Intrauterine arsenic exposure induces glucose metabolism disorders in adult offspring by targeting TET2-mediated DNA hydroxymethylation reprogramming of HNF4α in developing livers, an effect alleviated by ascorbic acid.

Exposure to arsenic during gestation has lasting health-related effects on the developing fetus, including an increase in the risk of metabolic disease later in life. Epigenetics is a potential mechanism involved in this process. Ten-eleven translocation 2 (TET2) has been widely considered as a transferase of 5-hydroxymethylcytosine (5hmC). Here, mice were exposed, via drinking water, to arsenic or arsenic combined with ascorbic acid (AA) during gestation. For adult offspring, intrauterine arsenic exposure exhibited disorders of glucose metabolism, which are associated with DNA hydroxymethylation reprogramming of hepatic nuclear factor 4 alpha (HNF4α). Further molecular structure analysis, by SEC-UV-DAD, SEC-ICP-MS, verified that arsenic binds to the cysteine domain of TET2. Mechanistically, arsenic reduces the stability of TET2 by binding to it, resulting in the decrease of 5hmC levels in Hnf4α and subsequently inhibiting its expression. This leads to the disorders of expression of its downstream key glucose metabolism genes. Supplementation with AA blocked the reduction of TET2 and normalized the 5hmC levels of Hnf4α, thus alleviating the glucose metabolism disorders. Our study provides targets and methods for the prevention of offspring glucose metabolism abnormalities caused by intrauterine arsenic exposure.

SIRT1/PGC-1α is involved in arsenic-induced male reproductive damage through mitochondrial dysfunction, which is blocked by the antioxidative effect of zinc.

Exposure to arsenic poses threats to male reproductive system, including impairing the testes and sperm quality. Although an association regarding arsenic exposure and male reproductive damage has been reported, the undergoing molecular mechanisms and interventions for prevention remain unclear. For the present work, male mice were exposed to 0, 2.5, 5, or 10 ppm sodium arsenite (NaAsO2) for 8 months. The results showed that arsenic-exposed mice had reduced fertility with abnormalities in the testes, epididymides, and sperm. Exposure of mice to arsenic caused a redox imbalance, decreased SIRT1 and PGC-1α levels, and affected mitochondrial biogenesis and proteins related to mitochondrial dynamics. For immortalized spermatogenic (GC-2) cells, arsenic caused apoptosis and oxidative stress, reduced SIRT1/PGC-1α levels and ATP production, inhibited mitochondrial respiration, and changed the mitochondrial membrane potential (MMP). Mitochondrial biogenesis and dynamics were also impaired. However, by reducing mitochondrial damage in GC-2 cells, upregulation of SIRT1 or zinc (Zn) supplementation reversed the apoptosis induced by arsenic. For mice, Zn supplementation blocked arsenic-induced oxidative stress, the decreases of SIRT1 and PGC-1α levels, and the impairment of mitochondrial function, and it reversed the damage to testes, low sperm quality, and low litter size. Collectively, these results suggest that arsenic causes excessive production of ROS, inhibits the SIRT1/PGC-1α pathway, and causing mitochondrial dysfunction by mediating impairment of mitochondrial biogenesis and dynamics, which results in germ cells apoptosis and male reproductive damage, processes that are blocked by Zn via an antioxidative effect. Our study contributes to understanding of the mechanisms for arsenic-induced male reproductive damage and points to the therapeutic significance of Zn.

Responses of Soil Carbon Pools and Carbon Management Index to Nitrogen Substitution Treatments in a Sweet Maize Farmland in South China.

In China, excessive nitrogen fertilizer application in sweet maize fields contributes to greenhouse gas emissions. This study used maize straw (MS), cow dung (CD), biogas residue (BR), and straw-based biochar (CB) to substitute the mineral nitrogen fertilizer at 20% and 50% ratios in the Pearl River Delta in China. In comparison with a conventional amount of mineral nitrogen fertilizer (CK), the soil organic carbon (SOC) storages of the different treatments increased by 6.5-183.0%. The CB treatment significantly improved the inert organic carbon pool in the soil, while other types of organic materials promoted the formation of activated carbon pools. The treatments increased the soil carbon pool management index by 21.1-111.0% compared to the CK. Moreover, the CB treatments increased the soil carbon sequestration index by 78.3% and 155.8% compared to the CK. In general, substituting the mineral N fertilizer with BR, CB, and CD could improve the SOC accumulation in sweet maize farmland in South China. The CB at the high substitution level was the best measure for stabilizing carbon sequestration in the sweet maize cropping system. This experiment provides valuable information for ensuring the clean production of sweet maize in a typical subtropical area in East Asia.

