Fasting or 2-hour postprandial plasma glycemic criteria for gestational diabetes mellitus are aassociated with distinct adverse outcomes.

OBJECTIVE: We aimed to evaluate the heterogeneity of gestational diabetes mellitus (GDM) patients diagnosed with various screening criteria. METHODS: We stratified pregnant women using consecutive fasting plasma glucose (FPG) and 2-hour postprandial plasma glucose (2hPPG) intervals of 0.2 mmol/L. The incidence of abnormal neonatal birthweight and birth-related adverse outcomes was compared with that of pregnant women without GDM. RESULTS: The study included 39,988 pregnant women (18-45 years, mean [SD], 31.5 [4.7] years) in Ningbo, China. The means (SDs) of FPG and 2hPPG within 24-28 weeks of gestation were 4.5 (0.5) and 6.8 (1.3) mmol/L, respectively. A total of 3025 (7.6%) women had 5.1-6.9 mmol/L FPG and 4560 (11.4%) had 8.5-11.0 mmol/L 2hPPG. The incidence of GDM according to the two combination criteria was 17.3% (6908 cases). The relative risk (RR) for < 10th percentile birthweight (< 10th WT) was 0.82 (95% CI, 0.74-0.91, p < 0.001) by 5.1 mmol/L FPG criterion and 1.14 (95% CI, 1.06-1.23, p < 0.001) by 8.5 mmol/L 2hPPG criterion, while the RRs for > 90th percentile birthweight (> 90th WT) were 1.48 (95% CI, 1.35-1.63, p < 0.001) and 0.95 (95% CI, 0.86-1.04, p = 0.29) according to the corresponding criteria. The FPG criterion was more strongly associated with maternal hypertension than the 2hPPG criterion. Both criteria did not show a distinct association with other composite adverse outcomes. CONCLUSION: High FPG is significantly associated with high birth weight, whereas high 2hPPG is slightly associated with low birth weight. Our findings highlight the heterogeneity of patients with GDM diagnosed by different criteria.

Role of cGAS-STING signaling pathway in cardiometabolic diseases. / cGAS-STINGé€šè·¯åœ¨ä»£è°¢æ€§å¿ƒè¡€ç®¡ç–¾ç— ä¸­çš„ä½œç”¨.

Cardiometabolic disease is a common clinical syndrome with exact causal relationship between the aberrant of glucose/lipid metabolism and cardiovascular disfunction, but its pathogenesis is unclear. Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon gene (STING) signaling pathway regulates the activation of innate immunity by sensing intracellular double stranded DNA. Metabolic risk factors drive the activation of cGAS-STING pathway through mitochondrial DNA, nuclear DNA and endoplasmic reticulum stress. In addition, the activation of the cGAS-STING pathway triggers chronic sterile inflammation, excessive activation of autophagy, senescence and apoptosis in related cells of cardiovascular system. These changes induced by cGAS-STING pathway might be implicated in the onset and deterioration of cardiometabolic disease. Therefore, the targeting intervention of cGAS-STING signaling pathway may emerge as a novel treatment for cardiometabolic disease.

Downregulation of Circ_0088196 Contributes to the Development of Trophoblastic Cells through miR-133b Sponging Function to Affect the AHNAK Expression.

