Maternal body mass index and cerebral palsy in children: A systematic review and dose-response meta-analysis.

BACKGROUND: Accumulating studies indicate that maternal obesity is associated with the risk of cerebral palsy (CP); however, their conclusions have been inconsistent. OBJECTIVES: To quantitatively estimate the association between maternal body mass index (BMI) and CP in offspring. DATA SOURCES: PubMed, Embase and Web of Science. STUDY SELECTION AND DATA EXTRACTION: Articles published up to 18 September 2022 were searched that reported the correlation between maternal BMI and CP in children. Two reviewers independently extracted data and critically assessed articles. SYNTHESIS: Pooled relative risks (RR) and 95% confidence intervals (CI) were estimated by the random-effects model. Subgroup analysis and meta-regression were performed to explore sources of heterogeneity. RESULTS: In total, 11 articles (8,407,668 participants) were identified for inclusion in our meta-analysis. For maternal underweight, no significant association was found with CP risk (RR 1.11, 95% CI 0.90, 1.38). The risk of CP was increased by 25% (RR 1.25, 95% CI 1.06, 1.47), 38% (RR 1.38, 95% CI 1.18, 1.61) and 127% (RR 2.27, 95% CI 1.82, 2.83) for maternal overweight, obesity and obesity grade 3, respectively. In addition, we observed a positive linear dose-response relationship, with the pooled risk of cerebral palsy in offspring increasing by 3% with each unit increase in maternal BMI. CONCLUSION: This meta-analysis indicates that the risk of CP in offspring grew with maternal overweight or obesity grades increasing, and was positively correlated with maternal BMI.

Paired box 6 inhibits cardiac fibroblast differentiation.

Cardiac fibroblast (CF) differentiation plays a crucial role in cardiac fibrosis, which is a specific manifestation distinguishing pathological cardiac hypertrophy from physiological hypertrophy. The DNA-binding activity of paired box 6 (Pax6) has been shown to be oppositely regulated in physiological and pathological hypertrophy; however, it remains unclear whether Pax6 is involved in CF differentiation during cardiac fibrosis. We found that Pax6 is expressed in the heart of and CFs isolated from adult mice. Moreover, angiotensin II (Ang II) induced the downregulation of Pax6 mRNA and protein expression in fibrotic heart tissue and cardiac myofibroblasts. Pax6 knockdown in CFs promoted the expression of the myofibroblast marker α-smooth muscle actin (α-SMA) and the synthesis of the extracellular matrix (ECM) proteins collagen I and fibronectin. Furthermore, we validated the ability of Pax6 to bind to the promoter regions of Cxcl10 and Il1r2 and the intronic region of Tgfb1. Pax6 knockdown in CFs decreased CXC chemokine 10 (CXCL10) and interleukin-1 receptor 2 (IL-1R2) expression and increased transforming growth factor ß1 (TGFß1) expression, mimicking the effects of Ang II. In conclusion, Pax6 exerts an inhibitory effect on CF differentiation and ECM synthesis by transcriptionally activating the expression of the anti-fibrotic factors CXCL10 and IL-1R2 and repressing the expression of the pro-fibrotic factor TGFß1. Therefore, maintaining Pax6 expression in CFs is essential for preventing CF differentiation, and provides a new therapeutic target for cardiac fibrosis.

α1-AR overactivation induces cardiac inflammation through NLRP3 inflammasome activation.