Diagnostic performance of C-TIRADS combined with SWE for the diagnosis of thyroid nodules.

Objective: To explore the value of the optimal parameters of shear wave elastography (SWE) to enhance the identification of benign and malignant thyroid nodules by C-TIRADS. Methods: The two-dimensional ultrasonography images and SWE images of 515 patients with a total of 586 thyroid nodules were retrospectively analyzed. The nodules were divided into the D ≤10 mm and D >10 mm groups according to size and were graded by C-TIRADS. With the pathological results as the gold standard, the receiver operating characteristic (ROC) curves were drawn, and the area under the curve (AUC) was calculated to compare the diagnostic performances of C-TIRADS, SWE, and the combination of the two on the benign and malignant thyroid nodules. Results: The ROC showed that the AUC of the maximum elastic modulus (0.875) was higher than that of the mean elastic modulus (0.798) and elasticity ratio (0.772), with an optimal cutoff point of 51 kPa, which was the optimal parameter to distinguish the malignant from the benign nodules (P < 0.001). In the D ≤10 mm group, the AUC of TIRADS combined with SWE (0.955) was elevated by 0.172 compared with the application of C-TIRADS alone (0.783), and the difference was statistically significant (P < 0.05). In the D >10 mm group, the AUC of TIRADS combined with SWE (0.904) was elevated by 0.076 compared with the application of C-TIRADS alone (0.828), and the difference was statistically significant (P < 0.05). Among all nodules, the application of C-TIRADS alone had a sensitivity of 88.14%, a specificity of 74.56%, and an accuracy of 85.50% in diagnosing benign and malignant thyroid nodules, while the sensitivity, specificity, and accuracy were 93.22%, 90.35%, and 92.66%, respectively, in combination with SWE. Conclusion: The diagnostic performance of SWE in combination with TIRADS was better than that of SWE or C-TIRADS alone. Here, SWE enhanced the diagnostic performance of C-TIRADS for the benign and malignant thyroid nodules, most significantly for nodules with D ≤10 mm.

Prevalence of Latent Tuberculosis Infection Among Healthy Young Children and Adolescents and a Two-step Approach for the Diagnosis of Tuberculosis Infection in Chengdu, China.

BACKGROUND: China has a high burden of tuberculosis and latent tuberculosis infection (LTBI). The aim of this study was to estimate the prevalence of LTBI among healthy young children and adolescents and test a 2-step approach to explore the threshold for the diagnosis of tuberculosis infection in Chengdu, China. METHODS: Healthy preschool children and school-going children in Chengdu, Sichuan Province, were screened for LTBI using the tuberculin skin test (TST). Preschool children with TST ≥ 5 mm also underwent interferon-γ release assay (IGRA) to explore the threshold of this 2-step approach. RESULTS: In total, 5667 healthy young children and adolescents completed TST test between July 2020 and January 2021 and were included in the present analysis. The age of the participants ranged from 2.4 to 18 years (median 7.25 ± 4.514 years), of which 2093 (36.9%) were younger than 5 years. The overall prevalence of LTBI was 6.37% and 6.64% in children younger than 5 years old. Fourteen of the 341 preschool children with TST ≥5 mm were interferon-γ release assay positive, of which 4 showed a TST result of 5-10 mm, and 6 preschool children received preventive treatment for LTBI. CONCLUSIONS: Healthy young children and adolescents should also be considered as important target populations for LTBI screening. TST can be recommended for first-line screening as part of a 2-step approach for LTBI screening using a positive threshold of 5 mm.

Detection of pulmonary tuberculosis in children using the Xpert MTB/RIF Ultra assay on sputum: a multicenter study.