OBJECTIVE: Preeclampsia (PE) is the most common gestational disease related to various biomolecules, including circular RNA. Hsa_circ_0088196 (circ_0088196) was aberrantly upregulated in PE tissues. DESIGN: This study focused on the further exploration of circ_0088196 in PE. METHODS: Circ_0088196, microRNA-133b (miR-133b), and AHNAK Nucleoprotein (AHNAK) levels were examined using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). EDU assay was used for proliferation detection. Cell cycle and apoptosis were analyzed using flow cytometry. Wound healing assay and transwell assay were performed to assess migration and invasion. The protein levels were determined via Western blot. Target analysis was conducted through dual-luciferase reporter assay and RNA pull-down assay. RESULTS: Circ_0088196 upregulation was detected in PE patients. The knockdown of circ_0088196 induced the promotion of proliferation, cell cycle, migration, and invasion but not the inhibition of apoptosis in trophoblastic cells. Then, circ_0088196 was found to act as a sponge of miR-133b in HTR-8/SVneo cells. The inhibition of miR-133b abolished the regulation of si-circ_0088196 in trophoblastic cells. In addition, miR-133b targeted AHNAK and circ_0088196 evoked the expression change of AHNAK by sponging miR-133b. The function of circ_0088196 was also achieved by regulating AHNAK in trophoblastic cells. LIMITATIONS: The role of circ_0088196 in PE was not verified by in vivo experiments. CONCLUSION: The current evidence demonstrated that circ_0088196 knockdown facilitated trophoblastic cell development by regulating the levels of miR-133b and AHNAK, suggesting that circ_0088196 promoted the PE progression via the miR-133b/AHNAK axis.

Long intergenic noncoding RNA 00473 promoting migration and invasion of trophoblastic cell line HTR-8/SVneo via regulating miR-424-5p-mediated wnt3a/ß-catenin signaling pathway.

BACKGROUND: Preeclampsia (PE) is a serious obstetric complication. Recent studies point out that the functions of long intergenic noncoding RNA 00473 (linc00473), miR-424-5p, and Wnt/ß-catenin signaling pathway were involved in the invasion and migration of extravillous trophoblast. Here, we investigated the role and mechanism of linc00473 in HTR-8/SVneo trophoblastic cell line and its role in PE. METHOD: The expression levels of linc00473 and miR-424-5p in placental tissues and the transfection efficiency of miR-424-5p were detected by quantitative real-time polymerase chain reaction (qRT-PCR). HTR-8/SVneo cell invasion and proliferation were determined by transwell and Cell Counting Kit-8 (CCK-8) assays. The protein expressions of wnt3a, p-GSK3ß, GSK3ß, active ß-catenin, and total ß-catenin were detected by Western blot. The apoptosis and migration of HTR-8/SVneo cells were detected by flow cytometry and wound healing assays. The targeting relationships between linc00473, miR-424-5p, and wnt3a were predicted by ENCORI database and TargetScan V7.2 and were determined using dual-luciferase reporter assay. RESULTS: The expression level of linc00473 was low and miR-424-5p was high in placenta of PE patients. Linc00473 can target miR-424-5p, while miR-424-5p target wnt3a. High expression of linc00473 and wnt3a promoted cell proliferation, migration, invasion, and inhibited cell apoptosis. However, miR-424-5p mimic inhibited HTR-8/SVneo cells proliferation, migration, invasion, while promoted cell apoptosis, partially reversed the effect of linc00473, while wnt3a overexpression partially counteracted the effect of miR-424-5p mimic. CONCLUSION: Linc00473 mediates the regulation of Wnt/ß-catenin signaling pathway by miR-424-5p to affect the invasion and migration ability of trophoblastic cell line HTR-8/SVneo. It indicated that linc00473 is involved in PE and could be a therapeutic target.

[Benefit of network education to college students' knowledge about sexual and reproductive health in Ningbo city].

OBJECTIVE: To investigate how network education can improve college students' knowledge on sexual and reproductive health in Ningbo city. METHODS: From December 2012 to June 2013, we conducted a questionnaire investigation among college students in Ningbo city about the effects of network education on their knowledge about sexual psychology, sexual physiology, sexual ethics, and reproductive health. RESULTS: A total of 7 362 college students accomplished the investigation, of whom 2 483 (42.1% males and 57.9% females) received network education, while the other 4 879 (24.1% males and 75.9% females) did not. Approximately 47.1% of the male and 28.0% of the female students acquired sexual and reproductive knowledge via network education. Reproductive health-related network education significantly enriched the students' knowledge about the reproductive system and sex, pubertal development, sexual physiology, conception and embryonic development, methods of contraception, sexual psychology, sexually transmitted diseases and their prevention, pregnancy care and eugenics, and environment- and occupation-related reproductive health (P < 0.01). It also remarkably improved their cognitive attitude towards reproductive health knowledge (P < 0.01). Those who received reproductive health-related network education showed a significantly higher rate of masturbation (P < 0.01) but markedly later time of the first masturbation (P < 0.01) than those who did not. CONCLUSION: Network education can enhance the effect of reproductive health education among college students and improve their sexual experience and health.

