ABSTRACT
AIMS: Acute lung injury (ALI) is a leading cause of mortality as a result of inflammatory cytokine overexpression and increased rates of apoptosis. Therapies for ALI are yet to be thoroughly investigated. Recent evidence has shown that irisin exerts protective effects against many types of pathologies. The present study aimed to determine the function of irisin in an ALI mouse model induced by lipopolysaccharide (LPS) and the corresponding underlying mechanisms at the tissue, cellular, and molecular levels. MAIN METHODS: We assessed irisin function in A549 cells using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assays. The cell apoptosis was evaluated by flow cytometry. Western blotting and RT-PCR were used to test expression level. Animal models of ALI was established. KEY FINDINGS: We found that irisin treatment maintained lung weight, significantly reduced inflammatory cytokine expression, and alleviated lung injury by downregulating miR-199a. In LPS-stimulated cells, forced miR-199a expression downregulated Rad23b expression by targeting its 3' untranslated region, indicating that Rad23b is a direct target of miR-199a. SIGNIFICANCE: These findings reveal that irisin can alleviate ALI by inhibiting miR-199a and upregulating Rad23b expression, suggesting that irisin has clinical potential for the treatment of ALI.
Subject(s)
Acute Lung Injury/metabolism , Cytokines/metabolism , DNA-Binding Proteins/metabolism , Fibronectins/pharmacology , MicroRNAs/metabolism , Acute Lung Injury/chemically induced , Animals , Apoptosis/drug effects , DNA-Binding Proteins/drug effects , Disease Models, Animal , Fibronectins/metabolism , Lipopolysaccharides/pharmacology , Lung/pathology , Mice, Inbred C57BL , MicroRNAs/drug effects , Signal Transduction/drug effects , Up-Regulation/drug effectsABSTRACT
BACKGROUND: The aim of this study was to investigate the expression of Paxillin in colorectal carcinoma and its significance in clinical prognosis. MATERIAL AND METHODS: Tissue specimens from 242 colorectal cancer patients who underwent radical resection were collected in Shaanxi Provincial People's Hospital from 2010 to 2014. The mRNA levels of Paxillin in colorectal cancer tissue and tissue adjacent to carcinoma of 62 patients were measured by quantitative real-time PCR. Immunohistochemistry staining was used to detect the expression of Paxillin in 242 samples of paraffin-embedded tissues. RESULTS: The mRNA and protein level of Paxillin in colorectal cancer tissues were significantly higher than those in the tissue adjacent to carcinoma (P<0.001 and P=0.003, respectively). The expression of Paxillin was significantly correlated to tumor histological grade (P<0.001), tumor size (P=0.01), serum CA199 level (P<0.001), the clinical TNM stage (P<0.001), and distant metastasis (P<0.001). Survival analysis showed that the prognosis of the patients with high expression of Paxillin was poorer than those with low expression of Paxillin (P=0.03). Cox proportional hazards model with stepwise selection showed that age, Paxillin expression level, and the clinical TNM stage were independent prognostic factors influencing survival for patients (P=0.01, P=0.004 and P<0.001, respectively). CONCLUSIONS: Paxillin was expressed at significantly higher levels in colorectal cancer tissues and might serve as a potential prognostic indicator in patients with colorectal cancer.
Subject(s)
Biomarkers, Tumor/metabolism , Colorectal Neoplasms/metabolism , Paxillin/metabolism , Colorectal Neoplasms/pathology , Colorectal Neoplasms/surgery , Female , Humans , Male , Middle Aged , Paxillin/genetics , Prognosis , Real-Time Polymerase Chain ReactionABSTRACT
BACKGROUND: This study aimed to illustrate the characteristics of suicide attempters treated in the Emergency Departments of 7 general hospitals in Xi'an and to provide relevant data for early psychological treatment. MATERIAL AND METHODS: Between October 2010 and September 2014, 155 suicide attempters were treated in the Emergency Departments. Data were collected using a semi-structured questionnaire. Descriptive statistics, chi-square tests, and multivariate analyses were used to identify the factors associated with suicidal behaviors. RESULTS: Females outnumbered males at a ratio of 3.7 to 1. The greatest proportion of cases was in the age group of 21 to 30 years (52.9%). Patients who finished middle school or high school accounted for most of the suicide attempters (50.3%). The most common method used for attempted suicide was drug ingestion (86.5%). The majority of cases attempted suicide at home (74.8%) during the night. Marriage frustration, work and study problems, family fanaticism and conflict, somatic disease, and history of mental disorders were all significantly associated with suicide attempts. The ratio of patients to be discharged or to die were similar in occupation, marital status, and the place of suicide attempt; however, the results were different in gender, age, educational level, methods used for suicide, time of day, and reason. CONCLUSIONS: Suicide is an important public health problem and is multidimensional in nature. Future studies with larger samples are expected to provide more specific knowledge of the effect of each social factor on the suicide risk in Chinese in order to improve the prevention of suicides.