Microbiological confirmation is rare in children with active tuberculosis; therefore, a more accurate test is needed to detect pulmonary tuberculosis in children. In this multicenter study, we evaluated the utility of the Xpert MTB/RIF Ultra (Ultra) on sputum, an assay recommended by the World Health Organization to test for childhood tuberculosis in high-burden settings. Children with symptoms suggestive of tuberculosis were enrolled at three hospitals in China and categorized as having active tuberculosis or nontuberculosis. The sensitivity and specificity of Ultra were 42.1% (48/114) and 99.0% (208/210), respectively. Using three MTB culture results as the reference, the sensitivity of Ultra in the subset of 38 children with culture-positive and 76 children with culture-negative was 68.4% (26/38) and 28.9% (22/76), respectively(p < 0.001). A single MTB culture combined with a single Ultra could detect 54 (54/114,47.4%) cases with active TB, while repeated MTB culture combined with a single Ultra detected 60 (60/114, 52.6%) cases with active TB(p = 0.427). Among 155 children (58 with TB and 97 with RTIs) simultaneously tested with the Ultra and Xpert MTB/RIF (Xpert), the sensitivity of the Xpert (24.1%, 14/58) was lower than that of the Ultra (41.4%, 24/58; p = 0.048). Eight children were found to have rifampin-resistant MTB strains. The Xpert MTB/RIF Ultra assay should be implemented to test for pulmonary tuberculosis in children to achieve higher confirmation rates.

Evaluation of the Diagnostic Value of the Ultrasound ADNEX Model for Benign and Malignant Ovarian Tumors.

OBJECTIVE: To investigate the diagnostic performance of the ADNEX model in the International Ovarian Tumor Analysis diagnostic models for ovarian tumors and further explore its application value in the staging of ovarian tumors. METHODS: A total of 224 patients who underwent ultrasound for evaluation of adnexal masses and were treated surgically owing to adnexal masses from January 2018 to June 2020 in our hospital were selected for research on the diagnostic accuracy of the ADNEX model. The clinical information and ultrasonographic findings of the patients were collected, and the pathological diagnosis was taken as the gold standard. According to the ADNEX model, the ovarian tumors were divided into five subtypes: benign and borderline, stage I, stage II-IV, and metastatic cancer. The sensitivity, specificity, positive predictive value, negative predictive value, diagnostic odds ratio, and area under the receiver operating characteristics curve (AUC) of the ADNEX model were calculated. RESULTS: Of the 224 patients, 119 (53.1%) developed benign tumors and 105 (46.9%) had malignant tumors. When the cut-off value for malignancy risk was 10%, the ADNEX model including CA 125 achieved a sensitivity of 94.3% (95% CI: 88.0-97.9%), specificity of 74.0% (95% CI: 65.1-81.6%), positive predictive value of 76.2% (95% CI: 70.2-81.3%), negative predictive value of 93.6% (95% CI: 87.0-97.0%), diagnostic odds ratio of 45.25, and an AUC of 0.94 (95% CI: 0.90-0.97) for differentiating between benign and malignant ovarian tumors. The AUC in the model excluding CA 125 was 0.93 (95% CI: 0.89-0.96), but the difference was not statistically significant (P=0.20). The accuracy of the ADNEX model for the diagnosis of ovarian tumors of all subtypes exceeds 80% when CA 125 measurements were included in the application, but the sensitivity for diagnosing borderline, stage I, and metastatic ovarian tumors was only 60.0% (95% CI:36.1-80.9%), 28.6% (95% CI:8.4-58.1%) and 45.5% (95% CI:16.7-76.6%). CONCLUSION: The ADNEX model shows good diagnostic performance in differentiating between benign and malignant ovarian tumors. The model has a certain clinical value in the diagnosis of all subtypes of ovarian tumors, but the sensitivity is unsatisfactory for the diagnosis of borderline, stage I, and metastatic ovarian tumors and needs to be verified.

Epidemiology, risk factors and outcomes of bloodstream infection caused by ESKAPEEc pathogens among hospitalized children.

