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Two new Ag(I) coordination polymers, namely [Ag(bpp)]·0.5 n(1,5-NDSA)·n(H2O) (1) and [Ag2(bpp)2]n·n(2,7-NDSA)·2 n(H2O)·n(CH3CN) (2) (Na2(1,5-NDSA) = sodium 1,5-naphthalenedisulfonate dibasic, Na2(2,7-NDSA) = sodium 1,5-naphthalenedisulfonate dibasic, bpp is 1,3-bis(4-pyridyl)propane), were generated via the solution evaporation method under room temperature. Moreover, the solids of these two compounds display strong luminescence emission at RT. And the application values of the compounds against the glioblastoma treatment were determined, and the corresponding mechanism was simultaneously tested. The analysis of CCK-8 was first implemented and the glioblastoma viability was measured. The real-time RT-PCR was next performed, and the signaling pathway activation of VEGF in glioblastoma cells was tested after treating by the above compound. [ABSTRACT FROM AUTHOR]

Alloying is an effective method for improving the resistance of V metals to hydrogen embrittlement. The effects of the doping with a third element (Pd, Ru, Ta) on the structure and hydrogen permeation properties of V–10Mo solid solutions have been investigated in this study. As-prepared V–5Mo-5TM (TM = Mo, Pd, Ru, Ta) alloy samples composed of V-based solid solution with a bcc structure are hydrogenated into their corresponding solid solutions (α-phase). Structural changes caused by TM-doping have notable effects on the hydrogen permeation properties (particularly the hydrogen solubility) of V–10Mo alloy, and the ability of the doping element in decreasing the hydrogen solubility of the V–10Mo alloy follows the sequence: Pd > Ru > Ta. Their doping causes a slight decrease in the hydrogen diffusion coefficient as well as an increase in the Vickers hardness of the resulting alloys. This work demonstrates that the mechanical property of V–10Mo alloy can be improved via suitable structure control caused by alloying it with an appropriate element. In addition, this approach might be suitable for improving properties of other relevant binary alloys. • Alloying do good to the resistance to hydrogen embrittlement of V metal. • Hydrogen diffusivity and solubility are closely related to lattice distortions. • Hydrogen permeability can be controlled by changing alloy composition and structure. [ABSTRACT FROM AUTHOR]

To improve clinical outcomes for patients with traumatic brain injury (TBI), it is necessary to explore the mechanism of traumatic brain injury (TBI)–induced neuroinflammation. Connective tissue growth factors (CTGF) have been reported to be involved in the process of inflammatory response or tissue repair, whereas whether and how CTGF participates in the astrocyte-mediated inflammation after TBI remains unclear. In the present study, the TBI-induced activation of astrocytes and augmentation of inflammatory response were simulated by stimulating rat astrocytes with TGF-β1 or CTGF in cultured conditions. TGF-β1 and CTGF both upregulated the expression of GFAP in astrocytes and facilitated the production of inflammatory cytokines and chemokines. Activation of astrocytes by CTGF is in an autocrine manner. According to the results of Boyden chamber assay, CTGF enhanced the recruitment of peripheral blood mononuclear cells (PBMCs) by reactive astrocytes. Besides, CTGF-mediated activation of astrocytes and augmentation of inflammatory response can be terminated by the inhibitor of ASK1 or p38 and JNK. Thus, our data suggested that CTGF could activate astrocytes in an autocrine manner and promote astrocyte-mediated inflammatory response by triggering the ASK1-p38/JNK-NF-κB/AP-1 pathways in astrocytes. Collectively, our study provided evidence that astrocyte-secreted CTGF serves as an amplifier of neuroinflammatory and could be a potential target for alleviating TBI-induced inflammation. [ABSTRACT FROM AUTHOR]

Background: Acute histoplasmosis is a rare fungal disease in China. This study is aimed to summarize the clinical characteristics of the first large-scale outbreak of imported acute histoplasmosis in Chinese, so as to provide suggestions for clinical diagnosis and treatment. Methods: We collected the symptoms, signs, laboratory examination and imaging data of 10 patients in so far the biggest outbreak of imported acute histoplasmosis in immunocompetent Chinese. Their clinical characteristics and time-varying cytokine/chemokine levels were analyzed, and rank correlation analysis between these markers was utilized to show their condition. Results: The 10 patients of imported acute histoplasmosis were working without any respiratory protection in an abandoned mine tunnel in Guyana. The most common symptoms were fever and cough. Their chest CT imaging showed multiple nodular shadows in lungs. Laboratory examination showed that at admission the CRP, PCT, LDH, CysC, G-test, β2-MG were all increased in at least 9 patients, and the CD4/CD8 was decreased to < 1 in all patients. Most cytokines/chemokines (other than IL-4, IL-12, INF-α, TNF-α) varied widely with patients and time, but their overall trend is higher at admission and decreasing gradually during hospitalization, especially for the IL-6, IL-8, IL-10 and IFN-γ. The LDH, CysC, G-test, β2-MG, N/L, IL-6, IL-8, IL-10, IFN-γ, IL-27 are in positive associations to both CRP and PCT. Conclusions: The diagnosis of acute histoplasmosis needs a comprehensive analysis of epidemiological history, clinical symptoms and signs, and results of imaging, laboratory, microbiological and pathological examinations. Although none of the CRP, PCT, G-test, N/L, LDH, CysC, β2-MG, IL-6, IL-8, IL-10, IFN-γ shows specificity in the diagnosis of acute histoplasmosis, there is possibility that the above factors might help in the inflammation and prognosis estimation. However, more studies and further investigation are still required for the verification. [ABSTRACT FROM AUTHOR]