MAD2L2, a key regulator in ovarian cancer and promoting tumor progression.

Ovarian cancer (OVCA), a prevalent gynecological malignancy, ranks as the fourth most common cancer among women. Mitotic Arrest Deficient 2 Like 2 (MAD2L2), a chromatin-binding protein and a component of DNA polymerase ζ, has been previously identified as an inhibitor of tumor growth in colorectal cancer. However, the roles of MAD2L2 in OVCA, including its expression, impact, and prognostic significance, remain unclear. We employed bioinformatics tools, Cox Regression analysis, and in vitro cell experiments to investigate its biological functions. Our findings reveal that MAD2L2 typically undergoes genomic alterations, such as amplifications and deep deletions. Moreover, we observed an overexpression of MAD2L2 mRNA in OVCA patients, correlating with reduced survival rates, particularly in those with Grade IV tumors. Furthermore, analysis of mRNA biofunctions indicated that MAD2L2 is predominantly localized in the organellar ribosome, engaging mainly in NADH dehydrogenase activity. This was deduced from the results of gene ontology enrichment analysis, which also identified its role as a structural constituent in mitochondrial translation elongation. These findings were corroborated by KEGG pathway analysis, further revealing MAD2L2's involvement in tumor metabolism and the cell death process. Notably, MAD2L2 protein expression showed significant associations with various immune cells, including CD4+T cells, CD8+T cells, B cells, natural killer cells, and Myeloid dendritic cells. Additionally, elevated levels of MAD2L2 were found to enhance cell proliferation and migration in OVCA cells. The upregulation of MAD2L2 also appears to inhibit the ferroptosis process, coinciding with increased mTOR signaling activity in these cells. Our study identifies MAD2L2 as a novel regulator in ovarian tumor progression and offers new insights for treating OVCA.

RNA-seq reveals differentially expressed lncRNAs and circRNAs and their associated functional network in HTR-8/Svneo cells under hypoxic conditions.

Placental hypoxia is hazardous to maternal health as well as fetal growth and development. Preeclampsia and intrauterine growth restriction are common pregnancy problems, and one of the causes is placental hypoxia. Placental hypoxia is linked to a number of pregnancy illnessesv. To investigate their potential function in anoxic circumstances, we mimicked the anoxic environment of HTR-8/Svneo cells and performed lncRNA and circRNA studies on anoxic HTR-8/Svneo cells using high-throughput RNA sequencing. The miRNA target genes were predicted by integrating the aberrant expression of miRNAs in the placenta of preeclampsia and intrauterine growth restriction, and a ceRNA network map was developed to conduct a complete transcriptomic and bioinformatics investigation of circRNAs and lncRNAs. The signaling pathways in which the genes were primarily engaged were predicted using GO and KEGG analyses. To propose a novel explanation for trophoblastic organism failure caused by lncRNAs and circRNAs in an anoxic environment.

The association between atherogenic index of plasma and metabolic dysfunction-associated fatty liver disease as detected by FibroScan.