BACKGROUND: Bloodstream infection (BSI) resulting from ESKAPEEc pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp) is relevant to high mortality and economic cost. Data concerning the impact of BSI due to ESKAPEEc in pediatric population was virtually scant. Our purpose was to summarize the epidemiology, risk factors and outcomes of ESKAPEEc BSI among hospitalized children. METHODS: Inpatients diagnosed with BSI with definite etiology between January 2016 and December 2018 were enrolled retrospectively at the West China Second University Hospital. Data were systematically reviewed on patients' clinical characteristics and laboratory findings to ascertain independent predictors, clinical features and outcomes. RESULTS: Of the 228 patients with BSI, 174 (76.3%) were caused by ESKAPEEc (124 MDR-ESKAPEEc). Multivariate analysis demonstrated that premature and/ or low birth weight (odds ratio [OR] = 2.981, P = 0.036), previous surgery and/or trauma (OR = 5.71, P = 0.029) and source of urinary tract infection (OR = 10.60, P = 0.004) were independently associated with ESKAPEEc BSI. The independent risk factor for MRD-ESKAPEEc BSI was nosocomial infection (OR = 3.314, P = 0.037). The overall mortality rate in patients with ESKAPEEc BSI was 14.4% (25/174), and no significant difference was ascertained in mortality between MRD-ESKAPEEc and non-MRD ESKAPEEc BSI groups (13.7% vs. 11.4%, P = 0.692). In addition, previous surgery and/or trauma, thrombocytopenia, and mechanical ventilation were significant risk factors for mortality caused by ESKAPEEc BSI. CONCLUSIONS: More than two-thirds of BSI among hospitalized children were caused by ESKAPEEc. Previous surgery and/or trauma, thrombocytopenia and mechanical ventilation increased the risk rate for mortality in ESKAPEEc BSI. The risk factors ascertained could assist physicians to early suspect ESKAPEEc BSI and MDR ESKAPEEc BSI.

Cetuximab-conjugated perfluorohexane/gold nanoparticles for low intensity focused ultrasound diagnosis ablation of thyroid cancer treatment.

We report the formulation of nanoassemblies (NAs) comprising C225 conjugates Au-PFH-NAs (C-Au-PFH-NAs) for low-intensity focused ultrasound diagnosis ablation of thyroid cancer. C-Au-PFH-NAs showed excellent stability in water, phosphate-buffered saline (PBS), and 20% rat serum. Transmission electron microscopy (TEM) images also revealed the effective construction of C-Au-PFH-NAs as common spherical assemblies. The incubation of C625 thyroid carcinoma with C-Au-PFH-NAs triggers apoptosis, as confirmed by flow cytometry analysis. The C-Au-PFH-NAs exhibited antitumour efficacy in human thyroid carcinoma xenografts, where histopathological results further confirmed these outcomes. Furthermore, we were able to use low-intensity focused ultrasound diagnosis imaging (LIFUS) to examine the efficiency of C-Au-PFH-NAs in thyroid carcinoma in vivo. These findings clearly show that the use of LIFUS agents with high-performance imaging in different therapeutic settings will have extensive potential for future biomedical applications.

Prevalence and antimicrobial resistance patterns of bacteria isolated from cerebrospinal fluid among children with bacterial meningitis in China from 2016 to 2018: a multicenter retrospective study.

BACKGROUND: Pediatric bacterial meningitis (PBM) remains a devastating disease that causes substantial neurological morbidity and mortality worldwide. However, there are few large-scale studies on the pathogens causing PBM and their antimicrobial resistance (AMR) patterns in China. The present multicenter survey summarized the features of the etiological agents of PBM and characterized their AMR patterns. METHODS: Patients diagnosed with PBM were enrolled retrospectively at 13 children's hospitals in China from 2016 to 2018 and were screened based on a review of cerebrospinal fluid (CSF) microbiology results. Demographic characteristics, the causative organisms and their AMR patterns were systematically analyzed. RESULTS: Overall, 1193 CSF bacterial isolates from 1142 patients with PBM were obtained. The three leading pathogens causing PBM were Staphylococcus epidermidis (16.5%), Escherichia coli (12.4%) and Streptococcus pneumoniae (10.6%). In infants under 3 months of age, the top 3 pathogens were E. coli (116/523; 22.2%), Enterococcus faecium (75/523; 14.3%), and S. epidermidis (57/523; 10.9%). However, in children more than 3 months of age, the top 3 pathogens were S. epidermidis (140/670; 20.9%), S. pneumoniae (117/670; 17.5%), and Staphylococcus hominis (57/670; 8.5%). More than 93.0% of E. coli isolates were sensitive to cefoxitin, piperacillin/tazobactam, cefoperazone/sulbactam, amikacin and carbapenems, and the resistance rates to ceftriaxone, cefotaxime and ceftazidime were 49.4%, 49.2% and 26.4%, respectively. From 2016 to 2018, the proportion of methicillin-resistant coagulase-negative Staphylococcus isolates (MRCoNS) declined from 80.5 to 72.3%, and the frequency of penicillin-resistant S. pneumoniae isolates increased from 75.0 to 87.5%. The proportion of extended-spectrum ß-lactamase (ESBL)-producing E. coli fluctuated between 44.4 and 49.2%, and the detection rate of ESBL production in Klebsiella pneumoniae ranged from 55.6 to 88.9%. The resistance of E. coli strains to carbapenems was 5.0%, but the overall prevalence of carbapenem-resistant K. pneumoniae (CRKP) was high (54.5%). CONCLUSIONS: S. epidermidis, E. coli and S. pneumoniae were the predominant pathogens causing PBM in Chinese patients. The distribution of PBM causative organisms varied by age. The resistance of CoNS to methicillin and the high incidence of ESBL production among E. coli and K. pneumoniae isolates were concerning. CRKP poses a critical challenge for the treatment of PBM.

