Exposure to cigarette smoke (CS) is a major threat to human health worldwide. It is well established that smoking increases the risk of respiratory diseases, cardiovascular diseases and different ...forms of cancer, including lung, liver, and colon. CS-triggered inflammation is considered to play a central role in various pathologies by a mechanism that stimulates the release of pro-inflammatory cytokines. During this process, epigenetic alterations are known to play important roles in the specificity and duration of gene transcription.
Epigenetic alterations include three major modifications: DNA modifications via methylation; various posttranslational modifications of histones, namely, methylation, acetylation, phosphorylation, and ubiquitination; and non-coding RNA sequences. These modifications work in concert to regulate gene transcription in a heritable fashion. The enzymes that regulate these epigenetic modifications can be activated by smoking, which further mediates the expression of multiple inflammatory genes. In this review, we summarize the current knowledge on the epigenetic alterations triggered by CS and assess how such alterations may affect smoking-mediated inflammatory responses.
The recognition of the molecular mechanisms of the epigenetic changes in abnormal inflammation is expected to contribute to the understanding of the pathophysiology of CS-related diseases such that novel epigenetic therapies may be identified in the near future.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
To study the regulatory effect of Long non-coding RNA (LncRNA) HOX transcript antisense RNA (HOTAIR) on pulmonary vascular endothelial cell (HPVEC) apoptosis and determine whether the HOTAIR ...facilitate HPVEC apoptosis via DNMT1 mediated hypermethylation of Bcl-2 promoter in chronic obstructive pulmonary disease (COPD).
LncRNA array was used to measure the differentially expressed lncRNAs in COPD and non-COPD lung tissues. Expression of HOTAIR in COPD patient lungs and cigarette smoke extract (CSE)-induced HPVEC was assessed by qRT-PCR. The location of HOTAIR was determined in COPD patient lungs and HPVEC by RNA in situ hybridization (RNA-ISH). The emphysema mouse model and HOTAIR knockdown mice were each established by inhaling cigarette smoke or intratracheal lentiviral vectors instillation. The dysregulation of DNA methyltransferase enzyme 1 (DNMT1), B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax) and Cleaved-caspase 3 protein expression were detected by Western blotting. HOTAIR, DNMT1, Bcl-2 and Bax mRNA expression were measured by quantitative real-time polymerase chain reaction. TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) assays were used to assess apoptotic ratio in mice and CSE-induced HPVEC. Methylation-specific PCR (MSP) assay was conducted to observe the alterations in the methylation of the Bcl-2 promoter in specimens. RNA pull-down assay was used for analysis of the correlation between HOTAIR and DNMT1.
The expression levels of the HOTAIR were up-regulated in COPD patient lungs and CSE-induced HPVEC. HPVEC apoptosis with down-regulated Bcl-2 expression, increased promoter methylation, DNMT1, Bax and Cleaved-caspase 3 expression was found in emphysema mouse model and CSE-induced HPVEC. Knockdown HOTAIR can attenuate cell apoptosis and emphysema via DNMT1 mediated hypermethylation of Bcl-2 promoter in mice. In vitro, HOTAIR can aggravate the apoptosis of CSE-exposed HPVEC. DNMT1 was a target of HOTAIR and had a positive correlation with HOTAIR.
