OBJECTIVETo investigate the molecular mechanism of tumor necrosis factor-alpha (TNF-a) monoclonal antibody (McAb) in hepatopulmonary syndrome using a rat model.

METHODSSixty adult male Sprague-Dawley rats, weighing 250 ± 25 g, were randomized to a sham operation group, a common bile duct ligation (CBDL) group, or a CBDL+TNF-alphat McAb treatment group. The CBDL operation group was further divided into five subgroups, and the CBDL+TNF-alpha McAb treatment group was further divided into four subgroups. After the experimental period, all rats were sacrificed for excision of lung and liver tissues. Hematoxylin-eosin (HE) and Masson staining were performed to observe the extent of liver fibrosis,and HE staining was used to histopathologically assess changes in the lung tissue. Immunohistochemistry and western blotting were used to investigate the changes in expression levels of FAK, p-FAK and PTEN in lung.

RESULTSThe extent of inflammatory responses and fibrosis in the liver was significantly lower in the CBDL+TNF-alpha McAb treatment group as compared to those in the CBDL group. The inflammatory responses in the lung were also significantly lower in the CBDL+TNF-alpha McAb treatment group as compared to that in the CBDL group. The CBDL+TNF-alpha McAb treatment group also showed less extensive distribution of FAK and p-FAK protein in lung tissues,but more extensive distribution of PTEN protein.

CONCLUSIONFAK and PTEN are associated with hepatopulmonary syndrome in rats. The therapeutic effect of TNF-alpha McAb may involve modulation of the expression of FAK and PTEN.

Animals ; Antibodies, Monoclonal ; Blotting, Western ; Common Bile Duct ; Hepatopulmonary Syndrome ; Immunohistochemistry ; Ligation ; Liver Cirrhosis ; Lung ; Male ; Rats ; Rats, Sprague-Dawley ; Tumor Necrosis Factor-alpha

OBJECTIVETo investigate patterns of action potential firing in cortical heurons of neonatal mice and their electrophysiological properties.

METHODSThe passive and active membrane properties of cortical neurons from 3-d neonatal mice were observed by whole-cell patch clamp with different voltage and current mode.

RESULTSThree patterns of action potential firing were identified in response to depolarized current injection. The effects of action potential firing patterns on voltage-dependent inward and outward current were found. Neurons with three different firing patterns had different thresholds of depolarized current. In the morphology analysis of action potential, the three type neurons were different in rise time, duration, amplitude and threshold of the first action potential evoked by 80 pA current injection. The passive properties were similar in three patterns of action potential firing.

CONCLUSIONThese results indicate that newborn cortical neurons exhibit different patterns of action potential firing with different action potential parameters such as shape and threshold.

OBJECTIVE: Abnormalities of liver-related indices are common in ICU patients, but the effects of cholestasis and hypoxic hepatitis in critically ill patients remains unclarified. The purpose of this study was to investigate the effects of cholestasis and hypoxic liver dysfunction on the prognosis of ICU patients. METHODS: A retrospective study was conducted based on the data of patients admitted to the ICU for the first time between 2001 and 2011 archived in the MIMIC-Ⅲ database. The patients were divided into cholestasis, hypoxic hepatitis and control groups, and their 28-day case fatality rate as the primary outcome was compared among the groups. RESULTS: A total of 5852 ICU patients were included in the analysis. The incidence of cholestasis and hypoxic liver dysfunction was 31.9% (1869/5852) and 17.9% (1046/5852), respectively. There was no significant difference in 28-day case fatality rate between cholestasis group and the control group. Compared with the control group, the patients with hypoxic hepatitis had a significantly higher 28-day case fatality rate (46% 35%, < 0.01), a higher hospital case fatality rate (40% 31%, < 0.01), and a higher ICU case fatality rate (35.7% 22.2%, < 0.01). Logistic regression analysis showed that lactic acid (LAC), aspartate transaminase (AST), and international standard ratio (INR) were independent risk factors for 28-day case fatality rate. CONCLUSIONS The incidence of cholestatic liver dysfunction is higher than that of hypoxic hepatitis, but it does not increase the 28-day case fatality rate of the ICU patients, suggesting that cholestatic liver dysfunction may be the early adaptation of the liver to critical diseases.
Cholestasis ; Hepatitis ; Humans ; Intensive Care Units ; Prognosis ; Retrospective Studies

