spatial transcriptome analysis of the hippocampus showed an excitatory-inhibitory imbalance mediated by glutamatergic synapses, and GRM1 in hippocampus was identified as a critical mediator of anxiety behavior in colitis mice via differential gene screening and AAV virus interference. CONCLUSION: Our work suggests that the hippocampus plays an important role in brain anxiety caused by peripheral inflammation, and over-excitation of hippocampal glutamate synapses by GRM1 activation induces anxiety-like behavior in colitis mice. These findings provide new insights into the central mechanisms underlying anxiety in UC and may contribute to the development of novel therapeutic strategies for UC-associated anxiety.

Sequential Screening Strategy in Early, Middle, and Late Pregnancy in Women at High Risk of Hyperglycemia.

Background: Hyperglycaemia in pregnancy (HIP) is closely associated with short- and long-term adverse fetal and maternal outcomes. However, the screening and diagnostic strategies for pregnant women with risk factors for HIP are not set. This prospective study aimed to explore a screening strategy for women at high risk for HIP. Methods: A total of 610 pregnant women were divided into experimental (n=305) and control (n=305) groups. Pregnant women underwent a 75-g OGTT in early (<20 weeks), middle (24-28 weeks), and late pregnancy (32-34 weeks) in the experimental group and only in middle pregnancy in the control group. The general conditions, HIP diagnosis, and perinatal outcomes of the two groups were compared. Results: In the experimental group, HIP was diagnosed in 29.51% (90/305), 13.44% (41/305), and 10.49% (32/305) of patient in early, middle, and late pregnancy, respectively. The total HIP diagnosis rate was significantly higher in the experimental group (53.44% vs. 35.74%, P<0.001). Multivariate logistic regression analysis revealed that previous gestational diabetes mellitus (GDM) (odds ratio, OR=9.676, P<0.001), pre-pregnancy body mass index (BMI) ≥23 kg/m2 (OR=4.273, P<0.001), and maternal age ≥35 years (OR=2.377, P=0.010) were risk factors for HIP diagnosis in early pregnancy. Previous GDM (OR=8.713, P=0.002) was a risk factor for HIP diagnosis in late pregnancy. No significant differences in perinatal clinical data were observed between the experimental and control groups. The gestational age at delivery was significantly earlier in the experimental subgroup with early-HIP than in the experimental and control subgroups with normal blood glucose (NBG). The weight gain during pregnancy was lower in the experimental early-HIP, middle-HIP, and control NBG subgroups. Conclusions: We recommend sequential screening in early and middle pregnancy for high-risk pregnant women with maternal age ≥35 years or pre-pregnancy BMI ≥23 kg/m2, and in early, middle, and late pregnancy for high-risk pregnant women with a previous history of GDM. Trial Registration: This study was registered in the Chinese Clinical Trial Registry (no. ChiCTR2000041278).

Use of angiotensin II receptor blocker during pregnancy: A case report.

BACKGROUND: Drugs that affect the renin-angiotensin system, such as angiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors are not typically recommended for pregnant women because of their potential fetal toxicity. CASE STUDY: A 32-year-old pregnant woman with nephrotic syndrome lasting more than 5 years became pregnant for the first time. She had been taking losartan tablets before and during pregnancy. Ultrasound at 24+2 weeks of pregnancy showed oligohydramnios, and the maximum vertical depth of amniotic fluid volume was 1.4 cm. Follow-up ultrasound examinations every 2 weeks showed persistent oligohydramnios [amniotic fluid volume: 1.1-3.4 cm, amniotic fluid index 1.9-6.9 cm]. B-ultrasound at 30+2 weeks showed slightly enhanced fetal renal cortex echo. The patient was treated at 32+2 weeks of pregnancy at our hospital. DIAGNOSES: Nephrotic syndrome and oligohydramnios. INTERVENTIONS: Losartan was discontinued and replaced by nifedipine controlled-release tablets to lower blood pressure. The amount of amniotic fluid gradually increased to normal levels within 8 days. The patient was discharged at 33+2 weeks of pregnancy for follow-up. At 34+4 weeks, blood pressure had increased to 177/113 mm Hg and the patient was re-hospitalized with nephrotic syndrome complicated by preeclampsia. Due to progression of severe preeclampsia, elective cesarean section was performed at 35+3 weeks. After delivery, losartan and nifedipine were prescribed to continue lowering blood pressure. The patient was discharged 4 days after surgery. OUTCOMES: Losartan use was terminated at 32+2 weeks of pregnancy. Amniotic fluid returned to normal after 8 days and the baby was delivered after 22 days. At last follow-up, the infant was 24 months old and healthy. CONCLUSION: Although ARBs are effective for treating hypertension, they should be replaced by other classes of anti-hypertensive drugs in pregnant women. Pregnant women who elect to continue using ARBs should be informed about risks, they should be carefully monitored during pregnancy, and their pregnancy should be allowed to proceed as long as clinically feasible in order to optimize maternal and infant outcomes.