Background. Alcoholic fatty liver disease (AFLD) is the first stage of the alcoholic liver disease course. Yin-Chen-Hao-Tang (YCHT) has a good clinical effect on the treatment of AFLD, but its molecular mechanism has not been elucidated. In this study, we tried to explore the molecular mechanism of YCHT in improving hepatocyte steatosis in AFLD mice through network pharmacology and RNA sequencing (RNA-Seq) transcriptomics. Methods. Network pharmacological methods were used to analyze the potential therapeutic signaling pathways and targets of YCHT on AFLD. Then, the AFLD mice model was induced and YCHT was administered concurrently. Liver injury was measured by serum alanine aminotransferase (ALT) activity and liver tissue H&E staining, and liver steatosis was determined by serum triglyceride (TG) level and liver tissue Oil Red staining. The molecular mechanism of YCHT on prevention and treatment of mice AFLD was investigated according to the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of the differential expression genes data obtained by liver tissue RNA-Seq. Finally, ethanol-induced AFLD AML12 hepatocyte model was established, YCHT with or without PPARα agonist pemafibrate or PPARγ inhibitor GW9662 was administered, Nile Red fluorescent staining was used to evaluate steatosis levels in AML12 hepatocytes, and qRT-PCR was used to detect PPARα and PPARγ gene expression. Results. The results of network pharmacology analysis showed that YCHT may exert its pharmacological effect on AFLD through 312 potential targets which are involved in many signaling pathways including the PPAR signaling pathway. AFLD mice experiments results showed that YCHT markedly decreased mice serum ALT activity and serum TG levels. YCHT also significantly improved alcohol-induced hepatic injury and steatosis in mice livers. Furthermore, KEGG pathway enrichment results of RNA-Seq showed that the PPAR signaling pathway should be the most relevant pathway of YCHT in the prevention and treatment of AFLD. AFLD hepatocyte model experiment results showed that YCHT could remarkably reduce hepatocyte steatosis through reducing PPARγ expression and increasing PPARα expression. Conclusions. Our study discovered that PPARγ and PPARα are the key targets and the PPAR signaling pathway is the main signaling pathway for YCHT to prevent and treat AFLD. [ABSTRACT FROM AUTHOR]

Abstract: Descending facilitation from the rostral ventromedial medulla (RVM) contributes to some pathological pain states. The intra-RVM microinjection with dermorphin–saporin could specifically abolish this facilitation in rodent models by selectively ablating the RVM neurons expressing mu opioid receptors. Thus, this targeted lesion may be an alternative mechanism-based approach for intractable pain. This research was performed to investigate potential side effects after a single intra-RVM application of dermorphin–saporin in rats. Results showed though some acute cardiovascular signs were observed with dermorphin–saporin, the treatment exhibited no long-lasting significant influence on some physiological functions for up to 3-month observation period, including normal sensory function, locomotor activity, ingestive behaviors, body weight, rectal temperature, respiratory rate, heart rate, systolic blood pressure, cardiac structure and function. Moreover, there were only mild microglial responses on day 7 post-microinjection, while no significant increase in the immunostaining of astrocytes and no noticeable up-regulation in the production of proinflammatory cytokines were detected in the RVM treated with dermorphin–saporin. Taken together, these data would suggest that this selective ablation of mu opioid receptor bearing descending facilitatory neurons in the RVM with dermorphin–saporin did not elicit the long-standing evident adverse toxicity in terms of some physiological parameters and neurochemical alterations we determined, plausibly providing us a safe and reliable approach to treat some intractable pain. [Copyright &y& Elsevier]

