Steroid receptor coactivator-1 enhances the stemness of glioblastoma by activating long noncoding RNA XIST/miR-152/KLF4 pathway.

Glioblastoma (GBM) recurrence is attributed to the presence of therapy-resistant glioblastoma stem cells. Steroid receptor coactivator-1 (SRC-1) acts as an oncogenic regulator in many human tumors. The relationship between SRC-1 and GBM has not yet been studied. Herein, we investigate the role of SRC-1 in GBM. In this study, we found that SRC-1 expression is positively correlated with grades of glioma and inversely correlated with glioma patient's prognosis. Steroid receptor coactivator-1 promotes the proliferation, migration, and tumor growth of GBM cells. Notably, SRC-1 knockdown suppresses the stemness of GBM cells. Mechanistically, long noncoding RNA X-inactive specific transcript (XIST) is regulated by SRC-1 at the posttranscriptional level and mediates the function of SRC-1 in promoting stemness-like properties of GBM. Steroid receptor coactivator-1 can promote the expression of Kruppel-like factor 4 (KLF4) through the XIST/microRNA (miR)-152 axis. Additionally, arenobufagin and bufalin, SRC small molecule inhibitors, can reduce the proliferation and stemness of GBM cells. This study reveals SRC-1 promotes the stemness of GBM by activating the long noncoding RNA XIST/miR-152/KLF4 pathway and provides novel markers for diagnosis and therapy of GBM.

NF-κB "decoy" inhibits COX-2 expression in epileptic rat brain.

There is a need to investigate the role of nuclear factor kappa B in the regulation of cyclooxygenase-2 expression in the epileptic rat brain and cultured hippocampal neurons. Immunofluorescence and polymerase chain reaction was used to detect the expression of nuclear factor kappa B and cyclooxygenase-2. In cultured hippocampal neurons and rat brain: the control group compared with the normal group, nuclear factor kappa B expression in the hippocampal dentate gyrus, cerebral cortex, the piriform cortex brain regions were significantly increased (P < 0.01). This is accompanied by a significant increase in cyclooxygenase-2 protein and mRNA expressions in the hippocampus (P < 0.01). In the experimental group compared to the control group, the nuclear factor-kappa B expression in the hippocampal dentate gyrus, cerebral cortex, piriform cortex, and other brain regions was significantly lower (P < 0.01), with the accompanying decrease in cyclooxygenase-2 protein and mRNA expression (P < 0.01) in the hippocampus. In conclusion, κB-decoy can inhibit nuclear factor kappa B activation in epileptic rat brain and cyclooxygenase-2 overexpression.

Design of diffractive optical element projector for a pseudorandom dot array by an improved encoding method.

Here we achieved the structured light patterns of a pseudorandom dot array by a single diffractive optical element. The dot array can be applied to achieve three-dimensional imaging. First, the pseudorandom dot array was generated by the proposed improved encoding methods, which are an improved formula-method-based encoding algorithm and an improved enumeration-method-based encoding algorithm. Second, diffractive optical elements were designed as dot projectors to generate pseudorandom dots by the Gerchberg-Saxton algorithm. Pseudorandom dot arrays with different sizes were generated to validate the proposed encoding methods. A pseudorandom dot array with a maximal size of 713×449 was experimentally achieved. By analyzing the intensity distribution of the projecting pattern, the projected dots have a unique window of 7×7, and the dot array is distortion free. The proposed encoding methods, optimization algorithm, and applied fabrication technology have potential applications in three-dimensional imaging, three-dimensional sensing, shape measurement, and deformation measurement with high decoding speed.

DNA damage-induced NF-κB activation in human glioblastoma cells promotes miR-181b expression and cell proliferation.

