Clinical and genetic characteristics of CEL-MODY (MODY8): a literature review and screening in Chinese individuals diagnosed with early-onset type 2 diabetes.

OBJECTIVE: CEL-related maturity-onset diabetes of the young (CEL-MODY, MODY8) is a special type of monogenetic diabetes caused by mutations in the carboxyl-ester lipase (CEL) gene. This study aimed to summarize the genetic and clinical characteristics of CEL-MODY patients and to determine the prevalence of the disease among Chinese patients with early-onset type 2 diabetes (EOD). METHODS: We systematically reviewed the literature associated with CEL-MODY in PubMed, Embase, Web of Science, China National Knowledge Infrastructure and Wanfang Data to analyze the features of patients with CEL-MODY. We screened and evaluated rare variants of the CEL gene in a cohort of 679 Chinese patients with EOD to estimate the prevalence of CEL-MODY in China. RESULTS: In total, 21 individuals reported in previous studies were diagnosed with CEL-MODY based on the combination of diabetes and pancreatic exocrine dysfunction as well as frameshift mutations in exon 11 of the CEL gene. CEL-MODY patients were nonobese and presented with exocrine pancreatic affection (e.g., chronic pancreatitis, low fecal elastase levels, pancreas atrophy and lipomatosis) followed by insulin-dependent diabetes. No carriers of CEL missense mutations were reported with exocrine pancreatic dysfunction. Sequencing of CEL in Chinese EOD patients led to the identification of the variant p.Val736Cysfs*22 in two patients. However, these patients could not be diagnosed with CEL-MODY because there were no signs that the exocrine pancreas was afflicted. CONCLUSION: CEL-MODY is a very rare disease caused by frameshift mutations affecting the proximal VNTR segments of the CEL gene. Signs of exocrine pancreatic dysfunction provide diagnostic clues for CEL-MODY, and genetic testing is vital for proper diagnosis. Further research in larger cohorts is needed to investigate the characteristics and prevalence of CEL-MODY in the Chinese population.

To explore the change of motor cognitive function in pituitary tumor rats after operation.

To study the changes of motor and cognitive function of pituitary tumor rats after the operation. Methods: The experiment was divided into three groups: control group, model group and operation group (30 animals for each group). Female Fischer344 rats were selected. Model group rats were subcutaneously embedded with 10 mg estrogen sustained-release pump to induce a pituitary tumor model, and control group rats were subcutaneously embedded with a normal saline sustained-release pump as control. The operation group was successfully treated by microsurgery after the model was established. The quantitative expressions of PTTG, FGF-2 and VEGF were detected by Western blot. Morris test was used to detect the spatial learning and memory ability of rats. Western blot results showed that compared with the model group, the expression of the operation group was decreased, but still higher than that of the control group (p < 0.05). The water maze test results showed that the incubation period of searching the safe island in the model group was significantly longer than that in the control group on the 8th and 9th day after the injury, and the difference was statistically significant (p < 0.05). The incubation period of searching the safe island on the 8th and 9th day after injury in the operation group was significantly shorter than that in the control group. Through the detection of behavioral-related experimental and protein, the motor memory of rats after pituitary tumor surgery can be improved to some extent.

Chemotherapy of Capecitabine plus Temozolomide for Refractory Pituitary Adenoma after Tumor Resection and Its Impact on Serum Prolactin, IGF-1, and Growth Hormone.

