Antibacterial Activity and Mechanism of Candesartan Cilexetil against Enterococcus faecalis.

Enterococcus faecalis infections pose a significant clinical challenge due to their multidrug resistance and propensity for biofilm formation. Exploring alternative treatment options, such as repurposing existing drugs, is crucial in addressing this issue. This study investigates the antibacterial activity of candesartan cilexetil against E. faecalis and elucidates its mechanism of action. Candesartan cilexetil exhibited notable antibacterial activity against both E. faecalis and Enterococcus faecium, with minimum inhibitory concentration (MIC) of ≤25 µM. Time-kill curves demonstrated concentration-dependent bactericidal effects. Candesartan cilexetil could significantly inhibited biofilm formation at the concentration of 1/4× MIC and induced alterations in biofilm structure. Permeability assays revealed compromised bacterial membranes, accompanied by the dissipation of membrane potential in E. faecalis cells after treatment with candesartan cilexetil. Checkerboard analysis showed that bacterial membrane phospholipids phosphatidylglycerol and cardiolipin could neutralize the antibacterial activity of candesartan cilexetil in a dose-dependent manner. Biolayer interferometry (BLI) assay indicated specific interactions between candesartan cilexetil and phosphatidylglycerol or cardiolipin. This study demonstrates the promising antibacterial and antibiofilm activities of candesartan cilexetil against multidrug-resistant E. faecalis. The mechanism of action involves disruption of bacterial membranes, possibly by interacting with membrane phospholipids. These findings underscore the potential utility of candesartan cilexetil as an effective therapeutic agent for combating E. faecalis infections, offering a valuable strategy in the battle against antibiotic-resistant pathogens.

Immune Dysregulation in Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) is a disease whose incidence increase with age and is characterised by chronic inflammation and significant immune dysregulation. Inhalation of toxic substances cause oxidative stress in the lung tissue as well as airway inflammation, under the recruitment of chemokines, immune cells gathered and are activated to play a defensive role. However, persistent inflammation damages the immune system and leads to immune dysregulation, which is mainly manifested in the reduction of the body's immune response to antigens, and immune cells function are impaired, further destroy the respiratory defensive system, leading to recurrent lower respiratory infections and progressive exacerbation of the disease, thus immune dysregulation play an important role in the pathogenesis of COPD. This review summarizes the changes of innate and adaptive immune-related cells during the pathogenesis of COPD, aiming to control COPD airway inflammation and improve lung tissue remodelling by regulating immune dysregulation, for further reducing the risk of COPD progression and opening new avenues of therapeutic intervention in COPD.

AMXT-1501 targets membrane phospholipids against Gram-positive and -negative multidrug-resistant bacteria.

The rapid proliferation of multidrug-resistant (MDR) bacterial pathogens poses a serious threat to healthcare worldwide. Carbapenem-resistant (CR) Enterobacteriaceae, which have near-universal resistance to available antimicrobials, represent a particularly concerning issue. Herein, we report the identification of AMXT-1501, a polyamine transport system inhibitor with antibacterial activity against Gram-positive and -negative MDR bacteria. We observed minimum inhibitory concentration (MIC)50/MIC90 values for AMXT-1501 in the range of 3.13-12.5 µM (2.24-8.93 µg /mL), including for methicillin-resistant Staphylococcus aureus (MRSA), CR Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. AMXT-1501 was more effective against MRSA and CR E. coli than vancomycin and tigecycline, respectively. Subinhibitory concentrations of AMXT-1501 reduced the biofilm formation of S. aureus and Enterococcus faecalis. Mechanistically, AMXT-1501 exposure damaged microbial membranes and increased membrane permeability and membrane potential by binding to cardiolipin (CL) and phosphatidylglycerol (PG). Importantly, AMXT-1501 pressure did not induce resistance readily in the tested pathogens.

Potential diagnostic markers and therapeutic targets for periodontitis and Alzheimer's disease based on bioinformatics analysis.