BACKGROUND: Glioblastoma (GBM) is the most common and most aggressive form of brain cancer. After surgery, radiotherapy is the mainstay of treatment for GBM patients. Unfortunately, the vast majority of GBM patients fail responding to radiotherapy because GBM cells remain highly resistant to radiation. Radiotherapy-induced DNA damage response may correlate with therapeutic resistance. METHODS: Ionizing radiation (IR) was used to induce DNA damage. Cell proliferation and migration were detected by wound-healing, MTT and apoptosis assays. Dual-luciferase assays and Western blot analysis were performed to evaluate NF-κB activation and validate microRNA targets. Real-time PCR was used to study mRNA and microRNA levels. RESULTS: IR-induced DNA damage activated NF-κB in GBM cells which promoted expression of IL-6, IL-8 and Bcl-xL, thereby contributing to cell survival and invasion. Knockdown SENP2 expression enhanced NF-κB essential modulator (NEMO) SUMOylation and NF-κB activity following IR exposure. miR-181b targets SENP2 and positively regulated NF-κB activity. CONCLUSION: NF-κB activation by DNA damage in GBM cells confers resistance to radiation-induced death.

Research on the Cold Rolling Process, Microstructure and Properties of 305 Austenitic Stainless Steel Thin Strips.

Austenitic stainless steel has high toughness and plasticity; however, it tends to exhibit low yield strength, which severely limits the widespread application of this steel. It can be strengthened by cold working; however, this will cause many defects in the structure. Therefore, annealing treatment must be carried out before use. In this paper, the effects of annealing treatment at different temperatures and times on the microstructure and mechanical properties of cold-rolled 305 stainless steel sheet were studied and the theoretical mechanism was further analyzed to provide better theoretical guidance for production and application. It was found that the microstructure grains obtained by annealing at 850 °C for 30 s were finer and more uniform, and the mechanical properties were also the best, which met the requirements of strong plasticity. Therefore, the rolling and annealing experiments could be carried out again under this annealing condition, and the requirements of the finished product could be finally obtained. At this time, the thickness of the plate was about 0.15 mm, the yield strength was 1238 MPa, and the permeability was below 1.02, which met the production requirements of the metal mask plate.

Pyrimidine compounds BY4003 and BY4008 inhibit glioblastoma cells growth via modulating JAK3/STAT3 signaling pathway.

Glioblastoma (GBM) is a brain tumor characterized by its aggressive and invasive properties. It is found that STAT3 is abnormally activated in GBM, and inhibiting STAT3 signaling can effectively suppress tumor progression. In this study, novel pyrimidine compounds, BY4003 and BY4008, were synthesized to target the JAK3/STAT3 signaling pathway, and their therapeutic efficacy and mechanisms of action were evaluated and compared with Tofacitinib in U251, A172, LN428 and patient-derived glioblastoma cells. The ADP-Glo™ kinase assay was utilized to assessed the inhibitory effects of BY4003 and BY4008 on JAK3, a crucial member of the JAK family. The results showed that both compounds significantly inhibited JAK3 enzyme activity, with IC50 values in the nanomolar range. The antiproliferative effects of BY4003, BY4008, and Tofacitinib on GBM and patient-derived glioblastoma cells were evaluated by MTT and H&E assays. The impact of BY4003 and BY4008 on GBM cell migration and apoptosis induction was assessed through wound healing, transwell, and TUNEL assays. STAT3-regulated protein expression and relative mRNA levels were analyzed by western blotting, immunocytochemistry, immunofluorescence, and qRT-PCR. It was found that BY4003, BY4008 and Tofacitinib could inhibit U251, A172, LN428 and patient-derived glioblastoma cells growth and proliferation. Results showed decreased expression of STAT3-associated proteins, including p-STAT3, CyclinD1, and Bcl-2, and increased expression of Bax, a pro-apoptotic protein, as well as significant down-regulation of STAT3 and STAT3-related genes. These findings suggested that BY4003 and BY4008 could inhibit GBM growth by suppressing the JAK3/STAT3 signaling pathway, providing valuable insights into the therapeutic development of GBM.

Β-elemene inhibits Hsp90/Raf-1 molecular complex inducing apoptosis of glioblastoma cells.