Objective: To investigate the efficiency of capecitabine (CAP) plus temozolomide (TEM) in refractory pituitary adenoma after tumor resection and its impact on serum prolactin (PRL), insulin-like growth factor 1 (IGF-1), and growth hormone (GH) levels. Methods: From January 2017 to January 2020, 80 patients assessed for eligibility receiving transsphenoidal tumor resection for refractory pituitary adenoma in the Department of Neurosurgery of our hospital were recruited. They were randomly distributed at a ratio of 1 : 1 via the random number table method to receive either bromocriptine and TEM (control group) or bromocriptine plus combination chemotherapy of TEM and CAP (study group). The two groups were compared in terms of clinical efficacy and serum levels of PRL, IGF-1, and GH. Results: The objective response rate (ORR) was 87.50% and 67.50% in the study group and the control group, respectively (P=0.032). Before treatment, two groups had similar levels of PRL, IGF-1, and GH. After treatment, PRL levels in the study group were lower than that in the control group (278.35 ± 39.25 versus 326.35 ± 42.45, P < 0.001). Compared with the control group, IGF-1 levels in the study group were also lower (311.78 ± 28.82 versus 364.35 ± 31.35, P < 0.001). The study group presented markedly lower levels of thyroid-stimulating hormone (TSH) and higher serum levels of free thyroxine-4 (FT-4) and adrenocorticotropic hormone (ACTH) versus the control group (P < 0.05). The incidence of adverse events was comparable between the study group (30.0%) and the control group (22.5%) (P > 0.05). All eligible patients had similar progression-free survival (PFS) after chemotherapy. Conclusion: For patients with refractory pituitary adenoma, the combination chemotherapy of CAP and TEM significantly improves clinical outcomes and corrects hormonal disturbances, with a good safety profile, but its long-term efficacy requires further investigation.

Model-free robust adaptive integral sliding mode impedance control of knee-ankle-toe active transfemoral prosthesis.

BACKGROUND: Wearing appropriate active prosthesis is the guarantee of daily life for amputees. Normally the controller of the traditional active transfemoral prosthesis is designed based on the mathematical model. The modelling error and the external interference will reduce the control accuracy of the system and make the prosthesis unable to operate in the desired trajectory. METHODS: Firstly, combined with time delay estimation (TDE), a model-free robust integral sliding mode impedance controller is designed. This method not only suppress the impedance error, but also eliminate the nonlinear relationship and disturbance in the dynamic model. Secondly, an adaptive law is proposed to update the controller gain, which provide stable control effect. Thirdly, the stability of prosthesis closed-loop system is proved by Lyapunov stability theory. Finally, the motor torque is used to drive each joint, and Matlab/Simscape is used to verify the prosthesis control system. RESULTS: From the result of the simulation experiment, the control method has a good tracking effect on each joint. The root mean square error and mean absolute errors of each joint's angle tracking error are 0.6123°, 1.9976°, 0.5574° and 0.2635°, 1.8175°, 0.4796°. Compared with the controller without adaptive gain and impedance control, the control effect is improved, and the plantar pressure of amputees is closer to the sound side. CONCLUSIONS: Comparing the results of different controllers, the adaptive integral sliding mode impedance controller with TDE can better track the expected angles of each joint. The gait is more normal. The walking performance of the prosthesis wearers is improved.

Cudraxanthone L inhibits gastric cancer by regulating the MAPK signalling and promoting FAS-mediated pathway.

Gastric cancer (GC) is one of the most common malignancies and has the second highest lethal rate in the world; thus, finding new medicines with high potency and low toxicity is urgent. Cudrania tricuspidata (Carr.) Bur. ex Lavallee (Moraceae) is a traditional medicinal herb that is considered to have antitumour efficacy. We extracted and isolated cudraxanthone L (CXL) from Cudrania tricuspidata and evaluated its anti-cancer efficacy. CXL treatment inhibited angiogenesis of chorioallantoic membrane (CAM) and repressed the cell viability of various human cancer cells, indicating it presented the antitumour potential. Among them, CXL presented the best inhibitory effects on MGC803 cells. In addition, the invasion, migration and clonogenicity were significantly repressed, S phase of the cell cycle was arrested, and apoptosis was induced when MGC803 cells were treated with CXL. The results of RNA sequencing, qRT-PCR and western blotting verified that CXL regulated the MAPK signalling pathway and induced apoptosis by FAS-mediated pathway. The in vivo data revealed that CXL arrested tumour growth without toxic effects and upregulated the protein levels in FAS-mediated pathway in MGC803 gastric cancer-bearing mice. In summary, we demonstrate CXL presents impactful anti-GC efficacy by regulating the MAPK signalling pathway and promoting the FAS-mediated pathway.

