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PubMed | The Third Hospital of Jinan, Shandong University and Zoucheng Traditional Chinese Medicine Hospital
Type: Journal Article | Journal: Biochemical and biophysical research communications | Year: 2015

Diabetic nephropathy (DN) is the most severe diabetic microvascular complication. The pathogenesis of diabetic nephropathy is complex, and oxidative stress plays an important role in the development of diabetic nephropathy. Elevated reactive oxygen species (ROS) levels activate various signaling pathways and influence the activities of transforming growth factor- (TGF-) and matrix metalloproteinase-9 (MMP-9), which contributes to glomerular hypertrophy. Branched-chain amino acids (BCAAs) are widely used in clinical treatment, and BCAAs can reduce the oxidative stress associated with the diabetic pancreas and some liver diseases. Thus, the aim of the present study was to determine whether BCAAs could attenuate oxidative stress in the kidneys of streptozotocin (STZ)-induced diabetic rats to prevent early diabetic kidney injury. Male Wistar rats were fed for two weeks with a normal chow diet or a high-fat diet in which 40% of calories were derived from fat. After this two-week period, the mice fed normal chow were injected with vehicle, while the high-fat diet group was injected intraperitoneally (i.p.) with 40mg/kg STZ. The STZ-treated group was randomly divided into four subgroups that were treated with different doses of BCAAs or vehicle for two months by oral gavage. Plasma glucose, plasma creatinine, urinary protein and JNK, TGF-, and MMP-9 mRNA and protein expression levels were measured in the rats. The ROS levels and proteinuria in the STZ-induced diabetic rats were significantly higher than those in the control groups. Moreover, early kidney injury occurred in the STZ-induced diabetic rats. However, BCAAs treatment decreased ROS levels, proteinuria and kidney injury. Moreover, JNK, TGF- and MMP-9 mRNA and protein levels were significantly increased in the diabetic rats when compared with the control rats, and BCAAs treatment reversed these changes. Our results suggest that BCAAs counter oxidative stress in the kidneys of diabetic rats and alleviate diabetic kidney injury via the JNK/TGF-/MMP-9 pathway.

PubMed | Shanghai Fire Corps Hospital, The Third Hospital of Jinan, Shanghai JiaoTong University and Soochow University of China
Type: | Journal: Materials science & engineering. C, Materials for biological applications | Year: 2016

Posttraumatic tendon adhesion limits the motion of the limbs greatly. Biomimetic tendon sheaths have been developed to promote tendon healing and gliding. However, after introduction of these biomaterials, the associated inflammatory responses can decrease the anti-adhesion effect. Celecoxib is a non-steroidal anti-inflammatory drug (NSAID) that can decrease inflammation responses. We blended hyaluronic acid and poly(l-lactic acid)-polyethylene glycol (PELA) with microgel electrospinning technology to form an inner layer of a bi-layer biomimetic sheath using sequential electrospinning of an outer celecoxib-PELA layer. Electrospun bi-layer fibrous membranes were mechanically tested and characterized by morphology, surface wettability, and drug release. The tensile strength showed a decreased trend and water contact angles were 114.7 3.9, 103.6 4.4, 116.3 5.1, 122.8 4.7, and 126.5 4.2 for the surface of PELA, hyaluronic acid-PELA, 2, 6, and 10% celecoxib-PELA electrospun fibrous membranes, respectively. In vitro drug release studies confirmed burst release and then sustained release from the fibrous membranes containing celecoxib for 20 days. In a chicken model of flexor digitorum profundus tendon surgery, the outer celecoxib/PELA layer offered advanced anti-adhesion roles compared to the outer PELA layer and the inner hyaluronic acid-loaded PELA layer still offered tendon healing and gliding. Thus, celecoxib-loaded anti-adhesive tendon sheaths can continuously offer bi-layer biomimetic tendon sheath effects with celecoxib release from the outer layer to prevent tendon adhesion.

