Zinc finger and SCAN domain-containing 18 suppresses the proliferation, self-renewal, and drug resistance of glioblastoma cells.

Elucidation of cellular and molecular mechanisms key to glioblastoma growth, self-renewal, survival, and metastasis is important for developing novel therapeutic strategies. In this study, the expression and function of zinc finger and SCAN domain-containing 18 (ZSCAN18) in human glioblastoma cell lines were characterized. Compared with normal astrocytes, ZSCAN18 was significantly down-regulated in all tested glioblastoma cell lines, with the LN-229 cell line having the lowest ZSCAN18 expression. Lentivirus-mediated ZSCAN18 overexpression suppressed glioblastoma cell proliferation, sphere formation, and SOX2 and OCT4 expression, implying the negative role of ZSCAN18 in glioblastoma development. ZSCAN18 overexpression enhanced the sensitivity of glioblastoma cells to Temozolomide. The glioblastoma implantation model showed a consistent inhibitory effect of ZSCAN18 on the proliferation and self-renewal of glioblastoma cells in vivo. Notably, ZSCAN18 overexpression resulted in the down-regulation of glioma-associated oncogene homolog 1 (GLI1) which is the terminal component of the Hedgehog signaling. Lentivirus-mediated GLI1 overexpression restored the proliferation and promoted the resistance of glioblastoma cells to Temozolomide. However, GLI1 overexpression did not affect the self-renewal of ZSCAN18-overexpressing glioblastoma cells. Taken together, this research uncovers the role of ZSCAN18 in regulating glioblastoma cell growth and maintenance. ZSCAN18 could be a potential glioblastoma biomarker.

Matrix stiffness regulates bone repair by modulating 12-lipoxygenase-mediated early inflammation.

Lipid metabolism in macrophages has been increasingly emphasized in exerting an anti-inflammatory effect and accelerating fracture healing. 12-lipoxygenase (12-LOX) is expressed in several cell types, including macrophages, and oxidizes polyunsaturated fatty acids (PUFAs) to generate both pro- and anti-inflammatory lipid mediators, of which the n-3 PUFAs play an important part in tissue homeostasis/fibrosis. Although mechanical factor regulates the lipid metabolic axis of inflammatory cells, specifically matrix stiffness influences macrophages metabolic responses, little is known about how matrix stiffness affects the 12-LOX-mediated early inflammation in bone repair. In the present study, demineralized bone matrix (DBM) scaffolds with different matrix stiffness were constructed by controlling the duration of decalcification (0 h (control), 1 h (high), 12 h (medium), and 5 d (low)) to repair the defected rat skull. The expression of inflammatory cytokines and macrophages polarization were analyzed. The lipid metabolites and lipid mediators' biosynthesis by matrix stiffness-regulated were further detected. The results showed that the low matrix stiffness could polarize macrophages into an anti-inflammatory phenotype, promote the expression of anti-inflammatory cytokines and specialized pro-resolving lipid mediators (SPMs) biosynthesis beneficial for the osteogenesis of mesenchymal stem cells (MSCs). After treated with ML355, the expression of anti-inflammatory cytokines/proteins and SPMs biosynthesis in macrophages cultured on low-matrix stiffness scaffolds were repressed, and there were almost no statistical differences among all groups. Findings from this study support that matrix stiffness regulates bone repair by modulating 12-LOX-mediated early inflammation, which suggest a direct mechanical impact of matrix stiffness on macrophages lipid metabolism and provide a new insight into the clinical application of SPMs for bone regeneration.

Sheathed in-situ room-temperature growth covalent organic framework solid-phase microextraction fiber for detecting ultratrace polybrominated diphenyl ethers from environmental samples.