LncRNA NEAT1 promotes glioma cancer progression via regulation of miR-98-5p/BZW1.

BACKGROUND: Glioma is the most common malignant tumor in the human central nervous system. Long noncoding RNA nuclear paraspeckle assembly transcript 1 (NEAT1) promotes oncogenesis in various tumors. In the present study, we aimed to examine the role of NEAT1 in altering the properties of gliomas. METHODS: Quantitative real-time PCR technology was used to determine the expression levels of relevant genes in tumor tissues and cell lines. The protein expression levels were validated by Western blotting. Cell counting kit-8 (CCK-8) and colony formation assays were used to test the cell proliferation ability. A luciferase reporter assay was used to determine the interactions of the genes. Tumor xenografts were used to detect the role of NEAT1 in gliomas in vivo. RESULTS: We demonstrated that NEAT1 up-regulated glioma cells and negatively correlated with miR-98-5p in glioma tissues. A potential binding region between NEAT1 and miR-98-5p was confirmed by dual-luciferase assays. NEAT1 knockdown inhibited glioma cell proliferation. The inhibition of miR-98-5p rescued the knockdown of NEAT1 in glioma cells. Basic leucine zipper and W2 domain containing protein 1 (BZW1) was identified as a direct target of miR-98-5p. We also identified that BZW1 was positively correlated with NEAT1 in glioma tissues. NEAT1 knockdown inhibited glioma cell proliferation in vivo via miR-98-5p/BZW1. CONCLUSION: Our results suggest that NEAT1 plays an oncogenic function in glioma progression. Targeting NEAT1/miR-98-5p/BZW1 may be a novel therapeutic treatment approach for glioma patients.

One pot facile transformation of CO2 to an unusual 3-D nano-scaffold morphology of carbon.

An electrosynthesis is presented to transform CO2 into an unusual nano and micron dimensioned morphology of carbon, termed Carbon Nano-Scaffold (CNS) with wide a range of high surface area graphene potential usages including batteries, supercapacitors, compression devices, electromagnetic wave shielding and sensors. Current CNS value is over $323 per milligram. The morphology consists of a series of asymmetric 20 to 100 nm thick flat multilayer graphene platelets 2 to 20 µm long orthogonally oriented in a 3D neoplasticism-like geometry, and appears distinct from the honeycomb, foam, or balsa wood cell structures previously attributed to carbon scaffolds. The CNS synthesis splits CO2 by electrolysis in molten carbonate and has a carbon negative footprint. It is observed that transition metal nucleated, high yield growth of carbon nanotubes (CNTs) is inhibited in electrolytes containing over 50 wt% of sodium or 30 wt% of potassium carbonate, or at electrolysis temperatures less than 700 °C. Here, it is found that a lower temperature of synthesis, lower concentrations of lithium carbonate, and higher current density promotes CNS growth while suppressing CNT growth. Electrolyte conditions of 50 wt% sodium carbonate relative to lithium carbonate at an electrolysis temperature of 670 °C produced over 80% of the CNS desired product at 85% faradaic efficiency with a Muntz brass cathode and an Inconel anode.

Endothelial progenitor cells in the peripheral blood of patients with moyamoya disease labeled with superparamagnetic iron oxide in vitro for MRI detection.