PubMed | Guangzhou University of Chinese Medicine, the Third Hospital of Jinan and the First Peoples Hospital of Shangqiu
Type: | Journal: Drug design, development and therapy | Year: 2016

Estrogen receptors (ERs) are nuclear transcription factors that are involved in the regulation of many complex physiological processes in humans. ERs have been validated as important drug targets for the treatment of various diseases, including breast cancer, ovarian cancer, osteoporosis, and cardiovascular disease. ERs have two subtypes, ER- and ER-. Emerging data suggest that the development of subtype-selective ligands that specifically target ER- could be a more optimal approach to elicit beneficial estrogen-like activities and reduce side effects.Herein, we focused on ER- and developed its in silico quantitative structure-activity relationship models using machine learning (ML) methods.The chemical structures and ER- bioactivity data were extracted from public chemogenomics databases. Four types of popular fingerprint generation methods including MACCS fingerprint, PubChem fingerprint, 2D atom pairs, and Chemistry Development Kit extended fingerprint were used as descriptors. Four ML methods including Nave Bayesian classifier, k-nearest neighbor, random forest, and support vector machine were used to train the models. The range of classification accuracies was 77.10% to 88.34%, and the range of area under the ROC (receiver operating characteristic) curve values was 0.8151 to 0.9475, evaluated by the 5-fold cross-validation. Comparison analysis suggests that both the random forest and the support vector machine are superior for the classification of selective ER- agonists. Chemistry Development Kit extended fingerprints and MACCS fingerprint performed better in structural representation between active and inactive agonists.These results demonstrate that combining the fingerprint and ML approaches leads to robust ER- agonist prediction models, which are potentially applicable to the identification of selective ER- agonists.

Zhang F.-Y.,Peoples Hospital Of Yucheng City | Tang W.,Yantaishan Hospital | Zhang Z.-Z.,First Peoples Hospital Of Jinan City | Huang J.-C.,First Peoples Hospital Of Jinan City | And 2 more authors.
Tumor Biology | Year: 2014

The objective of this study is to evaluate whether high-dose chemotherapy is more efficacious than standarddose chemotherapy in the treatment of primary welldifferentiated osteosarcoma. The Cochrane systematic evaluation method was adopted. A database search was conducted in MEDLINE, Embase, OVID, the Cochrane Central Register of Controlled Trials database and the Chinese Biomedical Literature CD-ROM Database. The quality of the included studies was jointly evaluated by two reviewers, and homogeneous studies were included for meta-analysis. A total of five studies were included in this meta-analysis, with 1,415 subjects with primary, nonmetastatic, well-differentiated osteosarcoma in the limbs. No statistically significant differences were found between the high-dose chemotherapy group and the low-dose group in 5-year event-free survival [RR 1.04, 95 %CI (0.95, 1.13)], 5-year overall survival [RR 1.02, 95 %CI (0.95, 1.10)], local recurrence rate [RR 0.90, 95 %CI (0.59, 1.39)], proportion of subjects with good histological response [RR 0.93, 95 %CI (0.81, 1.07)], or limb salvage rate [RR 0.97, 95 %CI (0.92, 1.02)]. A statistically significant difference was observed in the 5-year event-free survival between the subjects with good histological response to preoperative chemotherapy and the subjects with poor histological response [RR 1.55, 95 %CI (1.19, 2.00), P<0.001]. High-dose chemotherapy did not show superior efficacy to low-dose chemotherapy in the treatment of primary well-differentiated osteosarcoma. Further high-quality randomized controlled trials are needed to provide additional reliable evidence for our observation. © International Society of Oncology and BioMarkers (ISOBM) 2014.