The extraction performance of solid-phase microextraction (SPME) fiber is significantly influenced by coating materials and fabricating process. It is urgently needed for fabricating robust SPME fiber with facile preparation methods. Herein, a novel polyimide (PI) @ covalent organic framework (COF) synthesized by 1,3,5-Tris (4-aminophenyl) benzene (TPB) and 2,5-dimethoxyterephthalaldehyde (DMTP) fiber, named PI@TPB-DMTP fiber, was successfully fabricated with facile method at room temperature. Firstly, a COF crystals TPB-DMTP was in situ grown on stainless steel fiber, where the COF crystals was synthesized by the Schiff-base reaction between TPB and DMTP. Subsequently, the COF coating was covered with an ultrathin layer of PI through a simple dip-coating method to improve the fiber stability. By coupled PI@TPB-DMTP SPME fiber with gas chromatography-negative chemical ion-mass spectrometry (GC-NCI-MS), a sensitive analytical method was established for the determination of ultratrace polybrominated diphenyl ethers (PBDEs) in water sample. To achieve the best efficiency and sensitivity for the analysis of PBDEs, six potential influencing factors in extraction step and desorption step were optimized. Under optimized conditions, the established method showed high enhancement factors of 1470-3555, wide linear range of 0.05-100 ng L-1, low detection limits of 0.0083-0.0190 ng L-1, good repeatability for intra-day in the range of 3.71%-7.62% and inter-day in the range of 5.12%-8.81%, good reproducibility in the range of 6.83%-9.21%. The satisfactory recovery was ranged from 79.2% to 117.3% in determining real water samples. The excellent experimental performance was mainly attributed to the large specific surface area of TPB-DMTP, as well as the high permeability of porous PI film. The results demonstrated that the COF-based fiber showed great potential for analysis of PBDEs in complex environmental samples.

Gefitinib-Induced Cutaneous Toxicities in Brown Norway Rats Are Associated with Macrophage Infiltration.

Gefitinib (Iressa), is a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), used in the targeted treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC). Skin toxicity is the major adverse effect observed in patients treated with EGFR-targeted TKIs such as gefitinib and erlotinib. To date, a corresponding skin animal model has not been established to address the mechanisms of these effects. Therefore, we analyzed the skin rash phenotype and its pathological features in Brown Norway (BN) rats treated with gefitinib 2.5 mg, 5.0 mg, or 10 mg/100 g/day for 4 weeks. We found that treatment with gefitinib led to weight loss, rash, itching, and hair loss in a dose-dependent manner. We also investigated the skin pathology and found that the animal model showed thickening of the epidermis, loss of moisture, and apoptosis of keratinocytes. Immunohistochemistry, flow cytometry, and analysis of monocytes and leukocytes in the blood revealed increased macrophage infiltration was associated with the cutaneous toxicities induced by gefitinib in the BN rats. Finally, we found that gefitinib-induced cutaneous toxicity is significantly associated with three inflammatory cytokines known to be secreted by activated macrophages, TREM-1, CINC-2, and CINC-3.

Neovascularization and Synaptic Function Regulation with Memantine and Rosuvastatin in a Rat Model of Chronic Cerebral Hypoperfusion.

Cerebral hypoperfusion is an important factor in the pathogenesis of cerebrovascular diseases and neurodegenerative disorders. We investigated the effects of memantine and rosuvastatin on both neovascularization and synaptic function in a rat model of chronic cerebral hypoperfusion, which was established by the bilateral common carotid occlusion (2VO) method. We tested learning and memory ability, synaptic function, circulating endothelial progenitor cell (EPC) number, expression of neurotrophic factors, and markers of neovasculogenesis and cell proliferation after memantine and/or rosuvastatin treatment. Rats treated with memantine and/or rosuvastatin showed significant improvement in Morris water maze task and long-term potentiation (LTP) in the hippocampus, compared with untreated 2VO model rats. Circulating EPCs, expression of brain-derived neurotrophic factor, and vascular endothelial growth factor, markers of microvessel density were increased by each of the three interventions. Rosuvastatin also increased cell proliferation in the hippocampus. Combined treatment with memantine and rosuvastatin showed greater effect on enhancement of LTP and expression of neurotrophic factors than either single medication treatment alone. Both memantine and rosuvastatin improved learning and memory, enhanced neovascularization and synaptic function, and upregulated neurotrophic factors in a rat model of chronic cerebral hypoperfusion.

