[Research advance on the role of mitochondrial dysfunction and releasing mitochondrial DNA in sepsis-induced acute lung injury].

Sepsis-induced acute lung injury (ALI) is a serious condition with a high incidence. Mitochondrial dysfunction and the release of mitochondrial DNA (mtDNA) play a crucial role in the occurrence and development of sepsis-induced ALI. In sepsis, mitochondrial dysfunction causes energy depletion of cells and dysfunction of tissue cell repair mechanisms, leading to ALI. In addition, the release of mtDNA leads to a more intense inflammatory response, exacerbating sepsis-induced ALI. This article reviews the pathophysiological mechanism of mitochondrial dysfunction and mtDNA release in sepsis and the current research status, in order to provide direction for the evaluation, treatment and prevention of sepsis-induced ALI.

miR-423-5p suppresses high-glucose-induced podocyte injury by targeting Nox4.

Podocyte injury plays crucial roles in the pathogenesis of diabetic nephropathy (DN). Aberrant microRNAs (miRNAs) have been suggested to contribute to podocyte injury. However, whether miR-423-5p could alleviate high glucose (HG)-mediated podocyte injury and the underlying mechanisms remains unclear. In this study, we found that patients with DN have reduced miR-423-5p and elevated Nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4) expressions in clinical renal tissues, and HG induced Nox4 but suppressed miR-423-5p expressions in cultured podocytes in a time-dependent manner. Moreover, overexpression of miR-423-5p antagonized HG-stimulated podocyte injury by enhancing cell viability, inhibiting reactive oxygen species (ROS) production, suppressing cell apoptosis, reducing inflammatory activity, and repressing cytoskeleton damage accompanied with alternations of podocyte specific proteins. Furthermore, functional assays substantiated that Nox4 was a direct target and negatively regulated by miR-423-5p. Additionally, restoration of Nox4 impeded the protective effect of miR-423-5p on podocyte injury via activation of p38 MAPK pathway. Therefore, this study manifested that miR-423-5p overexpression protected HG-induced podocyte damage by inhibiting ROS generation via targeting Nox4, providing a potential therapeutic strategy against DN.

Effects of safflower yellow on beta-amyloid deposition and activation of astrocytes in the brain of APP/PS1 transgenic mice.

Safflower yellow (SY), one of traditional Chinese medicine extracted from safflower, has been shown to have neuroprotective effects on animal models of vascular dementia and Alzheimer's diseases (AD), by inhibiting oxidative injury, neuronal apoptosis and tau hyperphosphorylation. In this study, we investigated whether safflower yellow (SY) can improve cognitive function, decrease Amyloid ß (Aß) accumulation and overactivation of astrocytes in AD mouse model. We found that SY treatment significantly ameliorated the learning and memory deficits of APP/PS1 mice. By hematoxylin-eosin staining, we found that the neuronal loss and death in APP/PS1 mice was decreased by SY treatment. Immunohistochemical staining showed that SY treatment dramatically down-regulated Aß1-42 deposition and glial fibrillary acidic protein (GFAP) level in APP/PS1 mice. Biochemical analysis also showed that SY treatment reduced soluble and insoluble Aß1-42 level in the cortex and soluble Aß1-42 level in the hippocampus of APP/PS1 mice. Moreover, we found that SY treatment decreased the expression of proteins related to generation of Aß, and markedly increased expression of enzymes associated with clearance of Aß in the brain of APP/PS1 mice. These results indicate that the SY can serve as a promising therapeutic approach for the treatment of AD.

Muscle-derived extracellular superoxide dismutase inhibits endothelial activation and protects against multiple organ dysfunction syndrome in mice.

Multiple organ dysfunction syndrome (MODS) is a detrimental clinical complication in critically ill patients with high mortality. Emerging evidence suggests that oxidative stress and endothelial activation (induced expression of adhesion molecules) of vital organ vasculatures are key, early steps in the pathogenesis. We aimed to ascertain the role and mechanism(s) of enhanced extracellular superoxide dismutase (EcSOD) expression in skeletal muscle in protection against MODS induced by endotoxemia. We showed that EcSOD overexpressed in skeletal muscle-specific transgenic mice (TG) redistributes to other peripheral organs through the circulation and enriches at the endothelium of the vasculatures. TG mice are resistant to endotoxemia (induced by lipopolysaccharide [LPS] injection) in developing MODS with significantly reduced mortality and organ damages compared with the wild type littermates (WT). Heterogenic parabiosis between TG and WT mice conferred a significant protection to WT mice, whereas mice with R213G knock-in mutation, a human single nucleotide polymorphism leading to reduced binding EcSOD in peripheral organs, exacerbated the organ damages. Mechanistically, EcSOD inhibits vascular cell adhesion molecule 1 expression and inflammatory leukocyte adhesion to the vascular wall of vital organs, blocking an early step of the pathology in organ damage under endotoxemia. Therefore, enhanced expression of EcSOD in skeletal muscle profoundly protects against MODS by inhibiting endothelial activation and inflammatory cell adhesion, which could be a promising therapy for MODS.

[Analysis of characteristics and related risk factors of prognosis in elderly and young adult patients with acute respiratory distress syndrome].