BACKGROUND AND OBJECTIVE: As a chronic inflammatory disease, periodontitis threatens oral health and is a risk factor for Alzheimer's disease (AD). There is growing evidence that these two diseases are closely related. However, current research is still incomplete in understanding the common genes and common mechanisms between periodontitis and AD. In this study, we aimed to identify common genes in periodontitis and AD and analyze the relationship between crucial genes and immune cells to provide new therapeutic targets for clinical treatment. MATERIALS AND METHODS: We evaluated differentially expressed genes (DEGs) specific to periodontitis and AD. Co-expressed genes were identified by obtaining gene expression profile data from the Gene Expression Omnibus (GEO) database. Using the STRING database, protein-protein interaction (PPI) networks were constructed, and essential genes were identified. We also used four algorithms to identify critical genes and constructed regulatory networks. The association of crucial genes with immune cells and potential therapeutic effects was also assessed. RESULTS: PDGFRB, VCAN, TIMP1, CHL1, EFEMP2, and IGFBP5 were obtained as crucial common genes. Immune infiltration analysis showed that Natural killer cells and Myeloid-derived suppressor cells were significantly differentially expressed in patients with PD and AD compared with the normal group. FOXC1 and GATA2 are important TFs for PD and AD. MiR-23a, miR-23b, miR-23a, and miR-23b were associated with AD and PD. Finally, the hub genes retrieved from the DSigDB database indicate multiple drug molecule and drug-target interactions. CONCLUSION: This study reveals commonalities in common hub genes and immune infiltration between periodontitis and AD, and the analysis of six hub genes and immune cells may provide new insights into potential therapeutic directions for the pathogenesis of periodontitis complicated by AD.

A metal ion-coordinated DNA probe for sensitive fluorescence detection of metallothionein via a dual nucleic acid amplification strategy.

Sensitively monitoring metallothionein (MT), a heavy metal-binding protein with substantial cysteine content, is of significance for evaluating heavy metal poisoning in both humans and animals. Based on a new metal ion-coordinated DNA probe and the heavy metal ion binding capability of MT, as well as the substantial signal enhancement of the hybridization chain reaction (HCR) and rolling circle amplification (RCA), we demonstrate a highly sensitive fluorescence MT detection assay. MT binds the metal ions in the hairpin structured, metal ion-coordinated DNA probe to switch its hairpin structure into ssDNA, which triggers subsequent RCA reactions and HCRs to open plenty of fluorescently quenched signal hairpins to exhibit drastically amplified fluorescence recovery for assaying MT down to 0.58 nM within a dynamic range of 1-320 nM. In addition, the investigation of low contents of MT in diluted human serum by such an assay has also been verified, indicating its promising application potential for diagnosing heavy metal poisoning.

Insights into the mechanism in electrochemical CO2 reduction over single-atom copper alloy catalysts: A DFT study.

Copper single-atom alloy catalysts (M@Cu SAAs) have shown great promise for electrochemical CO2 reduction reaction (CO2RR). However, a clear understanding of the CO2RR process on M@Cu SAAs is still lacking. This study uses density functional theoretical (DFT) calculations to obtain a comprehensive mechanism and the origin of activity of M@Cu SAAs. The importance of the adsorption mode of M@Cu is revealed: key intermediates either adsorbed in the adjacent hollow site around Cu atoms (AD mode) or adsorbed directly on the top site of M (SE mode). AD mode generally exhibits finely tuned binding strengths of key intermediates, which significantly enhances the activity of the catalysts. Increasing the coverage of ∗CO on the M@Cu with SE mode leads to relocation of the active site, resulting in improved activity of C2 products. The insights gained in this work have significant implications for rational design strategy toward efficient CO2RR electrocatalysts.

Study on the mechanism of PM2.5 affecting Th1/Th2 immune imbalance through the notch signaling pathway in asthmatic mice.