Acute sympathetic stress causes excessive secretion of catecholamines and induces cardiac injuries, which are mainly mediated by ß-adrenergic receptors (ß-ARs). However, α1-adrenergic receptors (α1-ARs) are also expressed in the heart and are activated upon acute sympathetic stress. In the present study, we investigated whether α1-AR activation induced cardiac inflammation and the underlying mechanisms. Male C57BL/6 mice were injected with a single dose of α1-AR agonist phenylephrine (PE, 5 or 10 mg/kg, s.c.) with or without pretreatment with α-AR antagonist prazosin (5 mg/kg, s.c.). PE injection caused cardiac dysfunction and cardiac inflammation, evidenced by the increased expression of inflammatory cytokine IL-6 and chemokines MCP-1 and MCP-5, as well as macrophage infiltration in myocardium. These effects were blocked by prazosin pretreatment. Furthermore, PE injection significantly increased the expression of NOD-like receptor protein 3 (NLRP3) and the cleavage of caspase-1 (p20) and interleukin-18 in the heart; similar results were observed in both Langendorff-perfused hearts and cultured cardiomyocytes following the treatment with PE (10 µM). Moreover, PE-induced NLRP3 inflammasome activation and cardiac inflammation was blocked in Nlrp3-/- mice compared with wild-type mice. In conclusion, α1-AR overactivation induces cardiac inflammation by activating NLRP3 inflammasomes.

ß3-adrenergic receptor activation induces TGFß1 expression in cardiomyocytes via the PKG/JNK/c-Jun pathway.

In heart failure, the expression of cardiac ß3-adrenergic receptors (ß3-ARs) increases. However, the precise role of ß3-AR signaling within cardiomyocytes remains unclear. Transforming growth factor ß1 (TGFß1) is a crucial cytokine mediating the cardiac remodeling that plays a causal role in the progression of heart failure. Here, we set out to determine the effect of ß3-AR activation on TGFß1 expression in rat cardiomyocytes and examine the underlying mechanism. The selective ß3-AR agonist BRL37344 induced an increase in TGFß1 expression and the phosphorylation of c-Jun N-terminal kinase (JNK) and c-Jun in ß3-AR-overexpressing cardiomyocytes. Those effects of BRL37344 were suppressed by a ß3-AR antagonist. Moreover, the inhibition of JNK and c-Jun activity by a JNK inhibitor and c-Jun siRNA blocked the increase in TGFß1 expression upon ß3-AR activation. A protein kinase G (PKG) inhibitor also attenuated ß3-AR-agonist-induced TGFß1 expression and the phosphorylation of JNK and c-Jun. In conclusion, the ß3-AR activation in cardiomyocytes increases the expression of TGFß1 via the PKG/JNK/c-Jun pathway. These results help us further understand the role of ß3-AR signaling in heart failure.

The impact of folic acid/VB12 deficiency on essential hypertension in children and adolescents: from a nested case-control and a cohort study.

To explore the relationship between serum folic acid (FA) or Vitamin B12 (VB12) and elevated BP in children and adolescents. Both a nested case control and a cohort study were designed to explore the relationship between serum folic acid (FA) or Vitamin B12 (VB12) and elevated blood pressure (BP). All the included participants were from primary school. A total of 326 subjects (116:210) in nested case control were from an established cohort. And 270 participants without hypertension at baseline and followed in 2019 in cohort. FA and VB12 levels were lower in the elevated BP group than in the control group, and homocysteine level was higher than that in the control group. In the elevated BP group, overweight/obese children had lower FA than overweight/obese children in the normal BP group. FA was positively correlated with high-density lipoprotein (HDL) and Apo lipoprotein A (APOA), but negatively correlated with triglyceride (TG). FA was significantly correlated with elevated BP in children and adolescents (ß = -0.353, P = 0.032), after adjusting VB12, and homocysteine (HCY), and the interaction effect of FA*HCY was significant. Both systolic and diastolic BP levels were statistically lower in the FA high exposure group than in the FA low exposure group in the cohort study. This study found that FA and vitamin B12 deficiency in childhood was correlated with elevated BP levels, which may affect BP by regulating lipid levels, and confirmed the importance of maintaining high levels of FA and vitamin B12 in childhood either by diet or supplementation.

Cardiomyocyte NOX4 regulates resident macrophage-mediated inflammation and diastolic dysfunction in stress cardiomyopathy.