Background: World Health Organization recommends countries introducing new drug and short treatment regimen for drug resistant tuberculosis (DR-TB) should develop and implement a system for active pharmacovigilance that allows for detection, reporting and management of adverse events. The aim of the study is to evaluate the frequency and severity of adverse events (AEs) of bedaquiline-containing regimen in a cohort of Chinese patients with multidrug-resistant (MDR)/extensively drug-resistant (XDR)-TB based on active drug safety monitoring (aDSM) system of New Drug Introduction and Protection Program (NDIP). Methods: AEs were prospectively collected with demographic, bacteriological, radiological and clinical data from 54 sites throughout China at patient enrollment and during treatment between February, 2018 and December, 2019. This is an interim analysis including patients who are still on treatment and those that have completed treatment. A descriptive analysis was performed on the patients evaluated in the cohort. Results: By December 31, 2019, a total of 1162 patients received bedaquiline-containing anti-TB treatment. Overall, 1563 AEs were reported, 66.9% were classified as minor (Grade 1–2) and 33.1% as serious (Grade 3–5). The median duration of bedaquiline treatment was 167.0 [interquartile range (IQR): 75–169] days. 86 (7.4%) patients received 36-week prolonged treatment with bedaquiline. The incidence of AEs and serious AEs was 47.1% and 7.8%, respectively. The most frequently reported AEs were QT prolongation (24.7%) and hepatotoxicity (16.4%). There were 14 (1.2%) AEs leading to death. Out of patients with available corrected QT interval by Fridericia's formula (QTcF) data, 3.1% (32/1044) experienced a post-baseline QTcF ≥ 500 ms, and 15.7% (132/839) had at least one change of QTcF ≥ 60 ms from baseline. 49 (4.2%) patients had QT prolonged AEs leading to bedaquiline withdrawal. One hundred and ninety patients reported 361 AEs with hepatotoxicity ranking the second with high occurrence. Thirty-four patients reported 43 AEs of hepatic injury referred to bedaquiline, much lower than that referred to protionamide, pyrazinamide and para-aminosalicylic acid individually. Conclusions: Bedaquiline was generally well-tolerated with few safety concerns in this clinical patient population without any new safety signal identified. The mortality rate was generally low. These data inform significant positive effect to support the WHO recent recommendations for the wide use of bedaquiline. [ABSTRACT FROM AUTHOR]

Background: China is the second highest pulmonary tuberculosis (PTB) burden country worldwide. However, retreatment of PTB has often developed resistance to at least one of the four first-line anti-TB drugs. The cure rate (approximately 50.0–73.3%) and management of retreatment of PTB in China needs to be improved. Qinbudan decoction has been widely used to treat PTB in China since the 1960s. Previously clinical studies have shown that the Qinbudan tablet (QBDT) promoted sputum-culture negative conversion and lesion absorption. However, powerful evidence from a randomized controlled clinical trial is lacking. Therefore, the aim of this study was to compare the efficacy and safety of QBDT as an adjunct therapy for retreatment of PTB. Methods: We conducted a multicenter, randomized, double-blind, placebo-controlled clinical trial in China. People diagnosed with PTB were enrolled who received previous anti-TB treatment from April 2011 to March 2013. The treatment group received an anti-TB regimen and QBDT, and the control group was administered an anti-TB regimen plus placebo. Anti-TB treatment options included isoniazid, rifampicin, pyrazinamide, ethambutol, streptomycin for 2 months (2HRZES), followed by isoniazid, rifampicin, ethambutol for 6 months (6HRE), daily for 8 months. Primary outcome was sputum-culture conversion using the MGIT 960 liquid medium method. Secondary outcomes included lung lesion absorption and cavity closure. Adverse events and reactions were observed after treatment. A structured questionnaire was used to record demographic information and clinical symptoms of all subjects. Data analysis was performed by SPSS 25.0 software in the full analysis set (FAS) population. Results: One hundred eighty-one cases of retreatment PTB were randomly divided into two groups: the placebo group (88 cases) and the QBDT group (93 cases). A total of 166 patients completed the trial and 15 patients lost to follow-up. The culture conversion rate of the QBDT group and placebo group did not show a noticeable improvement by using the covariate sites to correct the rate differences (79.6% vs 69.3%; rate difference = 0.10, 95% confidence interval (CI): - 0.02–0.23; F = 2.48, P = 0.12) after treatment. A significant 16.6% increase in lesion absorption was observed in the QBDT group when compared with the placebo group (67.7% vs 51.1%; rate difference = 0.17, 95% CI: 0.02–0.31; χ2 = 5.56, P = 0.02). The intervention and placebo group did not differ in terms of cavity closure (25.5% vs 21.1%; rate difference = 0.04, 95% CI: - 0.21–0.12; χ2 = 0.27, P = 0.60). Two patients who received chemotherapy and combined QBDT reported pruritus/nausea and vomiting. Conclusions: No significant improvement in culture conversion was observed for retreatment PTB with traditional Chinese medicine plus standard anti-TB regimen. However, QBDT as an adjunct therapy significantly promoted lesion absorption, thereby reducing lung injury due to Mycobacterium tuberculosis infection. Trial registration: This trial is registered at ClinicalTrials.gov, NCT02313610. [ABSTRACT FROM AUTHOR]