Moyamoya disease (MMD) is currently thought to involve endothelial progenitor cells (EPCs). We investigated whether superparamagnetic iron oxide (SPIO) can be used to label EPCs. Mononuclear cells from 10 moyamoya disease patients were isolated, and cluster of differentiation 133 (CD133) positive cells sorted by magnetic-activated cell sorting were cultured in vitro. The positive rates of CD133, vascular endothelial growth factor receptor (VEGFR)-2, and cluster of differentiation 34 (CD34) were detected by flow cytometry. The cells were co-cultured with fluorescence labeled Dil-acetylated-low-density lipoprotein (Dil-ac-LDL) and Ulex europaeus agglutinin-1 (UEA-1) to observe the endocytosis of Dil-ac-LDL and binding to UEA-1. Prussian blue staining and transmission electron microscopy were used to observe the endocytosis of different SPIO concentrations in EPCs, and CCK-8 was used to detect proliferation of cells transfected with different concentrations of SPIO. T2 weighted imaging (T2WI) signals from magnetic resonance imaging after SPIO endocytosis were compared. Positive rates of CD133, VEGFR-2, and CD34 on sorted mononuclear cells were 68.2±3.8, 57.5±4.2, and 36.8±6.5%, respectively. The double-positive expression rate of CD34 and VEGFR-2 was 19.6±4.7%, and 83.1±10.4% of cells, which showed the uptake of Dil-ac-LDL and binding with UEA-1. The labeling efficiencies of SPIO at concentrations of 25 and 50 µg/mL were higher than for 12.5 µg/mL. The proliferation of cells was not influenced by SPIO concentrations of 12.5 and 25 µg/mL. After labeling, the T2WI of EPCs was reduced. The concentration of 25 µg/mL SPIO had high labeling efficiency detected by magnetic resonance imaging (MRI) without decreased EPCs viability.

Bacteria metabolites from Peganum harmala L. polysaccharides inhibits polyQ aggregation through proteasome-mediated protein degradation in C. elegans.

Huntington's disease (HD) is a relentlessly progressive neurodegenerative disease featured by the over-expanded polyglutamine (polyQ)-induced protein aggregation. Using Caenorhabditis elegans (C. elegans) as a model system, we show that water soluble polysaccharide extracted from the herb Peganum harmala L. (PS1) not only reduces polyQ aggregation but also alleviates the associated neurotoxicity. Genetic and pharmacologic analysis suggested that PS1 treatment acts though proteasome-mediated protein degradation pathway to inhibit polyQ aggregation. Notably, the efficacy of PS1 is aroused specifically by co-incubation with live Escherichia coli OP50, which is the sole food source for worms. Further UPLC-Q-TOF/MS analysis determined the bioactivity of polyQ inhibition, which is composed of several oligosaccharides, including stachyoses, verbascoses, trisaccharides and tetrasaccharides composed of galacturonic acids. Together, our study revealed a potential drug target for further HD treatment and pinpointed the possibility that the secreted metabolites produced from bacteria treated with various compounds may provide direct beneficial effect to human bodies.

Nickel and cobalt metal-organic-frameworks-derived hollow microspheres porous carbon assembled from nanorods and nanospheres for outstanding supercapacitors.

The development of efficient electrode materials is essential to promote the performance of energy storage equipment. Nowadays, metal organic frameworks (MOFs) have been widely regarded as active materials for supercapacitors mainly thanks to their adjustable structure and outstanding porosity. Here, highly optimized Nickel and Cobalt MOF-derived N-doped porous carbon (Ni/Co-MOF-NPC) are considered the best choice for electrode materials due to their unique structural properties and excellent electrochemical performance. Pure cobalt oxide rarely reaches a specific capacitance of 104.3 F g-1 when the current density is 1 A g-1, but the optimized Ni/Co-MOF-NPC-2:1 offers an ultra-high specific capacitance of 1214 F g-1, which is much higher than that of pure cobalt oxide in a three-electrode test system. When the current density is 10 A g-1, after 6000 cycles, the capacitance can still maintain 98.8% of the initial capacitance. Asymmetric supercapacitors were assembled using the prepared Ni/Co-MOF-NPC-2:1 as the positive electrode material, corrugated paper activated carbon (CPAC) as the negative electrode material, the prepared Ni/Co-MOF-NPC-2:1//CPAC exhibits an outstanding energy density of 55.4 Wh kg-1 at 758.5 W kg-1, and has a significant cycle stability of 75.2% retention after 20,000 cycles. This excellent MOF synthesis strategy reduced the gap between the experimental synthesis and practical application of MOF in fast energy storage.