Some research has shown that PM2.5 causes Th1/Th2 immune imbalance and aggravates asthma. However, the exact mechanism of PM2.5 causing aggravation of asthma remains unclear. The purpose of this study was to investigate whether exposure to PM2.5 exacerbates Th1/Th2 immune imbalance through the Notch signaling pathway. Eight-week-old SPF female BALF/c mice were sensitized by ovalbumin to establish an asthma mouse model. PM2.5 exposure was carried out by aerosol inhalation of PM2.5 (510 µg/m3) after each provocation. The lung function of mice was measured and Splenic T lymphocyte subsets were detected. Notch signaling pathway was tested. The levels of interferon (IFN)-γ and interleukin (IL)-4 in serum and bronchoalveolar lavage fluid were determined. The results showed that the expression of the mRNA and protein of Notch1 and Hes1 in the asthma group were significantly higher than those in healthy controls. The levels of IL-4 were also remarkably high; while the levels of IFN-γ were remarkably low in serum and BALF, the Th1% and Th1/Th2 ratios were significantly lower, and Th2% was significantly higher in the asthma group than in the healthy controls. PM2.5 promoted further activation of the Notch signaling pathway and aggravated Th1/Th2 immune imbalance in asthmatic mice. γ-secretase inhibitor can partially inhibit the activation of the Notch signaling pathway and alleviate aggravation of immune imbalance. In conclusion, the asthmatic mice had a Th1/Th2 immune imbalance and an overactivated Notch signaling pathway. PM2.5 further aggravated Th1/Th2 immune imbalance by activating the Notch signaling pathway.

International expert consensus on diagnosis and treatment of lung cancer complicated by chronic obstructive pulmonary disease.

Background: Lung cancer combined by chronic obstructive pulmonary disease (LC-COPD) is a common comorbidity and their interaction with each other poses significant clinical challenges. However, there is a lack of well-established consensus on the diagnosis and treatment of LC-COPD. Methods: A panel of experts, comprising specialists in oncology, respiratory medicine, radiology, interventional medicine, and thoracic surgery, was convened. The panel was presented with a comprehensive review of the current evidence pertaining to LC-COPD. After thorough discussions, the panel reached a consensus on 17 recommendations with over 70% agreement in voting to enhance the management of LC-COPD and optimize the care of these patients. Results: The 17 statements focused on pathogenic mechanisms (n=2), general strategies (n=4), and clinical application in COPD (n=2) and lung cancer (n=9) were developed and modified. These statements provide guidance on early screening and treatment selection of LC-COPD, the interplay of lung cancer and COPD on treatment, and considerations during treatment. This consensus also emphasizes patient-centered and personalized treatment in the management of LC-COPD. Conclusions: The consensus highlights the need for concurrent treatment for both lung cancer and COPD in LC-COPD patients, while being mindful of the mutual influence of the two conditions on treatment and monitoring for adverse reactions.

MiR-155 enhances phagocytosis of alveolar macrophages through the mTORC2/RhoA pathway.

Alveolar macrophage phagocytosis is significantly reduced in Chronic obstructive pulmonary disease, and cigarette smoke extract is one of the chief reasons for this decrease. Nevertheless, the specific underlying mechanism remains elusive. In this study, the role and possible mechanism of miR-155-5p/mTORC2/RhoA in the phagocytosis of mouse alveolar macrophages (MH-S) were explored. Our results revealed that cigarette smoke extract intervention reduced MH-S cell phagocytosis and miR-155-5p expression. Meanwhile, the dual-luciferase reporter assay validated that Rictor is a target of miR-155-5p. On the one hand, transfecting miR-155-5p mimic, mimic NC, miR-155-5p inhibitor, or inhibitor NC in MH-S cells overexpressing miR-155-5p increased the Alveolar macrophage phagocytotic rate, up-regulated the expression level of RhoA and p-RhoA, and down-regulated that of mTOR and Rictor mRNA and protein. On the other hand, inhibiting the expression of miR-155-5p lowered the phagocytotic rate, up-regulated the expression of mTOR, Rictor mRNA, and protein, and down-regulated the expression of RhoA and p-RhoA, which taken together, authenticated that miR-155-5p participates in macrophage phagocytosis via the mTORC2/RhoA pathway. Finally, confocal microscopy demonstrated that cells overexpressing miR-155-5p underwent cytoskeletal rearrangement during phagocytosis, and the phagocytic function of cells was enhanced, signaling that miR-155-5p participated in macrophage skeletal rearrangement and enhanced alveolar macrophage phagocytosis by targeting the expression of Rictor in the mTORC2/RhoA pathway.

