This paper explores the underlying mechanism through which ?-elemene inhibits the growth of intraocular melanoma in a mouse model. C57BL/6J mice were administered a subretinal injection of B16F10 melanoma cells and divided into two groups: treatment and control. The treatment group was administered ?-elemene through an intravitreal injection and the control group was injected with a blank emulsion. After 21 days of continuous treatment, tumor masses were removed and weighed. The mRNA expression levels of the urokinase-type plasminogen activator (uPA), uPA receptor (uPAR), matrix metalloproteinase (MMP)-2, and MMP-9 were assayed by real-time PCR, and the protein expression levels of uPA, uPAR, MMP-2, and MMP-9 were assayed by immunocytochemistry and western blotting. Tumor size was inhibited by ?-elemene in the treatment group, and the expressions of uPA, uPAR, MMP-2, and MMP-9 were all downregulated at both the mRNA and the protein level compared with the control group. In a mouse model of intraocular melanoma, ?-elemene inhibits tumor growth by downregulating the expression of uPA, uPAR, MMP-2, and MMP-9.
A fiber optical parametric amplified optical orthogonal frequency division multiplexing (OFDM) signal with intensity modulation transfer (IMT) blocking is proposed. A novel blank carrier blocking method is adopted to suppress pump to signal intensity interference. Compared with regular optical signal, the IMT induced interference can be well blocked in the experiment. The error vector magnitude (EVM) and signal gain are also investigated in the experiment.
Using selected-area low-energy electron diffraction analysis, we showed strict orientational alignment of monolayer hexagonal boron nitride (h-BN) crystallites with Cu(100) surface lattices of Cu foil substrates during atmospheric pressure chemical vapor deposition. In sharp contrast, the graphene-Cu(100) system is well-known to assume a wide range of rotations despite graphene's crystallographic similarity to h-BN. Our density functional theory calculations uncovered the origin of this surprising difference: The crystallite orientation is determined during nucleation by interactions between the cluster's edges and the substrate. Unlike the weaker B- and N-Cu interactions, strong C-Cu interactions rearrange surface Cu atoms, resulting in the aligned geometry not being a distinct minimum in total energy. The discovery made in this specific case runs counter to the conventional wisdom that strong epilayer-substrate interactions enhance orientational alignment in epitaxy and sheds light on the factors that determine orientational relation in van der Waals epitaxy of 2D materials.
A trityl ion-mediated practical C-H functionalization of a variety of benzopyrans with a wide range of nucleophiles (organoboranes and C-H molecules) at ambient temperature has been disclosed. The metal-free reaction has an excellent functional group tolerance and high chemoselectivity and displays a broad scope with respect to both benzopyran and nucleophile partners, efficiently affording a collection of benzopyrans bearing diverse skeletons and ?-functionalities in one step.
The aim was to investigate the relationship between apparent diffusion coefficient (ADC) values measured by diffusion-weighted magnetic resonance imaging (DW MRI) and the split glomerular filtration rate (GFR) in infants with congenital hydronephrosis. Diffusion-weighted imaging (DWI) (b = 0 and 700 seconds/mm(2)) was performed with a General Electric Company (GE) Signa 1.5T MR unit in 46 infants suffering single congenital hydronephrosis and in 30 healthy infants as normal control group. The ADCs were calculated with regions of interest (ROIs) positioned in the renal parenchyma. The 46 obstructed kidneys were classified into four groups according to the GFR level: renal dysfunction compensated group, renal dysfunction decompensated group, renal failure group, and uremia group. The renal ADCs in six groups (normal kidneys in control group, contralateral kidneys, and four groups of hydronephrotic kidneys) were compared statistically using analysis of variance (ANOVA), and the correlative relationship between ADCs and GFR was examined by Pearson's correlation test. There were statistically significant differences in renal ADCs among the six groups. The ADCs of hydronephrotic kidneys were lower than that of the normal kidneys. There was a moderate positive correlation between the ADCs of hydronephrotic kidneys and split GFR (r = 0.744). This study indicated that the ADCs of congenital hydronephrotic kidneys were lower than that of normal renal parenchyma, and there was a positive correlation between the ADCs and split renal GFR, which demonstrates that the ADCs can reflect the filtration function of hydronephrotic kidneys and may provide some reference to help clinical physician to explore a novel noninvasive approach to evaluate the single renal function.
We present an efficient segmented-stepwise method to design a short and low-loss mode-size converter. A silicon-on-insulator platform-based converter with 20 ?m length and 95.2% conversion efficiency is acquired by taking only 10 optimization generations using 2D-FDTD method. A 3D-FDTD simulation is performed to verify the calculated results, returning an efficiency of 92.1%. The proposed device can be used to connect a 12-?m-wide waveguide and a 0.5-?m-wide single-mode waveguide, with comparable performance of a regular scheme using 150-?m-long linear taper. For demonstration, the converter was fabricated by electron-beam-lithography and inductively-coupled-plasma etching. A conversion loss of -0.62±0.02??dB at 1550 nm was experimentally measured.
Abstract Objective. The incidence of propofol injection pain during induction of general anesthesia varies from 28% to 90%. This prospective, randomized, double-blind, placebo-controlled study evaluated the effect of dexmedetomidine (DEX) for reducing the incidence and severity of propofol injection pain. Methods. Patients undergoing elective surgical procedures were randomly allocated into seven groups of 30 patients each. Experimental treatments were intravenously administered over 10 min (total volume 10 mL) prior to intravenous propofol injection, as follows: group I, the control group, was given isotonic saline. Patients in groups II, III, and IV received DEX 0.25 µg/kg, 0.5 µg/kg, or 1.0 µg/kg, respectively, mixed with isotonic saline immediately before propofol injection. Patients in groups V, VI, and VII received DEX as above, but 5 minutes before propofol injection. Propofol consisted of 1% long-chain triglyceride propofol (2.5 mg/kg) injected at 1 mL/s. Results. Median propofol injection pain score was 0.00 (IQR 0.00-3.00) in patients who received 1.0 µg/kg DEX 5 min before the propofol injection (group VII), and only 1 patient (of 30) in this group received a pain score >2. The median pain score and number of patients with pain scores >2 in group VII were both significantly less than in the control (group I; p = 0.000, both). There were no differences in either mean arterial pressure or heart rate at any time point after DEX injection among the groups. Conclusions. Pretreatment with intravenous DEX 1 µg/kg 5 min prior to injection of long-chain triglyceride propofol is effective and safe in reducing the incidence and severity of pain due to propofol injection.