The effects of exercise on insulin, glucose, IGF-axis and CRP in cancer survivors: Meta-analysis and meta-regression of randomised controlled trials.

BACKGROUND: The purpose of this study was to investigate the relationship between physical activity and biological mediators of cancer recurrence and survival. METHODS: We conducted a comprehensive literature search of PubMed, ScienceDirect and Web of Science for randomised controlled trials examining the association between physical activity and C-reactive protein (CRP), glucose, insulin, insulin resistance and insulin growth factor-one (IGF-1) up to December 2017. Standardised mean difference (SMD) scores were calculated, and meta-regression was performed. RESULTS: The meta-analysis indicated that survivors randomised to physical activity conditions experienced greater improvements in Insulin (SMD = -0.59; 95% CI, -1.05 to -0.14), CRP (SMD = -0.52; 95% CI, -0.87 to -0.17), insulin resistance (SMD = -0.20; 95% CI, -0.41 to -0.003) and glucose (SMD = -0.19; 95% CI, -0.35 to -0.02) than survivors randomised to control conditions. The meta-regression showed that study duration was positively, albeit marginally related (p = .056) to change in CRP levels among survivors in the physical activity conditions. Furthermore, higher baseline insulin levels in the physical activity conditions were associated with improving insulin levels throughout the intervention (p = .007). CONCLUSIONS: Promoting physical activity throughout the survivorship continuum is an effective intervention strategy for improving levels of insulin, glucose control, insulin resistance and CRP among cancer survivors.

Endothelial progenitor cells in the peripheral blood of patients with moyamoya disease labeled with superparamagnetic iron oxide in vitro for MRI detection

Moyamoya disease (MMD) is currently thought to involve endothelial progenitor cells (EPCs). We investigated whether superparamagnetic iron oxide (SPIO) can be used to label EPCs. Mononuclear cells from 10 moyamoya disease patients were isolated, and cluster of differentiation 133 (CD133) positive cells sorted by magnetic-activated cell sorting were cultured in vitro. The positive rates of CD133, vascular endothelial growth factor receptor (VEGFR)-2, and cluster of differentiation 34 (CD34) were detected by flow cytometry. The cells were co-cultured with fluorescence labeled Dil-acetylated-low-density lipoprotein (Dil-ac-LDL) and Ulex europaeus agglutinin-1 (UEA-1) to observe the endocytosis of Dil-ac-LDL and binding to UEA-1. Prussian blue staining and transmission electron microscopy were used to observe the endocytosis of different SPIO concentrations in EPCs, and CCK-8 was used to detect proliferation of cells transfected with different concentrations of SPIO. T2 weighted imaging (T2WI) signals from magnetic resonance imaging after SPIO endocytosis were compared. Positive rates of CD133, VEGFR-2, and CD34 on sorted mononuclear cells were 68.2±3.8, 57.5±4.2, and 36.8±6.5%, respectively. The double-positive expression rate of CD34 and VEGFR-2 was 19.6±4.7%, and 83.1±10.4% of cells, which showed the uptake of Dil-ac-LDL and binding with UEA-1. The labeling efficiencies of SPIO at concentrations of 25 and 50 μg/mL were higher than for 12.5 μg/mL. The proliferation of cells was not influenced by SPIO concentrations of 12.5 and 25 μg/mL. After labeling, the T2WI of EPCs was reduced. The concentration of 25 μg/mL SPIO had high labeling efficiency detected by magnetic resonance imaging (MRI) without decreased EPCs viability.

