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Cancer Biology
Heterologous mammalian Akt disrupts plasma membrane homeostasis by taking over TORC2 signaling in Saccharomyces cerevisiae.
May 22, 2018   Scientific Reports
Rodríguez-Escudero I, Fernández-Acero T, Cid VJ, Molina M
Heterologous mammalian Akt disrupts plasma membrane homeostasis by taking over TORC2 signaling in Saccharomyces cerevisiae.
May 22, 2018
Scientific Reports
The Akt protein kinase is the main transducer of phosphatidylinositol-3,4,5-trisphosphate (PtdIns3,4,5P3) signaling in higher eukaryotes, controlling cell growth, motility, proliferation and survival. By co-expression of mammalian class I phosphatidylinositol 3-kinase (PI3K) and Akt in the Saccharomyces cerevisiae heterologous model, we previously described an inhibitory effect on yeast growth that relied on Akt kinase activity. Here we report that PI3K-Akt expression in yeast triggers the formation of large plasma membrane (PM) invaginations that were marked by actin patches, enriched in PtdIns4,5P2 and associated to abnormal intracellular cell wall deposits. These effects of Akt were mimicked by overproduction of the PtdIns4,5P2 effector Slm1, an adaptor of the Ypk1 and Ypk2 kinases in the TORC2 pathway. Although Slm1 was phosphorylated in vivo by Akt, TORC2-dependent Ypk1 activation did not occur. However, PI3K-activated Akt suppressed the lethality derived from inactivation of either TORC2 or Ypk protein kinases. Thus, heterologous co-expression of PI3K and Akt in yeast short-circuits PtdIns4,5P2- and TORC2-signaling at the level of the Slm-Ypk complex, overriding some of its functions. Our results underscore the importance of phosphoinositide-dependent kinases as key actors in the homeostasis and dynamics of the PM.
Advances in drug discovery for human beta cell regeneration.
May 17, 2018   Diabetologia
Karakose E, Ackeifi C, Wang P, Stewart AF
Advances in drug discovery for human beta cell regeneration.
May 17, 2018
Diabetologia
The numbers of insulin-secreting pancreatic beta cells are reduced in people with type 1 and type 2 diabetes. Driving beta cell regeneration in the pancreases of people with diabetes would be an attractive approach to reversing diabetes. While adult human beta cells have long been believed to be terminally differentiated and, therefore, irreversibly quiescent, it has become clear over recent years that this is not true. More specifically, both candidate and unbiased high-throughput screen approaches have revealed several classes of molecules that are clearly able to induce human beta cell proliferation. Here, we review recent approaches and accomplishments in human beta cell regenerative drug discovery. We also list the challenges that this rapidly moving field must confront to translate beta cell regenerative therapy from the laboratory to the clinic.
Decreased expression of ferritin light chain in osteosarcoma and its correlation with epithelial-mesenchymal transition.
May 17, 2018   European Review For Medical And Pharmacological Sciences
Yu GH, Fu L, Chen J, Wei F, Shi WX
Decreased expression of ferritin light chain in osteosarcoma and its correlation with epithelial-mesenchymal transition.
May 17, 2018
European Review For Medical And Pharmacological Sciences
OBJECTIVE: The purpose of this study was to detect ferritin light chain (FTL) expression level in osteosarcoma (OS), and to clarify whether FTL could offer additional help in diagnosis or therapy. MATERIALS AND METHODS: First, we assessed FTL level in OS tissues and cells through GEO dataset and tissue microarrays (TMAs). Then, we overexpressed FTL expression in MG-63 cell line. Lastly, we detected the expression of EMT-related signal pathway proteins to study its underlying molecular mechanisms. RESULTS: GEO dataset and TMAs showed that FTL was down-regulated in OS. After FTL was overexpressed, the proliferation, migration and invasion abilities of OS cells were significantly reduced. Moreover, after FTL overexpressing, the levels of CDH2 and Vimentin were down-regulated with CDH1 up-regulated. CONCLUSIONS: We revealed that FTL (1) is lower in OS then in normal tissue, (2) is related to metastasis, survival period, and therapeutic response, and (3) may be a tumor-inhibiting factor owing to its inhibition of EMT in OS.
MicroRNA-23a-3p promotes the perihematomal edema formation after intracerebral hemorrhage via ZO-1.
May 17, 2018   European Review For Medical And Pharmacological Sciences
Hu YL, Wang H, Huang Q, Wang G, Zhang HB
MicroRNA-23a-3p promotes the perihematomal edema formation after intracerebral hemorrhage via ZO-1.
May 17, 2018
European Review For Medical And Pharmacological Sciences
OBJECTIVE: To explore the relationship between microRNA-23a-3p expression and perihematomal edema (PHE) in patients with acute intracerebral hemorrhage (ICH) and its underlying mechanism. PATIENTS AND METHODS: Clinical data and blood samples on the 3rd day after ICH onset were collected. Head CT was performed in each subject when admitted. Serum expressions of microRNAs were detected by quantitative real-time PCR (qRT-PCR). The relationship between hematoma volume and perihematomal edema was analyzed by correlation analysis. The direct binding of microRNA-23a-3p and zonula occludens-1 (ZO-1) was verified by luciferase activity assay and Western blot, respectively. Moreover, in vitro experiments were carried out by flow cytometry and CCK-8 assay, respectively. RESULTS: Serum levels of microRNA-23a-3p and microRNA-130a in ICH patients were remarkably higher than those in the control group, microRNA-26a and microRNA-146a, however, were significantly decreased. A positive correlation was observed between the microRNA-23a-3p expression and the volume of relative perihematomal edema (rPHE) on the 3rd day after ICH (r2=0.3985; p=0.0002). Up-regulation of microRNA-23a-3p significantly decreased ZO-1 expression in hCMEC/D3 cells. Results of luciferase activity assay further indicated that microRNA-23a-3p directly targets the wild-type of ZO-1. In vitro results suggested that microRNA-23a-3p expression markedly affects the proliferation and apoptosis of hCMEC/D3 cells. Similar results were obtained after overexpression or knockdown of ZO-1. CONCLUSIONS: Up-regulated microRNA-23a-3p in ICH patients promotes the apoptosis of cerebral vascular endothelial cells by down-regulatingZO-1, thus participating in the perihematomal edema formation after intracerebral hematoma.
