PEBP4 deficiency aggravates LPS-induced acute lung injury and alveolar fluid clearance impairment via modulating PI3K/AKT signaling pathway.

Acute lung injury (ALI) is a common clinical syndrome, which often results in pulmonary edema and respiratory distress. It has been recently reported that phosphatidylethanolamine binding protein 4 (PEBP4), a basic cytoplasmic protein, has anti-inflammatory and hepatoprotective effects, but its relationship with ALI remains undefined so far. In this study, we generated PEBP4 knockout (KO) mice to investigate the potential function of PEBP4, as well as to evaluate the capacity of alveolar fluid clearance (AFC) and the activity of phosphatidylinositide 3-kinases (PI3K)/serine-theronine protein kinase B (PKB, also known as AKT) signaling pathway in lipopolysaccharide (LPS)-induced ALI mice models. We found that PEBP4 deficiency exacerbated lung pathological damage and edema, and increased the wet/dry weight ratio and total protein concentration of bronchoalveolar lavage fluid (BALF) in LPS-treated mice. Meanwhile, PEBP4 KO promoted an LPS-induced rise in the pulmonary myeloperoxidase (MPO) activity, serum interleuin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α levels, and pulmonary cyclooxygenase-2 (COX-2) expression. Mechanically, PEBP4 deletion further reduced the protein expression of Na+ transport markers, including epithelial sodium channel (ENaC)-α, ENaC-γ, Na,K-ATPase α1, and Na,K-ATPase ß1, and strengthened the inhibition of PI3K/AKT signaling in LPS-challenged mice. Furthermore, we demonstrated that selective activation of PI3K/AKT with 740YP or SC79 partially reversed all of the above effects caused by PEBP4 KO in LPS-treated mice. Altogether, our results indicated the PEBP4 deletion has a deterioration effect on LPS-induced ALI by impairing the capacity of AFC, which may be achieved through modulating the PI3K/AKT pathway.

Air pollution and pregnancy outcomes based on exposure evaluation using a land use regression model: A systematic review.

This review systematically assessed those studies investigating the association between air pollution and birth outcomes using land use regression (LUR) models for exposure assessment. Fifty-four studies were identified which were published between 2007 and 2019. Most of these were conducted in America, Spain and Canada, while only five were conducted in China. One hundred and ninety-seven LUR models were developed for different pollutants. The main pollutants that these studies assessed were NO2 and PM2.5, and the main pregnancy outcomes investigated were preterm birth (PTB), small for gestational age (SGA) and birth weight. Studies consistently found that NO2 exposure during pregnancy was associated with reduced fetal growth and development. The effect of NO2 on other adverse pregnancy outcomes is unclear. In addition, it was found that increased PM2.5 (aerodynamic equivalent diameter ≤ 2.5 um) exposure during pregnancy reduced birth weight. The effect of PM2.5 on other adverse pregnancy outcomes is also unclear. The relationship between other pollutants and adverse pregnancy outcomes is uncertain based on the existing research. Exposure assessment with LUR modeling has been widely used in Europe and North America, but used less in China. Future studies are recommended to use LUR modeling for individual exposure evaluation in China to better characterize the relationship between air pollution and adverse pregnancy outcomes. In addition, further research is required given that a lot of the associations looked at in the review were inconclusive.

BML-111, a lipoxin receptor agonist, protects against acute injury via regulating the renin angiotensin-aldosterone system.

BACKGROUND: The renin angiotensin-aldosterone system (RAAS) and lipoxins (LXs) have similar roles in many processes. We previously reported that BML-111, a Lipoxin receptor agonist, inhibited chronic injury hepatic fibrosis by regulating RAAS, but whether LXs are involved in BML-111-mediated protection from acute injury is unclear still. METHODS: We established models of acute liver/lung injury and confirmed them with histopathology and myeloperoxidase (MPO) measurements. BML-111, a lipoxin receptor agonist, was applied to mimic the effects of LXs. The contents and activities of angiotensin converting enzyme(ACE) and angiotensinconverting enzyme 2 (ACE2) were measured through ELISA and activity assay kits respectively. Angiotensin II (AngII), angiotensin-(1-7) (Ang-1-7), AngII type 1 receptor (AT1R), and Mas receptor were quantified with ELISA and Western blot. RESULTS: Models of acute injury were established successfully and BML-111 protected LPS-induced acute lung injury and LPS/D-GalN-induced acute liver injury. BML-111 repressed the activity of ACE, but increased the activity of ACE2. BML-111 decreased the expression levels of ACE, AngII, and AT1R, meanwhile increased the levels of ACE2, Ang-(1-7), and Mas. Furthermore, BOC-2, an inhibitor of lipoxin receptor, reversed all the effects. CONCLUSION: BML-111 could protect against acute injury via regulation RAAS.