Introduction: Objectives: this study aimed to explore the potential of the atherogenic index of plasma (AIP) as a predictor of metabolic dysfunction-associated fatty liver disease (MAFLD). Methods: a cross-sectional study, including data from 4473 participants in the National Health and Nutrition Examination Survey (NHANES) 2017-2018, was performed. A control attenuation parameter (CAP) ≥ 285 dB/m was used to confirm hepatic steatosis. Degrees of liver stiffness were confirmed according to liver stiffness measurement (LSM). Weighted multivariate logistic regression models were used to assess the association between AIP and the risk for MAFLD and liver fibrosis. Finally, receiver operating characteristic (ROC) curve analysis was used to test the accuracy of AIP in predicting MAFLD. Results: the association between AIP and the prevalence of MAFLD was positive in all three multivariate logistic regression models (model 1, odds ratio (OR), 18.2 (95 % confidence interval (CI), 14.4-23.1); model 2, OR, 17.0 (95 % CI, 13.3-21.8); model 3, OR, 5.2 (95 % CI, 3.9-7.0)). Moreover, this positive relationship was found to be significant in patients of different sexes and whether they had diabetes. However, no significant differences were observed between AIP and significant fibrosis or cirrhosis as assessed by different liver fibrosis indices. Finally, ROC curve analysis demonstrated that the AIP index also demonstrated positive diagnostic utility (area under the ROC curve, 0.733 (95 % CI, 0.718-0.747); p < 0.001). Conclusion: This study revealed a positive association between AIP and MAFLD among American adults. Furthermore, this association persisted in different sexes and whether they had diabetes.

Introducción: Objetivos: este estudio tuvo como objetivo explorar el potencial del índice aterogénico del plasma (AIP) como predictor de enfermedad hepática grasa asociada a disfunción metabólica (MAFLD). Métodos: se realizó un estudio transversal que incluyó datos de 4473 participantes de la encuesta nacional de exémenes de salud y nutrición (NHANES) 2017-2018. Se utilizó un parámetro de atenuación de control (CAP) ≥ 285 dB/m para confirmar la esteatosis hepática. Los grados de rigidez hepática se confirmaron de acuerdo con la medición de rigidez hepática (LSM). Se utilizaron modelos de regresión logística multivariponderponderados para evaluar la asociación entre AIP y el riesgo de MAFLD y fibrosis hepática. Por último, se utilizó el análisis de la curva ROC para probar la precisión de la AIP en la predicción de la MAFLD. Resultados: la asociación entre AIP y prevalencia de MAFLD fue positiva en los tres modelos de regresión logística multivariable (modelo 1, odds ratio (OR): 18,2 (intervalo de confianza (IC) del 95 %: 14,4-23,1); Modelo 2, OR: 17,0 (IC del 95 %: 13,3-21,8); Modelo 3, OR: 5,2 (IC del 95 %: 3,9-7,0)). Además, esta relación positiva se encontró significativa en pacientes de diferentes sexos ya tuvieran o no diabetes. Sin embargo, no se observaron diferencias significativas entre la AIP y la fibrosis o cirrosis significativa evaluada por diferentes índices de fibrosis hepática. Finalmente, el análisis de la curva ROC demostró que el índice AIP también demostró utilidad diagnóstica positiva (área bajo la curva ROC = 0,733 (IC del 95 %: 0,718-0,747); p < 0,001). Conclusión: este estudio reveló una asociación positiva entre AIP y MAFLD en los adultos estadounidenses. Además, esta asociación persistió en los diferentes sexos ya tuvieran o no diabetes.

Relationship between skeletal muscle mass loss and metabolic dysfunction-associated fatty liver disease among Chinese patients with metabolic dysregulation.