PubMed | Affiliated Hospital of Jining Medical College, The Third Hospital of Jinan and Shandong University
Type: Journal Article | Journal: Oncotarget | Year: 2016

Prohibitin (PHB) is a highly conserved protein implicated in various cellular functions including proliferation, apoptosis, tumor suppression, transcription, and mitochondrial protein folding. However, its function in diabetic cardiomyopathy (DCM) is still unclear. In vivo, type 2 diabetic rat model was induced by using a high-fat diet and low-dose streptozotocin. Overexpression of the PHB protein in the model rats was achieved by injecting lentivirus carrying PHB cDNA via the jugular vein. Characteristics of type 2 DCM were evaluated by metabolic tests, echocardiography and histopathology. Rats with DCM showed severe insulin resistance, left ventricular dysfunction, fibrosis and apoptosis. PHB overexpression ameliorated the disease. Cardiofibroblasts (CFs) and H9c2 cardiomyoblasts were used in vitro to investigate the mechanism of PHB in altered function. In CFs treated with HG, PHB overexpression decreased expression of collagen, matrix metalloproteinase activity, and proliferation. In H9c2 cardiomyoblasts, PHB overexpression inhibited apoptosis induced by HG. Furthermore, the increased phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 was significantly decreased and the inhibited phosphorylation of Akt was restored in DCM. Therefore, PHB may be a new therapeutic target for human DCM.

PubMed | The Third Hospital of Jinan and Shandong Provincial Hospital
Type: Journal Article | Journal: Genetics and molecular research : GMR | Year: 2016

The objective of this study was to identify hub genes and pathways associated with acute respiratory infection (ARI) in infants based on gene expression profiles. Differentially expressed genes (DEGs) between ARI and normal (controls) infants were identified based on linear modeling of the microarray data using Limma package. A protein-protein interaction (PPI) network was constructed using the Search Tool for the Retrieval of Interacting Genes/proteins and clusters were obtained by employing the molecular complex detection algorithm. Topological centrality was applied to characterize the biological importance of genes in the network. Functional enrichment analysis of the genes was performed based on the expression analysis systematic explore test. In total, 116 DEGs between ARI and controls were identified. Of the 61 nodes and 189 edges in the PPI network generated with the DEGs, three clusters were mined. Six hub genes namely RPL6, RPL3, EEF1B2, RPL15, EEF1A1, and RPS2, which were identified based on the topological centrality measures, were evaluated further. Functional enrichment analysis revealed that DEGs were significantly enriched in terms of Gene Ontology translational elongation, structural constituent of ribosome, and cytosol. The most significant term of pathway analysis was ribosome. In summary, this study suggests RPL6, RPL3, and RPL15 as hub genes and the ribosome pathway to be significantly associated with viral ARI in infants, which might also be used as potential markers for the viral etiology.

PubMed | The Third Hospital of Jinan
Type: Journal Article | Journal: World journal of gastroenterology | Year: 2016

To determine the association of p53, carcinoembryonic antigen (CEA) and CA19-9 protein expression with esophageal carcinogenesis.An iodine staining endoscopic screening program of esophageal lesions was carried out in the high-incidence area of Feicheng County, China. Seventy-seven patients with basal cell hyperplasia (BCH), 247 with low-grade dysplasia (LGD), 51 with high-grade dysplasia (HGD), 134 with invasive cancer, and 80 normal controls diagnosed by mucous membrane biopsy pathology were enrolled. Immunohistochemical detection of p53, CEA and CA19-9 proteins was performed. In the ROC curve analysis, the expression of a single biomarker and the expression of a combination of biomarkers were used to predict the risk of these four esophageal lesions.The positive rates of p53 protein expression in invasive cancer, HGD, LGD, BCH and the normal control groups were 53.0%, 52.9%, 35.6%, 27.3% and 20.0%, respectively; the positive rates of CA19-9 protein expression were 44.0%, 33.3%, 16.5%, 9.2% and 6.2%, respectively; the positive rates of CEA protein expression were 74.6%, 60.8%, 23.3%, 23.7% and 16.2%, respectively. The positive rates of the combined expression of the three biomarkers were 84.3%, 76.5%, 47.6%, 42.9% and 27.5%, respectively. In the receiver operating characteristic curves of the combination of the three biomarkers, the specificity was 88.8% for the normal controls, and the sensitivity was 58.2% for invasive cancer, 25.5% for HGD, 11.2% for LGD, and 6.5% for BCH.p53, CEA and CA19-9 protein expression was correlated with esophageal carcinogenesis, and testing for the combination of these biomarkers is useful for identifying high-risk patients with precancerous lesions.

