Protective effect of apelin-13 on ventilator-induced acute lung injury.

BACKGROUND: Mechanical Ventilation (MV) is an essential mechanism of life support in the clinic. It may also lead to ventilator-induced acute lung injury (VILI) due to local alveolar overstretching and/or repeated alveolar collapse. However, the pathogenesis of VILI is not completely understood, and its occurrence and development may be related to physiological processes such as the inflammatory response, oxidative stress, and apoptosis. Some studies have found that the the apelin/APJ axis is an endogenous antagonistic mechanism activated during acute respiratory distress syndrome(ARDS), that can counteract the injury response and prevent uncontrolled lung injury. To indicate that apelin-13 plays a protective role in VILI, an animal model of VILI was established in this study to explore whether apelin-13 can alleviate VILI in rats by inhibiting inflammation, apoptosis and oxidative stress. METHODS: SD rats were divided into four groups: control, high tidal volume, high tidal volume + normal saline and high tidal volume + apelin-13. After tracheotomy, the rats in control maintained spontaneous breathing, and the other rats were connected to the small animal ventilator for 4 h to establish the rat VILI model. The mRNA expression of apelin was measured by real-time quantitative polymerase chain reaction(qRT-PCR), immunofluorescence and Western blotting(WB) were used to detect the expression level of APJ, and WB was used to detect the expression of the apoptotic proteins Bax and bcl-2. The degree of lung injury was evaluated by pathological staining of lung tissue,W/D ratio, and BALF total protein concentration. The expression of inflammatory factors(IL-1ß, IL-6, TNF-α) in alveolar lavage fluid was measured using ELISA. The activities of MPO and cat and the content of MDA, an oxidative product, in lung tissue were measured to evaluate the degree of oxidative stress in the lung. RESULTS: After treatment with apelin-13, the apelin/APJ axis in the lung tissue of VILI model rats was activated, and the effect was further enhanced. The pathological damage of lung tissue was alleviated, the expression of the antiapoptotic protein Bcl-2 and the proapoptotic protein Bax was reversed, and the levels of the inflammatory cytokines IL-1ß, IL-6, TNF-α levels were all decreased. MPO activity and MDA content decreased, while CAT activity increased. CONCLUSION: The apelin/apj axis is activated in VILI. Overexpression of apelin-13 further plays a protective role in VILI, mainly by including reducing pathological damage, the inflammatory response, apoptosis and antioxidant stress in lung tissue, thus delaying the occurrence and development of VILI.

Effect and mechanical mechanism of spontaneous breathing on oxygenation and lung injury in mild or moderate animal ARDS.

OBJECTIVE: The present study aimed to determine the effect and mechanical mechanism of spontaneous breathing during mechanical ventilation on oxygenation and lung injury using Beagles dogs mild or moderate acute respiratory distress syndrome (ARDS) model. METHODS: After inducing mild or moderate ARDS by infusion of oleic acid, Eighteen Beagles dogs were randomly split into Spontaneous breathing group (BIPAPSB, n = 6), and Complete muscle paralysis group (BIPAPPC, n = 6),Six Beagles without ventilator support comprised the control group. Both groups were ventilated for 8 h under BIPAP mode. High-pressure was titrated TV to 6 ml/kg. A multi-pair esophageal balloon electrode catheter was used to measure respiratory mechanics and electromyogram. End-expiratory lung volume (EELV), gas exchange and respiratory variables were recorded in the process of mechanical ventilation. The contents of Interleukin (IL)-6 and IL-8 in lung tissue were measure using qRT-PCR. Besides, lung injury score was calculated in the end of mechanical ventilation. RESULTS: Based on the comparable setting of ventilator, BIPAPSB group exhibited higher safety peak transpulmonary pressure, abdominal pressure, EELV and P/F(PaO2/FiO2) than BIPAPPC group, whereas mean transpulmonary pressure, the mRNA levels of the IL-6 and IL-8 in the lung tissues and lung injury score in BIPAPSB group were lower than those in BIPAPPC group. CONCLUSION: In mild to moderate ARDS animal models, during mechanical ventilation, SB may improve respiratory function and reduce ventilator-induced lung injury. The mechanism may be that spontaneous inspiration up-regulates peak transpulmonary pressure and EELV; Spontaneous expiration decreases mean transpulmonary pressure by up-regulating intra-abdominal pressure, thereby reducing stress and strain.

[Research progress on mechanism of biotrauma caused by ventilation-induced lung injury].