Mechanism of microRNA-431-5p-EPB41L1 interaction in glioblastoma multiforme cells.

INTRODUCTION: Glioblastoma multiforme (GBM) is a kind of malignant brain tumor prevalent in adults, with the characteristics well adapted to poorly immunogenic and hypoxic conditions. Effective treatment of GBM is impeded due to the high proliferation, migration and invasion of GBM cells. GBM cells migrate by degrading the extracellular matrix, so it is difficult to have GBM cells eradicated completely by surgery. This study aims to confirm that miR-431-5p could influence the proliferation, invasion and migration of human glioblastoma multiforme cells by targeting EPB41L1 (erythrocyte membrane protein band 4.1). MATERIAL AND METHODS: The expression levels of miR-431-5p and EPB41L1 were detected in GBM cells and tissues using qRT-PCR. Dual luciferase reporter gene assay and western blot were applied to confirm the targeting relationship between miR-431-5p and EPB41L1. GBM cell line U87 was used in MTT, flow cytometry, Transwell, and wound healing assays to determine cell proliferation, migration and invasion. RESULTS: MiR-431-5p was overexpressed in GBM tissues while EPB41L1 was under-expressed. The results of dual luciferase reporter gene assay and western blot demonstrated that miR-431-5p could target EPB41L1 and suppress its expression. Down-regulating the expression of miR-431-5p or up-regulating the expression of EPB41L1 could inhibit the proliferation, invasion and migration but promote the apoptosis of GBM cells. CONCLUSIONS: MiR-431-5p facilitated the progression of GBM by inhibiting EPB41L1 expression.

Genetic variants and increased risk of meningioma: an updated meta-analysis.

PURPOSE: Various genetic variants have been reported to be linked to an increased risk of meningioma. However, no confirmed conclusion has been obtained. The purpose of the study was to investigate potential meningioma-associated gene polymorphisms, based on published evidence. MATERIALS AND METHODS: An updated meta-analysis was performed in September 2016. After electronic database searching and study screening, we selected eligible case-control studies and extracted data for meta-analysis, using Mantel-Haenszel statistics. P-values, pooled odds ratios (ORs), and 95% confidence intervals were calculated. RESULTS: We finally selected eight genes with ten polymorphisms: MLLT10 rs12770228, CASP8 rs1045485, XRCC1 rs1799782, rs25487, MTHFR rs1801133, rs1801131, MTRR rs1801394, MTR rs1805087, GSTM1 null/present, and GSTT1 null/present. Results of meta-analyses showed that there was increased meningioma risk in case groups under all models of MLLT10 rs12770228 (all OR >1, P<0.001), compared with control groups. Similar results were observed under the allele, homozygote, dominant, and recessive models of MTRR rs1801394 (all OR >1, P<0.05), and the heterozygote and dominant models of MTHFR rs1801131 in the Caucasian population (all OR >1, P<0.05). However, no significantly increased meningioma risks were observed for CASP8 rs1045485, XRCC1 rs25487, rs1799782, MTHFR rs1801133, MTR rs1805087, or GSTM1/GSTT1 null mutations. CONCLUSION: Our updated meta-analysis provided statistical evidence for the role of MLLT10 rs12770228, MTRR rs1801394, and MTHFR rs1801131 in increased susceptibility to meningioma.

Effectiveness of Superficial Temporal Artery-to-Middle Cerebral Artery Anastomosis in Treating Moyamoya Disease by Reducing Endothelial Progenitor Cells.