To evaluate the application of midpalatal cortex osteotomy assisted rapid maxillary expansion for correction of maxillary transverse deficiency in young adults.Fourteen young adult patients with maxillary transverse deficiency were treated with midpalatal cortex osteotomy assisted rapid maxillary expansion. Lateral cephalogram and cone beam CT (CBCT) were taken before and 3 months after treatment. The width of basal bone, arch of maxilla and the torque of anchorage teeth were compared before and after treatment.The width of dental arch of maxilla was increased from 40.54±5.26 mm before treatment to 46.83±5.83 mm after treatment (<0.05) and the width of basal bone was increased from 64.86±4.16 mm to 67.60±4.66 mm (<0.05) at the plane of the maxillary first molars. Accordingly, the width of dental arch of maxilla was increased from 31.92±2.55 mm to 38.65±3.14 mm (<0.05) and the width of basal bone was increased from 43.33±3.70 mm to 45.78±4.57 mm (<0.05) at the plane of first premolar. And the torque of maxillary anchorage teeth were increased (<0.05).Midpalatal cortex osteotomy assisted rapid maxillary expansion is an effective micro-invasive method in expansion of basal bone and arch of maxilla for young adult patients with maxillary transverse deficiency.

To prepare and characterize Pluronic-PEI micelles as a drug/gene delivery system.We used the low-molecular-weight PEI as a cross-linking agent to prepare the Pluronic-PEI micelles. The particle size, zeta potential and critical micelle concentration (CMC) were measured by dynamic light scattering (DLS) and pyrene fluorescence probe. The cytotoxicity, transfection efficiency and the impact on the intracellular ATP and P-gp levels of Pluronic-PEI micelles were investigated at the cellular level.Pluronic-PEI micelles were successfully prepared with a suitable particle size (120-180 nm), zeta potential (+6-+9 mv), and a good ability to carry the drug/gene. Anstudy showed that Pluronic-PEI had low cytotoxicity, and the P123-PEI600 possessed high gene transfection efficiency and could downregulate the intracellular ATP and P-gp levels.Pluronic-PEI is a good drug/gene delivery system, and P123-PEI600 is an ideal vector, which may be used in the combination therapy for reversing multidrug resistance.

Objective To investigate the effect of 15-Deoxy-△(12,14)-prostaglandin J2 (15 d-PGJ2) on the expression of macrophage migration inhibitory factor (MIF) and its underlying mechanism in J774A.1. Methods The murine monocyte/macrophage cell line J774A.1 were divided into six groups:lipopolysaccharide (LPS) group,incubated with 1 μg/ml LPS for 1 h;normal control group,incubated with PBS for 1 h;negative control group,incubated with 5 μmol/L 15 d-PGJ2 for 1 h;15 d-PGJ2 group,incubated with 5 μmol/L 15 d-PGJ2 for 1 h followed by 1 μg/ml LPS for 1 h;GW9662 group,incubated with 5 μmol/L 15 d-PGJ2 for 1 h following GW9662 10 μmol/L for 1 h,and then incubated with 1 μg/ml LPS for 1 h;and Vehicle group,control of GW9662,GW9662 was replaced by its solvent DMSO. The expression of MIF was detected via immunofluorescence and agarose gel electrophoresis. RT-qPCR and Western blotting were used to test whether 15 d-PGJ2 could regulate mRNA and protein expression of MIF in J774A.1 upon LPS challenge. The effect of peroxisome proliferator-activated receptor-γ (PPAR-γ) antagonist GW9662 on the regulation of MIF by 15 d-PGJ2 was observed. The effects of 15 d-PGJ2 on the nuclear translocation of PPAR-γ upon LPS challenge were detected via high content screening analysis. Results MIF DNA and protein expressions were detected in J774A.1. MIF mRNA expression was up-regulated (1.75±0.09,P=0.037) when challenged with LPS and 15 d-PGJ2 inhibited its upregulation (0.84±0.08,P=0.026) in J774A.1. The protein level was consistent with the mRNA level. PPAR-γ antagonist GW9662 reversed the effect of 15 d-PGJ2 (mRNA,1.48±0.06,P=0.016;protein,1.28). Furthermore,nuclear translocation of PPAR-γ was regulated by 15 d-PGJ2 in J774A.1 upon LPS challenge(1.39±0.02 vs. 1.01±0.03,P=0.003). Conclusion 15 d-PGJ2 may down-regulate the MIF expression in J774A.1 in a PPAR-γ-dependent manner.
Anilides ; pharmacology ; Animals ; Cell Line ; Intramolecular Oxidoreductases ; metabolism ; Lipopolysaccharides ; Macrophage Migration-Inhibitory Factors ; metabolism ; Mice ; Monocytes ; drug effects ; PPAR gamma ; antagonists & inhibitors ; Prostaglandin D2 ; analogs & derivatives ; pharmacology