Evaluation of Xpert MTB/RIF Ultra Assay for Diagnosis of Childhood Tuberculosis: a Multicenter Accuracy Study.

A multicenter study was performed to evaluate the value of testing gastric aspirate (GA) with Xpert MTB/RIF Ultra assay (Ultra) for childhood tuberculosis (TB) detection in China. In total, 129 children with active TB and 173 children without TB were enrolled. The sensitivity of Ultra in bacteriologically confirmed TB and probable TB cases was 87.5% (42/48) and 44.4% (36/81), respectively. The specificity of Ultra was high (99.4%, 172/173). When Ultra, culture, and acid-fast bacilli outcomes were integrated as a composite reference standard, the percentage of children with definite TB increased from 37.2% (48/129) to 67.4% (87/129). The sensitivity of Ultra is 80.0% (40/50) in children aged <4 years, which is significantly higher than that in older children (48.1%, 38/79) (P < 0.001). Ultra conducted using GA samples can provide faster results, allowing an early and accurate TB diagnosis, especially in younger children with difficulty producing sputum.

Lymphatic Vessels: A Potential Approach to the Treatment of Atherosclerosis?

Many basic and clinical studies have demonstrated that atherosclerosis is a chronic inflammatory disease. Although there are many factors affecting atherosclerosis, the role of lymphatic vessels in this disease has been neglected. Traditionally, lymphatic vessels have been considered to be passages for transporting interstitial fluid to the blood circulation. However, as early as the last century, researchers found that there are numerous lymphatic vessels surrounding sites of atherosclerosis; however, the relationship between lymphatic vessels and atherosclerosis is not clear. With further research, lymphatic vessels were determined to be involved in the induction and resolution of arterial inflammation and also to play a positive role in plaque cholesterol transport. There are abundant immune cells around atherosclerosis, and these immune cells not only have a significant impact on plaque formation but also affect local lymphangiogenesis (IAL). This promotion of IAL seems to relieve the progression of atherosclerosis. Therefore, research into the relationship between lymphatic vessels and atherosclerosis is of great importance for improving atherosclerosis treatment. This review highlights what is known about the relationship between lymphatic vessels and atherosclerosis, including the effect of immune cells on IAL, and reverse cholesterol transport. In addition, we present some of our views on the improvement of atherosclerosis treatment, which have significant clinical value in research.

MicroRNA-24 aggravates atherosclerosis by inhibiting selective lipid uptake from HDL cholesterol via the post-transcriptional repression of scavenger receptor class B type I.