ß-Elemene, an active component of herb medicine Curcuma wenyujin, has been shown to antagonize glioblastoma cells by inducing apoptosis. However, how ß-elemene induces apoptosis of these cells remains unclear. In this study, we report that ß-elemene disrupted the formation of the Hsp90/Raf-1 complex, a key step in maintaining the conformation stability of Raf-1, and caused deactivation of Raf-1 and inhibition of the ERK pathway, thereby leading to apoptosis of glioblastoma cells. Specifically, treatment of glioblastoma cell lines with ß-elemene attenuated phosphorylation of multiple members of the kinase families in the Ras/Raf/MEK/ERK cascade, including Raf-1 and ERK as well as downstream signaling targets such as Bcl-2. These results suggest that the Hsp90/Raf-1 complex could be a promising molecular target for new drug development for the treatment of glioblastoma.

Characterization of three naturally occurring lignans, sesamol, sesamolin, and sesamin, as potent inhibitors of human cytochrome P450 46A1: Implications for treating excitatory neurotoxicity.

CYP46A1 is a brain-specific enzyme responsible for cholesterol homeostasis. Inhibition of CYP46A1 activity serves as a therapeutic target for excitatory neurotoxicity. Sesame is a common medicine and food resource; its component lignans possess various pharmacological activities. In this study, the inhibitory effects of sesame lignans on CYP46A1 activity were investigated. Inhibition kinetics analyses revealed that sesamin and sesamolin produce mixed partial competitive inhibition of CYP46A1, while sesamol produces non-competitive inhibition. Notably, molecular simulations revealed that the sesame lignans have excellent orientations within the active cavity of CYP46A1. Importantly, the sesame lignans had high permeability coefficients and low efflux ratios. Furthermore, sesamin significantly reduced the levels of 24S-hydroxycholesterol in rat plasma and brain tissues, and down-regulated the protein expressions of CYP46A1, NMDAR2A, NMDAR2B, and HMGCR. Collectively, sesame lignans exhibit significant inhibitory effects on CYP46A1 activity, highlighting their potential therapeutic role in treating excitatory neurotoxicity.

Observer-based sliding mode control for synchronization of delayed chaotic neural networks with unknown disturbance.

This paper considers the synchronization of delayed chaotic neural networks with unknown disturbance via observer-based sliding mode control. We design a sliding surface involving integral structure and a discontinuous control law such that the trajectories of error system converge to the sliding surface in finite time and remain on it thereafter. Then, by constructing Lyapunov-Krasovskii functional and using the linear matrix inequality (LMI) technique, some sufficient conditions are derived to guarantee the synchronization of chaotic neural networks. The advantages of our proposed results include:(i) It can be applied to synchronous control for drive and response systems with different structures; (ii) It can be applied to the response system with unknown disturbance. Finally, a simulation example is shown to illustrate the proposed methods.

Cultivable anaerobic and aerobic bacterial communities in the fermentation chambers of Holotrichia parallela (coleoptera: scarabaeidae) larvae.

As important pests, scarab beetle larvae survive on plant biomass and the microbiota of the fermentation chamber play an important role in the digestion of lignocellulose-rich diets. However, the cultivable microbes, especially the anaerobic cultivable microbes, are still largely unknown. Here, both cultivable anaerobic and aerobic bacterial communities associated with the fermentation chamber of Holotrichia parallela larvae were investigated. In total bacteria cells directly enumerated by the 4', 6-diamidino-2-phenylindole (DAPI) staining method, the viable plate counts of cultivable bacteria in the fermentation chamber accounted for 0.92% of proportion. These cultivable bacteria were prone to attach to the fermentation chamber wall (88.41%) compared to the chamber contents. Anaerobic bacteria were dominant in the cultivable bacteria attaching to the fermentation chamber wall (70.20%), while the quantities of anaerobes and aerobes were similar in the chamber contents. Polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE), fingerprinting and sequence analysis of isolated colonies revealed that the cultivable bacteria are affiliated with class γ-Proteobacteria, Bacteroidia, Actinobacteria, Clostridia and ß-Proteobacteria. γ-Proteobacteria was the major type of anaerobic cultivable bacteria and even the only one type of aerobic cultivable bacteria. Taken together, our results suggest, for the first time, that anaerobic microbiota are dominant in cultivable bacteria in the special anoxia niche of the fermentation chamber from H. parallela larvae. These bacterial isolates could be a treasure trove for screening lignocellulytic microbes which are essential for the plant biomass digestion of this scarab species.