Regulatory mechanism of microRNA-377 on CDH13 expression in the cell model of Alzheimer's disease.
May 17, 2018   European Review For Medical And Pharmacological Sciences
Liu FF, Zhang Z, Chen W, Gu HY, Yan QJ
Regulatory mechanism of microRNA-377 on CDH13 expression in the cell model of Alzheimer's disease.
May 17, 2018
European Review For Medical And Pharmacological Sciences
OBJECTIVE: To explore whether microRNA-377 could participate in the development of Alzheimer's disease (AD) by regulating CDH13. MATERIALS AND METHODS: In this research, AD model was constructed by the SH-SY5Y cells. The expression levels of microRNA-377 and CDH13 in the AD model were detected by quantitative Real-time polymerase chain reaction (qRT-PCR). The cell viability and apoptosis after knockdown of microRNA-377 and CDH13 were measured by cell counting kit-8 (CCK-8) assay and flow cytometry, respectively. The regulatory mechanism of microRNA-377 on CDH13 was confirmed by dual-luciferase reporter gene assay, qRT-PCR and Western blot. RESULTS: Downregulated microRNA-377 and upregulated CDH13 were observed after successful construction of the AD model. Cell viability in the AD model group was significantly reduced compared with that of the control group. Moreover, downregulated microRNA-377 could further inhibit the cell viability, which was reversed by CDH13 knockdown. Cell apoptosis in the AD model group was enhanced after microRNA-377 knockdown, which was rescued by decreasing the expression level of CDH13. MicroRNA-377 was confirmed to regulate the expression level of CDH13 by dual-luciferase reporter gene assay, qRT-PCR and Western blot. CONCLUSIONS: MicroRNA-377 could regulate the expression level of CDH13 by promoting cell proliferation and inhibiting cell apoptosis, thus participating in the occurrence of the Alzheimer's disease.
Effect of downregulated lncRNA NBAT1 on the biological behavior of glioblastoma cells.
May 17, 2018   European Review For Medical And Pharmacological Sciences
Liu J, Wang WM, Zhang XL, Du QH, Li HG, Zhang Y
Effect of downregulated lncRNA NBAT1 on the biological behavior of glioblastoma cells.
May 17, 2018
European Review For Medical And Pharmacological Sciences
OBJECTIVE: To investigate the expression of lncRNA neuroblastoma associated transcript 1 (NBAT1) in human glioma cell lines and its underlying mechanism. Effect of NBAT1 on biological behaviors of T98 and U87 cells are also explored. PATIENTS AND METHODS: The mRNA expressions of NBAT1 in 48 cases of glioblastoma tissues and 30 cases of normal brain tissues were accessed by Real-time fluorescence quantitative PCR (RT-PCR). The relationship between mRNA expression of NBAT1 and tumor size, malignancy, and prognosis were analyzed. Effects of NBAT1 on the proliferation of glioblastoma T98 and U87 cells were determined by CCK-8 assay and colony formation assay, respectively. RESULTS: NBAT1 expressions in glioblastoma tissues were lower than those in normal brain tissues, which was negatively correlated with malignancy degree (p
Long non-coding RNA DUXAP8 regulates proliferation and invasion of esophageal squamous cell cancer.
May 17, 2018   European Review For Medical And Pharmacological Sciences
Xu LJ, Yu XJ, Wei B, Hui HX, Sun Y, Dai J, Chen XF
Long non-coding RNA DUXAP8 regulates proliferation and invasion of esophageal squamous cell cancer.
May 17, 2018
European Review For Medical And Pharmacological Sciences
OBJECTIVE: The purpose of this research was to detect the expression of long non-coding RNA DUXAP8 in esophageal cancer, and to explore its underlying mechanism in the development of esophageal squamous cell carcinoma (ESCC). PATIENTS AND METHODS: We collected 78 pairs of esophageal cancer tissues and normal adjacent tissues. The mRNA level of DUXAP8 in these esophageal cancer tissues and corresponding adjacent tissues was detected by quantitative Real-time polymerase chain reaction (qRT-PCR). The relationship between DUXAP8 expression and the prognosis of esophageal cancer was analyzed. Small interfering RNA (siRNA) was applied to reduce the expression of DUXAP8 in ESCC cell lines (TE-1 and KYSE520). Meanwhile, the specific effect of DUXAP8 on the biological functions of ESCC cells was analyzed by CCK-8 assay (cell counting kit-8), colony formation assay and transwell assay, respectively. Furthermore, the regulatory effect of DUXAP8 on Wnt/β-catenin pathway was detected by Western blot. RESULTS: DUXAP8 was overexpressed in ESCC tissues than that of normal adjacent tissues. DUXAP8 expression was positively correlated to tumor stage and lymph node metastasis, whereas negatively correlated to the survival rate of ESCC patients. Cell proliferation, colony formation and invasion abilities were significantly decreased after knockdown of DUXAP8 in ESCC cells. Western blot results showed that DUXAP8 could regulate the occurrence of ESCC via Wnt/β-catenin pathway. CONCLUSIONS: DUXAP8 expression was significantly correlated with tumor stage, lymph node metastasis and poor prognosis of ESCC patients. DUXAP8 may promote the occurrence of ESCC via Wnt/β-catenin pathway.