Lipoxin A4 attenuates LPS-induced acute lung injury via activation of the ACE2-Ang-(1-7)-Mas axis.

Previous studies have reported that lipoxin A4 (LXA4) and the angiotensin I-converting enzyme 2 (ACE2), angiotensin-(1-7) [Ang-(1-7)], and its receptor Mas [ACE2-Ang-(1-7)-Mas] axis play important protective roles in acute lung injury (ALI). However, there is still no direct evidence of LXA4-mediated protection via the ACE2-Ang-(1-7)-Mas axis during ALI. This work was performed using an LPS-induced ALI mouse model and the data indicated the following. First, the animal model was established successfully and LXA4 ameliorated LPS-induced ALI. Second, LXA4 could increase the concentration and activity of ACE2 and the levels of Ang-(1-7) and Mas markedly. Third, LXA4 decreased the levels of TNF-α, IL-1ß, and reactive oxygen species while increasing IL-10 levels. Fourth, LXA4 inhibited the activation of the NF-κB signal pathway and repressed the degradation of inhibitor of NF-κB, the phosphorylation of NF-κB, and the translocation of NF-κB. Finally, and more importantly, BOC-2 (LXA4 receptor inhibitor), MLN-4760 (ACE2 inhibitor), and A779 (Mas receptor antagonist) were found to reverse all of the effects of LXA4. Our data provide evidence that LXA4 protects the lung from ALI through regulation of the ACE2-Ang-(1-7)-Mas axis.

Elevated FOXO6 expression correlates with progression and prognosis in gastric cancer.

The FOXO6 correlated with tumor progression in a wide range of carcinomas, yet little is known in gastric cancer. The expression of FOXO6 and matrix metallopeptidase 9 (MMP-9) was assessed by immunohistochemistry in 192 gastric carcinoma specimens. The correlation between FOXO6 expression with MMP-9, clinicopathological/prognostic value in gastric cancer was examined. FOXO6 overexpression was significantly associated with depth of invasion, lymph node metastasis and stage of disease. In univariate and multivariate analyses, FOXO6 was an independent prognostic factor for both overall survival (OS) and recurrence-free survival (RFS). Moreover, FOXO6 over-expression was correlated with poor prognosis in patients subgroups stratified by tumor size, depth of invasion and lymph node metastasis. FOXO6 expression was increased in both prominent serosal invasion group and lymph node metastasis group. In addition, FOXO6 expression was positively correlated with MMP-9 among 192 gastric cancer tissues. Patients with FOXO6 over-expression had poor OS and shorter RFS in low and high invasiveness groups. Furthermore, stratified analysis showed that the TNM stage I patients with high FOXO6 expression had poor prognosis than those with low FOXO6 expression. In conclusion, FOXO6 overexpression promotes tumor aggressiveness and prognosis, and could be a promising target for prognostic prediction in gastric cancer patients. CONDENSED ABSTRACT: The aim of this study was to analyze the role of FOXO6 in patients with gastric carcinoma. FOXO6 may play an important role on tumor invasion, metastasis and prognosis. It may also serve as a novel target for prognostic prediction.

BML-111 Protected LPS/D-GalN-Induced Acute Liver Injury in Rats.