OBJECTIVE: To explore the effectiveness of superficial temporal artery-to-middle cerebral artery (STA-MCA) anastomosis in treating moyamoya disease (MMD). METHODS: A total of 30 patients with MMD (hemorrhagic type, n = 13; ischemic type, n = 17) who had undergone STA-MCA anastomosis were enrolled in this study (anastomosis group). Cerebral blood flow was evaluated before and after surgery using cerebral angiography and computed tomography (CT) perfusion imaging. In addition, 27 patients with MMD (hemorrhagic type, n = 11; ischemic type, n = 16) who had received only conservative treatment were enrolled as the control group. Patients in both the anastomosis group and the control group were followed up for 5 years, and the incidences of cerebral hemorrhage and cerebral ischemia were analyzed. Blood samples were collected in both groups before and after treatment. Mononuclear cells were separated by density gradient centrifugation. After labeling with 3 direct fluorescent antibodies (CD133, CD34, and vascular endothelial growth factor receptor 2), the number of endothelial progenitor cells (EPCs) was detected using flow cytometry. RESULTS: Cerebral blood flow was remarkably improved after STA-MCA anastomosis. The incidences of cerebral hemorrhage and cerebral ischemia were significantly lower in the anastomosis group than in the control group. The number of EPCs showed no significant change before and after treatment in the control group; in contrast, it was decreased significantly after surgery in the anastomosis group. CONCLUSIONS: STA-MCA anastomosis can reduce the number of EPCs in MMD patients, lower the risk of rebreeding, and improve cerebral ischemic attacks.

Inhibition of activated Ras suppresses multiple oncogenic Hub genes in human epithelial tumors.

Cancer cells may involve diverse mutations, but they often rely on continued expression of a single oncoprotein for survival, as a response to targeting this protein. Generally, Ras is overexpressed in human epithelial tumors and cancellation of activated Ras inhibits carcinoma cell proliferation and differentiation ability, and induces apoptotosis of tumor cells. However, the mechanisms of inhibition of activated Ras that suppress the malignancy activity of human epithelial tumors remain to be illuminated. We utilized text-mining of MEDLINE abstracts with natural language processing to establish the Ras biologic association network, and identified several interactions of this network with the Ras pathway. Our investigation not only examined the expression of Ras and Hub genes (PIK3CA, MDM2, CCND1, EGFR, JUN, MYC, VEGFA, ERK1 and ERK2) but also confirmed inhibition of activated Ras reduced expression of multiple oncogene in vitro studies. Our studies provide strong support for the conclusion that cancellation of activated Ras specifically regulates defective Ras pathways in human tumor cells.

IL-24 Induces Apoptosis via Upregulation of RNA-Activated Protein Kinase and Enhances Temozolomide-Induced Apoptosis in Glioma Cells.

Human interleukin-24 (IL-24) has been found recently to play a tumor-suppressor role in a variety of tumors, including gliomas. However, the exact mechanism of glioma tumor suppression by IL-24 remains unclear. We collected by surgery 30 gliomas at different grades and evaluated IL-24 and double-stranded RNA-activated protein kinase (PKR) expression using fluorescence quantitative real-time PCR and immunohistochemical techniques. Two human glioma cell lines, U87 and U251, were transfected with Ad5F35-IL24 via recombinant adenovirus-mediated gene transfer and apoptosis, as well as PKR and eIF-2α expression analyzed. The results showed that IL-24 and PKR expression decreased with increasing tumor grade. Compared with cells of the control groups, Ad5F35-IL24-infected U87 and U251 cells exhibited a significantly increased apoptosis and elevated PKR, eIF-2α, p-PKR, and p-eIF-2α levels, while the expression of Bcl-2 was decreased. Finally, IL-24 also sensitized apoptosis of glioma cells to temozolomide (TMZ). This study indicates that IL-24 upregulates expression and activation of PKR, further increasing expression and activation of eIF-2α, and decreasing Bcl-2 to promote apoptosis. IL-24 also increases chemosensitivity of glioma cells to TMZ.

Overexpressed let-7a inhibits glioma cell malignancy by directly targeting K-ras, independently of PTEN.