Mechanical ventilation is an advanced life support treatment for patients with acute respiratory failure. While stabilizing respiratory function, it also acts as an injury factor to exacerbate or lead to lung injury, that is, ventilation-induced lung injury (VILI). There may be a more subtle form of damage to VILI known as "biotrauma". However, the mechanism of biotrauma in VILI is still unclear. This article intends to review the mechanism of biotrauma of VILI from the aspects of inflammatory response, oxidative stress and complement activation, in order to provide a new strategy for clinical prevention and treatment of biotrauma caused by VILI.

The Wnt/ß-catenin pathway regulates inflammation and apoptosis in ventilator-induced lung injury.

Ventilator-induced lung injury (VILI) may be caused by incorrect mechanical ventilation (MV), and its progression is mainly related to inflammatory reaction, apoptosis, and oxidative stress. The Wnt/ß-catenin pathway can modulate inflammation and apoptosis; however, its role in VILI is unknown. This research aims to explore the role of the Wnt/ß-catenin pathway in VILI. VILI models were established using rats and type II alveolar epithelial (ATII) cells. Glycogen synthase kinase 3ß (GSK-3ß), ß-catenin, and cyclin D1 were determined using western blotting and immunofluorescence. Apoptosis of lung tissues was evaluated using TUNEL, flow cytometry, Bax, and Bcl2 protein. Interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were detected via enzyme-linked immunosorbent assay (ELISA). Lung pathological injury was evaluated through hematoxylin and eosin (H&E) staining. Lung permeability was evaluated by the ratio of dry to wet weight of lung tissue and the total protein level of bronchoalveolar lavage fluid (BALF). The results showed that GSK-3ß expression was enhanced and ß-catenin expression was diminished in lung tissue under MV. SB216763 increased ß-catenin and cyclin D1 expression by inhibiting GSK-3ß expression and inhibited the inflammatory response and apoptosis of lung, alleviated pulmonary edema and lung tissue permeability, and significantly mitigated lung injury. However, inhibition of ß-catenin expression by MSAB attenuated the anti-inflammatory and antiapoptotic effects of SB216763 in VILI. Overall, the present study demonstrates that the Wnt/ß-catenin pathway activation in MV may play an anti-inflammatory and antiapoptotic role, thereby alleviating lung injury and delaying VILI progression, which may be a key point of intervention in VILI.

MiR-9a-5p alleviates ventilator-induced lung injury in rats by inhibiting the activation of the MAPK signaling pathway via CXCR4 expression downregulation.

BACKGROUND: Globally, Mechanical ventilation is the most commonly used short-term life support technology. Ventilator-induced lung injury (VILI) is an inflammatory injury caused by mechanical ventilation. MicroRNAs (miRNAs) are considered as new gene regulators that play an important role in lung injury and inflammation. However, the role and mechanism of action of miR-9a-5p in VILI remain unclear. METHODS: Herein, a rat model of VILI was established. To determine the expression levels of miR-9a-5p and CXCR4 mRNA, real-time quantitative polymerase chain reactions (qRT-PCR) were conducted. As well as western blot (WB) and immunofluorescence analyses, we determined the expression of CXCR4, SDF-1 and MAPK signaling pathway-related kinases. Hematoxylin and eosin (H&E) staining and the wet-dry ratio of the lung tissue were used to evaluate organ injury. An enzyme-linked immunosorbent assay (Elisa) and myeloperoxidase (MPO) activity measurements were performed to evaluate the inflammatory response. In addition, double luciferase reporter assays were used to verify the association between miR-9a-5p and CXCR4. RESULTS: The expression of miR-9a-5p was low, whereas that of CXCR4 was high in the lung tissues of VILI rats. The overexpression of miR-9a-5p alleviated the degree of pathological injury in the lung tissues of rats with VILI, downregulating inflammatory cytokine expression and MPO activity. In the VILI rat model, miR-9a-5p targeted the negative regulation of CXCR4, and CXCR4 overexpression to reverse the lung-protective and anti-inflammatory effects of miR-9a-5p overexpression in VILI rats. miR-9a-5p also inhibited the phosphorylation of extracellular signal receptor-activated kinase (ERK), a protein related to the MAPK signaling pathway, by downregulating CXCR4 expression. CONCLUSION: miR-9a-5p can hinder the activation of the MAPK/ERK signaling pathway and reduce inflammatory reactions and lung injury in VILI rats through the targeted regulation of CXCR4 expression. Therefore, miR-9a-5p could serve as an intervention target to supply a new strategy for the care of VILI.