Many studies have shown that microvessel density (MVD) could play a potential value as prognostic biomarkers of tumors. The aim of this systematic review and meta-analysis is to evaluate the association between MVD and survival in patients with bladder cancer.
The present study was aimed to investigate the effect of pretreatment with Danshensu (DSS) on rat aortic endothelial cells (RAECs) senescence and the underlying mechanisms. Cultured RAECs at fourth and twelfth passages were taken as young and old groups, respectively. DSS and DSS+nicotinamide (DSS+N) groups were incubated with DSS and DSS in combination with nicotinamide, an inhibitor of silent information regulator 1 (SIRT1), from the fourth to twelfth passage, respectively. The cell status of senescence was determined by the senescence-associated ?-galactosidase (SA ?-gal) staining, and 4,6-diamino-2-phenyl indole (DAPI) fluorescent dye was used to detect senescence associated heterochromatin foci (SAHF) formation; Thiobarbituric acid (TBA) and colorimetric methods were used to evaluate malondialdehyde (MDA) and H2O2 contents; Western blot was employed to analysis the expressions of xanthine oxidase (XOD), SIRT1 and superoxide dismutase 2 (SOD2) in the RAECs. The results showed that, in comparison with young group, the old group exhibited higher SA ?-gal positive and SAHF formation rates, as well as higher MDA and H2O2 levels (P < 0.05 or P < 0.01), whereas DSS pretreatment reduced SA ?-gal positive and SAHF formation rates, decreased MDA and H2O2 contents (P < 0.05 or P < 0.01). The protection of DSS was reversed by nicotinamide. Compared with the young group, the old group showed higher expression levels of XOD, but lower SIRT1 and SOD2 expression levels (P < 0.05 or P < 0.01). With the pretreatment of DSS, the expression of XOD was declined, and the expression levels of SIRT1 and SOD2 were elevated, while nicotinamide reversed the effects of DSS. These results suggest that DSS delays senescence of RAECs via up-regulation of SIRT1.
This study was to compare clinical and radiographic outcomes with three different implants and evaluate the effectiveness of minimally invasive plate osteosynthesis (MIPO) technique for the distal fibular fractures.
Although tumor necrosis factor alpha (TNF-?) is known to play a critical role in intervertebral disc (IVD) degeneration, the effect of TNF-? on nucleus pulposus (NP) cells has not yet been elucidated. The aim of this study was to explore the effect of TNF-? on proliferation of human NP cells. NP cells were treated with different concentrations of TNF-?. Cell proliferation was determined by cell counting kit-8 (CCK-8) analysis and Ki67 immunofluorescence staining, and expression of cyclin B1 was studied by quantitative real-time RT-PCR. Cell cycle was measured by flow cytometry and cell apoptosis was analyzed using an Annexin V-fluorescein isothiocyanate (FITC) & propidium iodide (PI) apoptosis detection kit. To identify the mechanism by which TNF-? induced proliferation of NP cells, selective inhibitors of major signaling pathways were used and Western blotting was carried out. Treatment with TNF-? increased cell viability (as determined by CCK-8 analysis) and expression of cyclin B1 and the number of Ki67-positive and S-phase NP cells, indicating enhancement of proliferation. Consistent with this, NP cell apoptosis was suppressed by TNF-? treatment. Moreover, inhibition of NF-?B, c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK) blocked TNF-?-stimulated proliferation of NP cells. In conclusion, the current findings suggest that the effect of TNF-? on IVD degeneration involves promotion of the proliferation of human NP cells via the NF-?B, JNK, and p38 MAPK pathways.
Context: Betatrophin has recently attracted increasing interests as a potential ?-cell regenerative therapy in diabetes. However, differences in betatrophin profiles in patients with type 2 diabetes mellitus (T2DM) remain unclear. Objective: To examine circulating betatrophin levels in subjects with different glucose tolerance status and its correlation with insulin resistance. Design, Setting and Participants: Serum betatrophin levels were measured using ELISA in age-, sex-, BMI- and blood lipids- matched subjects with normal glucose tolerance (NGT) (n=137), isolated impaired fasting glucose (IFG) (n=69), isolated impaired glucose tolerance (IGT) (n=120) and newly diagnosed T2DM (n=112) from the Risk Evaluation of cAncers in Chinese diabeTic Individuals: a lONgitudinal (REACTION) study. Results: Serum betatrophin levels were elevated in patients with T2DM compared to subjects with NGT, isolated IFG or isolated IGT (798.6 ± 42.5 vs. 692.7 ± 29.0, P < 0.05; vs. 682.7 ± 43.0, P < 0.05; vs. 646.8 ± 34.3, P < 0.01). Betatrophin levels positively correlated with index of homeostasis model assessment of insulin resistance (HOMA-IR) (partial r = 0.11); inversely correlated with quantitative insulin sensitivity check index (QUICKI) (partial r = -0.11), the Gutt insulin sensitivity index (ISIG) (partial r = -0.12) and the Matsuda insulin sensitivity index (ISIM) (partial r = -0.11) after controlling for age, sex, BMI and blood lipid in all participants (all P values < 0.05). Conclusion: Circulating betatrophin levels are increased in patients with T2DM and associated with indexes of insulin resistance.