Subject(s)
Suicide, Attempted/statistics & numerical data , Suicide/statistics & numerical data , Adolescent , Adult , China , Demography , Emergency Service, Hospital/statistics & numerical data , Female , Hospitals, General , Humans , Male , Middle Aged , Multivariate Analysis , Sex Factors , Social Class , Suicidal Ideation , Suicide, Attempted/psychology , Surveys and Questionnaires , Tertiary Prevention , Young AdultABSTRACT
Peroxiredoxins (PRDXs) are a highly conserved family of thiol peroxidases that scavenge peroxides in cells. PRDX3 is one member of PRDXs localized in the mitochondria, and has been shown to be involved in antioxidant defense and redox signaling. In this study, we investigated the role of PRDX3 in neuronal trauma using a traumatic neuronal injury (TNI) model in primary cultured cortical neurons. We found that TNI significantly decreased the expression of PRDX3 at both mRNA and protein levels. Overexpression of PRDX3 by lentivirus (LV-PRDX3) transfection attenuated lactate dehydrogenase (LDH) release and neuronal apoptosis after TNI. The results of immunostaining showed that LV-PRDX3 transfection markedly reduced TNI-induced intracellular ROS production, protein radical formation and lipid peroxidation. In addition, overexpression of PRDX3 preserved mitochondrial membrane potential (MMP) levels and ATP generation, and inhibited mitochondrial cytochrome c release in TNI-injured neurons. The results of polymerase chain reaction (PCR) showed that PRDX3 overexpression also increased mitochondrial DNA (mtDNA) content and upregulated the expression of mitochondrial biogenesis-related factors. Taken together, our data demonstrate that PRDX3 protects against TNI insult by preserving mitochondrial function and mitochondrial biogenesis, and may have potential therapeutic value for traumatic brain injury (TBI).
Subject(s)
Cerebral Cortex/injuries , Cerebral Cortex/metabolism , Mitochondria/physiology , Neurons/metabolism , Peroxiredoxin III/biosynthesis , Animals , Cells, Cultured , DNA, Mitochondrial/biosynthesis , Oxidative Stress/physiology , Rats , Rats, Sprague-DawleyABSTRACT
Mitochondrial division inhibitor (mdivi-1), a selective inhibitor of a mitochondrial fission protein dynamin-related protein 1 (Drp1), has been shown to exert protective effects in heart and cerebral ischemia-reperfusion models. The present study was designed to investigate the beneficial effects of mdivi-1 against spinal cord ischemia-reperfusion (SCIR) injury and its associated mechanisms. SCIR injury was induced by glutamate treatment in cultured spinal cord neurons and by descending thoracic aorta occlusion for 20 min in rats. We found that mdivi-1 (10 µM) significantly attenuated glutamate induced neuronal injury and apoptosis in spinal cord neurons. This neuroprotective effect was accompanied by decreased expression of oxidative stress markers, inhibited mitochondrial dysfunction and preserved activities of antioxidant enzymes. In addition, mdivi-1 significantly increased the expression of the large-conductance Ca(2+)- and voltage-activated K(+) (BK) channels, and blocking BK channels by paxilline partly ablated mdivi-1 induced protection. The in vivo experiments showed that mdivi-1 treatment (1 mg/kg) overtly mitigated SCIR injury induced spinal cord edema and neurological dysfunction with no organ-related toxicity in rats. Moreover, mdivi-1 increased the expression of BK channels in spinal cord tissues, and paxilline pretreatment nullified mdivi-1 induced protection after SCIR injury in rats. Thus, mdivi-1 may be an effective therapeutic agent for SCIR injury via activation of BK channels as well as reduction of oxidative stress, mitochondrial dysfunction and neuronal apoptosis. This article is part of a Special Issue entitled SI: Spinal cord injury.
Subject(s)
Large-Conductance Calcium-Activated Potassium Channels/metabolism , Mitochondria/drug effects , Quinazolinones/administration & dosage , Reperfusion Injury/prevention & control , Spinal Cord Ischemia/prevention & control , Animals , Apoptosis/drug effects , Dynamins/antagonists & inhibitors , In Vitro Techniques , Mitochondria/metabolism , Neurons/drug effects , Neurons/metabolism , Oxidative Stress/drug effects , Rats , Rats, Sprague-Dawley , Reperfusion Injury/metabolism , Spinal Cord/drug effects , Spinal Cord/metabolism , Spinal Cord/pathology , Spinal Cord Ischemia/metabolismABSTRACT
Post-synaptic density protein 95 (PSD-95) links neuronal nitric oxide synthase (nNOS) with the N-methyl-D-aspartic acid (NMDA) receptor in the central nervous system, and this molecular complex has been implicated in regulating neuronal excitability in several neurological disorders. Here, small-molecule inhibitors of the PSD-95/nNOS interaction, IC87201 and ZL006 were tested for neuroprotective effects in an in vitro Parkinson's disease (PD) model. We now report that IC87201 and ZL006 reduced MPP(+)-induced neuronal injury and apoptotic cell death in a dose-dependent manner in cultured cortical neurons. These protective effects were associated with suppressed mitochondrial dysfunction, as evidenced by decreased reactive oxygen species (ROS) generation, cytochrome c release, mitochondrial membrane potential (MMP) collapse, and the preserved mitochondrial complex I activity and ATP synthesis. IC87201 and ZL006 also preserved intracellular homeostasis through mitigating mitochondrial Ca(2+) uptake and promoting mitochondrial Ca(2+) buffering capacity. Moreover, treatment with IC87201 and ZL006 significantly increased the expression of Sirt3 after MPP(+) exposure, and knockdown of Sirt3 using specific targeted small interfere RNA (siRNA) partially nullified the protective effects induced by these two inhibitors. These data strongly support the hypothesis that targeting the PSD-95/nNOS interaction produces neuroprotective effects and may represent a novel class of therapeutics for PD as well as other neurological diseases where detrimental NMDA receptor signaling plays a major role.