Airway remodeling consists of the structural changes of airway walls, which is often considered the result of longstanding airway inflammation, but it may be present to an equivalent degree in the airways of children with asthma, raising the need for early and specific therapeutic interventions. The arachidonic acid cytochrome P-450 (CYP) pathway has thus far received relatively little attention in its relation to asthma. In this study, we studied the inhibition of soluble epoxide hydrolase (sEH) on airway remodeling and hyperresponsiveness (AHR) in a chronic asthmatic model which long-term exposure to antigen over a period of 12 weeks. The expression of sEH and CYP2J2, the level of 14, 15-epoxyeicosatrienoic acids (EETs), airway remodeling, hyperresponsiveness and inflammation were analyzed to determine the inhibition of sEH. The intragastric administration of 3 or 10 mg/kg ZDHXB-101, which is a structural derivative of natural product honokiol and a novel soluble epoxide hydrolase (sEH) inhibitor, daily for 9 weeks significantly increased the level of 14, 15-EETs by inhibiting the expression of sEH and increasing the expression of CYP2J2 in lung tissues. ZDHXB-101 reduced the expression of remodeling-related markers such as interleukin (IL)-13, IL-17, MMP-9 N-cadherin, α-smooth muscle actin, S100A4, Twist, goblet cell metaplasia, and collagen deposition in the lung tissue or in bronchoalveolar lavage fluid. Moreover, ZDHXB-101 alleviated AHR, which is an indicator that is used to evaluate the airway remodeling function. The inhibitory effects of ZDHXB-101 were demonstrated to be related to its direct inhibition of the extracellular signal-regulated kinase (Erk1/2) phosphorylation, as well as inhibition of c-Jun N-terminal kinases (JNK) and the signal transducer and activator of transcription-3 (STAT3) signal transduction. These findings first revealed the anti-remodeling potential of ZDHXB-101 lead in chronic airway disease. [ABSTRACT FROM AUTHOR]

Cigarette smoke (CS) is a major risk factor for the development of chronic obstructive pulmonary disease (COPD). Our previous studies have indicated that Rac1 is involved in lipopolysaccharide-induced pulmonary injury and CS-mediated epithelial-mesenchymal transition. However, the contribution of Rac1 activity to CS-induced lung inflammation remains not fully clear. In this study, we investigated the regulation of Rac1 in CS-induced pulmonary inflammation. Mice or 16HBE cells were exposed to CS or cigarette smoke extract (CSE) to induce acute inflammation. The lungs of mice exposed to CS showed an increase in the release of interleukin-6 (IL-6) and keratinocyte-derived chemokine (KC), as well as an accumulation of inflammatory cells, indicating high Rac1 activity. The exposure of 16HBE cells to CSE resulted in elevated Rac1 levels, as well as increased release of IL-6 and interleukin-8 (IL-8). Selective inhibition of Rac1 ameliorated the release of IL-6 and KC as well as inflammation in the lungs of CS-exposed mice. Histological assessment showed that treatment with a Rac1 inhibitor, NSC23766, led to a decrease in CD68 and CD11b positive cells and the infiltration of neutrophils and macrophages into the alveolar spaces. Selective inhibition or knockdown of Rac1 decreased IL-6 and IL-8 release in 16HBE cells induced by CSE, which correlated with CSE-induced Rac1-regulated Erk1/2 mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription-3 (STAT3) signaling. Our data suggest an important role for Rac1 in the pathological alterations associated with CS-mediated inflammation. Rac1 may be a promising therapeutic target for the treatment of CS-induced pulmonary inflammation. [ABSTRACT FROM AUTHOR]

Background Caspase-cleaved Cytokeratin-18 (CCCK-18) is released during apoptosis. Serum CCCK-18 concentrations are associated with prognosis of some critical illness. We investigated the potential relationships between serum CCCK-18 concentrations and disease severity and long-term clinical outcomes after intracerebral hemorrhage. Methods Serum CCCK-18 concentrations were determined in a total of 102 patients and 102 controls. Multivariate models were used to predict high concentration of CCCK-18 and 6-month clinical outcomes. The predictive values were evaluated based on areas under receiver operating curve. Results Compared with controls, serum CCCK-18 concentrations were increased in patients (245.8 ± 108.3 U/l vs. 23.6 ± 18.1 U/l, P < 0.001). National Institute of Health Stroke Scale scores [odds ratio (OR), 1.164; 95% confidence interval (CI), 1.027–1.320; P = 0.003] and hematoma volumes (OR, 1.079; 95% CI, 1.018–1.205; P = 0.008) were independent predictors of high concentration of CCCK-18. CCCK-18 was identified as an independent predictor of 6-month mortality (OR, 1.019; 95% CI, 1.010–1.038; P = 0.013) and 6-month unfavorable outcome (OR, 1.017; 95% CI, 1.008–1.029; P = 0.032) and possessed high predictive values. Conclusion Increased serum CCCK-18 concentrations are associated with disease severity and clinical outcomes, suggesting that CCCK represent a novel prognostic predictive biomarker after intracerebral hemorrhage. [ABSTRACT FROM AUTHOR]