ß-Elemene enhances the efficacy of gefitinib on glioblastoma multiforme cells through the inhibition of the EGFR signaling pathway.

Glioblastoma multiforme (GBM) is the most common and severe form of primary tumor in the central nervous system of adults which has poor prognosis and limited therapeutic options. Epidermal growth factor receptor (EGFR) inhibitor, such as gefitinib (brand name Iressa, ZD1839), has been approved as a targeted medicine for several types of tumor including glioblastoma multiforme. However, gefitinib exerted very limited effects on some glioblastoma multiforme patients after a period of treatment due to intrinsic and acquired drug resistance. ß-Elemene, a natural plant drug extracted from Curcuma wenyujin, has shown promising anticancer effects against a broad spectrum of tumors. In the present study, we found that ß-elemene could enhance the chemosensitivity of glioblastoma multiforme cells to gefitinib. The combination medication of ß-elemene and gefitinib not only inhibited the survival and proliferation of glioblastoma multiforme cells via inhibition of EGFR signaling pathway but also induced more distinct apoptosis and autophagy in the glioblastoma multiforme cells than the gefitinib monotherapy. These results showed that ß-elemene might be one potential adjuvant to enhance the effect of EGFR inhibitor and reduce the resistance of gefitinib in glioblastoma multiforme.

ß-elemene enhances both radiosensitivity and chemosensitivity of glioblastoma cells through the inhibition of the ATM signaling pathway.

Glioblastoma multiforme (GBM), a tumor associated with poor prognosis, is known to be resistant to radiotherapy and alkylating agents such as temozolomide (TMZ). ß-elemene, a monomer found in Chinese traditional herbs extracted from Curcuma wenyujin, is currently being used as an antitumor drug for different types of tumors including GBM. In the present study, we investigated the roles of ß-elemene in the radiosensitivity and chemosensitivity of GBM cells. Human GBM cell lines U87-MG, T98G, U251, LN229 and rat C6 cells were treated with ß-elemene combined with radiation or TMZ. We used MTT and colony forming assays to evaluate the proliferation and survival of the cells, and the comet assay to observe DNA damage. Expression of proteins was analyzed by immunoblotting. In the present study, we found that ß-elemene inhibited the proliferation and survival of different GBM cell lines when combined with radiotherapy or TMZ via inhibition of DNA damage repair. Treatment of GBM cells with ß-elemene decreased the phosphorylation of ataxia telangiectasia mutated (ATM), AKT and ERK following radiotherapy or chemotherapy. These results revealed that ß-elemene could significantly increase the radiosensitivity and chemosensitivity of GBM. ß-elemene may be used as a potential drug in combination with the radiotherapy and chemotherapy of GBM.

[USE OF ARTIFICIAL BONE OF TRICALCIUM PHOPHATE IN SELLAR FLOOR RECONSTRUCTION AFTER TRANSSPHENOIDAL MICROSURGERY FOR PITUITARY ADEOMA].

OBJECTIVE: To explore the effectiveness of the usage of artificial bone of tricalcium phophate in sellar floor reconstruction after transsphenoidal microsurgery for pituitary adeoma. METHODS: Between January and December 2014, 85 patients with pituitary adema underwent transsphenoidal microsurgery, and the clinical data were retrospectively analyzed. "Sandiwich" was used for sellar floor reconstruction in 46 cases (control group), and "sandiwich" combined with the artificial bone of tricalcium phophate in 39 cases (trial group). There was no significant difference in gender, age, disease duration, size of tumor, invasiveness, and the degree of damage to the sellar floor between 2 groups (P > 0.05). RESULTS: Total removal and subtotal removal of tumors were achieved in 39 cases and 7 cases of the control group, and in 33 cases and 6 cases of the trial group, showing no significant difference between 2 groups (Z = -1.303, P = 0.193). Cerebrospinal leakage occurred in 8 cases of the control group and in 10 cases of the trial group during operation, showing no significant difference (Z = -1.748, P = 0.080). The case number of cerebrospinal leakage in the control group (4 cases) was significantly more than that in the trial group (0) after operation (P = 0.020). The time of gauze removal in the trial group (3 days) was significant shorter than that in the control group [(4.3 ± 1.6) days] (t = 2.236, P = 0.033). The patients were followed up 3-14 months in the control group and 5-13 months in the trial group. No cerebrospinal leakage occurred during follow-up. CONCLUSION: Sellar floor reconstruction with artificial bone of tricalcium phophate is safe, and it can reduce cerebrospinal leakage and shorten the time of gauze removal.