LncRNA SNHG7 promotes the proliferation of esophageal cancer cells and inhibits its apoptosis.
May 17, 2018   European Review For Medical And Pharmacological Sciences
Xu LJ, Yu XJ, Wei B, Hui HX, Sun Y, Dai J, Chen XF
LncRNA SNHG7 promotes the proliferation of esophageal cancer cells and inhibits its apoptosis.
May 17, 2018
European Review For Medical And Pharmacological Sciences
OBJECTIVE: Our research studied the expression of long noncoding RNA (lncRNA) SNHG7 in esophageal cancer cells and tissues. The effect of lncRNA SNHG7 on proliferation and apoptosis of esophageal cancer cells has been discussed. PATIENTS AND METHODS: Si-SNHG7 was transfected into esophageal cancer cells, and qRT-PCR was performed to detect the expression of lncRNA SNHG7 in esophageal cancer cells and tissues. The effect of SNHG7 on the proliferation of esophageal cancer cells was measured by CCK8 assay and plate cloning assay, respectively. Flow cytometry was used to detect the effect of SNHG7 on the cell cycle and apoptosis rate of esophageal cancer cells. Changes in expression of downstream protein p15 and p16 after si-SNHG7 intervention were analyzed by qRT-PCR and Western blot. RESULTS: QRT-PCR showed that the expression of SNHG7 in esophageal cancer tissues and cells was significantly up-regulated. After the si-SNHG7 intervention, the proliferation of esophageal cancer cells was inhibited, the apoptosis rate increased, and the cell cycle was blocked in G1-G0 phase. QRT-PCR and Western blot showed that, after the si-SNHG7 intervention, the expression of p15 and p16 increased significantly. CONCLUSIONS: The expression of SNHG7 in the tissues and cells of esophageal cancer is significantly up-regulated. SNHG7 can partly promote the development of esophageal cancer by regulating the expression of p15 and p16.
LncRNA CCHE1 in the proliferation and apoptosis of gastric cancer cells.
May 17, 2018   European Review For Medical And Pharmacological Sciences
Xu G, Zhang Y, Li N, Zhang JB, Xu R
LncRNA CCHE1 in the proliferation and apoptosis of gastric cancer cells.
May 17, 2018
European Review For Medical And Pharmacological Sciences
OBJECTIVE: We aimed at investigating the effects of long non-coding RNA (lncRNA) CCHE1 on proliferation and apoptosis of gastric cancer cells. MATERIALS AND METHODS: qRT-PCR method was used to detect lncRNA CCHE1 in cancer cell lines. Cells with relative expression were selected to change the expression by transfecting with corresponding lentiviral vector, and nonsense transfection group and blank control group were also constructed; cell counting kit-8 (CCK-8) method was used to assess cell proliferation activity; colony formation assay was used to evaluate the rate of cell cloning; flow cytometry assay was used to determine the apoptosis rate and cell cycle. Western blot was utilized to detect the expressions of Bax and Bcl-2. RESULTS: Expression of lncRNA CCHE1 in the tumor cell lines was increased (p
BAY-11-7082 induces apoptosis of multiple myeloma U266 cells through inhibiting NF-κB pathway.
May 17, 2018   European Review For Medical And Pharmacological Sciences
Wang Y, Zhang XL, Sun CM
BAY-11-7082 induces apoptosis of multiple myeloma U266 cells through inhibiting NF-κB pathway.
May 17, 2018
European Review For Medical And Pharmacological Sciences
OBJECTIVE: To study the effects of BAY-11-7082 on proliferation and apoptosis of U266 cells and its mechanism of action. MATERIALS AND METHODS: Multiple myelomas U266 cells were cultured and divided into control group and gradient-concentration BAY-11-7082 groups (1 μmol/L, 2 μmol/L, 4 μmol/L and 8 μmol/L). Cells in BAY-11-7082 groups were treated with drugs in different concentrations for 4 h, while those in control group were added with an equal volume of solvent. The cell viability was detected via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, and lactate dehydrogenase (LDH) release assay was used to detect the cytotoxicity. Furthermore, cells in low-concentration and high-concentration BAY-11-7082 groups were compared with those in control group. The cell proliferation level was evaluated via cell cycle assay, the interleukin-6 (IL-6) level in cells was detected via enzyme-linked immunosorbent assay (ELISA), and the β-catenin protein expression was detected via Western blotting. Moreover, flow cytometry and Hoechst staining were performed to detect the number of apoptotic cells, and the apoptosis level was detected via caspase3 activity and apoptosis-related protein expression. Finally, the levels of p65, p50 and inhibitor kappa B kinase β (IKKβ) were detected via polymerase chain reaction (PCR), and the expressions and changes of phosphorylated (p)-p65 and p-IKKβ were detected via Western blotting. RESULTS: BAY-11-7082 could reduce the U266 cell viability and increase the cytotoxic effect. Based on gradient concentration, 2 μmol/L was selected as the low concentration, while 4 μmol/L was selected as the high concentration. Compared with those in control group, the number of cells in the S and G2/M phases in drug administration groups was significantly decreased, but that in the G0/G1 phase was significantly increased. Besides, the secretion of IL-6 in cells in drug administration groups was significantly decreased compared with that in control group. The β-catenin protein expression was decreased in drug administration groups, and there was also a difference between high concentration group and low concentration group. Flow cytometry and Hoechst staining showed that the proportion of apoptotic cells in drug administration groups was significantly increased. Western blotting and detection of caspase3 activity revealed that the expression and activation of apoptosis-related protein were increased in drug administration groups. It was found in the detection of nuclear factor-κB (NF-κB) pathway that the NF-κB pathway was inhibited in drug administration groups, and there was also a statistically significant difference between high concentration group and low concentration group. CONCLUSIONS: BAY-11-7082 inhibits the proliferation and induces the apoptosis of U266 cells through inhibiting NF-κB pathway.