Rotenone, a common pesticide and inhibitor of mitochondrial complex I, induces loss of dopaminergic neurons and consequential aspects of Parkinson's disease (PD). However, the exact mechanism of rotenone neurotoxicity is not fully elucidated. Here, we show that rotenone induced reactive oxygen species (ROS), leading to apoptotic cell death in PC12 cells and primary neurons. Pretreatment with catalase (CAT), a hydrogen peroxide-scavenging enzyme, attenuated rotenone-induced ROS and neuronal apoptosis, implying hydrogen peroxide (H2O2) involved, which was further verified by imaging intracellular H2O2 using a peroxide-selective probe H2DCFDA. Using thenoyltrifluoroacetone (TTFA), antimycin A, or Mito-TEMPO, we further demonstrated rotenone-induced mitochondrial H2O2-dependent neuronal apoptosis. Rotenone dramatically inhibited mTOR-mediated phosphorylation of S6K1 and 4E-BP1, which was also attenuated by CAT in the neuronal cells. Of interest, ectopic expression of wild-type mTOR or constitutively active S6K1, or downregulation of 4E-BP1 partially prevented rotenone-induced H2O2 and cell apoptosis. Furthermore, we noticed that rotenone-induced H2O2 was linked to the activation of caspase-3 pathway. This was evidenced by the finding that pretreatment with CAT partially blocked rotenone-induced cleavages of caspase-3 and poly (ADP-ribose) polymerase. Of note, zVAD-fmk, a pan caspase inhibitor, only partially prevented rotenone-induced apoptosis in PC12 cells and primary neurons. Expression of mTOR-wt, S6K1-ca, or silencing 4E-BP1 potentiated zVAD-fmk protection against rotenone-induced apoptosis in the cells. The results indicate that rotenone induction of H2O2 inhibits mTOR-mediated S6K1 and 4E-BP1/eIF4E pathways, resulting in caspase-dependent and -independent apoptosis in neuronal cells. Our findings suggest that rotenone-induced neuronal loss in PD may be prevented by activating mTOR signaling and/or administering antioxidants.
Ciclopirox olamine (CPX), a fungicide, has been demonstrated as a potential anticancer agent. However, the underlying anticancer mechanism is not well understood. Here, we found that CPX induced autophagy in human rhabdomyosarcoma (Rh30 and RD) cells. It appeared that CPX-induced autophagy was attributed to induction of reactive oxygen species (ROS), as N-acetyl-L-cysteine (NAC), a ROS scavenger and antioxidant, prevented this process. Furthermore, we observed that CPX induced activation of mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK) and p38 MAPK, which was also blocked by NAC. However, only inhibition of JNK (with SP600125) or expression of dominant negative c-Jun partially prevented CPX-induced autophagy, indicating that ROS-mediated activation of JNK signaling pathway contributed to CPX-induced autophagy. Of interest, inhibition of autophagy by chloroquine (CQ) enhanced CPX-induced cell death, indicating that CPX-induced autophagy plays a pro-survival role in human rhabdomyosarcoma cells. Our finding suggests that the combination with autophagy inhibitors may be a novel strategy in potentiating the anticancer activity of CPX for treatment of rhabdomyosarcoma.
We report first-principles theoretical investigations of quantum transport in a monolayer WSe2 field effect transistor (FET). Due to strong spin-orbit interaction (SOI) and the atomic structure of the two-dimensional lattice, monolayer WSe2 has an electronic structure that exhibits Zeeman-like up-down spin texture near the K and [Formula: see text] points of the Brillouin zone. In a FET, the gate electric field induces an extra, externally tunable SOI that re-orients the spins into a Rashba-like texture thereby realizing electric control of the spin. The conductance of FET is modulated by the spin texture, namely by if the spin orientation of the carrier after the gated channel region, matches or miss-matches that of the FET drain electrode. The carrier current [Formula: see text] in the FET is labelled by both the valley index and spin index, realizing valleytronics and spintronics in the same device.
Distal arthrogryposis type 2B (DA2B) is an important genetic disorder in humans. However, the mechanisms governing this disease are not clearly understood. In this study, we generated knock-in mice carrying a DA2B mutation (K175del) in troponin I type 2 (skeletal, fast) (TNNI2), which encodes a fast-twitch skeletal muscle protein. Tnni2K175del mice (referred to as DA2B mice) showed typical DA2B phenotypes, including limb abnormality and small body size. However, the current knowledge concerning TNNI2 could not explain the small body phenotype of DA2B mice. We found that Tnni2 was expressed in the osteoblasts and chondrocytes of long bone growth plates. Expression profile analysis using radii and ulnae demonstrated that Hif3a expression was significantly increased in the Tnni2K175del mice. Chromatin immunoprecipitation assays indicated that both wild-type and mutant tnni2 protein can bind to the Hif3a promoter using mouse primary osteoblasts. Moreover, we showed that the mutant tnni2 protein had a higher capacity to transactivate Hif3a than the wild-type protein. The increased amount of hif3a resulted in impairment of angiogenesis, delay in endochondral ossification, and decrease in chondrocyte differentiation and osteoblast proliferation, suggesting that hif3a counteracted hif1a-induced Vegf expression in DA2B mice. Together, our data indicated that Tnni2K175del mutation led to abnormally increased hif3a and decreased vegf in bone, which explain, at least in part, the small body size of Tnni2K175del mice. Furthermore, our findings revealed a new function of tnni2 in the regulation of bone development, and the study of gain-of-function mutation in Tnni2 in transgenic mice opens a new avenue to understand the pathological mechanism of human DA2B disorder.