Paeoniflorin inhibits proliferation and induces apoptosis of human glioma cells via microRNA-16 upregulation and matrix metalloproteinase-9 downregulation.

Paeoniflorin is one of the active ingredients of the commonly used herbal medicine derived from Paeonia, which exhibits anticancer properties. MicroRNA-16 (miR-16) is upregulated in CD133(-) cells, but downregulated in CD133(+) cells from glioma tissue. Matrix metalloproteinase-9 (MMP-9) expression in glioma tissue samples is significantly higher than that in healthy brain tissue samples. Therefore, miR-16 and MMP-9 expression may be associated with glioma pathogenesis. In the present study, the effects of paeoniflorin on glioma were analyzed. U87 cells were treated with paeoniflorin at 0, 5, 10 and 20 µΜ concentrations. The results suggested that paeoniflorin inhibited U87 cell proliferation and accelerated cell apoptosis. In the present study paeoniflorin treatment increased miR-16 expression and reduced MMP-9 protein expression in U87 cells. Additionally, the results of the present study suggested that miR-16 may regulate MMP-9 expression in miR-16-transfected U87 cells. Furthermore, anti-miR-16 antibodies were used in order to investigate the apoptotic effects of paeoniflorin on U87 cells. The results demonstrated that paeoniflorin inhibits proliferation and induces apoptosis of human glial cells, via miR-16 upregulation and MMP-9 downregulation.

Changes in neural stem cells in the subventricular zone in a rat model of communicating hydrocephalus.

Communicating hydrocephalus is a common type of hydrocephalus. At present, the prevalent treatment is to perform a ventriculo-peritoneal shunt, which, for reasons that are not clear, is sometimes ineffective. The subventricular zone (SVZ) of the lateral ventricles has been established as the primary site of adult neurogenesis. Following cerebral ischemia or brain injury, neural stem cells (NSCs) increase in the SVZ and can both differentiate into neurons and glial cells and respond to the injury. Neural stem cells, enabled by a complex repertoire of factors that precisely regulate the activation, proliferation, differentiation and integration of newborn cells, continuously generate new neurons. However, only a few systematic studies of the role of NSCs in hydrocephalus have been reported. In a rat model of communicating hydrocephalus, we recently showed that hydrocephalus caused the ventricular system to expand over time. We found that the number of NSCs in the SVZ peaked rapidly after hydrocephalus was established and decreased gradually over time until the cells disappeared. NSCs may be involved in the pathophysiology changes and repair process of hydrocephalus.

FOXC2 often overexpressed in glioblastoma enhances proliferation and invasion in glioblastoma cells.

Glioblastoma (GBM) is the most common primary brain tumor and the leading cause of tumor-related death in the central nervous system. To date, the mechanisms of GBM genesis remain elusive. Forkhead box protein C2 (FOXC2) is a transcription factor that has been reported in many cancers, but its function in GBM tumorigenesis is not clearly elucidated. This study found that FOXC2 was overexpressed in GBM cell lines and GBM tissues. The proliferation and invasive potential of GBM cells were significantly increased by ectopic expression of FOXC2 but significantly decreased by RNA interference targeting FOXC2. EGFR expression was modulated by FOXC2 both in mRNA and protein levels. EGFR inhibition by siRNA reversed the FOXC2-induced proliferation and invasion. These findings suggested that FOXC2 expressed in GBM has a function in GBM cell proliferation and invasion and may be partly associated with the EGFR overexpression.