Modeling study of divertor particle flow pattern and in-out plasma density asymmetry due to drifts with SOLPS and BOUT+.

A study of the effects of drifts on the particle flow pattern and in-out divertor plasma density asymmetry for L-mode and H-mode plasmas is carried out for EAST discharges by the edge plasma transport codes SOLPS and BOUT++ . The simulation of L-mode plasmas is done by SOLPS while the simulation of H-mode plasmas is done by BOUT++ . The toroidal magnetic field direction for the simulated discharge is artificially reversed in the codes to study the effects of different drift directions on the divertor particle flow pattern and the in-out asymmetry of divertor plasma density. The divertor particle flows induced by diamagnetic and E × B drifts are found to have similar directions in the divertor region for the same discharge. The directions of the flows induced by drifts would be reversed with the reverse of toroidal magnetic field direction. The diamagnetic drift seems to have no effect on the in-out asymmetry of divertor plasma density due to its divergence-free nature. However, the E × B drift could result in a pronounced asymmetry of plasma density between the inner and outer divertor targets. The density in-out asymmetry caused by E × B drift is reversed with the reverse of E × B drift flow direction. Detailed analysis shows that the radial component of the E × B drift flow is the main cause of density asymmetry. The results from the simulation of H-mode plasmas with BOUT++ are similar to those of the L-mode plasmas with SOLPS except that the drift effects seem to be slightly larger in the H-mode plasmas compared to the L-mode plasmas.

Identification of hypoxia-related genes and exploration of their relationship with immune cells in ischemic stroke.

Ischemic stroke (IS) is a major threat to human health, and it is the second leading cause of long-term disability and death in the world. Impaired cerebral perfusion leads to acute hypoxia and glucose deficiency, which in turn induces a stroke cascade response that ultimately leads to cell death. Screening and identifying hypoxia-related genes (HRGs) and therapeutic targets is important for neuroprotection before and during brain recanalization to protect against injury and extend the time window to further improve functional outcomes before pharmacological and mechanical thrombolysis. First, we downloaded the GSE16561 and GSE58294 datasets from the NCBI GEO database. Bioinformatics analysis of the GSE16561 dataset using the limma package identified differentially expressed genes (DEGs) in ischemic stroke using adj. p. values < 0.05 and a fold change of 0.5 as thresholds. The Molecular Signature database and Genecards database were pooled to obtain hypoxia-related genes. 19 HRGs associated with ischemic stroke were obtained after taking the intersection. LASSO regression and multivariate logistic regression were applied to identify critical biomarkers with independent diagnostic values. ROC curves were constructed to validate their diagnostic efficacy. We used CIBERSORT to analyze the differences in the immune microenvironment between IS patients and controls. Finally, we investigated the correlation between HRGs and infiltrating immune cells to understand molecular immune mechanisms better. Our study analyzed the role of HRGs in ischemic stroke. Nineteen hypoxia-related genes were obtained. Enrichment analysis showed that 19 HRGs were involved in response to hypoxia, HIF-1 signaling pathway, autophagy, autophagy of mitochondrion, and AMPK signaling pathway. Because of the good diagnostic properties of SLC2A3, we further investigated the function of SLC2A3 and found that it is closely related to immunity. We have also explored the relevance of other critical genes to immune cells. Our findings suggest that hypoxia-related genes play a crucial role in the diversity and complexity of the IS immune microenvironment. Exploring the association between hypoxia-related critical genes and immune cells provides innovative insights into the therapeutic targets for ischemic stroke.

Cinacalcet exhibits rapid bactericidal and efficient anti-biofilm activities against multidrug-resistant Gram-positive pathogens.