Viruses utilize host factors for their efficient proliferation. By evaluating the inhibitory effects of compounds in our library, we identified inhibitors of cyclophilin A (CypA), a known immunosuppressor with peptidyl-prolyl cis-trans isomerase activity, can significantly attenuate EV71 proliferation. We demonstrated that CypA played an essential role in EV71 entry and that the RNA interference-mediated reduction of endogenous CypA expression led to decreased EV71 multiplication. We further revealed that CypA directly interacted with and modified the conformation of H-I loop of the VP1 protein in EV71 capsid, and thus regulated the uncoating process of EV71 entry step in a pH-dependent manner. Our results aid in the understanding of how host factors influence EV71 life cycle and provide new potential targets for developing antiviral agents against EV71 infection.
The pH-related fluorescence quenching mechanism of 2-amino-4-hydroxypteridine (pterin), a biologic functional molecule, in the presence of acetate ion has been fully investigated for the first time. Using a combined experimental and theoretical approach, we discover that the fluorescence quenching observed in acid condition originated from a barrierless excited-state proton-transfer process. The proton on the acid form of pterin is transferred to acetate after photoexcitation. The hydrogen-bonding patterns are found to change with the pH values that govern the occurrence of excited-state proton transfer (ESPT). As revealed by investigating the excitation and relaxation processes of pterin, this ESPT process shows impressive site specificity intrinsically due to the photoinduced acidic center shifting. The experimentally observed fluorescence quenching and lifetime shortening of pterin in acid condition are thus attributed to the site-specific proton transfer from the N5 site. Pterin exists extensively in living organisms and has been found to show favorable proton-donating ability, which may transfer its proton to biofunctional molecules with hydrogen-accepting groups and induce related bioeffects.
The anatomically and functionally complex nature of the temporomandibularjoint (TMJ) makes its reconstruction one of the most challenging tasks faced by surgeons who operate in the head and neck. TMJ prosthesis is one of the important techniques in the reconstruction of TMJ. The main indications for TMJ prosthesis include ankylosis, fractures of condylar that can't be fixed, trauma or tumor, end-stage TMJ disturbance, and TMJ dysplasia caused by Hallermann-Streiff syndrome. TMJ replacement aims to enhance the function of TMJ, alleviate pain, and prevent serious complications. TMJ prosthesis is advantageous in oral and maxillofacial surgery because it can imitate normal anatomic morphology and adhere to the host. Moreover, the use of other materials is no longer necessary and functional training can be started postoperatively at once, among others. Prosthetic materials have leading and promoting functions in the development of joint prosthesis. Good design, fit shape, and fixation are the necessary conditions for prosthesis to serve its function. Investigation of joint biomechanics is also necessary. With the rapid developments in material science, joint biomechanics, and other related subjects, TMJ prosthesis has been significantly improved in terms of its materials, design, fit shape, and fixation techniques. In addition, the development of TMJ prosthesis would expand its applications. This review intends to provide an overview about the progress and clinical application of TMJ prosthesis.
Wnt-?-catenin (?-catenin is also known as CTNNB1 in human) signaling through the ?-catenin-TCF complex plays crucial roles in tissue homeostasis. Wnt-stimulated ?-catenin-TCF complex accumulation in the nucleus regulates cell survival, proliferation and differentiation through the transcription of target genes. Compared with their levels in G1, activation of the receptor LRP6 and cytosolic ?-catenin are both upregulated in G2 cells. However, accumulation of the Wnt pathway negative regulator AXIN2 also occurs in this phase. Therefore, it is unclear whether Wnt signaling is active in G2 phase cells. Here, we established a bimolecular fluorescence complementation (BiFC) biosensor system for the direct visualization of the ?-catenin-TCF interaction in living cells. Using the BiFC biosensor and co-immunoprecipitation experiments, we demonstrate that levels of the nucleus-localized ?-catenin-TCF complex increase during the S and G2 phases, and declines in the next G1 phase. Accordingly, a subset of Wnt target genes is transcribed by the ?-catenin-TCF complex during both the S and G2 phases. By contrast, transient inhibition of this complex disturbs both cell survival and G2/M progression. Our results suggest that in S and G2 phase cells, Wnt-?-catenin signaling is highly active and functions to ensure cell survival and cell cycle progression.
A novel method for the synthesis of non-natural L- and D-amino acids by a Ni-catalyzed reductive cross-coupling reaction is described. This strategy enables the racemization-free cross-coupling of serine/homoserine- derived iodides with aryl/acyl/alkyl halides. It provides convenient access to varieties of enantiopure and functionalized amino acids, which are important building blocks in bioactive compounds and pharmaceuticals.
Proton pump inhibitor (PPI) was the main prescription for gastric ulcer after endoscopic submucosal dissection (ESD). Some randomized controlled trials showed that a combination of rebamipide and PPI appears to be more efficient than PPI alone for the treatment of ESD-induced gastric ulcer. However, the sample sizes in these trials were limited and the conclusions were underpowered.This meta-analysis was conducted with 5 randomized controlled trials using the combination of rebamipide and PPI for healing ESD-induced ulcer compared with PPI monotherapy. Relevant studies were searched via MEDLINE, PubMed, Embase, and Cochrane Library databases by using terms such as "rebamipide," "proton pump inhibitor," "endoscopic submucosal dissection," "drug therapy," and "gastric ulcer or artificial ulcer."Five studies were included in this meta-analysis. The number of total patients was 626, with 317 patients in the combination group and 309 patients in the PPI alone group. The heterogeneity among these 5 studies was low (I?=?22%, P?=?0.28). All 5 studies considered scarring stage 1 rate as a primary endpoint, and the scarring stage 1 rate in combination group (115/317) was higher than that in PPI alone group (63/309) (odds ratio 2.61, 95% confidence interval [CI] 1.76-3.88). The mean difference of initial ulcer size between 2 groups was -4.46 (95% CI -266.61 to -257.69, P?=?0.97), but it enlarged to 68.38 (95% CI 35.72-101.05, P?0.00001) in the 4th week.This meta-analysis demonstrates that combination therapy is more efficient than PPI monotherapy in healing ESD-induced gastric ulcer.