Proteomic analysis of lysine acetylation reveals that metabolic enzymes and heat shock proteins may be potential targets for DSS-induced mice colitis.

BACKGROUND: Research on acetylation modification and its modification sites will be of great significance for revealing the mechanism of disease and developing new targeted medicines. In this study, we aim to construct a complete atlas of acetylome in the DSS-induced ulcerative colitis mice model (UC model) METHODS: A high-resolution mass spectrometry-based quantitative approach was employed to identify lysine-acetylated proteins and acetylation sites. Bioinformatics analysis and in vitro experiments verified anti-inflammatory effects of HSP90B1-K142ac. RESULTS: 2597 acetylation events and 1914 sites were quantified, highlighting 140 acetylation site changes in the colitis colon tissue. 91 acetylation sites in 75 proteins were up-regulated, and 49 acetylation sites in 39 proteins were down-regulated in the UC models. The differentially acetylated proteins mainly consisted of non-histone proteins located in the cytoplasm and mitochondria. KEGG and protein-protein interaction networks analysis showed that the differentially acetylated proteins were enriched in the TCA cycle, fatty acid metabolism, and protein processing in the endoplasmic reticulum. 68% of the differentially metabolized enzymes have a down-regulated trend in acetylation levels. The acetylation level of lysine 142 in HSP90B1 was found to be obvious in the UC colon, and point mutation of HSP90B1-K142ac would result in the decreasing secretion of TNF-α and IL-2 in LPS-stimulated cultured cells. CONCLUSION: Our work built a complete atlas of acetylome and revealed the potential role of metabolic enzymes and heat shock proteins in DSS-induced colitis.

NID2 can serve as a potential prognosis prediction biomarker and promotes the invasion and migration of gastric cancer.

BACKGROUND: Nidogen-2 (NID2) is a ubiquitous component in the basement membrane and plays an important role in the development of malignant tumors. However, the specific function and mechanism of the NID2 gene in gastric cancer remains unclear. In this study, we aimed to investigate the role of NID2 in gastric cancer(GC). METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression of NID2 in 67 GC tissues and adjacent normal tissues. The relationship between NID2 expression and clinicopathological features was further analyzed. In addition, we evaluated the expression of NID2 in GC based on data from the GEPIA and Kaplan-Meier Plotter database and compared the database results with our own experimental results. Invasion and wound healing assays were used to detect the function of NID2 in MKN45 and SGC7901 cells. Finally, the NID2 network and its possible related genes are constructed by the bioinformatics framework. RESULTS: The expression level of NID2 was found to be significantly over-expressed in gastric cancer cells and tissues compared with normal controls and positively associated with TNM stage, showing a poor prognosis of GC patients. In vitro experiments indicated that NID2 was able to promote the ability of invasion and migration in GC cells. Bioinformatics prediction showed NID2 might regulate the progression of GC via protein digestion and absorption, amoebiasis, PI3K-AKt-signaling pathway, focal adhesion and ECM-receptor interaction pathways. CONCLUSION: Our study demonstrates that up-regulated NID2 plays an important role in promoting the invasion and migration of GC cells and has a potential of being a novel biomarker for diagnosis, treatment and prognosis of GC in the future.