[The role of autophagy in the invasion and metastasis of the squamous cell carcinoma of head and neck].
May 21, 2018   Lin Chuang Er Bi Yan Hou Tou Jing Wai Ke Za Zhi = Journal Of Clinical Otorhinolaryngology, Head, And Neck Surgery
Chen CH, Zhu GC, Pi LM, Wei M, She L, Tan HL, Liu GC, Liu Y, Zhang X
[The role of autophagy in the invasion and metastasis of the squamous cell carcinoma of head and neck].
May 21, 2018
Lin Chuang Er Bi Yan Hou Tou Jing Wai Ke Za Zhi = Journal Of Clinical Otorhinolaryngology, Head, And Neck Surgery
Objective:The aim of this study is to explore the effects of autophagy on the metastasis of the Squamous Cell Carcinoma of Head and Neck (SCCHN) via epithelial to mesenchymal transition (EMT) induced by TGF-β1. Method:Establish the EMT model induced by TGF-β1 in the SCCHN in time/concentration, and the expression of autophagy related protein microtubule associated protein 1 light chain3 (LC3) detected by western blot; Autophagy inhibitor chloroquine (CQ), depressing autophagy, the expression of E-cadherin, cytokeratin, Vimentin and LC3 were examined by Western blot. Wound healing and Transwell invasion assay indicate the effects to metastasis for SCCHN. Result:Autophagy was activated within TGF-β1 induced EMT model in the SCCHN in time/concentration dependently. After autophagy was suppressed, the expression of E-cadherin and cytokeratin increased while vimentin and the capacity of metastasis was reduced compared with control group. Conclusion:TGF-β1 induce EMT and Autophagy in the SCCHN. Autophagy could enhances metastasis in the SCCHN via EMT induced by TGF-β1.
Post-surgical resection prognostic value of combined OPN, MMP7, and PSG9 plasma biomarkers in hepatocellular carcinoma.
May 17, 2018   Frontiers Of Medicine
Rong W, Zhang Y, Yang L, Feng L, Wei B, Wu F, Wang L, Gao Y, Cheng S, Wu J, Xiao T
Post-surgical resection prognostic value of combined OPN, MMP7, and PSG9 plasma biomarkers in hepatocellular carcinoma.
May 17, 2018
Frontiers Of Medicine
Biomarkers for hepatocellular carcinoma (HCC) following curative resection are not currently sufficient for prognostic indication of overall survival (OS) and disease-free survival (DFS). The aim of this study was to investigate the prognostic performance of osteopontin (OPN), matrix metalloproteinase 7 (MMP7), and pregnancy specific glycoprotein 9 (PSG9) in patients with HCC. A total of 179 prospective patients with HCC provided plasma before hepatectomy. Plasma OPN, MMP7, and PSG9 levels were determined by enzyme-linked immunosorbent assay. Correlations between plasma levels, clinical parameters, and outcomes (OS and DFS) were overall analyzed. High OPN ( ≥ 149.97 ng/mL), MMP7 ( ≥ 2.28 ng/mL), and PSG9 ( ≥ 45.59 ng/mL) were prognostic indicators of reduced OS (P < 0.001, P < 0.001, and P = 0.007, respectively). Plasma PSG9 protein level was an independent factor in predicting OS (P = 0.008) and DFS (P = 0.038). Plasma OPN + MMP7 + PSG9 elevation in combination was a prognostic factor for OS (P < 0.001). OPN was demonstrated to be a risk factorassociated OS in stage I patients with HCC and patients with low α-fetoprotein levels ( < 20 ng/mL). These findings suggested that OPN, MMP7, PSG9 and their combined panels may be useful for aiding in tumor recurrence and mortality risk prediction of patients with HCC, particularly in the early stage of HCC carcinogenesis.
A radiomics nomogram for preoperative prediction of microvascular invasion risk in hepatitis B virus-related hepatocellular carcinoma.
May 20, 2018   Diagnostic And Interventional Radiology (Ankara, Turkey)
Peng J, Zhang J, Zhang Q, Xu Y, Zhou J, Liu L
A radiomics nomogram for preoperative prediction of microvascular invasion risk in hepatitis B virus-related hepatocellular carcinoma.
May 20, 2018
Diagnostic And Interventional Radiology (Ankara, Turkey)
PURPOSE: We aimed to develop and validate a radiomics nomogram for preoperative prediction of microvascular invasion (MVI) in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). METHODS: A total of 304 eligible patients with HCC were randomly divided into training (n=184) and independent validation (n=120) cohorts. Portal venous and arterial phase computed tomography data of the HCCs were collected to extract radiomic features. Using the least absolute shrinkage and selection operator algorithm, the training set was processed to reduce data dimensions, feature selection, and construction of a radiomics signature. Then, a prediction model including the radiomics signature, radiologic features, and alpha-fetoprotein (AFP) level, as presented in a radiomics nomogram, was developed using multivariable logistic regression analysis. The radiomics nomogram was analyzed based on its discrimination ability, calibration, and clinical usefulness. Internal cohort data were validated using the radiomics nomogram. RESULTS: The radiomics signature was significantly associated with MVI status (P < 0.001, both cohorts). Predictors, including the radiomics signature, nonsmooth tumor margin, hypoattenuating halos, internal arteries, and alpha-fetoprotein level were reserved in the individualized prediction nomogram. The model exhibited good calibration and discrimination in the training and validation cohorts (C-index [95% confidence interval]: 0.846 [0.787-0.905] and 0.844 [0.774-0.915], respectively). Its clinical usefulness was confirmed using a decision curve analysis. CONCLUSION: The radiomics nomogram, as a noninvasive preoperative prediction method, shows a favorable predictive accuracy for MVI status in patients with HBV-related HCC.