BACKGROUND AND AIMS: Liver scavenger receptor class B type I (SR-BI) exerts atheroprotective effects through selective lipid uptake (SLU) from high-density lipoprotein cholesterol (HDL-C). Low hepatic SR-BI expression leads to high HDL-C levels in the circulation and an increased risk of atherosclerosis. Furthermore, macrophage SR-BI mediates bidirectional cholesterol flux and may protect against atherogenesis. Previous studies have revealed that miR-24 is closely related to cardiovascular disease (CVD) progression. We aimed to investigate the molecular mechanisms by which miR-24 participates in SR-BI-mediated selective HDL cholesteryl ester (HDL-CE) uptake and further atherogenesis in apoE-/- mice. METHODS: Bioinformatic predictions and luciferase reporter assays were utilized to detect the association between miR-24 and the SR-BI 3' untranslated region (3' UTR), and RT-PCR and western blotting were used to evaluate SR-BI mRNA and protein expression, respectively. The effects of miR-24 on Dil-HDL uptake were determined by flow cytometry assay. Double-radiolabeled HDL (125I-TC-/[3H] CEt-HDL) was utilized to measure the effects of miR-24 on HDL and CE binding and SLU in HepG2 and PMA-treated THP-1 cells. In addition, total cholesterol (TC) levels in HepG2 cells were analyzed using enzymatic methods, and macrophage lipid content was evaluated by high-performance liquid chromatography (HPLC) assay. Small interfering RNA (siRNA) and pcDNA3.1(-)-hSR-BI plasmid transfection procedures were utilized to confirm the role of SR-BI in the effects of miR-24 on Dil-HDL uptake, SLU and cholesterol levels in both cell types. Hepatic SR-BI level in apoE-/- mice was measured by western blotting. Liver TC, FC and CE levels and plasma triglycerides (TG), TC and HDL-C levels were evaluated enzymatically using commercial test kits. Atherosclerotic lesion sizes were measured using Oil Red O and hematoxylin-eosin staining. RESULTS: miR-24 directly repressed SR-BI expression by targeting its 3'UTR. In addition, miR-24 decreased Dil-HDL uptake and SLU in HepG2 and THP-1 macrophages. In the presence of HDL, miR-24 decreased TC levels in HepG2 cells and TC, free cholesterol (FC) and CE levels in macrophages. Overexpression and down-regulation assays showed that SR-BI mediated the effects of miR-24 on Dil-HDL uptake, SLU and cholesterol levels. Lastly, miR-24 administration decreased hepatic SR-BI expression and promoted atheromatous plaque formation in apoE-/- mice, findings in line with those of our in vitro studies. CONCLUSIONS: These findings indicate that miR-24 accelerates atherogenesis by repressing SR-BI-mediated SLU from HDL-C.

ApoA-I/SR-BI modulates S1P/S1PR2-mediated inflammation through the PI3K/Akt signaling pathway in HUVECs.

Endothelial dysfunction plays a vital role during the initial stage of atherosclerosis. Oxidized low-density lipoprotein (ox-LDL) induces vascular endothelial injury and vessel wall inflammation. Sphingosine-1-phosphate (S1P) exerts numerous vasoprotective effects by binding to diverse S1P receptors (S1PRs; S1PR1-5). A number of studies have shown that in endothelial cells (ECs), S1PR2 acts as a pro-atherosclerotic mediator by stimulating vessel wall inflammation through the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Scavenger receptor class B member I (SR-BI), a high-affinity receptor for apolipoprotein A-I (apoA-I)/high-density lipoprotein (HDL), inhibits nuclear factor-κB (NF-κB) translocation and decreases the plasma levels of inflammatory mediators via the PI3K/Akt pathway. We hypothesized that the inflammatory effects of S1P/S1PR2 on ECs may be regulated by apoA-I/SR-BI. The results showed that ox-LDL, a pro-inflammatory factor, augmented the S1PR2 level in human umbilical vein endothelial cells (HUVECs) in a dose- and time-dependent manner. In addition, S1P/S1PR2 signaling influenced the levels of inflammatory factors, including tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and IL-10, aggravating inflammation in HUVECs. Moreover, the pro-inflammatory effects induced by S1P/S1PR2 were attenuated by SR-BI overexpression and enhanced by an SR-BI inhibitor, BLT-1. Further experiments showed that the PI3K/Akt signaling pathway was involved in this process. Taken together, these results demonstrate that apoA-I/SR-BI negatively regulates S1P/S1PR2-mediated inflammation in HUVECs by activating the PI3K/Akt signaling pathway.

TGF-ß Down-regulates Apolipoprotein M Expression through the TAK-1-JNK-c-Jun Pathway in HepG2 Cells.

Apolipoprotein M (apoM) is a relatively novel apolipoprotein that plays pivotal roles in many dyslipidemia-associated diseases; however, its regulatory mechanisms are poorly understood. Many cytokines have been identified that down-regulate apoM expression in HepG2 cells, among which transforming growth factor-ß (TGF-ß) exerts the most potent effects. In addition, c-Jun, a member of the activated protein 1 (AP-1) family whose activity is modulated by c-Jun N-terminal kinase (JNK), decreases apoM expression at the transcriptional level by binding to the regulatory element in the proximal apoM promoter. In this study, we investigated the molecular mechanisms through which TGF-ß decreases the apoM level in HepG2 cells. The results revealed that TGF-ß inhibited apoM expression at both the mRNA and protein levels in a dose- and time-dependent manner and that it suppressed apoM secretion. These effects were attenuated by treatment of cells with either SP600125 (JNK inhibitor) or c-Jun siRNA. 5Z-7-oxozeaenol [(a TGF-ß-activated kinase 1 (TAK-1) inhibitor)] also attenuated the TGF-ß-mediated inhibition of apoM expression and suppressed the activation of JNK and c-Jun. These results have demonstrated that TGF-ß suppresses apoM expression through the TAK-1-JNK-c-Jun pathway in HepG2 cells.