In acute sympathetic stress, catecholamine overload can lead to stress cardiomyopathy. We tested the hypothesis that cardiomyocyte NOX4 (NADPH oxidase 4)-dependent mitochondrial oxidative stress mediates inflammation and diastolic dysfunction in stress cardiomyopathy. Isoproterenol (ISO; 5 mg/kg) injection induced sympathetic stress in wild-type and cardiomyocyte (CM)-specific Nox4 knockout (Nox4CM-/-) mice. Wild-type mice treated with ISO showed higher CM NOX4 expression, H2O2 levels, inflammasome activation, and IL18, IL6, CCL2, and TNFα levels than Nox4CM-/- mice. Spectral flow cytometry and t-SNE analysis of cardiac cell suspensions showed significant increases in pro-inflammatory and pro-fibrotic embryonic-derived resident (CCR2-MHCIIhiCX3CR1hi) macrophages in wild-type mice 3 days after ISO treatment, whereas Nox4CM-/- mice had a higher proportion of embryonic-derived resident tissue-repair (CCR2-MHCIIloCX3CR1lo) macrophages. A significant increase in cardiac fibroblast activation and interstitial collagen deposition and a restrictive pattern of diastolic dysfunction with increased filling pressure was observed in wild-type hearts compared with Nox4CM-/- 7 days post-ISO. A selective NOX4 inhibitor, GKT137831, reduced myocardial mitochondrial ROS, macrophage infiltration, and fibrosis in ISO-injected wild-type mice, and preserved diastolic function. Our data suggest sympathetic overstimulation induces resident macrophage (CCR2-MHCII+) activation and myocardial inflammation, resulting in fibrosis and impaired diastolic function mediated by CM NOX4-dependent ROS.

Galectin-3-centered paracrine network mediates cardiac inflammation and fibrosis upon ß-adrenergic insult.

Rapid over-activation of ß-adrenergic receptors (ß-AR) following acute stress initiates cardiac inflammation and injury by activating interleukin-18 (IL-18), however, the process of inflammation cascades has not been fully illustrated. The present study aimed to determine the mechanisms of cardiac inflammatory amplification following acute sympathetic activation. With bioinformatics analysis, galectin-3 was identified as a potential key downstream effector of ß-AR and IL-18 activation. The serum level of galectin-3 was positively correlated with norepinephrine or IL-18 in patients with chest pain. In the heart of mice treated with ß-AR agonist isoproterenol (ISO, 5 mg kg-1), galectin-3 expression was upregulated markedly later than IL-18 activation, and Nlrp3-/- and Il18-/- mice did not show ISO-induced galectin-3 upregulation. It was further revealed that cardiomyocyte-derived IL-18 induced galectin-3 expression in macrophages following ISO treatment. Moreover, galectin-3 deficiency suppressed ISO-induced cardiac inflammation and fibrosis without blocking ISO-induced IL-18 increase. Treatment with a galectin-3 inhibitor, but not a ß-blocker, one day after ISO treatment effectively attenuated cardiac inflammation and injury. In conclusion, galectin-3 is upregulated to exaggerate cardiac inflammation and injury following acute ß-AR activation, a galectin-3 inhibitor effectively blocks cardiac injury one day after ß-AR insult.

Pathological matrix stiffness promotes cardiac fibroblast differentiation through the POU2F1 signaling pathway.

Cardiac fibroblast (CF) differentiation into myofibroblasts is a crucial cause of cardiac fibrosis, which increases in the extracellular matrix (ECM) stiffness. The increased stiffness further promotes CF differentiation and fibrosis. However, the molecular mechanism is still unclear. We used bioinformatics analysis to find new candidates that regulate the genes involved in stiffness-induced CF differentiation, and found that there were binding sites for the POU-domain transcription factor, POU2F1 (also known as Oct-1), in the promoters of 50 differentially expressed genes (DEGs) in CFs on the stiffer substrate. Immunofluorescent staining and Western blotting revealed that pathological stiffness upregulated POU2F1 expression and increased CF differentiation on polyacrylamide hydrogel substrates and in mouse myocardial infarction tissue. A chromatin immunoprecipitation assay showed that POU2F1 bound to the promoters of fibrosis repressors IL1R2, CD69, and TGIF2. The expression of these fibrosis repressors was inhibited on pathological substrate stiffness. Knockdown of POU2F1 upregulated these repressors and attenuated CF differentiation on pathological substrate stiffness (35 kPa). Whereas, overexpression of POU2F1 downregulated these repressors and enhanced CF differentiation. In conclusion, pathological stiffness upregulates the transcription factor POU2F1 to promote CF differentiation by inhibiting fibrosis repressors. Our work elucidated the crosstalk between CF differentiation and the ECM and provided a potential target for cardiac fibrosis treatment.