Hypoxia-induced microRNA-191 contributes to hepatic ischemia/reperfusion injury through the ZONAB/Cyclin D1 axis.
May 17, 2018   Cell Death And Differentiation
Pan W, Wang L, Zhang XF, Zhang H, Zhang J, Wang G, Xu P, Zhang Y, Hu P, Zhang XD, Du RL, Wang H
Hypoxia-induced microRNA-191 contributes to hepatic ischemia/reperfusion injury through the ZONAB/Cyclin D1 axis.
May 17, 2018
Cell Death And Differentiation
Hepatic ischemia/reperfusion injury (IRI) is a common cause of morbidity and mortality in liver transplantation settings and involves severe cell death and inflammatory responses. MicroRNA-191 has recently been reported to be abnormally expressed in hepatocellular carcinoma and other liver diseases in the regulation of important cellular processes. However, little is known about its function and molecular mechanism in IRI. Here, we demonstrate that miR-191 is significantly upregulated in a cultured cell line during hypoxia/reperfusion (H/R) and in liver tissue during IRI in mice. The activation of miR-191 under hypoxic conditions is mediated by hypoxia-inducible factor-1α (HIF1α) binding to its promoter region. Global miR-191 KO mice were constructed by CRISPR/Cas9 system, and we found that miR-191 deficiency markedly reduces liver tissue damage, cell inflammatory responses and cell death in a mouse hepatic IRI model. Under the H/R condition, miR-191 overexpression promotes G0/G1 cell cycle arrest and cell apoptosis, but inhibition of miR-191 facilitates cell cycle progression and decreases cell death. Mechanistically, upon induction by hypoxia or ischemia, miR-191 suppresses expression of ZO-1-associated Y-box factor (ZONAB) and its downstream factor Cyclin D1, consequently resulting in cell death and tissue injury. Moreover, the effects of miR-191 on cell cycle arrest and cell apoptosis are abrogated by ZONAB overexpression, and vice versa. Taken together, our results indicate an important role of the HIF1α/miR-191/ZONAB signaling pathway in hepatic IRI and suggest miR-191 as a novel therapeutic target for the treatment of liver IRI.
Arsenic Trioxide-Coated Stent Is an Endothelium-Friendly Drug Eluting Stent.
May 17, 2018   Advanced Healthcare Materials
Zhao Y, Du R, Zhou T, Yang D, Huang Y, Wang Y, Huang J, Ma X, He F, Qiu J, Wang G
Arsenic Trioxide-Coated Stent Is an Endothelium-Friendly Drug Eluting Stent.
May 17, 2018
Advanced Healthcare Materials
An ideal vascular stent would both inhibit in-stent restenosis (ISR) and promote rapid re-endothelialization. In the current study, the performance of arsenic trioxide (ATO)-drug eluting stent (AES) is compared with the bare metal stent, poly-lactic-co-glycolic acid-coating metal stent, and rapamycin-drug eluting stent (RES). In vivo AES is shown to prevent neointimal hyperplasia more efficiently than the others when implanted into the carotid arteries of rabbits. Moreover, AES promotes endothelial cells proliferation and re-endothelialization more quickly than RES. In vitro ATO exposure significantly increases the viability, proliferation, adhesion, and spreading of primary porcine coronary artery endothelial cells (PCAECs), which are critical for endothelialization. However, ATO exposure reduces the viability of porcine coronary artery smooth muscle cells (PCASMCs). The evaluation of mitochondrial morphology, membrane potential, and function demonstrates that ATO at 2 µmol L-1 causes enlargement of the mitochondrion, enhancement of mitochondrial membrane potential, and adenosine triphosphate (ATP) production in PCAECs but not in PCASMCs. Thus, both in vivo and in vitro studies demonstrate that AES is an effective strategy for rapid re-endothelialization and inhibition of ISR.
Combination of IFITM1 knockdown and radiotherapy inhibits the growth of oral cancer.
May 17, 2018   Cancer Science
Yang J, Li L, Xi Y, Sun R, Wang H, Ren Y, Zhao L, Wang X, Li X
Combination of IFITM1 knockdown and radiotherapy inhibits the growth of oral cancer.
May 17, 2018
Cancer Science
This research aimed to analyze the effect of IFITM1 on the radioresistance of oral neoplasm. IFITM1 emerged using multi-group heat map from GSE9716 analysis of GEO database as the relevant radioresistance gene. IFITM1 was screened by TCGA database before its expression was analyzed. IFITM1 expression was quantified by qRT-PCR and immunohistochemistry in 19 paired oral neoplasm cases. The effects of time and dose of radiation on IFITM1 expression level in CAL27 and TSCC1 cell lines was tested via qRT-PCR. Oral neoplasm cells were transfected with siRNA after radiotherapy to disturb IFITM1 expression. After this the survival rates, cell apoptosis, caspase3 viability, expression and γ-H2AX were detected using colony formation, flow cytometry, western blot and immunofluorescence respectively. Western blot was used for STAT1/2/3/p21 related protein and phosphorylation changes. Finally, an in vivo nude mice tumor model was established to verify the effect of IFITM1 on oral neoplasm cells radioresistance. Head and neck neoplasm radioresistance-related gene IFITM1 was overexpressed using microarray. IFITM1 overexpression was verified not only in TCGA database but also in 19 paired cases of oral neoplasm tissues and cells. With increases of dose and time of radiation, the expression of IFITM1 was increased in CAL27 and TSCC1 cell lines. Further, si-IFITM1 may restrain cell proliferation; DNA damage and cell apoptosis in oral neoplasm cell lines. Finally, pSTAT1/2/p21 was found up-regulated while pSTAT3/p-p21 was down-regulated due to IFITM1 inhibition after radiotherapy. The evidence suggested IFITM1 in combination with radiotherapy can inhibit oral neoplasm cells. This article is protected by copyright. All rights reserved.