ApoA-I induces S1P release from endothelial cells through ABCA1 and SR-BI in a positive feedback manner

Sphingosine-1-phosphate (S1P), which has emerged as a pivotal signaling mediator that participates in the regulation of multiple cellular processes, is derived from various cells, including vascular endothelial cells. S1P accumulates in lipoproteins, especially HDL, and the majority of free plasma S1P is bound to HDL. We hypothesized that HDL-associated S1P is released through mechanisms associated with the HDL maturation process. ApoA-I, a major HDL apolipoprotein, is a critical factor for nascent HDL formation and lipid trafficking via ABCA1. Moreover, apoA-I is capable of promoting bidirectional lipid movement through SR-BI. In the present study, we confirmed that apoA-I can facilitate the production and release of S1P by HUVECs. Furthermore, we demonstrated that ERK1/2 and SphK activation induced by apoA-I is involved in the release of S1P from HUVECs. Inhibitor and siRNA experiments showed that ABCA1 and SR-BI are required for S1P release and ERK1/2 phosphorylation induced by apoA-I. However, the effects triggered by apoA-I were not suppressed by inhibiting ABCA1/JAK2 or the SR-BI/Src pathway. S1P released due to apoA-I activation can stimulate the (ERK1/2)/SphK1 pathway through S1PR (S1P receptor) 1/3. These results indicated that apoA-I not only promotes S1P release through ABCA1 and SR-BI but also indirectly activates the (ERK1/2)/SphK1 pathway by releasing S1P to trigger their receptors. In conclusion, we suggest that release of S1P induced by apoA-I from endothelial cells through ABCA1 and SR-BI is a self-positive-feedback process: apoA-I-(ABCA1 and SR-BI)-(S1P release)-S1PR-ERK1/2-SphK1-(S1P production)-(more S1P release induced by apoA-I) (AU)

No disponible

ApoA-I induces S1P release from endothelial cells through ABCA1 and SR-BI in a positive feedback manner.

Sphingosine-1-phosphate (S1P), which has emerged as a pivotal signaling mediator that participates in the regulation of multiple cellular processes, is derived from various cells, including vascular endothelial cells. S1P accumulates in lipoproteins, especially HDL, and the majority of free plasma S1P is bound to HDL. We hypothesized that HDL-associated S1P is released through mechanisms associated with the HDL maturation process. ApoA-I, a major HDL apolipoprotein, is a critical factor for nascent HDL formation and lipid trafficking via ABCA1. Moreover, apoA-I is capable of promoting bidirectional lipid movement through SR-BI. In the present study, we confirmed that apoA-I can facilitate the production and release of S1P by HUVECs. Furthermore, we demonstrated that ERK1/2 and SphK activation induced by apoA-I is involved in the release of S1P from HUVECs. Inhibitor and siRNA experiments showed that ABCA1 and SR-BI are required for S1P release and ERK1/2 phosphorylation induced by apoA-I. However, the effects triggered by apoA-I were not suppressed by inhibiting ABCA1/JAK2 or the SR-BI/Src pathway. S1P released due to apoA-I activation can stimulate the (ERK1/2)/SphK1 pathway through S1PR (S1P receptor) 1/3. These results indicated that apoA-I not only promotes S1P release through ABCA1 and SR-BI but also indirectly activates the (ERK1/2)/SphK1 pathway by releasing S1P to trigger their receptors. In conclusion, we suggest that release of S1P induced by apoA-I from endothelial cells through ABCA1 and SR-BI is a self-positive-feedback process: apoA-I-(ABCA1 and SR-BI)-(S1P release)-S1PR-ERK1/2-SphK1-(S1P production)-(more S1P release induced by apoA-I).

Application of mixed oxide catalysts to the removal of lean NOx and N2O using transient-mode cyclic operations.