Cytochrome P-450 epoxygenase (EPOX)-derived epoxyeicosatrienoic acids (EETs), 5-lipoxygenase (5-LO), and leukotriene B4 (LTB4), the product of 5-LO, all play a pivotal role in the vascular inflammatory process. We have previously shown that EETs can alleviate oxidized low-density lipoprotein (ox-LDL)-induced endothelial inflammation in primary rat pulmonary artery endothelial cells (RPAECs). Here, we investigated whether ox-LDL can promote LTB4 production through the 5-LO pathway. We further explored how exogenous EETs influence ox-LDL-induced LTB4 production and activity. We found that treatment with ox-LDL increased the production of LTB4 and further led to the expression and release of both monocyte chemoattractant protein-1 (MCP-1/CCL2) and intercellular adhesion molecule-1 (ICAM-1). All of the above ox-LDL-induced changes were attenuated by the presence of 11,12-EET and 14,15-EET, as these molecules inhibited the 5-LO pathway. Furthermore, the LTB4 receptor 1 (BLT1 receptor) antagonist U75302 attenuated ox-LDL-induced ICAM-1 and MCP-1/CCL2 expression and production, whereas LY255283, a LTB4 receptor 2 (BLT2 receptor) antagonist, produced no such effects. Moreover, in RPAECs, we demonstrated that the increased expression of 5-LO and BLT1 following ox-LDL treatment resulted from the activation of nuclear factor-κB (NF-κB) via the p38 mitogen-activated protein kinase (MAPK) pathway. Our results indicated that EETs suppress ox-LDL-induced LTB4 production and subsequent inflammatory responses by downregulating the 5-LO/BLT1 receptor pathway, in which p38 MAPK phosphorylation activates NF-κB. These results suggest that the metabolism of arachidonic acid via the 5-LO and EPOX pathways may present a mutual constraint on the physiological regulation of vascular endothelial cells. [ABSTRACT FROM AUTHOR]

Abstract: Background: Epithelial–mesenchymal transition (EMT) is the major pathophysiological process in lung fibrosis observed in chronic obstructive pulmonary disease (COPD) and lung cancer. Smoking is a risk factor for developing EMT, yet the mechanism remains largely unknown. In this study, we investigated the role of Rac1 in cigarette smoke (CS) induced EMT. Methods: EMT was induced in mice and pulmonary epithelial cells by exposure of CS and cigarette smoke extract (CSE) respectively. Results: Treatment of pulmonary epithelial cells with CSE elevated Rac1 expression associated with increased TGF-β1 release. Blocking TGF-β pathway restrained CSE-induced changes in EMT-related markers. Pharmacological inhibition or knockdown of Rac1 decreased the CSE exposure induced TGF-β1 release and ameliorated CSE-induced EMT. In CS-exposed mice, pharmacological inhibition of Rac1 reduced TGF-β1 release and prevented aberrations in expression of EMT markers, suggesting that Rac1 is a critical signaling molecule for induction of CS-stimulated EMT. Furthermore, Rac1 inhibition or knockdown abrogated CSE-induced Smad2 and Akt (PKB, protein kinase B) activation in pulmonary epithelial cells. Inhibition of Smad2, PI3K (phosphatidylinositol 3-kinase) or Akt suppressed CSE-induced changes in epithelial and mesenchymal marker expression. Conclusions and general significance: Altogether, these data suggest that CS initiates EMT through Rac1/Smad2 and Rac1/PI3K/Akt signaling pathway. Our data provide new insights into the fundamental basis of EMT and suggest a possible new course of therapy for COPD and lung cancer. [Copyright &y& Elsevier]

Abstract: Oxidized low-density lipoprotein (Ox-LDL) is associated with atherosclerotic events through the modulation of arachidonic acid (AA) metabolism and activation of inflammatory signaling. Cytochrome P450 (CYP) epoxygenase-derived epoxyeicosatrienoic acids (EETs) mitigate inflammation through nuclear factor-κB (NF-κB). In this study, we explored the effects and mechanisms of exogenous EETs on the ox-LDL-induced inflammation of pulmonary artery endothelial cells (PAECs), which were cultured from rat pulmonary arteries. We determined that pre-treatment with 11,12-EET or 14,15-EET attenuated the ox-LDL-induced expression and release of intercellular adhesion molecule-1 (ICAM-1), E-selectin, and monocyte chemoattractant protein-1 (MCP-1) in a concentration-dependent manner. In addition, the ox-LDL-induced expression of CYP2J4 was upregulated by 11,12-EET and 14,15-EET (1μM). Furthermore, the endothelial receptor of lectin-like oxidized low-density lipoprotein (LOX-1) was downregulated in PAECs treated with EETs. The inflammatory responses evoked by ox-LDL (100μg/mL) were blocked by pharmacological inhibitors of Erk1/2 mitogen-activated protein kinase (MAPK) (U0126), p38 MAPK (SB203580), and NF-κB (PDTC). In addition, we confirmed that 11,12-EET suppresses phosphorylation of p38, degradation of IκBα, and activation of NF-κB (p65), whereas 14,15-EET can significantly suppress the phosphorylation of p38 and Erk1/2. Our results indicate that EETs exert beneficial effects on ox-LDL-induced inflammation primarily through the inhibition of LOX-1 receptor upregulation, MAPK phosphorylation, and NF-κB activation and through the upregulation of CYP2J4 expression. This study helps focus the current understanding of the contribution of EETs to the regulation of the inflammation of pulmonary vascular endothelial cells. Furthermore, the therapeutic potential of targeting the EET pathway in pulmonary vascular disease will be highlighted. [Copyright &y& Elsevier]