AEG-1 Contributes to Metastasis in Hypoxia-Related Ovarian Cancer by Modulating the HIF-1alpha/NF-kappaB/VEGF Pathway.
May 20, 2018   BioMed Research International
Yu X, Wang Y, Qiu H, Song H, Feng D, Jiang Y, Deng S, Meng H, Geng J
AEG-1 Contributes to Metastasis in Hypoxia-Related Ovarian Cancer by Modulating the HIF-1alpha/NF-kappaB/VEGF Pathway.
May 20, 2018
BioMed Research International
Objective: Ovarian carcinoma represents one of the deadliest malignancies among female cancer patients. Astrocyte-elevated gene-1 (AEG-1) participates in the ontogenesis of multiple human malignant diseases. Here we evaluated AEG-1, hypoxia-inducible factor- (HIF-) 1α, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and vascular endothelial growth factor (VEGF) amounts in hypoxia induced ovarian carcinoma cells. This study aimed to explore the mechanism by which AEG-1 regulates metastasis in hypoxia induced ovarian carcinoma. Patients and Methods: AEG-1, HIF-1α, and VEGF protein amounts were evaluated by immunohistochemistry in 40 and 170 normal ovary and ovarian cancer tissue specimens, respectively. In addition, AEG-1, HIF-1α, NF-κB, and VEGF mRNA and protein levels were determined by reverse quantified RT-PCR and WB, respectively, at different time periods (0-24 h) in epithelial ovarian cancer (EOC) SKOV3 cells treated in a hypoxia incubator. Furthermore, NF-κB and VEGF gene and protein expression levels in AEG-1 knockdown EOC cells were quantitated by RT-PCR and WB, respectively. Results: AEG-1, HIF-1α, and VEGF amounts were significantly elevated in EOC tissue samples compared with normal ovary specimens (p < 0.001). Positive expression of HIF-1α and AEG-1 was associated with higher metastatic rate (p < 0.01), lower FIGO stage (p < 0.001), and degree of differentiation (p < 0.001). Meanwhile, EOC SKOV3 cells grew upon exposure to hypoxia for 8 h (p < 0.001); at this time point, AEG-1, HIF-1α, NF-κB, and VEGF amounts peaked (p < 0.001), at both the gene and the protein levels. After AEG-1 knockdown, HIF-1α, NF-κB, and VEGF amounts were significantly decreased in EOC SKOV3 cells, also under hypoxic conditions (p < 0.01). Conclusions: As an independent prognostic factor, AEG-1 was found to be significantly associated with hypoxia in ovarian cancer by regulating the HIF-1alpha/NF-kappaB/VEGF pathway. Therefore, AEG-1 may be useful in determining disease stage and prognosis in ovarian cancer.
NY-ESO-1 Based Immunotherapy of Cancer: Current Perspectives.
May 20, 2018   Frontiers In Immunology
Thomas R, Al-Khadairi G, Roelands J, Hendrickx W, Dermime S, Bedognetti D, Decock J
NY-ESO-1 Based Immunotherapy of Cancer: Current Perspectives.
May 20, 2018
Frontiers In Immunology
NY-ESO-1 or New York esophageal squamous cell carcinoma 1 is a well-known cancer-testis antigen (CTAs) with re-expression in numerous cancer types. Its ability to elicit spontaneous humoral and cellular immune responses, together with its restricted expression pattern, have rendered it a good candidate target for cancer immunotherapy. In this review, we provide background information on NY-ESO-1 expression and function in normal and cancerous tissues. Furthermore, NY-ESO-1-specific immune responses have been observed in various cancer types; however, their utility as biomarkers are not well determined. Finally, we describe the immune-based therapeutic options targeting NY-ESO-1 that are currently in clinical trial. We will highlight the recent advancements made in NY-ESO-1 cancer vaccines, adoptive T cell therapy, and combinatorial treatment with checkpoint inhibitors and will discuss the current trends for future NY-ESO-1 based immunotherapy. Cancer treatment has been revolutionized over the last few decades with immunotherapy emerging at the forefront. Immune-based interventions have shown promising results, providing a new treatment avenue for durable clinical responses in various cancer types. The majority of successful immunotherapy studies have been reported in liquid cancers, whereas these approaches have met many challenges in solid cancers. Effective immunotherapy in solid cancers is hampered by the complex, dynamic tumor microenvironment that modulates the extent and phenotype of the antitumor immune response. Furthermore, many solid tumor-associated antigens are not private but can be found in normal somatic tissues, resulting in minor to detrimental off-target toxicities. Therefore, there is an ongoing effort to identify tumor-specific antigens to target using various immune-based modalities. CTAs are considered good candidate targets for immunotherapy as they are characterized by a restricted expression in normal somatic tissues concomitant with a re-expression in solid epithelial cancers. Moreover, several CTAs have been found to induce a spontaneous immune response, NY-ESO-1 being the most immunogenic among the family members. Hence, this review will focus on NY-ESO-1 and discuss the past and current NY-ESO-1 targeted immunotherapeutic strategies.
Mucosal Immunity and Protective Efficacy of Intranasal Inactivated Influenza Vaccine Is Improved by Chitosan Nanoparticle Delivery in Pigs.
May 20, 2018   Frontiers In Immunology
Dhakal S, Renu S, Ghimire S, Shaan Lakshmanappa Y, Hogshead BT, Feliciano-Ruiz N, Lu F, HogenEsch H, Krakowka S, Lee CW, Renukaradhya GJ
Mucosal Immunity and Protective Efficacy of Intranasal Inactivated Influenza Vaccine Is Improved by Chitosan Nanoparticle Delivery in Pigs.