The storage and reduction of NO and N2O in the presence of excess O2 have been investigated over two mixed oxide catalysts. The catalysts, which were prepared via coprecipitation of solutions of mixed metal nitrates, followed by calcination, were found to have plenty storage capacities for nitrogen oxides. The storage and reduction performances varied with the catalyst composition and the duration of cycle time: the AlCoPd (1/1/0.05) mixed oxide catalyst exhibited higher efficiency for NO, and an AlCoFe (1/1/2) mixed oxide catalyst exhibited higher efficiency for N2O. The adsorptions of NO and N2O onto the mixed oxide catalysts progressed without an oxidation step, and the adsorptivity of NO surpassed that of O2. The mixed oxides showed spinel structures with sizes of 10-100 nm, and with well-developed mesopores that were formed by the evaporation of H2O and CO2 from layered double hydroxide (LDH) precursors. The storage and reduction of lean NOx and N2O over the mixed oxide catalysts were carried out via cyclic operations in a transient mode at 300 degrees C and at space velocities of around 30,000 h(-1). The removal efficiency of the cyclic operations generally increased with reduced adsorption cycle time, and reached 90% for NOx and N2O with the respective catalysts.

[Influence of stress from work and negative life events during pregnancy on different types of low birth weight].

OBJECTIVE: To explore the influence of occupational stress and negative life events that occur during pregnancy on different types of low birth weight (LBW). METHODS: 438 singleton LBW infants (birth weight of less than 2500 g and their pregnancy term from 28 to 42 weeks) were selected as case group, and they were further divided into symmetric LBW infants (337 cases) and asymmetric LBW infants (101 cases). According to situation of each LBW infant, a singleton with full term and normal birth weight was selected as control group matched by sex, pregnancy term, time during delivery and types of hospital. All of their mothers were inquired by well trained investigators on their socio-demographic characteristics, occupational stress, and negative life events that occurred in different pregnancy term. After controlling for mother's age, occupation, education level and family income, multinomial logistic regression was employed to asses the influence of occupational stress and negative life events on symmetric LBW and asymmetric LBW. RESULTS: Compared with those using low technical skills, mothers with high technical skill utilization significantly decreased the risk of laboring both symmetric LBW (OR = 0.69, 95% CI: 0.49-0.98) and asymmetric LBW (OR = 0.53, 95% CI: 0.31-0.89). Compared with those without exposure to negative life events, mothers with negative life event score > or = 3 in the whole duration of pregnancy had significantly increased the risk of delivering symmetric LBW (OR = 2.30, 95% CI: 1.08-4.88), mothers with negative life event score > or = 3 in the middle three months of pregnancy, > or = 3 in the last three months of pregnancy, = 2 and > or = 3 in the whole duration of pregnancy had significantly increased the risk of delivering asymmetric LBW, and their OR (95% CI) was 8.85 (1.97-39.68), 3.80 (1.40-10.29), 3.58 (1.33-9.66) and 3.48 (1.32-9.13), respectively. CONCLUSION: Occupational stress and negative life events might produce different influence on symmetric LBW and negative life events that occur in the different terms of pregnancy had different impact on symmetric LBW and asymmetric LBW.

[Relationship of occupational stress and negative life events with low birth weight].

OBJECTIVE: To explore the influence of occupational stress and negative life events on low birth weight (LBW). METHODS: 1:1 matched case-control study was employed, in which 438 singleton LBW infants with birth weight less than 2500 g (their pregnancy term being 28 to 42 weeks) served as case group while 438 with singleton term normal birth weight served as control group matched by sex, delivery time and hospital. All of their mothers were inquired by well trained investigators about their socio-demographic characteristics, occupational stress, and negative life events occurring in different pregnancy term. After controlling for mother's age, occupation, education level and family income, conditional logistic regression was employed to asses the influence of occupational stress and negative life events on LBW. RESULTS: Compared with those with low technical skill utilization and low job decision, mothers with high technical skill utilization (OR=0.62; 95% CI=0.43 approximately 0.91) and high job decision (OR=0.67; 95% CI=0.46 approximately 0.97) significantly decreased the risk of laboring LBW. Compared with those not exposed to negative life events, mothers with negative life event score being=3 in the middle three months of pregnancy (OR=18.85; 95% CI=1.58 approximately 225.02), with negative life event score being 1 in the later three months of pregnancy (OR=2.67; 95% CI=1.14 approximately 6.28), with negative life event score being 2 (OR=2.80; 95% CI=1.04 approximately 7.52) and=3 in the whole time of pregnancy (OR=2.94; 95% CI=1.22 approximately 7.09) were the risk factors of LBW. CONCLUSION: Negative life events might affect LBW and negative life events occurring in the different term of pregnancy impact LBW differently.