Phospholipids (PLs) play a prominent role in both grain cellular structure and nutritional function of cereal crops. Their lyso forms (lysophospholipids, LPLs) often combine with cereal starch to form an amylose-lipid complex (ALC), which may influence starch properties. In this study, 20 rice accessions were grown over two seasons at the same location to explore diversity in LPLs of milled rice. Levels of specific LPLs differed significantly among rice genotypes, demonstrating there is a wide diversity in LPLs in rice grain. The main LPL components were lysophosphatidylcholine (LPC) 16:0 (ranging from 3009.7 to 4697.8 ?g/g), LPC18:2 (836.6-2182.3 ?g/g), lysophosphatidylethanolamine (LPE) 16:0 (625.7-1139.8 ?g/g), and LPE18:2 (170.6-481.6 ?g/g). Total LPC, total LPE, and total LPL ranged from 4727.1 to 7685.2 ?g/g, from 882.8 to 1809.5 ?g/g, and from 5609.8 to 9401.1 ?g/g, respectively. Although significant (P < 0.001) environment and genotype × environment (G × E) interactions were detected by analysis of variance (ANOVA), these effects accounted for only 0.7-38.9 and 1.8-6.6% of the total variance, respectively. Correlation analysis between LPL components provided insight into the possible LPL biosynthesis pathway in plants. Hierarchical cluster analysis suggested that the 20 rice accessions could be classified into three groups, whereas principal component analysis also identified three groups, with the first two components explaining 57.7 and 16.2% of the total variance. Further genetic studies are needed to identify genes or quantitative trait loci (QTLs) underlying the genetic control of LPLs in rice grain.
A copper-catalyzed reductive cross-coupling reaction of nonactivated alkyl tosylates and mesylates with alkyl and aryl bromides was developed. It provides a practical method for efficient and cost-effective construction of aryl-alkyl and alkyl-alkyl C?C bonds with stereocontrol from readily available substrates. When used in an intramolecular fashion, the reaction enables convenient access to various substituted carbo- or heterocycles, such as 2,3-dihydrobenzofuran and benzochromene derivatives.
Amyloid peptides are considered to be the main contributor for the membrane disruption related to the pathogenesis of degenerative diseases. The variation of amino acids at the carboxylic terminus of amyloid peptide has revealed significant effects on the modulation of abnormal assemblies of amyloid peptides. In this work, molecular binding agents were tethered to the C-terminus of ?-amyloid peptide 1-42 (A?42). The molecular interaction between A?42 and molecule tethers was identified at single molecule level by using scanning tunneling microscopy (STM). The mechanistic insight into the feature variation of the self-assembly of A?42 peptide caused by molecular tethering at C-terminus was clearly revealed, which could appreciably affect the nucleation of amyloid peptide, thus reducing the membrane disruptions.
Neuronal necrosis induced by calcium overload causes devastating brain dysfunction in diseases such as stroke and brain trauma. It has been considered a stochastic event lacking genetic regulation, and pharmacological means to suppress neuronal necrosis are lacking. Using a Drosophila model of calcium overloading, we found JIL-1/mitogen- and stress-activated protein kinase 1/2 is a regulator of neuronal necrosis through phosphorylation of histone H3 serine 28 (H3S28ph). Further, we identified its downstream events including displacement of polycomb repressive complex 1 (PRC1) and activation of Trithorax (Trx). To test the role of JIL-1/PRC1/Trx cascade in mammals, we studied the necrosis induced by glutamate in rat cortical neuron cultures and rodent models of brain ischemia and found the cascade is activated in these conditions and inhibition of the cascade suppresses necrosis in vitro and in vivo. Together, our research demonstrates that neuronal necrosis is regulated by a chromatin-modifying cascade, and this discovery may provide potential therapeutic targets and biomarkers for neuronal necrosis.
Prevention and early detection of atherosclerosis are critical for protection against subsequent circulatory disease. In this study, an automated two-dimensional ultrasonic-measurement-integrated (2D-UMI) blood flow analysis system for clinical diagnosis was developed, and the feasibility of the system for hemodynamic analysis in a carotid artery was revealed. The system automatically generated a 2D computational domain based on ultrasound color Doppler imaging and performed a UMI simulation of blood flow field to visualize hemodynamics in the domain. In the UMI simulation, compensation of errors was applied by adding feedback signals proportional to the differences between Doppler velocities by measurement and computation while automatically estimating the cross-sectional average inflow velocity. The necessity of adjustment of the feedback gain was examined by analyzing blood flow in five carotid arteries: three healthy, one sclerosed, and one stenosed. The same feedback gain was generally applicable for the 2D-UMI simulation in all carotid arteries, depending on target variables. Thus, the present system was shown to be versatile in the sense that the parameter is patient independent. Moreover, the possibility of a new diagnostic method based on the hemodynamic information obtained by the 2D-UMI simulation, such as a waveform of the cross-sectional average inflow velocity and wall shear stress distributions, was suggested.
Chetomin is a promising molecule with anti-tumor activities in the epipolythiodioxopiperazine family of fungal secondary metabolites; however, strong hydrophobicity has limited its further applications. In this work, chetomin was encapsulated into polymeric micelles to obtain an aqueous formulation, and the chetomin loaded micelles (Che-M) exhibited small particle size and high encapsulation efficiency. When the concentration of copolymer was higher than the critical gelation concentration, the Che-M could form a thermosensitive hydrogel (Che-H), which was free-flowing sol at ambient temperature and converted into a non-flowing gel at body temperature. The molecular modeling study has indicated that chetomin interacted with PCL as a core, which was embraced by PEG as a shell. Che-M showed equal cytotoxicity with free chetomin, but the apoptosis inducing effects of Che-M were more significant. Besides, Che-M could increase the GSSG level, decrease the GSH level, and increase the ROS in CT26 cells. Furthermore, stronger inhibitory effects of Che-M were observed on embryonic angiogenesis, tumor-induced angiogenesis and tumor growth in transgenic zebrafish models. In addition, Che-M was effective in inhibiting tumor growth and prolonging survival in a subcutaneous CT26 tumor model. In a colorectal peritoneal carcinomatosis model, both Che-M and Che-H showed excellent therapeutic effects, but Che-H was more effective. In conclusion, Che-M and Che-H may serve as candidates for cancer therapy.