May 20, 2018
Frontiers In Immunology
Annually, swine influenza A virus (SwIAV) causes severe economic loss to swine industry. Currently used inactivated SwIAV vaccines administered by intramuscular injection provide homologous protection, but limited heterologous protection against constantly evolving field viruses, attributable to the induction of inadequate levels of mucosal IgA and cellular immune responses in the respiratory tract. A novel vaccine delivery platform using mucoadhesive chitosan nanoparticles (CNPs) administered through intranasal (IN) route has the potential to elicit strong mucosal and systemic immune responses in pigs. In this study, we evaluated the immune responses and cross-protective efficacy of IN chitosan encapsulated inactivated SwIAV vaccine in pigs. Killed SwIAV H1N2 (δ-lineage) antigens (KAg) were encapsulated in chitosan polymer-based nanoparticles (CNPs-KAg). The candidate vaccine was administered twice IN as mist to nursery pigs. Vaccinates and controls were then challenged with a zoonotic and virulent heterologous SwIAV H1N1 (γ-lineage). Pigs vaccinated with CNPs-KAg exhibited an enhanced IgG serum antibody and mucosal secretory IgA antibody responses in nasal swabs, bronchoalveolar lavage (BAL) fluids, and lung lysates that were reactive against homologous (H1N2), heterologous (H1N1), and heterosubtypic (H3N2) influenza A virus strains. Prior to challenge, an increased frequency of cytotoxic T lymphocytes, antigen-specific lymphocyte proliferation, and recall IFN-γ secretion by restimulated peripheral blood mononuclear cells in CNPs-KAg compared to control KAg vaccinates were observed. In CNPs-KAg vaccinated pigs challenged with heterologous virus reduced severity of macroscopic and microscopic influenza-associated pulmonary lesions were observed. Importantly, the infectious SwIAV titers in nasal swabs [days post-challenge (DPC) 4] and BAL fluid (DPC 6) were significantly (p < 0.05) reduced in CNPs-KAg vaccinates but not in KAg vaccinates when compared to the unvaccinated challenge controls. As well, an increased frequency of T helper memory cells and increased levels of recall IFNγ secretion by tracheobronchial lymph nodes cells were observed. In summary, chitosan SwIAV nanovaccine delivered by IN route elicited strong cross-reactive mucosal IgA and cellular immune responses in the respiratory tract that resulted in a reduced nasal viral shedding and lung virus titers in pigs. Thus, chitosan-based influenza nanovaccine may be an ideal candidate vaccine for use in pigs, and pig is a useful animal model for preclinical testing of particulate IN human influenza vaccines.
Placental growth factor promotes epithelial-mesenchymal transition-like changes in ARPE-19 cells under hypoxia.
May 20, 2018   Molecular Vision
Zhang Y, Zhao L, Wang L, Yang X, Zhou A, Wang J
Placental growth factor promotes epithelial-mesenchymal transition-like changes in ARPE-19 cells under hypoxia.
May 20, 2018
Molecular Vision
Purpose: To investigate the role of placental growth factor (PGF) in the epithelial-mesenchymal transition (EMT) of ARPE-19 cells under hypoxia, and whether the NF-κB signaling pathway is involved in this process. Methods: ARPE-19 cells were treated in five groups: a control group, hypoxia group, PGF group, hypoxia+PGF group, and NF-κB-blocked group. A chemical hypoxia model was established in the ARPE-19 cells by adding CoCl2 to the culture medium. The morphological changes after treatment were observed. The proliferation rates were measured with 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. The migration abilities were measured with scratch assay. The EMT biomarkers were measured with quantitative real-time PCR (qRT-PCR), western blotting, and immunofluorescence. The relative protein expression of components of the NF-κB signaling pathway was measured with western blotting and immunofluorescence. Results: Cells treated with PGF under hypoxia exhibited morphological changes consistent with the transition from an epithelial to a mesenchymal phenotype. In the ARPE-19 cells, exogenous PGF under hypoxia increased the proliferation rate compared to the rate under hypoxia alone (p
Modified citrus pectin inhibited bladder tumor growth through downregulation of galectin-3.
May 17, 2018   Acta Pharmacologica Sinica
Fang T, Liu DD, Ning HM, Dan Liu , Sun JY, Huang XJ, Dong Y, Geng MY, Yun SF, Yan J, Huang RM
Modified citrus pectin inhibited bladder tumor growth through downregulation of galectin-3.
May 17, 2018
Acta Pharmacologica Sinica
Modified citrus pectin (MCP) is a carbohydrate enriched complex, which has been implicated in cancer treatment and prevention. However, the effects of MCP on urinary bladder cancer (UBC) are unknown. In this study, MCP was first tested in T24 and J82 human UBC cells and showed the inhibition of cell viability by the sulforhodamine B (SRB) assay. The MCP-treated UBC cells exhibited G2/M phase arrest with the decrease of Cyclin B1 and phosphorylated Cdc2. Caspase-3 was also activated, leading to the cleavage of Caspase-3 and PARP. We further explored the possible molecular mechanisms upon MCP treatment in UBC cells. Reduction of galectin-3 was observed and followed with the inactivation of Akt signaling pathway. Of note, galectin-3 knockdown by RNA interference recapitulated the MCP-mediated anti-proliferation, cell cycle arrest and apoptosis. Moreover, oral administration of MCP to the T24 xenograft-bearing nude mice inhibited the tumor growth significantly (P < 0.05). Quantification analysis of immunohistochemistry staining for Ki67 and cleaved Caspase-3 confirmed the decrease of proliferation index (P < 0.05) and the increase of apoptosis index (P < 0.01) in 700 mg/kg MCP-fed UBC xenografts. Using the information from TCGA database, we revealed that the overexpression of galectin-3 was associated with high tumor grade with lymph node metastasis, poor overall survival in UBC patients. Considering the remarkable inhibitory effects of MCP on UBC cell proliferation and survival in vitro and in vivo mainly through galectin-3, which is upregulated in UBCs, MCP may become an attractive agent, as a natural dietary fiber, for prevention and therapy of UBCs.