Infections caused by Gram-positive bacteria pose a serious threat to global public health. Drug resistance, dormant persister cells, and biofilm formation are the key challenges affecting the efficacy of antibiotics against Gram-positive bacterial infections. In this study, cinacalcet exhibited good inhibitory activity against multidrug-resistant Gram-positive bacteria, with minimum inhibitory concentrations (MICs) ranging from 3.13 µg/mL to 25 µg/mL. Cinacalcet displayed more rapid and stronger bactericidal activity against planktonic and persister cells of Staphylococcus aureus and Enterococcus faecalis compared with the antibiotics vancomycin or ampicillin, as well as potent inhibition and eradication of mature biofilms of methicillin-resistant S. aureus (MRSA) and linezolid-resistant E. faecalis (LRE). In addition, the robust antibacterial activity was demonstrated in vivo by a pneumonia infection model and a biofilm formation and deep-seated infection model. Collectively, these findings indicate that cinacalcet may be a promising new candidate antibiotic to combat infections caused by multidrug-resistant Gram-positive pathogens.

Analysis of Communal Molecular Mechanism Between Chronic Obstructive Pulmonary Disease and Osteoporosis.

Background: Chronic obstructive pulmonary disease (COPD) patients with osteoporosis (OP) usually experience more frequent exacerbations, worse quality of life, and heavier economic burden, however, few studies have investigated common molecular mechanisms of COPD and OP. Objective: To explore the relationship between COPD and OP through bioinformatics analysis. Methods: The miRNA microarray data of COPD and OP were retrieved from the Gene Expression Database (GEO), and the differentially expressed microRNAs (DEmiRNAs) were screened and the intersection was obtained. The Targetscan, miRDB, and miRWalk databases were used to predict the target genes of DEmiRNA, and the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using the R package clusterProfiler, the STRING database was used to analyze the target protein-protein interaction network (PPI) and screens to determine the core modules and core genes. Results: Two DEmiRNAs (miR-23a-5p, miR-194-3p) have been found in COPD and OP, which have predicted 76 and 114 target genes, respectively. GO functional annotations of miR-23a-5p were significantly enriched in CD40 signaling pathway, ubiquitin-conjugating enzyme activity, etc; KEGG pathways of miR-23a-5p were significantly enriched in ubiquitin-mediated proteolysis, folate biosynthesis, and regulation of actin cytoskeleton. GO function annotations of miR-194-3p were significantly enriched in T cell activation regulation, ubiquitin protein ligase activity, and DNA transcription factor binding; KEGG pathways of miR-194-3p were significantly enriched in cell adhesion molecules, intercellular tight junctions, and lysosomal pathway. PPI analysis found target coding proteins formed complex regulatory networks. Ten core genes (TP53, SRC, PXN, CHD4, SYK, TNRC6B, PML, KAT5, BRD1 and IGF2) were picked out among them, then we used the MCODE plugin found three core subnetworks. Conclusion: Two identical DEmiRNAs (miR-23a-5p, miR-194-3p) exist in the peripheral blood of COPD and OP patients, which are important biomarkers for COPD patients with OP and may represent novel targets for diagnosis and treatment of COPD patients with OP.

Baixiangdan capsule and Shuyu capsule regulate anger-out and anger-in, respectively: GB1-mediated GABA can regulate 5-HT levels in multiple brain regions.

The identity of the mechanism by which the Baixiangdan capsule (BXD) and the Shuyu capsule (SY) control anger-out (AO) and anger-in (AI) in rodents is unclear. The current study clarified the intervention role of BXD and SY on AO and AI male rats. We further explored the differences between BXD and SY in the treatment of AO and AI rats. Social isolation combined with the resident-intruder paradigm was used to establish the anger-out and AI rats models. On this basis, GABA content in the dorsal raphe nucleus (DRN) and serotonin (5-HT) contents in these brain regions were detected using ELISA after various time courses (0, 1, 3, 5, and 7 days) treated with BXD and SY. Co-expression of 5-HT and GB1 in the DRN was detected. GB1-specific agonist baclofen and GB1-specific inhibitor CGP35348 were injected into the DRN. Changes in 5-HT levels in these brain regions were then detected. After treatment, rats in the BXD group exhibited lower aggressive behavior scores, longer latencies of aggression, lower total distances in the open field test, and a higher sucrose preference coefficient. Meanwhile, rats in the SY group exhibited higher aggressive behavior scores, shorter latencies of aggression, higher total distances in the open field test, and higher sucrose preference coefficients. With increasing medication duration, 5-HT levels in these brain regions were increased gradually, whereas GABA levels in the DRN were decreased gradually, and all recovered to normal levels by the 7th day. A large number of 5-HT-positive cells could be found in the immunofluorescence section in the DRN containing GABABR1 (GB1)-positive cells, indicating that 5-HT neurons in the DRN co-expressed with GB1. Furthermore, after the drug intervention, the 5-HT level in the DRN was elevated to a normal level, and the GB1 level in the DRN was decreased to a normal level. After the microinjection of baclofen into the DRN, the 5-HT contents in these brain regions were decreased. By contrast, the 5-HT contents were increased after injection with CGP35348. BXD and SY could effectively improve the abnormal behavior changes of AO and AI rats, and the optimal duration of action was 7 days. The improvement way is as follows: Decreased abnormal increase of GABA and GB1 in the DRN further mediated synaptic inhibition and increased 5-HT level in the DRN, leading to increased 5-HT levels in the PFC, hypothalamus, and hippocampus. Therefore, GB1-mediated GABA in the DRN could regulate 5-HT levels in these brain regions, which may be one of the ways by which BXD and SY treat AO and AI, respectively.