Drugs that can protect against organ damage are urgently needed, especially for diseases such as sepsis and brain stroke. We discovered that terazosin (TZ), a widely marketed ?1-adrenergic receptor antagonist, alleviated organ damage and improved survival in rodent models of stroke and sepsis. Through combined studies of enzymology and X-ray crystallography, we discovered that TZ binds a new target, phosphoglycerate kinase 1 (Pgk1), and activates its enzymatic activity, probably through 2,4-diamino-6,7-dimethoxyisoquinoline's ability to promote ATP release from Pgk1. Mechanistically, the ATP generated from Pgk1 may enhance the chaperone activity of Hsp90, an ATPase known to associate with Pgk1. Upon activation, Hsp90 promotes multistress resistance. Our studies demonstrate that TZ has a new protein target, Pgk1, and reveal its corresponding biological effect. As a clinical drug, TZ may be quickly translated into treatments for diseases including stroke and sepsis.
Most anticancer drugs are not able to cross the blood-brain barrier (BBB) effectively while surgery and radiation therapy cannot eradicate brain glioma cells and glioma stem cells (GSCs), hence resulting in poor prognosis with high recurrence rates. In the present study, a kind of multifunctional targeting daunorubicin plus quinacrine liposomes was developed for treating brain glioma and GSCs. Evaluations were performed on in-vitro BBB model, murine glioma cells, GSCs, and GSCs bearing mice. Results showed that the multifunctional targeting daunorubicin plus quinacrine liposomes exhibited evident capabilities in crossing the BBB, in killing glioma cells and GSCs and in diminishing brain glioma in mice. Action mechanism studies indicated that the enhanced efficacy of the multifunctional targeting drugs-loaded liposomes could be due to the following aspects: evading the rapid elimination from blood circulation; crossing the BBB effectively; improving drug uptake by glioma cells and GSCs; down-regulating the overexpressed ABC transporters; inducing apoptosis of GSCs via up-regulating apoptotic receptor/ligand (Fas/Fasl), activating apoptotic enzymes (caspases 8, 9 and 3), activating pro-apoptotic proteins (Bax and Bok), activating tumor suppressor protein (P53) and suppressing anti-apoptotic proteins (Bcl-2 and Mcl-1). In conclusion, the multifunctional targeting daunorubicin plus quinacrine liposomes could be used as a potential therapy for treating brain glioma and GSCs.
Bifidobacterium animalis RH is a probiotic bacterium producing exopolysaccharides, which was isolated from the feces of Bama centenarians in Guangxi, China. The genome consists of one chromosome (1,931,057bp) with no plasmid. The genomic sequence indicated that this strain includes a gene cluster involved in exopolysaccharides (EPS) biosynthesis. Genome sequencing information provides the basis for analysis of molecular mechanisms responsible for regulation of production of EPS.
Prostate cancer is one of the most common malignant diseases and is characterized by heterogeneity in the clinical course. To date, there are no efficient morphologic features or genomic biomarkers that can characterize the phenotypes of the cancer, especially with regard to metastasis--the most adverse outcome. Searching for effective surrogate genes out of large quantities of gene expression data is a key to cancer phenotyping and/or understanding molecular mechanisms underlying prostate cancer development.
The aim of this study was to investigate the function of miR-183 in renal cancer cells and the mechanisms miR-183 regulates this process. In this study, level of miR-183 in clinical renal cancer specimens was detected by quantitative real-time PCR. miR-183 was up- and down-regulated in two renal cancer cell lines ACHN and A498, respectively, and cell proliferation, Caspase 3/7 activity, colony formation, in vitro migration and invasion were measured; and then the mechanisms of miR-183 regulating was analyzed. We found that miR-183 was up-regulated in renal cancer tissues; inhibition of endogenous miR-183 suppressed in vitro cell proliferation, colony formation, migration, and invasion and stimulated Caspase 3/7 activity; up-regulated miR-183 increased cell growth and metastasis and suppressed Caspase 3/7 activity. We also found that miR-183 directly targeted tumor suppressor, specifically the 3'UTR of three subunits of protein phosphatase 2A (PP2A-C?, PP2A-C?, and PP2A-B56-?) transcripts, inhibiting their expression and regulated the downstream regulators p21, p27, MMP2/3/7 and TIMP1/2/3/4. These results revealed the oncogenes role of miR-183 in renal cancer cells via direct targeting protein phosphatase 2A.
Fibroblast growth factor 21 (FGF-21), which is a modulator of glucose and lipid homeostasis, acts as a novel therapeutic reagent for many metabolic perturbations. However, its potential as a treatment for cardiovascular disease, especially atherosclerosis (AS) has not been fully explored. Here, we report that recombinant FGF-21 improves resistance to cell damage from oxidative stress in vitro, and from atherosclerosis in vivo. Human umbilical vein endothelial cells (HUVECs) were induced with H2O2, followed by treatment with high purity recombinant FGF-21. The results indicated that FGF-21 significantly enhanced cell viability and decreased the degree of DNA fragmentation in HUVECs, as caused by H2O2 stress induction. Further studies revealed that FGF-21 inhibited H2O2-induced cell apoptosis by preventing the activation of mitogen-activated protein kinase (MAPK) signaling pathways. In an established rat model, FGF-21 dramatically improved the condition of atherosclerotic rats by decreasing serum levels of total triglyceride (TG), low density lipoprotein cholesterol (LDL-C), and total cholesterol (TC), and by increasing the serum levels of high density lipoprotein cholesterol (HDL-C). FGF-21 also has antioxidant effects in the atherosclerotic rat, such that increased levels of superoxide dismutase, reduced glutathione, and reduced malondialdehyde were observed. These data provide novel insight into the potential use of FGF-21 in the prevention and treatment of human cardiovascular diseases.