Atomic orbital-based SOS-MP2 with tensor hypercontraction. I. GPU-based tensor construction and exploiting sparsity.

We present a tensor hypercontracted (THC) scaled opposite spin second order Møller-Plesset perturbation theory (SOS-MP2) method. By using THC, we reduce the formal scaling of SOS-MP2 with respect to molecular size from quartic to cubic. We achieve further efficiency by exploiting sparsity in the atomic orbitals and using graphical processing units (GPUs) to accelerate integral construction and matrix multiplication. The practical scaling of GPU-accelerated atomic orbital-based THC-SOS-MP2 calculations is found to be N(2.6) for reference data sets of water clusters and alanine polypeptides containing up to 1600 basis functions. The errors in correlation energy with respect to density-fitting-SOS-MP2 are less than 0.5 kcal/mol for all systems tested (up to 162 atoms).

Nucleolin targeting AS1411 modified protein nanoparticle for antitumor drugs delivery.

Over recent years, cell surface nucleolin as an anticancer target has attracted many researchers' attentions. To improve the antitumor efficacy, we developed a nucleolin targeted protein nanoparticle (NTPN) delivery system in which human serum albumin (HSA) was used as drug carrier and a DNA aptamer named AS1411, which had high affinity to nucleolin, was used as a bullet. The HSA nanoparticles (NPs-PTX) were fabricated by a novel self-assembly method and then modified with AS1411 (Apt-NPs-PTX). The resulted Apt-NPs-PTX were spherical. Compared with NPs-PTX, the uptake of Apt-NPs-PTX displayed a significant increase in MCF-7 cells while there was a decrease in nontumor cell lines such as MCF-10A and 3T3 cells. In a cytotoxic study, Apt-NPs-PTX displayed an enhanced cytotoxicity in MCF-7 tumor cells while there was almost no cytotoxicity in MCF-10A cells. Endostatin, a nucleolin inhibitor, could significantly decrease the internalization of Apt-NPs-PTX, suggesting nucleolin mediates the transmembrane process of Apt-NPs-PTX. Therefore, the AS1411 modified NTPN delivery system might be a promising targeted drug delivery system.

A novel self-assembly albumin nanocarrier for reducing doxorubicin-mediated cardiotoxicity.

Doxorubicin is an antitumor drug commonly used against a wide spectrum of tumors. However, the clinical application of DOX is restricted by its cardiotoxicity. To reduce the cardiotoxicity, we develop an albumin-based nanocarrier via a new molecular switch method for DOX delivery. Spherically shaped DOX-loaded HSA nanoparticles (NPs-DOX) are prepared with a drug-loading capacity and particle size of 4.3% and 120.1 ± 26 nm, respectively. In vivo studies demonstrate that NPs-DOX is able to preferentially accumulate in tumor and show great tumor inhibition on H22 hepatocellular-carcinoma-bearing mice. As for the toxicity, compared with free DOX, the maximum tolerated dose of NPs-DOX is increased from 10 to over 30 mg/kg, indicating the reduced systematic toxicity. More importantly, the cardiotoxicity induced by NPs-DOX is also significantly reduced because both left ventricular ejection fraction and left ventricular fractional shortening are almost not changed and other cardiotoxicity markers such as serum creatine kinase-MB, lactate dehydrogenase, superoxide dismutase, and malonaldehyde are kept constant. The reduced cardiotoxicity of NPs-DOX is also confirmed by nonhistological changes in the heart tissue. Therefore, such albumin-based nanocarrier can be one of the most promising strategies for the delivery of DOX.