HOTAIR facilitates HPVEC apoptosis via DNMT1 mediated hypermethylation of Bcl-2 promoter in COPD, and attenuating the expression of HOTAIR may be a new therapy to prevent COPD.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This paper presents the investigation of the root causes of the fast degradation of a railway crossing. The dynamic performance of the crossing was assessed using the sensor-based crossing ...instrumentation, and the measurement results were verified using the multi-body system (MBS) vehicle-crossing model. Together with the field inspections, the measurement and simulation results indicate that the fast crossing degradation was caused by the high wheel-rail impact forces related to the hunting motion of the passing trains. Additionally, it was shown that the train hunting was activated by the track geometry misalignment in front of the crossing. The obtained results have not only explained the extreme values in the measured responses, but also shown that crossing degradation is not always caused by the problems in the crossing itself, but can also be caused by problems in the adjacent track structures. The findings of this study were implemented in the condition monitoring system for railway crossings, using which timely and correctly aimed maintenance actions can be performed.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract
Obstructive sleep apnea syndrome (OSAS), a state of sleep disorder, is characterized by repetitive apnea, chronic hypoxia, oxygen desaturation, and hypercapnia. Previous studies have ...revealed that intermittent hypoxia (IH) conditions in OSAS patients elicited neuron injury (especially in the hippocampus and cortex), leading to cognitive dysfunction, a significant and extraordinary complication of OSAS patients. The repeated courses of airway collapse and obstruction in OSAS patients resulted in apnea and arousal during sleep, leading to IH and excessive daytime sleepiness (EDS) and subsequently contributing to the development of inflammation. IH-mediated inflammation could further trigger various types of cognitive dysfunction. Many researchers have found that, besides continuous positive airway pressure (CPAP) treatment and surgery, anti-inflammatory substances might alleviate IH-induced neurocognitive dysfunction. Clarifying the role of inflammation in IH-mediated cognitive impairment is crucial for potentially valuable therapies and future research in the related domain. The objective of this article was to critically review the relationship between inflammation and cognitive deficits in OSAS.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
This paper presents the development of a multi-body system (MBS) vehicle-crossing model and its application in the structural health monitoring (SHM) of railway crossings. The vehicle and track ...configurations in the model were adjusted to best match the real-life situation. By using the measurement results obtained from an instrumented crossing and the simulation results from a finite element (FE) model, the MBS model was validated and verified. The results showed that the main outputs of the MBS model correlated reasonably well with those from both the measurements and the FE model. The MBS and FE models formed the basis of an integrated analysis tool, which can be applied to thoroughly study the performance of railway crossings. As part of the SHM system for railway crossings developed at Delft University of Technology, the MBS model was applied to identify the condition stage of a monitored railway crossing. The numerical results confirmed the highly degraded crossing condition. By using the measured degradation as the input in the MBS model, the primary damage sources were further verified. Through identifying the crossing condition stage and verifying the damage source, necessary and timely maintenance can be planned. These actions will help to avoid crossing failure and unexpected traffic interruptions, which will ultimately lead to sustainable railway infrastructure.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
This study presents the analogical assessment of the train-induced vibration and radiated noise in a proposed theater. The theater is to be constructed in a region with crowded metro lines, and the ...assessment is implemented in an analogical building with comparable structural type and metro condition. Prior to the assessment, the comparability of the analogical building with the theater is validated using the train-induced ground vibration. With the same horizontal distance from the metro line, the train-induced vibration level in the analogical building is 9 dB higher than that in the construction site of the theater. Such results indicate that the lack of soil layers may lead to a dramatic increase in train-induced vibration in the building. In the staircase of the analogical building, the train-induced radiated noise reached 55 dB (A), which is 10 dB (A) higher than the daytime allowable level. As the most important indicator, the noise rating number in the cinema of the analogical building is
-43, which put forward an enormous challenge on the construction of the theater with a denoise demand of 23 dB. The analogical method applied in this study provides an effective and practical way for the assessment of train-induced vibration and radiated noise in proposed vibration-sensitive buildings. The assessment results that provide necessary reference and support for the anti-vibration design will help guarantee the stage effect of the theater.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) are able to carry genetic and protein goods to mediate the interaction between MSCs and target cells. Recently, more and more researches ...have focused on the therapeutic role of MSC-EVs in chronic respiratory diseases. In this review, we summarize the cumulative strategies and mechanisms of MSC-EVs in treating chronic respiratory diseases. This review suggests that MSC-EVs may serve as a novel cell-free-based therapy for chronic respiratory diseases, including COPD, asthma, pulmonary fibrosis, and pulmonary arterial hypertension. In current studies of chronic respiratory diseases, umbilical cord and bone marrow are main sources of MSC-EVs, while adipose tissue, lung, and induced pluripotent stem cells are also applied. Isolation methods of MSC-EVs in treating chronic respiratory diseases involve ultracentrifugation, exosome extraction kits and anion-exchange chromatography. Intratracheal delivery and intravenous administration are the most widely used routes of MSC-EVs. MSC-EVs are able to transfer microRNAs and protein to target cells and further magnify the therapeutic effects.