To design and synthesize photosensitizers with different substituents and to identify its physicochemical characteritics and photodynamic effect on cancer cells.Two kinds of BODIPY photosensitizers BPOI and BPCI were synthesized through condensation reaction between aldehyde and reactive hydrogen of pyrrole, followed with electrophilic substitution reaction. Physicochemical properties were characterized byH NMR, FT-IR and UV-visible absorption spectra and fluorescence emission spectra. The ability to produce reactive oxygen species was detected by BPDF and DCFH-DA. Photodynamic therapy effect on rat glioma C6 cellswas determined by MTT method.Two kinds of BODIPY photosensitizers BPOI and BPCI were successfully synthesized with different substituents, which were confirmed byH NMR, FT-IR. Both materials had low toxicity and could be readily taken up by tumor cells. The ability of synthesized photosensitizers to produce reactive oxygen species was strongly influenced by solvent polarity when the substituent was electron-donating group, while no effect was found when the substituent was electron-withdrawing group.Photosensitizer BPOI with electron-donating substituent produces reactive oxygen species with a slow rate in a highly polar environment, while greatly enhanced this effect in a low polarity environment, which is expected to be used for environmental-selective photodynamic therapy in tumor cells.

Although genome-wide association studies have identified more than eighty genetic variants associated with non-small cell lung cancer (NSCLC) risk, biological mechanisms of these variants remain largely unknown. By integrating a large-scale genotype data of 15 581 lung adenocarcinoma (AD) cases, 8350 squamous cell carcinoma (SqCC) cases, and 27 355 controls, as well as multiple transcriptome and epigenomic databases, we conducted histology-specific meta-analyses and functional annotations of both reported and novel susceptibility variants. We identified 3064 credible risk variants for NSCLC, which were overrepresented in enhancer-like and promoter-like histone modification peaks as well as DNase I hypersensitive sites. Transcription factor enrichment analysis revealed that USF1 was AD-specific while CREB1 was SqCC-specific. Functional annotation and gene-based analysis implicated 894 target genes, including 274 specifics for AD and 123 for SqCC, which were overrepresented in somatic driver genes (ER = 1.95, P = 0.005). Pathway enrichment analysis and Gene-Set Enrichment Analysis revealed that AD genes were primarily involved in immune-related pathways, while SqCC genes were homologous recombination deficiency related. Our results illustrate the molecular basis of both well-studied and new susceptibility loci of NSCLC, providing not only novel insights into the genetic heterogeneity between AD and SqCC but also a set of plausible gene targets for post-GWAS functional experiments.
Adenocarcinoma of Lung/genetics* ; Carcinoma, Non-Small-Cell Lung/genetics* ; Carcinoma, Squamous Cell/genetics* ; Genetic Heterogeneity ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Humans ; Lung Neoplasms/genetics* ; Polymorphism, Single Nucleotide