OBJECTIVE: The aim of this study was to explore the correlation between skeletal muscle content and the presence and severity of metabolic dysfunction-associated fatty liver disease in patients with metabolic dysregulation in China. METHODS: A cross-sectional study was conducted among patients from the endocrinology outpatient department at Ningbo First Hospital, in Ningbo, China, in April 2021. Adult patients with metabolic dysregulation who accepted FibroScan ultrasound were included in the study. However, those without clinical data on skeletal muscle mass were excluded. FibroScan ultrasound was used to noninvasively evaluate metabolic dysfunction-associated fatty liver disease. The controlled attenuation parameter was used as an evaluation index for the severity of liver steatosis. Bioelectrical impedance analysis was used to measure the skeletal muscle index. RESULTS: A total of 153 eligible patients with complete data were included in the final analysis. As the grading of liver steatosis intensifies, skeletal muscle index decreases (men: Ptrend<0.001, women: Ptrend=0.001), while body mass index, blood pressure, blood lipid, uric acid, aminotransferase, and homeostatic model assessment of insulin resistance increase (Ptrend<0.01). After adjusting for confounding factors, a negative association between skeletal muscle index and the presence of metabolic dysfunction-associated fatty liver disease was observed in men (OR=0.691, p=0.027) and women (OR=0.614, p=0.022). According to the receiver operating characteristic curve, the best cutoff values of skeletal muscle index for predicting the metabolic dysfunction-associated fatty liver disease presence were 40.37% for men (sensitivity, 87.5%; specificity, 61.5%) and 33.95% for women (sensitivity, 78.6%; specificity, 63.8%). CONCLUSION: Skeletal muscle mass loss among patients with metabolic dysregulation was positively associated with metabolic dysfunction-associated fatty liver disease severity in both sexes. The skeletal muscle index cutoff value could be used to predict metabolic dysfunction-associated fatty liver disease.

The angelica Polysaccharide: a review of phytochemistry, pharmacology and beneficial effects on systemic diseases.

Angelica sinensis is a perennial herb widely distributed around the world, and angelica polysaccharide (APS) is a polysaccharide extracted from Angelica sinensis. APS is one of the main active components of Angelica sinensis. A large number of studies have shown that APS has hematopoietic, promoting blood circulation, radiation resistance, lowering blood glucose, enhancing the body immunity and other pharmacological effects in a variety of diseases. However, different extraction methods and extraction sites greatly affect the efficacy of APS. In recent years, with the emerging of new technologies, there are more and more studies on the combined application and structural modification of APS. In order to promote the comprehensive development and in-depth application of APS, this narrative review systematically summarizes the effects of different drying methods and extraction sites on the biological activity of APS, and the application of APS in the treatment of diseases, hoping to provide a scientific basis for the experimental study and clinical application of APS.

The effect of TFAP2A/ANXA8 axis on ferroptosis of cervical squamous cell carcinoma (CESC) in vitro.

Potential role and associated mechanisms of Annexin A8 (ANXA8), a member of the Annexins family, in cervical squamous cell carcinoma (CESC) are still unclear, despite being upregulated in various malignant tumors. Here, we observed a notably elevated expression of ANXA8 in CESC cells. The inhibition of ANXA8 amplified the susceptibility of CESC cells to Erastin and sorafenib-induced ferroptosis, whereas it exerted minimal influence on DPI7 and DPI10-induced ferroptosis. The results from the Fe2+ concentration assay showed no significant correlation between ANXA8 gene knockdown and intracellular Fe2+ concentration induced by ferroptosis inducers. Western blot analysis demonstrated that the knockdown of ANXA8 did not alter ACSL4 and LPCAT levels under ferroptosis-inducing conditions, but it did result in a reduction in intracellular GSH levels induced by the ferroptosis inducer. Subsequently, we identified TFAP2A as an upstream transcription factor of ANXA8, which plays a role in regulating cell ferroptosis. The knockdown of TFAP2A significantly elevated MDA levels and depressed GSH levels in the presence of a ferroptosis inducer, thereby inhibiting cell ferroptosis. However, this inhibitory effect could be reversed by ANXA8 overexpression. Therefore, our research suggests that the TFAP2A/ANXA8 axis exerts regulatory control over ferroptosis in CESC cells by mediating GSH synthesis in System Xc.

Cumulative blood pressure predicts risk of stroke in individuals with type 2 diabetes.