Xiangshao Granules reduce the aggressive behavior and hippocampal injury of premenstrual irritability in rats by regulating JIK/JNK/p38 signal pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: As a typical prescription for soothing the liver, Xiangshao granule has a good effect on the symptoms of irritability and anxiety. Clinical evidence suggests that it has significant efficacy in the treatment of Premenstrual dysphoria disorder (PMDD). However, the underlying mechanism remains unclear. AIM OF THE STUDY: PMDD is a common disease in women of childbearing age, seriously affecting their family, society, and daily work life. The registered herbal medicine, Xiangshao granules, is used for relieving PMDD dysphoria and irritability symptoms with excellent efficacy in China. This study was focused on the deep intervention mechanism of Xiangshao granules in treating PMDD. MATERIALS AND METHODS: The vaginal smear and open field test were used to screen rats in nonreception phase of estrus cycle with similar macroscopic behaviors and regular estrus cycle. The rat model of PMDD irritability was established through social isolation and residential invasion, with which, the irritability symptoms of PMDD patients with menstrual cycle dependence was also well simulated. Elevated plus Maze Test and Social interaction activities were used to measure the anxiety-like behavior of rats. TUNEL Staining and Hematoxylin-Eosin staining were used to measure apoptosis of hippocampal neurons. RT-PCR, Western blot and immunofluorescence were used to measure the expression of GR, JIK, p-JIK, p38, P-P38, JNK, caspase 3, and caspase 12. RESULTS: In this study, Xiangshao granules showed consistent therapeutic effects similar with those in clinic, significantly reducing aggressive and anxiety-like behaviors with improved social skills in PMDD rats. In mechanism, Xiangshao granules lowered the apoptosis of hippocampal neurons and weakened the morphological damage of the hippocampal brain evidenced by the decreased mRNA and protein expression of glucocorticoid receptor, caspase-3, and caspase-12. In addition, administration of Xiangshao granules led to the decreased expression of JIK in the PMDD irritability rat model which agreed well with the previous studies. The JNK/p38 mitogen-activated protein kinases (MAPKs) signaling pathway is abnormally activated in the hippocampal brain region of PMDD rats, while treated with Xiangshao granules could increase JIK expression and inhibit the abnormal activation of the JNK/p38 MAPK signaling pathway, effectively reducing the stress damage in the hippocampus. CONCLUSIONS: Xiangshao Granules Reduce the Aggressive Behavior and Hippocampal Injury of Premenstrual Irritability in Rats by Regulating JIK/JNK/p38 Signal Pathway.

Resveratrol attenuates cigarette smoke extract induced cellular senescence in human airway epithelial cells by regulating the miR-34a/SIRT1/NF-κB pathway.