Construction and comprehensive analysis of the competing endogenous RNA network in endometrial adenocarcinoma.

BACKGROUND: Endometrial carcinoma (EC) is one of the most common gynecological malignant tumors. In this study, we constructed gene co-expression networks to identify key modules and hub genes involved in the pathogenesis of EC. RESULTS: The MEturquoise module was found to be significantly related to hypertension and the MEbrown module was significantly related to the history of other malignancies. Functional enrichment analysis showed that the MEturquoise module was associated with the GO biological process terms of transcription from RNA polymerase II promoter, positive regulation of male gonad development, endocardial cushion development, and endothelial cell differentiation. The MEbrown module was associated with GO terms DNA binding, epithelial-to-mesenchymal transition, and transcription from RNA polymerase II promoter. A total of 10 hub genes were identified and compared with the available datasets at transcriptional and translational levels. CONCLUSIONS: The identified ceRNAs may play a critical role in the progression and metastasis of EC and are thus candidate therapeutic targets and potential prognostic biomarkers. The two modules constructed further provide a useful reference that will advance understanding of the mechanisms of tumorigenesis in EC.

Relationship of Circulating Copper Level with Gestational Diabetes Mellitus: a Meta-Analysis and Systemic Review.

BACKGROUND AND PURPOSE: Gestational diabetes mellitus (GDM) represents the frequently occurring medical disorder beginning in the process of pregnancy. No consensus has been reached about the relationship of circulating copper content with the risk of GDM. Therefore, the present work carried out a meta-analysis for summarizing epidemiological research regarding the copper level with the GDM risk. Furthermore, studies using categories of copper concentration as exposure were combined by dose-response meta-analysis. METHODS: Related studies were retrieved against the PubMed, Web of Science, and Scopus databases from inception till August 2020. The overall effects were expressed as standard mean difference (SMD). A dose-response meta-analysis was conducted to assess whether the higher copper concentration was associated with higher risks of GDM. Stata 16.0 and Review Manager 5.3 were utilized for data analysis. RESULTS: A total of fourteen articles involving were retrieved for meta-analysis; in the meantime, 2670 pregnant subjects including 910 GDM cases were enrolled for quantitative analysis. Based on the integrated findings, GDM cases showed increased circulating copper contents relative to those in normal pregnant subjects (SMD = 0.65, 95% CI 0.19 to 1.11; P = 0.005). There was no obvious evidence of publication bias among the studies enrolled. Subgroup analysis showed that such trend was consistent in the third trimester (SMD = 1.21, 95% CI 0.35 to 2.08; P = 0.006) but not second trimester. Meanwhile, circulating copper concentration was significantly higher in women with GDM than those without GDM within the Asian population but not within the Caucasian population (Asia: SMD = 0.73; 95% CI 0.12 to 1.34, P = 0.02; Europe: SMD = 0.49; 95% CI: - 0.23 to 1.20, P = 0.18). Further, serum copper analysis together with subgroup analysis was conducted, and the same result was obtained. For dose-response analysis, the linear associations between circulating copper and risks of GDM were revealed, that higher circulating copper concentration during pregnancy is closely associated with GDM. CONCLUSION: According to existing evidence, the serum copper concentration increased among GDM cases compared with subjects with normality in glucose tolerance pregnant subject, in particular among the Asians and during the third trimester. The finding from dose-response analysis suggested that increased copper level is associated with an increased risk of GDM. Nonetheless, more specially designed prospective articles should be carried out for understanding the dynamic relationship of copper concentration with the GDM risk.

Endogenous SHBG levels correlate with that of glucose transporters in insulin resistance model cells.

Gestational diabetes mellitus (GDM) is defined as glucose intolerance of any degree that occurs after onset of pregnancy. Sex hormone binding globulin (SHBG) plays an important regulatory role in insulin resistance and is a risk factor in GDM. In the current study, we aimed to examine whether SHBG can regulate glucose metabolism through glucose transporters (GLUTs). SHBG was transfected into established human insulin model cells and the expression of SHBG, GLUT1, GLUT3, and GLUT4 was detected and analyzed in normal cells, model cells, and all groups of transfected cells by real-time PCR and western blotting. Further, immunofluorescence staining was performed on cells from each group to observe protein expression. In insulin resistance model cells, the expression of SHBG was low, whereas that of GLUT1 was high and of GLUT3 and GLUT4 was low, when compared with expression in control cells. Moreover, the overexpression of SHBG inhibited the expression of GLUT1 mRNA and protein, and promoted the expression of GLUT3 and GLUT4. Our results indicate that SHBG could be involved in glucose metabolism through its regulation of multiple GLUTs. Transfection of SHBG into insulin-resistant cells may partially improve the level of GLUTs, providing a potential therapeutic approach for the treatment of insulin resistance in GDM. Although SHBG can regulate glucose metabolism through GLUTs and thus cause insulin resistance and induce gestational diabetes, the regulation mechanism of GLUTs mediated by SHBG has not been elucidated, which will be the focus of further studies.