The Prevalence of Thrice, Twice, and Once Human Papillomavirus DNA Positivity in Older Chinese Women.

Background: Human papillomavirus (HPV) DNA detection in cervical samples is widely used to identify HPV infection; however, there is little detailed evaluation of the characteristics of HPV prevalence by repeated DNA detection in community populations. Methods: Beginning in 2014, a Papanicolaou (Pap) smear and HPV cotesting program was implemented among older women living in the Minhang district of Shanghai. This report uses information from 225,000 participants, who provided person-time data. Of these, 632 subjects had 3 repeated visits and at least one HPV DNA-positive result in the last 5 years. Results: All 16 genotypes of HPV displayed thrice, twice, and once positivity results in 3 repeated tests and differed by proportions among and within genotypes. HPV52 and 58 are the two most dominant genotypes in total and in thrice positive person-time. The thrice positive person-time exceeded 50% in each of HPV58-, 35-, 52-, 56-, 18-, 68-, 31-, and 16-infected women. The single positive person-time ratio ranged from 7.9% (HPV35) to 38.9% (HPV11). Age differed among and within genotypes in thrice, twice, and once positive women. The average age of HPV-free controls was 59.0 ± 7.2 yo, which is close to the median of average ages for thrice and twice positive women and is older than most average ages for once positive women. The percentages of negative results for intraepithelial lesion or malignancy (NILM) for thrice HPV52-, 58-, 16-, 56-, and 59-positive women were significantly lower than the percentage of NILM for HPV-free women. Conclusion: Thrice and/or twice HPV DNA positivity are common in HPV-infected women and tend to occur in older women.

Naringenin attenuates non-alcoholic fatty liver disease by down-regulating the NLRP3/NF-κB pathway in mice.

BACKGROUND AND PURPOSE: Naringenin, a flavonoid compound with strong anti-inflammatory activity, attenuated non-alcoholic fatty liver disease (NAFLD) induced by a methionine-choline deficient (MCD) diet in mice. However, the mechanisms underlying this suppression of inflammation and NAFLD remain unknown. EXPERIMENTAL APPROACH: WT and NLRP3-/- mice were fed with MCD diet for 7 days to induce NAFLD and were given naringenin by gavage at the same time. in vitro experiments used HepG2 cells, primary hepatocytes, and Kupffer cells (KCs) stimulated by LPS or LPS plus oleic acid (OA). KEY RESULTS: Treating WT mice with naringenin (100 mg·kg-1 ·day-1 ) attenuated hepatic lipid accumulation and inflammation in the livers of mice given the MCD diet. NLRP3-/- mice showed less hepatic lipid accumulation than WT mice, but naringenin did not ameliorate hepatic lipid accumulation further in NLRP3-/- mice. Treating the HepG2 cells with naringenin or NLRP3 inhibitor MCC950 reduced lipid accumulation. Naringenin inhibited activation of the NLRP3/NF-κB pathway stimulated by OA together with LPS. In KCs isolated from WT mice, naringenin inhibited NLRP3 expression. Naringenin also inhibited lipid deposition, NLRP3 and IL-1ß expression in WT hepatocytes but was not effective in NLRP3-/- hepatocytes. After re-expressing NLRP3 in NLRP3-/- hepatocytes by adenovirus, the anti-lipid deposition effect of naringenin was restored. CONCLUSION AND IMPLICATIONS: Naringenin prevented NAFLD via down-regulating the NLRP3/NF-κB signalling pathway both in KCs and in hepatocytes, thus attenuating inflammation in the mice livers.