Pancreas regeneration.
May 17, 2018   Nature Add nature.com free-link Cancel
Zhou Q, Melton DA
Pancreas regeneration.
May 17, 2018
Nature
The pancreas is made from two distinct components: the exocrine pancreas, a reservoir of digestive enzymes, and the endocrine islets, the source of the vital metabolic hormone insulin. Human islets possess limited regenerative ability; loss of islet β-cells in diseases such as type 1 diabetes requires therapeutic intervention. The leading strategy for restoration of β-cell mass is through the generation and transplantation of new β-cells derived from human pluripotent stem cells. Other approaches include stimulating endogenous β-cell proliferation, reprogramming non-β-cells to β-like cells, and harvesting islets from genetically engineered animals. Together these approaches form a rich pipeline of therapeutic development for pancreatic regeneration.
Diverse mechanisms for endogenous regeneration and repair in mammalian organs.
May 17, 2018   Nature Add nature.com free-link Cancel
Wells JM, Watt FM
Diverse mechanisms for endogenous regeneration and repair in mammalian organs.
May 17, 2018
Nature
Mammalian organs comprise an extraordinary diversity of cell and tissue types. Regenerative organs, such as the skin and gastrointestinal tract, use resident stem cells to maintain tissue function. Organs with a lower cellular turnover, such as the liver and lungs, mostly rely on proliferation of committed progenitor cells. In many organs, injury reveals the plasticity of both resident stem cells and differentiated cells. The ability of resident cells to maintain and repair organs diminishes with age, whereas, paradoxically, the risk of cancer increases. New therapeutic approaches aim to harness cell plasticity for tissue repair and regeneration while avoiding the risk of malignant transformation of cells.
Novel internal regulators and candidate miRNAs within miR-379/miR-656 miRNA cluster can alter cellular phenotype of human glioblastoma.
May 22, 2018   Scientific Reports
Nayak S, Aich M, Kumar A, Sengupta S, Bajad P, Dhapola P, Paul D, Narta K, Purkrait S, Mehani B, Suri A, Chakraborty D, Mukhopadhyay A, Sarkar C
Novel internal regulators and candidate miRNAs within miR-379/miR-656 miRNA cluster can alter cellular phenotype of human glioblastoma.
May 22, 2018
Scientific Reports
Clustered miRNAs can affect functioning of downstream pathways due to possible coordinated function. We observed 78-88% of the miR-379/miR-656 cluster (C14MC) miRNAs were downregulated in three sub-types of diffuse gliomas, which was also corroborated with analysis from The Cancer Genome Atlas (TCGA) datasets. The miRNA expression levels decreased with increasing tumor grade, indicating this downregulation as an early event in gliomagenesis. Higher expression of the C14MC miRNAs significantly improved glioblastioma prognosis (Pearson's r = 0.62; p 
Simvastatin induces osteogenic differentiation of MSCs via Wnt/β-catenin pathway to promote fracture healing.
May 17, 2018   European Review For Medical And Pharmacological Sciences
Zhang M, Bian YQ, Tao HM, Yang XF, Mu WD
Simvastatin induces osteogenic differentiation of MSCs via Wnt/β-catenin pathway to promote fracture healing.
May 17, 2018
European Review For Medical And Pharmacological Sciences
OBJECTIVE: This study was designed to investigate whether Simvastatin could facilitate osteogenic differentiation of rat marrow mesenchymal stem cells (MSCs) by modulating the Wnt/β-catenin pathway, thus promoting fracture healing. MATERIALS AND METHODS: MSCs were isolated from rat bone marrow specimens and their purity was identified. The third generation of MSCs was cultured in osteoinduction medium containing simvastatin of gradient concentration, and the highest dose of simvastatin that did not cause cell proliferation was determined by the result of the CCK8 assay. The effects of simvastatin on osteogenic differentiation of MSCs were evaluated by ALP activity, Alizarin red staining, alkaline phosphatase staining and osteoblast-specific gene expression. Finally, Wnt pathway antagonist DKK1 and β-catenin disturbing agent were added to MSCs to detect the ALP activity, Alizarin red staining, alkaline phosphatase staining and osteoblast-specific genes of MSCs respectively, and to evaluate whether simvastatin promoted osteogenic differentiation of MSCs by activating Wnt/β-catenin pathway. RESULTS: After osteoinduction, simvastatin of 0.3 nmol/L was found to be the highest dose that did not induce the proliferation of MSCs. After treated with 0.3 nmol/L simvastatin for 7 days, the ALP activity of cells and the number of cell calcified nodules significantly increased. Meanwhile, the expression of osteoblast-related genes, including ALP, Runx2, OCN, and OPN, were clearly up-regulated. However, when the MSCs were treated with DKK1 for 7 days, the ALP activity and the expression of osteoblast-related genes, including ALP, Runx2, OCN, and OPN, were found decreased. Simvastatin markedly up-regulated the expression of the β-catenin protein, while transfection of β-catenin shRNA inhibited the expression of osteoblast-related genes including ALP, Runx2, OCN, and OPN. CONCLUSIONS: Simvastatin can promote the differentiation of rat MSCs into osteoblast-like cells, and its mechanism may be related to the Wnt/β-catenin pathway.

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