[Sex hormone-binding globulin of gestational diabetes mellitus pregnant women with well-controlled glucose and pregnancy outcomes].

OBJECTIVE: To explore the relationship between sex hormone-binding globulin (SHBG) of gestational diabetes mellitus (GDM) pregnant women with well-controlled glucose and pregnancy outcomes. METHODS: Two hundred and fifty-one GDM pregnant women of 24 - 28 weeks in Shengjing Hospital of China Medical University were recruited from Mar. 2005 to Mar. 2010. Two hundred and sixteen cases of GDM with well-controlled glucose were defined as glycemic satisfied group, and they were treated by diet therapy (169 cases) or insulin therapy (47 cases). Thirty-five cases with unsatisfied glucose were defined as glycemic unsatisfied group. One hundred and ninety-two healthy pregnant women of 24 - 28 weeks were defined as healthy control group. Serum SHBG and homeostasis model analysis of insulin resistance (HOMA-IR) at 24 - 28 weeks and above 36 weeks were measured. GDM was diagnosed by "two-step" method according to the National Diabetes Data Group (NDDG) criteria. The pregnancy outcomes and complications of the three groups were recorded. RESULTS: (1) Comparison of pregnancy outcomes and complications:glycemic satisfied group was less likely to develop hypertensive disorders in pregnancy (10.6%), premature birth (8.3%), large for gestational age (LGA) (8.8%), neonatal asphyxia (3.7%) and neonatal hypoglycemia (2.3%) compared to glycemic unsatisfied group (42.9%, 34.3%, 31.4%, 22.9% and 11.4%, respectively). And the difference was statistically significant (P < 0.05 or P < 0.01). There was no significant difference for incidence of polyhydramnios, pueperal infection, postpartum hemorrhage, neonatal hyperbilirubinemia between the two groups (P > 0.05). When compared to healthy control group (7.3%, 2.1%, 4.2%, 2.1% and 1.6%), no significant difference was found for incidence of premature birth (8.3%), pueperal infection (3.2%), postpartum hemorrhage (5.1%), neonatal asphyxia (3.7%) and neonatal hypoglycemia (2.3%, P > 0.05). (2) Comparison of results of 24 - 28 weeks and above 36 weeks: serum SHBG of glycemic satisfied group [(384 ± 88), (457 ± 48) nmol/L] was significantly higher than that of glycemic unsatisfied group [(313 ± 45), (401 ± 73) nmol/L]; HOMA-IR of glycemic satisfied group (5.3 ± 1.1, 5.5 ± 1.1) was significantly lower than that of glycemic unsatisfied group (7.0 ± 1.3, 7.6 ± 1.7; P < 0.01). Serum SHBG of glycemic satisfied group was significantly lower than that of healthy control group [(492 ± 95), (565 ± 40) nmol/L]; and HOMA-IR of glycemic satisfied group (5.3 ± 1.1, 5.5 ± 1.1) was significantly higher than that of healthy control group (3.6 ± 0.6, 3.9 ± 0.5; P < 0.01). FPG of glycemic satisfied group [(5.84 ± 0.28), (5.16 ± 0.13) mmol/L] was significantly lower than that of glycemic unsatisfied group [(6.13 ± 0.16), (5.68 ± 1.14) mmol/L;P < 0.01]. FINS of glycemic satisfied group [(20.4 ± 2.1), (24.1 ± 4.2) mmol/L] was significantly lower than that of glycemic unsatisfied group [(24.7 ± 4.5), (29.9 ± 2.7) mmol/L; P < 0.01]. (3) Correlation analysis. Between 24-28 weeks, SHBG was negatively correlated with HOMA-IR in the three groups (r = -0.952, P < 0.01); and SHBG was negatively correlated with HOMA-IR in glycemic satisfied group (r = -0.903, P < 0.01). CONCLUSIONS: Well-controlled glucose can not completely improve maternal and fetal outcomes of GDM pregnant women. High insulin resistance and low serum SHBG can influence pregnancy outcomes.