PubMed | The Third Hospital of Jinan and Shandong University
Type: Journal Article | Journal: Molecular medicine reports | Year: 2016

The aim of the present study was to identify the genetic defect responsible for familial coronary artery disease/myocardial infarction (CAD/MI), which exhibited an autosomal dominant pattern of inheritance, in an extended Chinese Han pedigree containing 34 members. Using exome and Sanger sequencing, a novel 6base pair (bp) CAGCCG deletion in exon11 of the myocyte enhancer factor 2A (MEF2A) gene was identified, which cosegregated with CAD/MI cases in this family. This 6bp deletion was not detected in 311sporadic cases of premature CAD/MI or in 323unrelated healthy controls. Determination of a genetic risk profile has a key role in understanding the pathogenesis of CAD and MI. Among the reported riskconferring genes and their variants, mutations in MEF2A have been reported to segregate with CAD/MI in Caucasian families. Causative missense mutations have also been detected in sporadic CAD/MI cases. However, this suggested genetic linkage is controversial, since it could not be confirmed by ensuing studies. The discovery of a novel MEF2A mutation in a Chinese family with premature CAD/MI suggests that MEF2A may have a significant role in the pathogenesis of premature CAD/MI. To better understand this association, further invitro and invivo studies are required.

PubMed | The Third Hospital of Jinan
Type: Journal Article | Journal: Journal of B.U.ON. : official journal of the Balkan Union of Oncology | Year: 2016

To evaluate the cytotoxic and apoptotic effects of bishydroxycoumarin (BHC) against human glioma cells and to study their mode of action.Three cells were used in the experiments. MTT and LDH assays were used to assess the cytotoxic effects of BHC while an in vitro wound healing assay was used to study the effect of BHC on cell migration. Fluorescence microscopy and annexin V-FITC assay were used to study the cellular morphology and apoptotic effects while flow cytometry in combination with propidium iodide (PI) were used to study cell cycle arrest induced by BHC.BHC induced substantial and dose-dependent cytotoxic effects against all three cell lines with U87MG cell line being most susceptible. BHC also inhibited cell migration and induced characteristic morphological changes including chromatin condensation, nuclear shrinkage which increased with increasing dose of BHC. The apoptotic cell population (both early and late apoptotic cells) increased with increasing dose of BHC which also induced substantial G0/G1 cell cycle growth arrest in U87MG cells.This study provides help to elucidate the translational potential of the in vitro results to be used for further in vivo studies on human glioma using animal or human subjects. The mechanistic pathway studied in this report could be helpful in explaining the mode of action of these classes of natural products.

PubMed | The Third Hospital of Jinan and Shandong University
Type: Journal Article | Journal: Genetics and molecular research : GMR | Year: 2016

Despite recent advances in osteosarcoma diagnosis and therapy, much remains unclear about the molecular mechanisms involved in the disorder, and the discovery of novel drug-targeted genes is essential. We explored the potential molecular mechanisms and target genes involved in the development and progression of osteosarcoma. First, we identified the differentially expressed genes in osteosarcoma patients and matching normal controls. We then constructed a differential expression network based on differential and non-differential interactions. Pathway-enrichment analysis was performed based on the nodes contained in the main differential expression network. Centrality analysis was used to select hub genes that may play vital roles in the progression of human osteosarcoma. Our research revealed a total of 176 differentially expressed genes including 82 upregulated and 94 downregulated genes. A differential expression network was constructed that included 992 gene pairs (1043 nodes). Pathway-enrichment analysis indicated that the nodes in the differential expression network were mainly enriched in several pathways such as those involved in cancer, cell cycle, ubiquitin-mediated proteolysis, DNA replication, ribosomes, T-cell receptor signaling, spliceosomes, neurotrophin signaling, oxidative phosphorylation, and tight junctions. Six hub genes (APP, UBC, CAND1, RPA, YWHAG, and NEDD8) were discovered; of these, two genes (UBC and RPA) were also found to be disease genes. Our study predicted that UBC and RPA had potential as target genes for the diagnosis and treatment of osteosarcoma.

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