OBJECTIVE: To compare the characteristics and risk factors of prognosis between elder and young patients with acute respiratory distress syndrome (ARDS) in intensive care unit (ICU). METHODS: The data of 150 patients meeting ARDS Berlin guideline who admitted to ICU of Affiliated First Hospital of Dalian Medical University from August 2011 to November 2013 were retrospectively analyzed. The patients over 65 years old were served as elderly group (n=78), and those younger than 65 years old were served as young group (n=72), and the patients were subdivided into survivors and non-survivors groups. The characteristics of patients at admission was recorded to investigate the characteristics of elder and young patients by univariate analysis. The univariate analysis was also conducted between different prognosis groups, and the risk factors of mortality were demonstrated by multivariate logistic analysis. RESULTS: Compared with the young group, the hospital length of stays [days: 27.0 (16.0, 36.0) vs. 15.0 (8.0, 21.0), P=0.000], ICU length of days [days: 25.0 (15.0, 32.0) vs. 13.0 (7.0, 19.00), P = 0.000], mechanical ventilation days [days: 19.0 (11.0, 27.0) vs. 8.0 (5.0, 15.0), P = 0.000], the proportion of tracheotomy: [39.74% (31/78) vs. 18.06% (13/17), P = 0.003], the number of organ dysfunction (3.78 ± 0.49 vs. 1.97 ± 1.03,P=0.043) and creatinine (µmol/L:153.85 ± 16.89 vs. 108.26 ± 9.14, P = 0.017) of elderly group were significantly increased. The mortality [67.95% (53/78) vs. 59.72% (43/72), P = 0.190] and acute physiology and chronic health evaluation II (APACHEII) score (17.94 ± 6.04 vs. 15.99 ± 6.93, P = 0.068) in the elderly group were higher than those in the young group but without the significant differences. The causes of death in elderly patients were mainly with respiratory failure; the mainly causes in young and middle-aged patients were complex with multiple organ dysfunction syndrome, circulatory failure and other reasons. APACHEII score, the number of organ dysfunction, and maximum positive end-expiratory pressure (PEEP) in the non-survivors of the elderly group were significantly higher than those of the survivors [APACHEII score:19.45 ± 6.00 vs. 14.72 ± 4.83,the number of organ dysfunction:4.13 ± 0.88 vs. 2.16 ± 1.01,maximum PEEP(cmH2O,1 cmH2O = 0.098 kPa): 13.93 ± 4.16 vs. 9.72 ± 3.72, all P<0.01],and the proportion of tracheotomy and pH value were significantly lower than those of the survivors [the proportion of tracheotomy:32.08% (17/53) vs. 56.00% (14/25), pH value: 7.35 ± 0.14 vs. 7.42 ± 0.08, both P < 0.05]. Logistic analysis showed that APACHEII score [odds ratio (OR) = 7.068, 95% confidence interval (95% CI)= 1.358-3.273, P = 0.023],the number of organ dysfunction (OR = 2.328, 95% CI = 1.193-4.520, P = 0.029) were related with prognosis in elderly patients with ARDS. APACHEII score, the number of organ dysfunction, blood lactate, maximum PEEP in non-survivors of the young group were significantly higher than those of the survivors [APACHEII score: 18.12 ± 6.88 vs. 12.83 ± 5.80,the number of organ dysfunction:3.16 ± 1.23 vs. 2.55 ± 1.29, blood lactate(mmol/L): 4.84 ± 4.07 vs. 2.56 ± 1.86,maximum PEEP (cmH2O): 13.93 ± 5.50 vs. 10.54 ± 4.05, P < 0.05 or P < 0.01], and the pH value, hospital length of stays, ICU length of days were significantly lower than those of the survivors [pH value: 7.30 ± 0.16 vs. 7.41 ± 0.10, hospital length of stays(days):11.09 ± 10.97 vs. 25.17 ± 19.05, ICU length of days (days): 8.0 (5.0, 13.0) vs. 20.0 (12.0, 31.0), all P < 0.01]. Multivariate logistic analysis showed that APACHEII score was related with the prognosis in young patients with ARDS (OR = 5.735, 95% C I= 1.921-3.310, P = 0.004). CONCLUSIONS: Higher APACHEII score and the number of organ dysfunction were independent predictors of worse outcome in elder ARDS patients. Higher APACHEII score was the independent predictor of worse outcome in young ARDS patients.

Meta-analysis of high doses of ambroxol treatment for acute lung injury/acute respiratory distress syndrome based on randomized controlled trials.

This study seeks to evaluate the potential benefits of high doses of ambroxol treatment for acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) by conducting a meta-analysis based on randomized controlled trials (RCTs). We searched the Pubmed, Embase, China National Knowledge Infrastructure, and Wanfang databases through December 2013. Only RCTs evaluating high doses of ambroxol (≥15 mg/kg or 1000 mg/day) treatment for patients with ALI/ARDS were selected. We included 10 RCTs involving 508 patients. Adjuvant treatment with high doses of ambroxol increased PaO(2)/FiO(2) (weight mean differences [WMD] = 69.18, 95% confidence intervals [CI]: 41.71-96.65), PO(2) (WMD = 11.74, 95% CI: 8.50-14.99), and SaO(2) (WMD = 2.15, 95% CI: 1.60-2.71) compared with usual treatment. Treatment with high doses of ambroxol appeared to reduce serum tumor necrosis factor-α level (WMD -7.92 µg/L; 95% CI, -10.94 to -4.9) and interleukin-6 level (WMD = -20.65 µg/L, 95% CI: -24.74 to -16.55) and to increase serum superoxide dismutase level (WMD = 19.07 NU/mL, 95% CI: 6.16-31.97). The findings suggest that treatment with high doses of ambroxol appears to improve PaO(2)/FiO(2), PO(2), and SaO(2), and the benefits might be related to ambroxol's anti-oxidant and anti-inflammatory properties.