Although increasing evidence suggests potential iatrogenic injury from supplemental oxygen therapy, significant exposure to hyperoxia in critically ill patients is inevitable. This study shows that ...hyperoxia causes lung injury in a time- and dose-dependent manner. In addition, prolonged inspiration of oxygen at concentrations higher than 80% is found to cause redox imbalance and impair alveolar microvascular structure. Knockout of C-X-C motif chemokine receptor 1 (Cxcr1) inhibits the release of reactive oxygen species (ROS) from neutrophils and synergistically enhances the ability of endothelial cells to eliminate ROS. We also combine transcriptome, proteome, and metabolome analysis and find that CXCR1 knockdown promotes glutamine metabolism and leads to reduced glutathione by upregulating the expression of malic enzyme 1. This preclinical evidence suggests that a conservative oxygen strategy should be recommended and indicates that targeting CXCR1 has the potential to restore redox homeostasis by reducing oxygen toxicity when inspiratory hyperoxia treatment is necessary.
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•Prolonged exposure to 80% O2 leads to pulmonary vascular injury•ECs are dependent on Gln metabolism to maintain the intracellular redox homeostasis•Targeting CXCR1 has the potential to cope with oxygen toxicity
Qin et al. evaluate the lung toxicity of different oxygenation parameters in vivo and in vitro. They also describe the role of CXCR1 in regulating non-classical glutamine metabolism and redox homeostasis in endothelial cells, and they propose that targeting CXCR1 has the potential to cope with hyperoxia-induced lung injury.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Tuberculous meningitis is the most devastating presentation of disease with Mycobacterium tuberculosis. We sought to evaluate treatment outcomes for adult patients with this disease.
The Ovid ...MEDLINE, EMBASE, Cochrane Library and Web of Science databases were searched to identify all relevant studies. We pooled appropriate data to estimate treatment outcomes at the end of treatment and follow-up.
Among the articles identified, 22 met our inclusion criteria, with 2437 patients. In a pooled analysis, the risk of death was 24.7% (95%CI: 18.7-31.9). The risk of neurological sequelae among survivors was 50.9% (95%CI: 40.2-61.5). Patients diagnosed in stage III or human immunodeficiency virus (HIV) positive were significantly more likely to die (64.8, 53.4% respectively) during treatment. The frequency of cerebrospinal fluid (CSF) acid-fast-bacilli smear positivity was 10.0% (95% CI 5.5-17.6), 23.8% (15.2-35.3) for CSF culture positivity, and 22.3% (17.8-27.5) for CSF polymerase chain reaction positivity. We found that the headache, fever, vomiting, and abnormal chest radiograph were the most common symptoms and diagnostic findings among tuberculous meningitis patients.
Despite anti-tuberculosis treatment, adult tuberculous meningitis has very poor outcomes. The mortality rate of patients diagnosed in stage III or HIV co-infection increased significantly during treatment.
•PCFA exhibited potent inhibitory effects on melanoma both in vitro and in vivo.•PCFA inhibited the activation of STAT3 through suppressing the phosphorylation of JAK2.•PCFA inhibits melanoma growth ...via the inhibition of JAK2/STAT3 pathway.
JAK2/STAT3 pathway is involved in the development and progression of melanoma once DNA damage is caused by environment and genetic factors.
Here, we aimed to identify novel inhibitor of JAK2/STAT3 pathway and reveal the underlying mechanisms.
Eighty MedChemExpress compounds were screened by using STAT3-Luc reporter in A375 cells. Podocarpusflavone A (PCFA) was identified as an inhibitor of STAT3, which was further verified in four melanoma cell lines. The anti-melanoma effects and mechanism of PCFA were examined and explored in melanoma cells and mouse xenograft models by using Western blot and cell-counting kit-8 assay.
PCFA exhibited potent inhibitory effects on melanoma both in vitro and in vivo. PCFA inhibited the activation of STAT3 through suppressing the phosphorylation of JAK2, and then restrained cell cycle and induced apoptosis of melanoma cells.
PCFA inhibits melanoma growth via the inhibition of JAK2/STAT3 pathway, which provides a promising therapeutic strategies of melanoma treatment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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