Lipoxins (LXs) display unique pro-resolving and anti-inflammatory functions in a variety of inflammatory conditions. The present study was undertaken to investigate the effects of BML-111 (5(S),6(R),7-trihydroxyheptanoic acid methyl ester), the agonist of lipoxin A4 receptor, in a model of Lipopolysaccharides (LPS) and d-Galactosamine (d-GalN) induced acute liver injury, and to explore the mechanisms. Histopathological analyses were carried out to quantify liver injury degree. The activities of myeloperoxidase (MPO) were examined to evaluate the levels of neutrophil infiltration. The activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in serum were detected to evaluate the functions of the liver. The amounts of tumor necrosis factor-α (TNF-α), interleukin-10 (IL-10), and interleukin-1ß (IL-1ß) were measured using enzyme-linked immunosorbent assay (ELISA), and the expression levels of transforming growth factor-ß1(TGF-ß1) and cyclooxygenase-2 (COX-2) were examined using Western blotting. The antioxidant capacity, the activities of inducible nitric oxide synthase (iNOS), the contents of malondialdehyde (MDA) and nitric oxide (NO) were analyzed with the kits via biochemical analysis. We established the model of acute liver injury with lipopolysaccharide and d-Galactosamine (LPS/d-GalN): (1) histopathological results and MPO activities, with the activities of AST and ALT in serum, consistently demonstrated LPS and d-GalN challenge could cause severe liver damage, but BML-111 could prevent pathological changes, inhibit neutrophil infiltration, and improve the hepatic function; (2) LPS/d-GalN increased TNF-α, IL-1ß, COX-2, and IL-10, while decreasing TGF-ß1. However, BML-111 could repress LPS/d-GalN -induced TNF-α, IL-1ß and COX-2, meanwhile increasing the expression levels of TGF-ß1 and IL-10; (3) LPS/d-GalN inhibited the activities of superoxide dismutase (SOD), catalase (CAT), total antioxidant capacity (T-AOC), and hydroxyl radical-scavenging ability, simultaneously increasing the levels of MDA and NO, so also the activity of iNOS. Otherwise, BML-111 could reverse all the phenomena. In a word, BML-111 played a protective role in acute liver injury induced by LPS and d-GalN in rats, through improving antioxidant capacity and regulating the balance of inflammatory cytokines.

Th22 cell accumulation is associated with colorectal cancer development.

AIM: To investigate the expression of Th22 cells and related cytokines in colorectal cancer (CRC) tissues, and the probably mechanism. METHODS: CRC tumor and paratumor tissues were collected to detect the expression levels of Th22 cells and of related cytokines by immunohistochemistry, flow cytometry and real-time quantitative polymerase chain reaction (RT-qPCR). Interleukin (IL)-22 alone or with a STAT3 inhibitor was co-cultured with RKO cells in vitro to study the effects of IL-22 on colon cancer cells. IL-22 alone or with a STAT3 inhibitor was injected into a BALB/c nude mouse model with subcutaneously transplanted RKO cells to study the effects of IL-22 on colon cancer growth. RESULTS: The percentage of Th22 cells in the CD4(+) T subset was significantly higher in tumor tissues compared with that in paratumor tissues (1.47% ± 0.083% vs 1.23% ± 0.077%, P < 0.05) as determined by flow cytometry. RT-qPCR analysis revealed that the mRNA expression levels of IL-22, aryl hydrocarbon receptor, CCL20 and CCL22 were significantly higher in tumor tissues compared with those in paratumor tissues. CCL27 mRNA also displayed a higher expression level in tumor tissues compared with that in paratumor tissues; however, these levels were not significantly different (2.58 ± 0.93 vs 2.30 ± 0.78, P > 0.05). IL-22 enhanced colon cancer cell proliferation in vitro and displayed anti-apoptotic effects; these effects were blocked by adding a STAT3 inhibitor. IL-22 promoted tumor growth in BALB/c nude mice; however, this effect was reversed by adding a STAT3 inhibitor. CONCLUSION: Th22 cells that accumulate in CRC may be associated with the chemotactic effect of the tumor microenvironment. IL-22 is associated with CRC development, most likely via STAT3 activation.

[A wavelength selection approach of near infrared spectra Based on SCARS strategy and its application].

According to the characteristics of near infrared spectral(NIR)data, a new tactic called stability competitive adaptive reweighted sampling (SCARS) is employed to select characteristic wavelength variables of NIR data to build PLS model. This method is based on the stability of variables in PLS model. SCARS algorithm consists of a number of loops. In each loop, the stability of each corresponding variable is computed at first. Then enforced wavelength selection and adaptive reweighted sampling (ARS) is used to select important variables according to the stability of variables. The selected variables are kept as a variable subset and further used in the next loop. After the running of all loops, a number of subsets of variables are obtained and root mean squared error of cross validation (RMSECV) of PLS models is computed. The subset of variables with the lowest RMSECV is considered as the optimal variable subset. Validated by NIR data set of protein fodder solid-state fermentation process, the SCARS-PLS prediction model is better than PLS models based on wavelengths selected by competitive adaptive reweighted sampling (CARS) and Monte Carlo uninformative variable elimination (MC-UVE) methods. As a result, twenty one wavelength variables are selected by SCARS method to build the PLS prediction model with the predicted root mean square error (RMSEP) valued at 0.0543 and correlation coefficient (Rp) 0.9908. The results show that SCARS tactic can efficiently improve the accuracy and stability of NIR wavelength variables selection and optimize the precision of prediction model in solid-state fermentation process. The SCARS method has a certain application value.