AIMS: To determine whether cumulative blood pressure (BP) could predict stroke in individuals with type 2 diabetes (T2D). METHODS: BP levels at baseline and the initial three visits were obtained from individuals participating in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial who had not experienced a stroke. Cumulative elevations in BP were assessed by adding the weighted mean BP values at various time intervals. The association of cumulative BP with stroke was evaluated by a multivariate-adjusted Cox proportional hazard model analysis. RESULTS: Overall, 8282 participants were included (62.10% males and 37.90% females; mean age, 62.73 years). With a median follow-up period of 6.36 years, 324 (3.91%) and 305 (3.68%) patients had any and nonfatal stroke events, respectively. Only baseline systolic BP (SBP) independently predicted any stroke after adjustment for potential confounders, whereas cumulative SBP and pulse pressure independently predicted elevated stroke events. A strong dose-response relationship between cumulative BP and stroke was identified, and conventional risk factors combined with cumulative SBP improved prediction efficiency. CONCLUSION: Cumulative SBP independently predicts stroke in individuals with T2D and provides an incremental predictive value for stroke compared with baseline BP assessments. TRIAL REGISTRATION: URL: http://www. CLINICALTRIALS: gov. Unique identifier: NCT00000620).

A large-scale production of mesenchymal stem cells and their exosomes for an efficient treatment against lung inflammation.

Mesenchymal stem cells (MSCs) and their produced exosomes have demonstrated inherent capabilities of inflammation-guided targeting and inflammatory modulation, inspiring their potential applications as biologic agents for inflammatory treatments. However, the clinical applications of stem cell therapies are currently restricted by several challenges, and one of them is the mass production of stem cells to satisfy the therapeutic demands in the clinical bench. Herein, a production of human amnion-derived MSCs (hMSCs) at a scale of over 1 × 109 cells per batch was reported using a three-dimensional (3D) culture technology based on microcarriers coupled with a spinner bioreactor system. The present study revealed that this large-scale production technology improved the inflammation-guided migration and the inflammatory suppression of hMSCs, without altering their major properties as stem cells. Moreover, these large-scale produced hMSCs showed an efficient treatment against the lipopolysaccharide (LPS)-induced lung inflammation in mice models. Notably, exosomes collected from these large-scale produced hMSCs were observed to inherit the efficient inflammatory suppression capability of hMSCs. The present study showed that 3D culture technology using microcarriers coupled with a spinner bioreactor system can be a promising strategy for the large-scale expansion of hMSCs with improved anti-inflammation capability, as well as their secreted exosomes.

Pan-cancer analyses reveal genomics and clinical outcome association of the fatty acid oxidation regulators in cancer.

Background: Fatty acid oxidation (FAO) is considered to play a vital part in tumor metabolic reprogramming. But the comprehensive description of FAO dysregulation in tumors has not been unknown. Methods: We obtained FAO genes, RNA-seq data and clinical information from the Msigdb, TCGA and GTEx databases. We assessed their prognosis value using univariate cox analysis, survival analysis and Kaplan-Meier curve. We determined the function of FAO genes using gene set variation analysis. The correlation analysis was calculated by corrplot R package. Immunotherapy response was assessed through TIDE scores. The protein expression levels of FAO genes were validated using immunohistochemistry (IHC). Results: The FAO scores were highest in COAD but lowest in PCPG. FAO scores were significantly associated with the prognosis of some cancers in OS, DSS, DFI and PFI. Besides, gene set variation analysis identified that FAO scores were related to immune-related pathways, and immune infiltration analysis showed FAO scores were positively related to cancer-associated fibroblasts and various immune-related genes. TIDE scores were significantly decreased in ACC, CHOL, ESCA, GBM, LAML, SARC, SKCM and THCA compared with normal samples, while it was significantly increased in BLCA, LUAD, LUSC, PCPG, PRAD and STAD. Besides, most FAO genes were downregulated in pan-cancer compared with normal samples. Moreover, we found copy number variation (CNV) of FAO genes played a positive role in their mRNA expression, while methylation was negative. We determined FAO genes were closely related to some drugs in pan-cancer. Conclusions: FAO score is a novel and promising factor for predicting outcomes.

Evodiamine inhibits malignant progression of ovarian cancer cells by regulating lncRNA-NEAT1/miR-152-3p/CDK19 axis.