Abstract: Manipulation of the shape and size distribution of porous polystyrene (PST) micro/nano-particles by premix membrane emulsification is a big challenge. Here by this technique, we successfully synthesized uniform PST micro/nano-particles with diameters from 700nm to 7μm and with pore sizes from 7nm to 200nm. The size uniformity of particles was discovered to be affected by 3 key factors: transmembrane pressure, number of emulsification cycles and membrane pore size. The structures of particles were found depend on both porogen system and particle size. Furthermore, the interaction mechanism between porogen and PST particles was analyzed by Quartz crystal microbalance (QCM) and atomic force microscopy (AFM). The addition of porogen reduced the oscillation frequency change (Δƒ) and increased the dissipation change (ΔD) of the tested PST film, which affect the phase separation process between the porogen and PST polymer, and then form different pore size of PST particles. Moreover, the type and dosage of porogen can create various structures of PST micro/nano-particles at different particles size effectively. [Copyright &y& Elsevier]

Abstract: Background: Visfatin, a proinflammatory mediator, has been associated with poor clinical outcomes after acute brain injury. The present study is designed to investigate the potential association between plasma visfatin levels and the risk of hematoma growth (HG) and early neurologic deterioration (END) after intracerebral hemorrhage. Methods: There were 85 patients as cases who presented with first-time hemorrhagic stroke that were assessed within 6h after the incident. The control group consisted of 85 healthy volunteers. HG was defined as hematoma enlargement >33% at 24h. END was defined as an increase of≥4 points in National Institute of Health Stroke Scale score at 24h from symptoms onset. Plasma visfatin levels were determined using enzyme immunoassay. Results: Plasma visfatin levels were significantly higher in patients compared to controls. Plasma visfatin level emerged as an independent predictor of HG [odds ratio (OR), 1.154; 95% confidence interval (CI), 1.046–3.108; P =0.009] and END (OR, 1.195; 95% CI, 1.073–3.516; P =0.005). For predicting HG, area under curve (AUC) of plasma visfatin level (0.814; 95% CI: 0.715–0.890) was similar to that of hematoma volume (0.839; 95% CI, 0.743–0.909) (P =0.703). For predicting END, AUC of plasma visfatin level (0.828; 95% CI: 0.730–0.901) was similar to that of hematoma volume (0.863; 95% CI, 0.771–0.928) (P =0.605). Visfatin did not improve AUC of hematoma volume for predicting HG and END (both P >0.05). Conclusion: Plasma visfatin level represents a novel biomarker for predicting HG and END. [Copyright &y& Elsevier]

Abstract: Background: Ginseng is a traditional Chinese herb that has been used for thousands of years. In the present study, effects and mechanisms of AD-1 were evaluated for its development as a novel anti-lung cancer drug. Methods: The cytotoxic activity was evaluated by MTT assay. Flow cytometry was employed to detect cell cycle, apoptosis and ROS. Western blot and immunohistochemistry were used to analyze signaling pathways. Lung cancer xenograft models were established by subcutaneous implantation of A549 or H292 cells into nude mice. Results: AD-1 concentration-dependently reduces lung cancer cell viability without affecting normal human lung epithelial cell viability. In A549 and H292 lung cancer cells, AD-1 induces G0/G1 cell cycle arrest, apoptosis and ROS production. The apoptosis can be attenuated by a ROS scavenger — N-acetylcysteine (NAC). In addition, AD-1 up-regulates the expression of p38 and ERK phosphorylation. Addition of a p38 inhibitor SB203580, suppresses the AD-1-induced decrease in cell viability. Furthermore, genetic silencing of p38 attenuates the expression of p38 and decreases the AD-1-induced apoptosis. Treatment with NAC reduces AD-1-induced p38 phosphorylation, which indicates that ROS generation is involved in the AD-1-induced p38 activation. In mice, oral administration of AD-1 (10–40mg/kg) dose-dependently inhibited the growth of xenograft tumors without affecting body weight and decreases the expression of VEGF, MMP-9 and CD34 in tumor tissue. TUNEL staining confirms that the tumors from AD-1 treated mice exhibit a markedly higher apoptotic index. Conclusions and general significance: These data support development of AD-1 as a potential agent for lung cancer therapy. [Copyright &y& Elsevier]