Morphology and ultrastructure of the hindgut fermentation chamber of a melolonthine beetle Holotrichia parallela (Coleoptera: Scarabaeidae) during larval development.

The morphology and ultrastructure of the hindgut fermentation chamber of a melolonthine beetle, Holotrichia parallela, were examined using light and electron microscopy. The results showed that the anterior portion of the hindgut expanded into a characteristic lobe-like structure described as a fermentation chamber. Hematoxylin-eosin staining revealed that the wall of the fermentation chamber was composed of three main layers: the longitudinal muscle layer, the circular muscle layer, and the columnar epithelial cells. Scanning electron microscopy showed that the ultrastructure of the inner surface of the fermentation chamber was subjected to significant changes during larval development. Only some folds and a few cocci attached to the folds were found in the first-instar larvae. In the fermentation chambers of the second-instar larvae, a cuticular intima began to emerge, and the bacteria multiplied to form bacterial groups attached to the intima. A special lobe-like structure was formed in the third-instar larvae, constituted by bacteria and the bacteria-covered cuticular intima. Transmission electron microscopy revealed that the lobe-like structure held large numbers of rod-shaped bacteria. These data suggest that the hindgut fermentation chamber may have an important role in the symbiotic relationship between microbes and their insect hosts.

A functional polymorphism in the epidermal growth factor gene is associated with risk for glioma in a Chinese population.

Epidermal growth factor (EGF) plays a key role in survival of neural and glial precursor cells. A single nucleotide polymorphism of the EGF gene +61G/A in the 5'-untranslated region has been reported to be associated with susceptibility to glioma. The purpose of this study was to investigate the potential association between EGF +61G/A and brain glioma in a Chinese population. A case-control study involving 180 patients with glioma and 360 controls was done. Polymerase chain reaction restriction fragment-length polymorphism assay was used to analyze the EGF +61G/A genotypes. Patients with glioma had a significantly higher frequency of AA genotype (odds ratio, 2.25; 95% confidence interval, 1.20, 4.21; p=0.01] than controls. When stratified by histologic features and World Health Organization grade of glioma, distribution of each genotype did not significantly differ. Our data suggested that the EGF +61G AA genotype was associated with a higher glioma risk in a Chinese population. This finding is in contrast with previous studies that reported the G allele as a risk factor for glioma in white patients.

ß-Elemene inhibits proliferation of human glioblastoma cells and causes cell-cycle G0/G1 arrest via mutually compensatory activation of MKK3 and MKK6.

ß-elemene, a natural plant drug extracted from Curcuma wenyujin, has shown a strong anti-glioblastoma effect. However, the antitumor mechanism of ß-elemene remains unclear. Mitogen-activated protein kinase kinase-3 (MKK3) and -6 (MKK6) can regulate cellular growth, fission, differentiation and apoptosis. To illustrate the role of MKK3 and MKK6 in the anti-glioblastoma proliferation effect of ß-elemene, U87 cells were treated with ß-elemene at various doses or for different times, and then phosphorylated MKK3 (p-MKK3), phosphorylated MKK6 (p-MKK6), MKK3 and MKK6 were detected by Western blot assay. After transient transfection with dominant-negative mutant plasmids of MKK3 and MKK6, cell viability and cell cycle stage were determined by methyl thiazolyl tetrazolium assay and flow cytometry, respectively. Results showed that ß-elemene inhibited the proliferation of U87 glioblastoma cells and arrested them in G0/G1 phase through up-regulating p-MKK3 and p-MKK6 levels. In contrast, inhibition of MKK3 and MKK6 reversed the antitumor effect of ß-elemene. Furthermore, when either MKK3 or MKK6 was inhibited by a dominant-negative plasmid, the other was compensatorily activated in the presence of ß-elemene. Taken together, our findings indicate that mutually compensatory activation of MKK3 and MKK6 mediates the anti-glioblastoma effect of ß-elemene. MKK3 and MKK6 might be two putative targets for molecular therapy against glioblastoma.