Chronic obstructive pulmonary disease (COPD) is characterized by accelerated lung aging. Smoking is the critical risk factor for COPD. Cellular senescence of airway epithelial cells is the cytological basis of accelerated lung aging in COPD, and the regulation of microRNAs (miRNAs) is the central epigenetic mechanism of cellular senescence. Resveratrol (Res) is a polyphenol with anti-aging properties. This study investigated whether Res attenuates cigarette smoke extract (CSE)-induced cellular senescence in human airway epithelial cells (BEAS-2B) through the miR-34a/SIRT1/nuclear factor-kappaB (NF-κB) pathway. BEAS-2B cells were treated with Res, CSE and transfected with miR-34a-5p mimics. Cellular senescence was evaluated by senescence -related ß-galactosidase (SA-ß-gal) staining and expression of senescence-related genes (p16, p21, and p53). The expressions of miR-34a-5p, SIRT1, and NF-κB p65 were examined using quantitative real time polymerase chain reaction and western blotting. The senescence-associated secretory phenotype (SASP) cytokines (IL-1ß, IL-6, IL-8, TNF-α) were assessed by enzyme-linked immunosorbent assay. The binding between miR-34a-5p and SIRT1 was confirmed by dual-luciferase reporter assay. The results showed that CSE dose-dependently decreased cell viability and elevated cellular senescence, characterized by increased SA-ß-gal staining and senescence-related gene expressions (p16, p21, and p53). Further, CSE dose-dependently increased the expression of miR-34a-5p and SASP cytokines (IL-1ß, IL-6, IL-8, TNF-α) in BEAS-2B cells. Pretreatment with Res inhibited CSE-induced cellular senescence and secretion of SASP cytokines (IL-1ß, IL-6, IL-8, TNF-α) in a dose-dependent manner. Moreover, Res reversed the CSE-induced down-regulation of SIRT1 and up-regulation of miR-34a-5p and NF-κB p65. SIRT1 is a target of miR-34a-5p. Overexpression of miR-34a-5p via transfection with miR-34a-5p mimic in BEAS-2B cells attenuated the inhibitory effect of Res on cellular senescence, accompanied by reversing the expression of SIRT1 and NF-κB p65. In conclusion, Res attenuated CSE-induced cellular senescence in BEAS-2B cells by regulating the miR-34a/SIRT1/NF-κB pathway, which may provide a new approach for COPD treatment.

In vitro activities of licochalcone A against planktonic cells and biofilm of Enterococcus faecalis.

This study aims to evaluate the in vitro antibacterial and anti-biofilm activities of licochalcone A on Enterococcus faecalis and to investigate the possible target genes of licochalcone A in E. faecalis. This study found that licochalcone A had antibacterial activities against E. faecalis, with the MIC50 and MIC90 were 25 µM. Licochalcone A (at 4 × MIC) indicated a rapid bactericidal effect on E. faecalis planktonic cells, and killed more E. faecalis planktonic cells (at least 3-log10 cfu/ml) than vancomycin, linezolid, or ampicillin at the 2, 4, and 6 h of the time-killing test. Licochalcone A (at 10 × MIC) significantly reduced the production of E. faecalis persister cells (at least 2-log10 cfu/ml) than vancomycin, linezolid, or ampicillin at the 24, 48, 72, and 96 h of the time-killing test. Licochalcone A (at 1/4 × MIC) significantly inhibited the biofilm formation of E. faecalis. The RNA levels of biofilm formation-related genes, agg, esp, and srtA, markedly decreased when the E. faecalis isolates were treated with licochalcone A at 1/4 × MIC for 6 h. To explore the possible target genes of licochalcone A in E. faecalis, the licochalcone A non-sensitive E. faecalis clones were selected in vitro by induction of wildtype strains for about 140 days under the pressure of licochalcone A, and mutations in the possible target genes were detected by whole-genome sequencing. This study found that there were 11 nucleotide mutations leading to nonsynonymous mutations of 8 amino acids, and among these amino acid mutations, there were 3 mutations located in transcriptional regulator genes (MarR family transcriptional regulator, TetR family transcriptional regulator, and MerR family transcriptional regulator). In conclusion, this study found that licochalcone A had an antibacterial effect on E. faecalis, and significantly inhibited the biofilm formation of E. faecalis at subinhibitory concentrations.

Associations between comorbidities and annual incidence plus frequency of asthma exacerbation hospitalisation during the past year: data from CARN study.