Cigarette smoking is associated with an increased incidence of chronic obstructive pulmonary disease (COPD). In this study, we hypothesized that liquiritin apioside (LA), a main flavonoid component from Glycyrrhiza uralensis, had antioxidant properties by inducing glutathione (GSH) biosynthesis via the inhibition of cytokines and protected lung epithelial cells against cigarette smoke-mediated oxidative stress. A549 cells were treated with cigarette smoke extract (CSE) and/or LA. ICR mice were exposed to cigarette smoke (CS) for four days with increasing exposure time for up to 6 h per day to elicit epithelial cells injury. One hour before smoke exposure, mice were treated with LA by gavage; 18 h after the last CS exposure all examinations were performed. Treatment with LA concentration-dependently prevented CSE-induced cytotoxicity, increase of TGF-β and TNF-α mRNA expression, depletion of GSH and apoptosis in A549 cells. LA at doses 3, 10 and 30 mg/kg dose-dependently inhibited pulmonary neutrophil and macrophage inflammation. Lung sections of the CS-exposed LA treated mice showed an apparently reduced pulmonary inflammation and a significant inhibitory effect on mucus containing goblet cells in the large airways. Furthermore, the CS-induced pulmonary release of TGF-β, TNF-α and myeloperoxidase activity was reduced, and superoxide dismutase activity was enhanced.These results indicate that protective roles of LA on CS-induced the lung epithelial cell injury are mediated by inhibiting TGF-β and TNF-α expression and increasing anti-oxidative levels of GSH, suggesting that LA might be effective as protective agent against epithelial injury in COPD. [ABSTRACT FROM AUTHOR]

Abstract: Aim of the study: To evaluate the effects and the possible mechanism of Cryptoporus polysaccharides (CP) extracted from fruiting body of Cryptoporus volvatus in lipopolysaccharide (LPS)-induced acute lung injury (ALI) in rats and mice. Materials and methods: Acute lung injury was induced by intratracheally instillation of LPS into lung in either rats or mice, assessing leukocyte numbers and myeloperoxidase activity in bronchoalveolar lavage fluid, as well as evaluating cytokines mRNA and protein expressions, and Toll-like receptor 2 (TLR2) and nuclear factor (NF)-κB mRNA levels in the lung tissues of mice. Vascular permeability and edema of lung in mice, and arterial blood gas in rats were also performed. Results: In ALI, CP-treated mice and rats exhibited significantly reduced leukocyte invasion, myeloperoxidase activity, vascular permeability, edema of lung, as well as tumor necrosis factor-α and Interleukin-1β mRNA and protein expressions in the lung tissues compared with vehicle-treated mice. TLR2 andNF-κB mRNA levels of the lung tissues were decreased in CP-treated mice in response to LPS. And decline in arterial blood gas was recovered in CP-treated rats. Conclusions: Our results supported a protective role of CP in ALI and suggested that the reduction of the activation of TLR2 and NF-κB signal pathway in lung injury may be relavant to the pretreatment of CP. [Copyright &y& Elsevier]

Abstract: Background: Rac small GTPases play important roles in cytoskeleton and many cell functions including cell cycle, cell growth, cell adhesion and gene transcription. Here, we investigated the roles of Rac including Rac1 and Rac2 in lipopolysaccharide (LPS)-induced pulmonary injury. Methods: After LPS was intratracheally instilled to lungs in mice, Rac, CDC42 and RhoA activation assay by pull-down and West blot, inflammatory cell infiltration assay by counting cell numbers and lung histological examination, pro-inflammatory mediator mRNA expression assay by quantitative RT-PCR, measurement of myeloperoxidase (MPO) activity, Evans Blue and albumin accumulation by spectrophotometry were performed to evaluate the roles of Rac in pulmonary injury by using its specific inhibitor, NSC23766. Results: LPS challenge led to increases of both Rac1 and Rac2, but not CDC42 or RhoA activities in lungs, and intraperitoneal administration with NSC23766 inhibited both Rac1 and Rac2, but not CDC42 or RhoA activities. Treatment with NSC23766 at 1 or 3mg/kg not only reduced the inflammatory cells infiltration and MPO activities, but also inhibited pro-inflammatory mediators, tumor necrosis factor-α and interleukin-1β, mRNA expression. Moreover, in vitro neutrophil migration assay and in vivo microvascular permeability assay indicated that NSC23766 not only inhibited neutrophil transwell migration toward a chemoattractant, fMLP, but also reduced Evans Blue and albumin accumulation in LPS-challenged lungs. LPS activated both Rac1 and Rac2, but not CDC42 or RhoA activities in lungs, and specific inhibition of Rac activities by NSC23766 effectively alleviated LPS-induced injury. General significance: Rac could be a potential target for therapeutic intervention of pulmonary inflammation. [Copyright &y& Elsevier]