Evodiamine (EVO) has been demonstrated to promote apoptosis of ovarian cancer cells, and upregulate miR-152-3p level in colorectal cancer. Here, we explore part of the network mechanism of EVO and miR-152-3p in ovarian cancer. The bioinformatics website, dual luciferase reporter assay, and quantitative real-time polymerase chain reaction were applied to analyze the network among EVO, lncRNA, miR-152-3p, and mRNA. The effect and mechanism of EVO on ovarian cancer cells were determined using cell counting kit-8, flow cytometry, TUNEL, Western blot, and rescue experiments. As a result, EVO dose-dependently attenuated cell viability, induced G2/M phase arrest and apoptosis, promoted miR-152-3p level (4.5- or 2-fold changes), and inhibited expressions of NEAT1 (0.225- or 0.367-fold changes), CDK8 (0.625- or 0.571-fold changes), and CDK19 (0.25- or 0.147-fold changes) in OVCAR-3 and SKOV-3 cells. In addition, EVO decreased Bcl-2 expression, but increased the expressions of Bax and c-caspase-3. NEAT1 targeted miR-152-3p which bound to CDK19. The impacts of EVO on cell viability, cycle, apoptosis, and apoptosis-related proteins were partially reversed by miR-152-3p inhibitor, NEAT1 overexpression, or CDK19 overexpression. Furthermore, miR-152-3p mimic offset the effects of NEAT1 or CDK19 overexpression. The role of NEAT1 overexpression in the biological phenotype of ovarian cancer cells was counteracted by shCDK19. In conclusion, EVO attenuates ovarian cancer cell progression via the NEAT1-miR-152-3p-CDK19 axis.

Case report: A compound heterozygous mutations in ASNS broadens the spectrum of asparagine synthetase deficiency in the prenatal diagnosis.

Asparagine synthetase deficiency (ASNSD) is a rare congenital disorder characterized by severe progressive microcephaly, global developmental delay, spastic quadriplegia, and refractory seizures. ASNSD is caused by variations of the ASNS gene. The present study showed a Chinese family with a fetus suffering microcephaly. Whole-exome sequencing and Sanger sequencing were used to identify the disease-associated genetic variants. Compound heterozygous variants c.97C>T p. (R33C) and c.1031-2_1033del were identified in the ASNS gene and the variants were inherited from the parents. The mutation site c.97C>T was highly conserved across a wide range of species and predicted to alter the local electrostatic potential. The variant c.1031-2_1033del was classified pathogenic. However, there is no case report of prenatal diagnosis of ASNSD. This is the first description of fetal compound mutations in the ASNS gene leading to ASNSD, which expanded the spectrum of ASNSD.

Dapagliflozin impedes endothelial cell senescence by activating the SIRT1 signaling pathway in type 2 diabetes.

Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) clinically reduce atherosclerosis and lower blood pressure. However, their impact on endothelial dysfunction in type 2 diabetes (T2D) remains unclear. In this study, we investigated the protective effect and underlying mechanism of the SGLT2 inhibitor dapagliflozin in diabetes. Methods: Vascular reactivity was measured to assess the vasoprotective effect of dapagliflozin in a mouse model of high glucose (HG)-induced T2D. Pulse wave velocity was measured to quantify arterial stiffness. Protein expression was assessed by western blotting and immunofluorescence, oxidative stress was evaluated using dihydroethidium, nitric oxide was evaluated using the Griess reaction, and cellular senescence was assessed based on senescence-associated beta-galactosidase (SA-ß-gal) activity and the expression of senescence markers. Furthermore, the endothelial nitric oxide synthase (eNOS) acetylation status was determined and eNOS interactions with SIRT1 were evaluated by coimmunoprecipitation assays. Results: Dapagliflozin protected against impaired endothelium-dependent vasorelaxation and improved arterial stiffness in the mouse model of T2D; mouse aortas had significantly reduced levels of senescence activity and senescence-associated inflammatory factors. HG-induced increases in senescence activity, protein marker levels, and oxidative stress in vitro were all ameliorated by dapagliflozin. The decreases in eNOS phosphorylation and nitric oxide (NO) production in senescent endothelial cells were restored by dapagliflozin. SIRT1 expression was reduced in HG-induced senescent endothelial cells, and dapagliflozin restored SIRT1 expression. SIRT1 inhibition diminished the antisenescence effects of dapagliflozin. Coimmunoprecipitation showed that SIRT1 was physically associated with eNOS, suggesting that the effects of dapagliflozin are dependent on SIRT1 activation. Conclusion: These findings indicate that dapagliflozin protects against endothelial cell senescence by regulating SIRT1 signaling in diabetic mice.