Lipoxin A4 inhibits NF-κB activation and cell cycle progression in RAW264.7 cells.

Lipoxins (LXs), including lipoxin A4 (LXA4), etc., have been approved for potent anti-inflammatory and immunomodulatory properties. Based on the important roles of macrophages in inflammation and immunomodulation, we investigate the effects of LXA4 on lipopolysaccharide (LPS)-induced proliferation and the possible signal transduction pathways in RAW264.7 macrophages. RAW264.7 cells were treated in vitro with or without LPS in the absence or presence of LXA4. [(3)H]-TdR incorporation assay and flow cytometry were used for detecting cell proliferation and cycle, respectively. Moreover, Western blot was applied to evaluate the protein expression levels of Cyclin E, IκBα, nuclear factor-κB (NF-κB), and IκB kinase (IKK). Our research showed that LXA4 suppressed LPS-induced proliferation, increased the proportion of the G0/G1 phase, decreased the proportion of the S phase, and downregulated the expression of Cyclin E. Besides these, LXA4 suppressed LPS-induced IκBα degradation, NF-κB translocation, and the expression of IKK. The data suggested that LXA4 inhibited LPS-induced proliferation through the G0/G1 phase arrest in RAW264.7 macrophages, and the inhibitory effect might depend on NF-κB signaling transduction pathway.

BML-11, a lipoxin receptor agonist, protected carbon tetrachloride-induced hepatic fibrosis in rats.

Inflammation plays an important role in the occurrence and development of fibrosis. Lipoxins (LXs) and BML-111 (lipoxin A4 agonist) have been approved for potent anti-inflammatory properties. Previously, we and others had showed LXs and BML-111 could protect acute hepatic injury, inhibit the growth and invasion of hepatic tumor. However, there are few reports dealing with their effects on hepatic fibrosis. To explore whether LXs and the analog could interrupt the process of hepatic fibrosis, the effects of BML-111 on tetrachloride-induced hepatic fibrosis were observed and the possible mechanism were discussed. Sprague-Dawley rats were induced liver fibrosis by carbon tetrachloride (CCl4) for 10 weeks with or without BML-111, and the histopathology and collagen content were employed to quantify hepatic necro-inflammation and fibrosis. Moreover, the expression levels of α-smooth muscle actin (α-SMA), transforming growth factor-ß1 (TGF-ß1), and platelet-derived growth factor (PDGF) were examined via Western blot or ELISA. Rats treated with BML-111 improved hepatic necro-inflammation and inhibited hepatic fibrosis in association with reduction of α-SMA expression and decreased collagen deposition. Furthermore, BML-111 could downregulate the expressions of TGF-ß1 and PDGF significantly. BML-111 played a critical protective role in CCl4-induced hepatic fibrosis through inhibiting the levels of TGF-ß1 and PDGF in rats.

Aquaporin 5 promotes the proliferation and migration of human gastric carcinoma cells.

Aquaporin 5 (AQP5) promotes the progression and invasion of several cancers, but its role in the tumorigenesis of human gastric carcinoma (GC) has not been clearly defined. Here, we investigated the potential functions of AQP5 in the proliferation and migration of human GC. RT-PCR and western blotting were used to detect the expression of AQP5 in human GC cell lines. Immunohistochemistry was applied to evaluate the expression of AQP5 in human GC tissues and corresponding normal tissues. Following ectopic overexpression of AQP5 or inhibition of AQP5 by its inhibitor, acetazolamide (AZA), cell proliferation and migration of AGS cells were analyzed by MTT assay, colony formation assay, and wound healing assay. Heterogeneous expression of AQP5 mRNA and protein was observed in human GC cell lines MKN45, MKN28, AGS, and SGC7901. AQP5 was up-regulated in GC tissues in comparison to corresponding normal tissues. AQP5 protein was mainly localized in the cell membrane. Overexpression of AQP5 was correlated with enhanced lymph node metastasis. In vitro, overexpression of AQP5 notably enhanced, while inhibition of AQP5 by AZA significantly attenuated the proliferation and migration of AGS cells. Our data indicate that AQP5 may play an important role in the tumorigenesis and progression of human GC and suggest that AQP5 is a potential therapeutic target against GC.

[Changes of the spectrum on thyroid disease after the ten-year implementation of universal salt iodization in Guangxi Zhuang Autonomous Region].