Abstract: M3 muscarinic receptors are localized on inflammatory cells, airway smooth muscle, and submucosal glands, known to mediate bronchoconstriction, mucus secretion, and airway remodeling. It is hypothesized bencycloquidium bromide (BCQB), a novel M3 receptor antagonist, might have potential effects on airway hyperresponsiveness, inflammation and airway remodeling in a murine model of asthma. Mice sensitized and challenged with ovalbumin developed airway inflammation. Bronchoalveolar lavage fluid was examined to determine the total and differential cell counts, and cytokine levels. Lung tissues were evaluated for cell infiltration, mucus hypersecretion, airway remodeling, and the expression of inflammatory biomarkers. Airway hyperresponsiveness was monitored by direct airway resistance analysis. Inhalation administration of BCQB significantly not only reduced ovalbumin-induced airway hyperresponsiveness comparing to methacholine, and prevented the ovalbumin-induced increase in total cell counts and eosinophil counts. Reverse transcriptase polymerase chain reaction analysis of whole lung lysates revealed that BCQB markedly suppressed ovalbumin-induced mRNA expression of eotaxin, IL-5, IL-4 and MMP-9, and increased mRNA expression of IFN-γ and TIMP-1 in a dose-dependent manner. Substantial IFN-γ/IL-4 (Th1/Th2) levels were recovered in bronchoalveolar lavage fluid after BCQB treatment. In addition, histological studies showed that BCQB dramatically inhibited ovalbumin-induced lung tissue eosinophil infiltration, airway mucus production and collagen deposition in lung tissues. Results reported in current paper suggest that M3 receptors antagonist may provide a novel therapeutic approach to treat airway inflammation, hyperresponsiveness and remodeling. [Copyright &y& Elsevier]

Abstract: Airway inflammation plays important roles in the pathogenesis of acute respiratory distress syndrome (ARDS), asthma and chronic obstructive pulmonary disease (COPD), and anti-inflammatory treatment effectively improves the symptoms of these diseases. To develop the potentially therapeutic compounds for the treatment of pulmonary inflammation, we investigated the effects of licorice flavonoids (LF) extracted from the roots of Glycyrrhiza uralensis (licorice) on lipopolysaccharide (LPS)-induced acute pulmonary inflammation in mice. Acute pulmonary inflammation was induced by intracheal instillation with LPS, treatment with LF at dosages of 3, 10 and 30 mg/kg significantly reduced the LPS-induced inflammatory cells, including neutrophils, macrophages and lymphocytes accumulation in bronchoalveolar lavage fluids (BALF), among these inflammatory cells, LF predominately inhibited neutrophil infiltration, and the maximal effect (30 mg/kg) was as comparable as dexamethasone treatment at 1 mg/kg. Consistent with its effects on neutrophil infiltration, LF treatment significantly increased LPS-induced BALF superoxide dismutase activity, and significantly decreased lung myeloperoxidase activity as well. Furthermore, treatment with LF at 30 mg/kg significantly reduced LPS-induced lung TNFα and IL-1β mRNA expression at 6 h and 24 h after LPS instillation, respectively. Finally, LF at different dosages not only significantly decreased the elevation of lung water content, but also markedly attenuated LPS-induced histological alteration. Therefore, we suggest that LF effectively attenuates LPS-induced pulmonary inflammation through inhibition of inflammatory cells infiltration and inflammatory mediator release which subsequently reduces neutrophil recruitment into lung and neutrophil-mediated oxidative injury, and this study provides with the potential rationale for development of anti-inflammatory compounds from flavonoid extracts of licorice. [Copyright &y& Elsevier]

We provide a way to precisely control the geometry of a SiNx nanopore by adjusting the applied electric pulse. The pore is generated by applying the current pulse across a SiNx membrane, which is immersed in potassium chloride solution. We can generate single conical and cylindrical pores with different electric pulses. A theoretical model based on the Poisson and Nernst—Planck equations is employed to simulate the ion transport properties in the channel. In turn, we can analyze pore geometries by fitting the experimental current-voltage (I–V) curves. For the conical pores with a pore size of 0.5–2nm in diameter, the slope angles are around −2.5° to −10°. Moreover, the pore orifice can be enlarged slightly by additional repeating pulses. The conic pore lumen becomes close to a cylindrical channel, resulting in a symmetry I–V transport under positive and negative biases. A qualitative understanding of these effects will help us to prepare useful solid-nanopores as demanded. [ABSTRACT FROM AUTHOR]