TRIM28 recruits E2F1 to regulate CBX8-mediated cell proliferation and tumor metastasis of ovarian cancer.

Chromobox protein homolog 8 (CBX8) is a transcriptional suppressor participated in various cancers. However, the function and mechanism of CBX8 in the progression of ovarian cancer (OC) are unclear. In this study, we found that CBX8 was upregulated in OC tissues originating from GEPIA and TNM databases, OC patients' samples from hospital, and OC cell lines. Furthermore, CBX8 knockdown by short hairpin RNA (shRNA) technology markedly inhibited proliferation and invasion, induced migration, cell cycle arrest, and apoptosis in vitro. Mechanistically, CBX8 activated PI3K/AKT/mTOR signaling pathway to take effect. In addition, TRIM28 and E2F1 were enriched in OC tissues from the TNM database and OC patients' samples similar to the results of CBX8. Correlation analysis indicated positive correlations among TRIM28, E2F1, and CBX8. E2F1 was proved to bind to the promoter regions of CBX8 and TRIM28, while TRIM28 recruited E2F1 to increase the expression of CBX8 to further increase cell viability, proliferation, and invasion, and decrease migration, apoptosis, and cell cycle progression. Finally, CBX8 or TRIM28 knockdown repressed tumor growth and metastasis of OC in vivo. Therefore, our study showed that the promoting effect of CBX8 on tumor growth and metastasis of OC was participated in the PI3K/AKT/mTOR signaling, TRIM28 and E2F1. Our findings suggested that CBX8 could serve as a potential marker and therapeutic target for OC patients.

CTRP9 decreases high glucose­induced trophoblast cell damage by reducing endoplasmic reticulum stress.

C1q/TNF­α­related protein 9 (CTRP9) is downregulated in gestational diabetes mellitus (GDM) and may exert a protective effect against GDM, although its mechanism of action is yet to be elucidated. To investigate the specific role of CTRP9 in GDM, the human placental trophoblast cell line HTR8/SVneo was treated with high glucose (HG) to simulate the environment of GDM in vitro. The effects of CTRP9 on the HTR8/SVneo cells and endoplasmic reticulum (ER) stress were analyzed before and after CTRP9 overexpression using reverse transcription­quantitative PCR and western blotting. The results obtained demonstrated that CTRP9 alleviated ER stress in the trophoblast cell line. After treating with the ER­stress inducer tunicamycin, cell viability was investigated by performing Cell Counting Kit­8, TUNEL and western blotting assays, which revealed that CTRP9 increased the activity of HTR8/SVneo cells induced by HG through the alleviation of ER stress. Subsequently, ELISA and western blotting assay results demonstrated that CTRP9 inhibited HG­induced inflammation of the HTR8/SVneo cells by the reduction in ER stress. Finally, the detection of reactive oxygen species, nitric oxide (NO) synthase and NO levels confirmed that CTRP9 inhibited the oxidative stress of HTR8/SVneo cells induced by HG through the reduction of ER stress. Collectively, the results of the present study suggested that CTRP9 may decrease trophoblast cell damage caused by HG through the suppression of ER stress, and therefore, CTRP9 may potentially be a therapeutic target in the treatment of GDM.