An activated manganese dioxide (MnO2)-BF3·OEt2 oxidation system was developed to efficiently mediate the intramolecular as well as intermolecular biaryl coupling. The oxidative coupling proceeds smoothly at ambient temperature to deliver the corresponding five- to eight-membered tricyclic products in good to excellent yields. The employment of the combination of MnO2 and BF3·OEt2 is attractive on the basis of economical and environmental issues.
A facile strategy was established to develop a drug delivery system (DDS) based on the graphene oxide nanoparticles (GON) with suitable size and shape to deliver drug effectively, by grafting the biocompatible PEGylated alginate (ALG-PEG) brushes onto the GON via the disulfide bridge bond. TEM analysis and drug-loading performance revealed that the 3-D nanoscaled, biocompatible, reduction-responsive nanocarriers (GON-Cy-ALG-PEG) were spherical in shape with diameters of 94.73 ± 9.56 nm. They possessed high doxorubicin (DOX)-loading capacity and excellent encapsulation efficiency, owing to their unique 3-D nanoscaled structure. They also had excellent stability in simulated physiological conditions and remarkable biocompatibility. Importantly, the in vitro release showed that the platform could not only prevent the leakage of the loaded DOX under physiological conditions but also detach the cytamine (Cy) modified PEGylated alginate (Cy-ALG-PEG) moieties, response to glutathione (GSH). Confocal microscopy and WST-1 assays provided clear evidence of the DOX-loaded GON-Cy-ALG-PEG endocytosis, whereas the drug-loaded nanocarriers exhibited high cytotoxicity to model cells. Furthermore, the cell apoptosis also was monitored via Flow cytometry. The results indicated that the DOX-loaded nanocarriers presented favorable efficiency of cell apoptosis. So these findings demonstrate that the accelerated release of the loaded DOX was realized in the presence of an elevated GSH that simulate the acidic endosomal compartments.
Everolimus, an oral inhibitor of mammalian target of mTOR, has been recently shown to have antitumor effect in a phase III, double-blind, randomized trial (RADIANT-3) of 410 patients with advanced pancreatic neuroendocrine tumors (PNETs). The purpose of this study was to investigate the specific efficacy and safety of everolimus in the Chinese patient with PNETs. In this randomized phase II study, the analysis on Chinese patients was performed comparing efficacy and safety between everolimus 10 mg/day orally (n = 44) and matching placebo (n = 35). The primary endpoint was progression-free survival (PFS). Adverse events were also examined. The median PFS was 15.47 months with everolimus [95 % confidence interval (CI) 10.52-26.37], as compared to 4.29 months with placebo (95 % CI 2.22-10.75), representing a 72 % reduction in the risk of progression or death (hazard ratio 0.27; 95 % CI 0.13-0.59; P < 0.001). Drug-associated adverse events (AEs) were mostly grade 1 or 2, observed in all 44 (100 %) patients receiving everolimus and in 29 (83 %) patients receiving placebo. The most common AEs (grade 1-4) associated with everolimus were rash (n = 38; 86 %), stomatitis (n = 30; 68 %), infections (n = 33; 75 %), epistaxis (n = 32; 73 %), pneumonitis (n = 27; 61 %) and anemia (n = 22; 50 %). Everolimus when compared with placebo is effectively in improving PFS in Chinese patients with PNETs.
Two cases of hypogonadotropic hypogonadism caused by pituitary stalk interruption syndrome treated by pulse infusion of gonadorelin via micropump were reported, and their clinical features and the treatment process of pulse infusion of gonadorelin via micropump summarized. Both of the 2 patients were presented primarily with hypogonadotropic hypogonadism. After the treatment with pulse infusion of gonadorelin via micropump, their syndrome of androgen deficiency improved and the gonadotropin levels promoted at the end of 12 weeks' follow-up. Pulse infusion of gonadorelin via micropump is an alternative to treat hypogonadotropic hypogonadism caused by pituitary stalk interruption syndrome.
Isolation and characterization of circulating tumor cells (CTCs) in patients suffering from a variety of different cancers have become hot biomarker topics. In this study, we evaluated the prognostic value of CTCs in pancreatic cancer.
Antioxidant may provide anti-arthritic effect that contributes to resolution of inflammation. Gallic acid (GA) and its derivatives were reported to be effective in treatment of arthritis. But GA-suppressed cell proliferation may compromise its effect on chondro-protection. In this study, we synthesized sulfonamido-based gallate-JEZTC and investigated its effect on rabbit articular chondrocytes through examination of the cell proliferation, morphology, viability, glycosaminoglycan (GAG) synthesis, and cartilage-specific gene expression. Results showed that JEZTC could effectively promote chondrocyte growth and enhance secretion and synthesis of cartilage extracellular matrix (ECM) by upregulating expression levels of aggrecan, collagen II, and Sox9 genes. Expression of collagen I which marked chondrocyte dedifferentiation was effectively downregulated by JEZTC. In addition, hypertrophy that may lead to chondrocyte ossification could not be detected in JEZTC groups. The results indicated JEZTC can well preserve the phenotype of chondrocytes. Range of 2.344 to 9.375 ?g/ml is the recommended dose of JEZTC, which showed increased cell proliferation. Especially, JEZTC of 4.688 ?g/ml showed the best performance. This study might provide a basis for development of a novel agent for the treatment of symptomatic chondral and osteochondral lesions.