BACKGROUND: Altered expression of micro(mi)RNAs has been shown to be associated with tumorigenesis and tumor progression. The expression of phosphatase and tensin homolog (PTEN) plays an important role in glioma and is regarded as a prognostic marker of glioma patients. The goal of this study was to investigate the function of lethal (let)-7a miRNA in glioma cell lines with different PTEN phenotypes. METHODS: One hundred ninety-eight glioma tissues were used to profile miRNA expression. RESULTS: Let-7a was shown to have lower expression in high-grade glioma than in low-grade glioma. Low expression of let-7a was correlated with poor prognosis of primary glioblastoma patients. We demonstrated that K-ras was a functional target for let-7a to induce cell cycle arrest, apoptosis, and inhibition of cell migration and invasion in vitro. Our further results showed no difference in malignancy inhibition induced by let-7a in 4 glioma cells, including U87 (PTEN null), U251 (PTEN mutant), LN229 (PTEN wild type), and LN229 (PTEN small interfering RNA). The phosphatidylinositol-3 kinase/Akt and mitogen-activated protein kinase/extracellular signal-regulated kinase pathways were inhibited by let-7a, and the inhibition effects had no difference in 4 glioma cells. We demonstrated that let-7a could induce suppression of glioma in vivo by generating a glioma xenograft model. CONCLUSION: Our results indicated that let-7a suppresses its target transcript K-ras and inhibits glioma malignancy independent of PTEN expression.

MiRNA-181b suppresses IGF-1R and functions as a tumor suppressor gene in gliomas.

MicroRNAs (miRNAs) are single-stranded, 18- to 23-nt RNA molecules that function as regulators of gene expression. Previous studies have shown that microRNAs play important roles in human cancers, including gliomas. Here, we found that expression levels of miR-181b were decreased in gliomas, and we identified IGF-1R as a novel direct target of miR-181b. MiR-181b overexpression inhibited cell proliferation, migration, invasion, and tumorigenesis by targeting IGF-1R and its downstream signaling pathways, PI3K/AKT and MAPK/ERK1/2. Overexpression of IGF-1R rescued the inhibitory effects of miR-181b. In clinical specimens, IGF-1R was overexpressed, and its protein levels were inversely correlated with miR-181b expression. Taken together, our results indicate that miR-181b functions in gliomas to suppress growth by targeting the IGF-1R oncogene and that miR-181b may serve as a novel therapeutic target for gliomas.

SUMOylation of ATF3 alters its transcriptional activity on regulation of TP53 gene.

Cyclic AMP-dependent transcription factor-3 (ATF3), a stress sensor, plays an essential role in cells to maintain homeostasis and has diverse functions in cellular survival and death signal pathways. ATF3 is a novel regulator of p53 protein stability and function. The activities of ATF3 are modulated by post-translational modifications (PTMs), such as ubiquitination, but whether it is modified by small ubiquitin-related modifier (SUMO) remains unknown. The aim of this study was to investigate whether ATF3 is post-translationally modified by SUMO proteins and also to elucidate SUMOylation of ATF3 on TP53 gene activity. Here we report that ATF3 is clearly defined as a SUMO target protein both in vitro SUMOylation assay using recombinant proteins and at the cellular levels. Furthermore, ATF3 interacted with UBE2I, the only SUMO E2 enzyme found so far. In addition, PIAS3ß (a SUMO E3 ligase) enhanced and SENP2 and SENP7 (two SUMOylation proteases) decreased SUMOylation of ATF3, respectively. Finally, we found that ATF3 is selectively SUMOylated at lysine residue 42 but the SUMOylation does not alter subcellular localization of ATF3. We then characterized the functional role of ATF3 SUMOylation on TP53 gene expression. We found that SUMOylation of ATF3 is required for full repression of TP53 gene. Overall, we provide the first evidence that ATF3 is post-translationally modified by SUMO and SUMOylation of ATF3 plays a functional role in regulation of TP53 gene activity.