PURPOSE: While asthma comorbidities are associated with higher health care utilisation, lower quality of life and poorer asthma control, the impact of asthma comorbidities on hospitalisation for asthma exacerbation (H-AX) remains less recognised. We aim to analyse the impact of asthma comorbidities on H-AX. METHODS: Based on a national survey on asthma control and disease perception (CARN 2015 study), we analysed the impact of comorbidities on annual incidence and frequency of H-AX in China. Information on demographic characteristics, asthma comorbidities and annual incidence and frequency of H-AX were presented in this study. RESULTS: Among 3875 ambulatory asthma patients, 75.9% (2941/3875) had comorbidities, and 26.4% (1017/3858) experienced H-AX during past year. After adjusting for confounding factors such as demographic data, smoking status and asthma control, COPD [OR = 2.189, 95% CI (1.673, 2.863)] and coronary heart disease [OR = 1.387, 95% CI (1.032, 1.864)] were associated with higher annual incidence, while allergic rhinitis [OR = 0.692, 95% CI (0.588, 0.815)] was associated with lower annual incidence, of H-AX. In terms of frequency, allergic rhinitis [OR = 1.630, 95% CI (1.214, 2.187)], COPD [OR = 1.472, 95% CI (1.021, 2.122)] and anxiety [OR = 2.609, 95% CI (1.051, 6.477)] showed statistically significant correlation with frequent H-AX. CONCLUSIONS: COPD and coronary heart disease were associated with higher annual incidence, while allergic rhinitis was associated with lower annual incidence of H-AX. Allergic rhinitis, COPD and anxiety were associated with frequent H-AX. Comorbidities may have an important role in the risk and frequency of annual hospitalisations due to asthma exacerbation. The goal of asthma control should rely on a multi-disciplinary treatment protocol.

The Effect of Occupational Health Risk Perception on Job Satisfaction.

This study explored the relationship between occupational health risk perception and job satisfaction. Based on the job demand-resources model and resource conservation theory, eight hypotheses were proposed in this study. In a survey of 237 production line workers and managers, we found that perceived occupational health risks significantly negatively affected job satisfaction. Both work stress and organizational commitment mediate the relationships between perceived occupational health risks and job satisfaction. We also examined whether safety culture could weaken the negative impact of perceived occupational health risks on job satisfaction. However, the results of our study did not support this hypothesis. This study not only helped managers to realize the hazards of occupational health risks, but also encouraged employees to actively participate in safety construction and pay attention to their own health. In addition, we also put forward some targeted intervention measures to reduce the negative impact of perceived occupational health risks on job satisfaction. Therefore, this study had certain practical implications.

Asthma Management Using the Mobile Asthma Evaluation and Management System in China.

PURPOSE: As stated in the Global Initiative for Asthma, there are still some asthmatic patients who have not achieved asthma control. Mobile is a useful tool for asthma management. We aimed to compare the advantages of mobile management with traditional management in improving adherence and control of asthma. METHODS: In this prospective, multicentre, randomized, controlled and parallel-group study, we enrolled patients with poor adherence and uncontrolled asthma at 32 hospitals in 28 provinces in China. Patients were randomly assigned to the mobile management or traditional management groups for 12 months. The primary endpoint was the proportion of patients with good adherence (Medication Adherence Report Scale for Asthma [MARS-A] score ≥ 45) for 6 months. This study is registered at ClinicalTrials.gov (NCT02917174). RESULTS: Between April 2017 and April 2018, 923 patients were eligible for randomization (mobile group, n = 461; traditional group, n = 462). Dropout was 84 (18.2%) in the mobile management group and 113 (24.4%) patients in the traditional management group. The proportion of patients with good adherence was significantly higher in the mobile management group than in the traditional management group (66.0% vs. 58.99%, P = 0.048). The mobile management group showed higher mean MARS-A score (at 1, 6, 9, and 12 months) and asthma control test scores (at 6 and 9 months), and lower total lost rate to follow-up within 12 months than the traditional management group. CONCLUSIONS: Mobile asthma management can improve adherence and asthma control compared to traditional management. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02917174.