OBJECTIVE: To reveal the relationship between iodine nutrition and the change of spectrum on thyroid diseases through comparing the different iodine environments pre- and post- the universal salt iodization(USI)campaign. METHODS: To compare the urinary iodine concentration between 1000 normal people and 5998 patients with thyroid disease who had undergone surgical operations, from 4 major cities, including iodine deficient and rich areas of Guangxi Zhuang Autonomous Region. RESULTS: After USI was put into practice, the urinary iodine concentration of patients with thyroid appeared higher than those of normal people(324.3 µg/L vs. 238.5 µg/L, P < 0.05). The urinary iodine concentrations of nodular goiter,Graves disease, toxic nodular goiter, thyroid papillary carcinoma and Hashimoto's thyroiditis were higher than those before the USI was taken(263.8 µg/L vs. 69.75 µg/L, 289.7 µg/L vs. 228.3 µg/L, 346.8 µg/L vs. 268.4 µg/L, 350.3 µg/L vs. 316.2 µg/L and 378.5 µg/L vs. 305.8 µg/L). The proportions of toxic nodular goiter, thyroid papillary carcinoma and Hashimoto's thyroiditis appeared as 7.59% vs. 4.80%, 5.85% vs. 4.02% and 3.88% vs. 2.46%, all higher than those before the implementation of USI, except the nodular goiter which showed a reduction (63.56% vs. 69.75%). CONCLUSION: The spectrum of thyroid diseases appeared an obvious change in Guangxi within the last 10-year implementation of USI. However, the excessive intake of iodine might serve as a risk factor for toxic nodular goiter, thyroid papillary carcinoma and Hashimoto's thyroiditis.

Quantitative proteomic analysis reveals that antioxidation mechanisms contribute to cold tolerance in plantain (Musa paradisiaca L.; ABB Group) seedlings.

Banana and its close relative, plantain are globally important crops and there is considerable interest in optimizing their cultivation. Plantain has superior cold tolerance compared with banana and a thorough understanding of the molecular mechanisms and responses of plantain to cold stress has great potential value for developing cold tolerant banana cultivars. In this study, we used iTRAQ-based comparative proteomic analysis to investigate the temporal responses of plantain to cold stress. Plantain seedlings were exposed for 0, 6, and 24 h of cold stress at 8 °C and subsequently allowed to recover for 24 h at 28 °C. A total of 3477 plantain proteins were identified, of which 809 showed differential expression from the three treatments. The majority of differentially expressed proteins were predicted to be involved in oxidation-reduction, including oxylipin biosynthesis, whereas others were associated with photosynthesis, photorespiration, and several primary metabolic processes, such as carbohydrate metabolic process and fatty acid beta-oxidation. Western blot analysis and enzyme activity assays were performed on seven differentially expressed, cold-response candidate plantain proteins to validate the proteomics data. Similar analyses of the seven candidate proteins were performed in cold-sensitive banana to examine possible functional conservation, and to compare the results to equivalent responses between the two species. Consistent results were achieved by Western blot and enzyme activity assays, demonstrating that the quantitative proteomics data collected in this study are reliable. Our results suggest that an increase of antioxidant capacity through adapted ROS scavenging capability, reduced production of ROS, and decreased lipid peroxidation contribute to molecular mechanisms for the increased cold tolerance in plantain. To the best of our knowledge, this is the first report of a global investigation on molecular responses of plantain to cold stress by proteomic analysis.

Value of ultrasound elastography in detecting small breast tumors.

BACKGROUND: Detecting small breast tumors is difficult for conventional ultrasound. The goal of this study was to assess the value of ultrasound elastography in characterizing small breast tumors and to compare its sensitivity, specificity and accuracy with conventional ultrasound. METHODS: A total of 308 breast tumors less than 2 cm in size from 283 in-hospital patients examined with both conventional ultrasound and ultrasound elastography were retrospectively analyzed. The results were compared to surgical pathology. RESULTS: There were 104 malignant and 204 benign lesions. The sensitivities of sonography and sonoelastography were similar (P < 0.05), and the sensitivity of the two modalities combined improved remarkably to 97.1%. The mean elastic score of malignant and benign tumors less than 2 cm were 3.76 ± 1.01 and 1.73 ± 0.99, respectively (P < 0.05), and the mean elastic score of the false-negative lesions on conventional ultrasound was 3.61 ± 1.14. CONCLUSIONS: Ultrasound elastography in combination with conventional ultrasound can improve the sensitivity for detecting small breast tumors. It is also valuable in detecting small malignant tumors which are difficult to diagnose with conventional ultrasound. Ultrasound elastography can be a useful adjunct to conventional ultrasound in diagnosing small breast tumors.