Membrane nanotubes facilitate the propagation of inflammatory injury in the heart upon overactivation of the ß-adrenergic receptor.

Acute sympathetic stress quickly induces cardiac inflammation and injury, suggesting that pathogenic signals rapidly spread among cardiac cells and that cell-to-cell communication may play an important role in the subsequent cardiac injury. However, the underlying mechanism of this response is unknown. Our previous study demonstrated that acute ß-adrenergic receptor (ß-AR) signaling activates inflammasomes in the heart, which triggers the inflammatory cascade. In the present study, ß-AR overactivation induced inflammasome activation in both the cardiomyocytes and cardiac fibroblasts (CFs) of mice hearts following a subcutaneous injection of isoproterenol (ISO, 5 mg/kg body weight), a selective agonist of ß-AR. In isolated cardiac cells, ISO treatment only activated the inflammasomes in the cardiomyocytes but not the CFs. These results demonstrated that inflammasome activation was propagated from cardiomyocytes to CFs in the mice hearts. Further investigation revealed that the inflammasomes were activated in the cocultured CFs that connected with cardiomyocytes via membrane nanotubes (MNTs), a novel membrane structure that mediates distant intercellular connections and communication. Disruption of the MNTs with the microfilament polymerization inhibitor cytochalasin D (Cyto D) attenuated the inflammasome activation in the cocultured CFs. In addition, the MNT-mediated inflammasome activation in the CFs was blocked by deficiency of the inflammasome component NOD-like receptor protein 3 (NLRP3) in the cardiomyocytes, but not NLRP3 deficiency in the CFs. Moreover, ISO induced pyroptosis in the CFs cocultured with cardiomyocytes, and this process was inhibited by disruption of the MNTs with Cyto D or by the NLRP3 inhibitor MCC950 and the caspase-1 inhibitor Z-YVAD-FMK (FMK). Our study revealed that MNTs facilitate the rapid propagation of inflammasome activation among cardiac cells to promote pyroptosis in the early phase of ß-adrenergic insult. Therefore, preventing inflammasome transfer is a potential therapeutic strategy to alleviate acute ß-AR overactivation-induced cardiac injury.

Nucleated Red Blood Cell Count in Maternal Peripheral Blood and Hypertensive Disorders in Pregnant Women.

OBJECTIVE: We investigated the correlations of nucleated red blood cell (NRBC) counts with hypertensive disorders in pregnancy (HDP) and fetal umbilical blood flow velocity. MATERIALS AND METHODS: We recruited 282 patients with HDP as experimental group including 107 with mild pre-eclampsia (A1 group), 100 with severe pre-eclampsia (A2 group) and 75 with eclampsia (A3 group), and 215 normal pregnant women as control group. Maternal peripheral venous blood was collected and isolated cells were stained with Wright-Giemsa. We estimated NRBC counts according to laboratory routine and Doppler ultrasound examinations were employed to measure the systolic/diastolic (S/D) ratios of fetal ductus venosus, umbilical artery and middle cerebral artery. RESULTS: The NRBC counts in A1, A2 and A3 groups were higher than control group (all P < 0.01). The S/D ratios in control, A1, A2 and A3 groups increased orderly (P < 0.05). Receiver operating characteristic curve analysis demonstrated that the sensitivity and specificity of NRBC count and S/D ratios in diagnosing HDP were 96.50% and 96.28%; 93.60% and 98.14%; 94.30% and 94.88% 99.30% and 100%, respectively. Pearson and Spearman correlation analysis revealed that the NRBC and S/D ratios were correlated with gestational age at birth, amniotic fluid volume, premature birth, mechanical ventilation, neonatal intensive care unit admission, neonatal asphyxia, birth weight, fetal distress, APGAR score, pH value, arterial oxygenation tension, bicarbonate and base excess (all P < 0.05). The NRBC count was positively associated with the S/D ratios (all P < 0.05). CONCLUSIONS: Our results provide evidence that NRBC count in patients with HDP increased significantly, showing positive correlations with umbilical S/D ratios.