Sirtuins are NAD-dependent protein deacetylases that were shown to have protective effects against different age-related diseases. SIRT2 is a strong deacetylase that is highly expressed in brain. It has been associated with neurodegenerative diseases. MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a dopaminergic neurotoxin that displays clinical features of Parkinson's Disease (PD). MPTP leads to the degeneration of nigrostriatal dopaminergic pathway after its systemic administration. Chronic administration of MPTP induces lesion via apoptosis. We show here that SIRT2 deacetylates Foxo3a, increases RNA and protein levels of Bim, and as a result enhances apoptosis in the MPTP model of PD. We also show that neurodegeneration induced by chronic MPTP regimen is prevented by genetic deletion of SIRT2 in mouse. Deletion of SIRT2 leads to the reduction of apoptosis due to an increase in acetylation of Foxo3a and a decrease in Bim levels. We demonstrate that SIRT2 deacetylates Foxo3a, activates Bim, and induces apoptosis only in MPP(+)-treated cells. Therefore, designing SIRT2 inhibitors might be helpful in developing effective treatments for PD.
The aim of this study was to investigate the clinical value of different criteria and to understand the relationship between genotype and phenotype in Chinese hereditary nonpolyposis colorectal cancer (HNPCC). A total of 116 unrelated probands of suspected HNPCC families from the Fudan Colorectal Registry were studied. A total of 32, 28, and 56 families fulfilled the Amsterdam criteria, the Fudan criteria and the revised Bethesda guideline, respectively. Direct DNA sequencing of all exons of hMSH2 and hMLH1 genes were performed on all 116 samples. Mutations and clinicopathological features were compared between the groups. Thirty-two pathological germline mutations were identified. Out of 32 mutations, 16 were located at hMLH1 and 16 at hMSH2. The sensitivity of Amsterdam criteria was 50%, specificity was 81%, and Youden's index was 31%. The sensitivity of Fudan criteria was 75%, specificity was 58%, and Youden's index was 33%. Among all the 32 families with mutations, families with hMSH2 mutation had a higher ratio of synchronous and metachronous colon cancers than families with hMLH1 mutation (33 vs. 6%, P=0.04). Patients with hMSH2 mutation more frequently harbour synchronous and metachronous colon cancers. Fudan criteria had a little higher sensitivity and accuracy than Amsterdam criteria for identification of Chinese HNPCC.
Purification, characterization and antioxidant activities of polysaccharides from thinned-young apple (TYA) were investigated in the study. A water-soluble polysaccharide (TYAP) was obtained with hot water extraction, which was further purified by chromatography of Cellulose DEAE-52 and Sephadex G-150 to get three purified fractions of TYAP-1, TYAP-2 and TYAP-3. HPLC analysis showed that the three fractions were mainly composed of galactose and arabinose with the average molecular weights of 115kDa, 479kDa and 403kDa, respectively and the monosaccharide compositions of TYAP-2 and TYAP-3 were more complicated than that of TYAP-1. Moreover, TYAP fractions of three had no absorptions at 260nm and 280nm in the UV spectrum, indicating the absence of protein and nucleic acid. Their structure properties were further confirmed by FT-IR. In vitro antioxidant activities of three fractions were characterized by DPPH(•), HO(•), O2(•-) and ferric-reducing antioxidant power systems. The results indicated that TYAP-1, TYAP-2 and TYAP-3 possessed significant antioxidant effects in a concentration-dependant manner in the tested concentration range of 0.25-5.0mg/mL. Among the fractions tested, TYAP-3 showed significantly higher antioxidant activity than that of TYAP-1 and TYAP-2. All of these findings provide a scientific basis for the further use of polysaccharides from thinned-young apple.
Glutamatergic projections from the medial prefrontal cortex (mPFC) to nucleus accumbens (NAc) contribute to cocaine relapse. Here we show that silent synapse-based remodeling of the two major mPFC-to-NAc projections differentially regulated the progressive increase in cue-induced cocaine seeking after withdrawal (incubation of cocaine craving). Specifically, cocaine self-administration in rats generated AMPA receptor-silent glutamatergic synapses within both infralimbic (IL) and prelimbic mPFC (PrL) to NAc projections, measured after 1 day of withdrawal. After 45 days of withdrawal, IL-to-NAc silent synapses became unsilenced/matured by recruiting calcium-permeable (CP) AMPARs, whereas PrL-to-NAc silent synapses matured by recruiting non-CP-AMPARs, resulting in differential remodeling of these projections. Optogenetic reversal of silent synapse-based remodeling of IL-to-NAc and PrL-to-NAc projections potentiated and inhibited, respectively, incubation of cocaine craving on withdrawal day 45. Thus, pro- and antirelapse circuitry remodeling is induced in parallel after cocaine self-administration. These results may provide substrates for utilizing endogenous antirelapse mechanisms to reduce cocaine relapse.
A self-powered polymeric micropump based on boronate chemistry is described. The pump is triggered by the presence of glucose in ambient conditions and induces convective fluid flows, with pumping velocity proportional to the glucose concentration. The pumping is due to buoyancy convection that originates from reaction-associated heat flux, as verified from experiments and finite difference modeling. As predicted, the fluid flow increases with increasing height of the chamber. In addition, pumping velocity is enhanced on replacing glucose with mannitol because of the enhanced exothermicity associated with the reaction of the latter.
As a unique and unappreciated protein posttranslational modification, arginine N-glycosylation was recently discovered to play an important role in the process that bacteria counteract host defenses. To provide chemical tools for further proteomic and biochemical studies on arginine N-glycosylation, we report the first general strategy for a rapid and cost-effective synthesis of glycopeptides carrying single or multiple arginine N-GlcNAcyl groups. These glycopeptides were successfully utilized to generate the first antibodies that can specifically recognize arginine N-GlcNAcylated peptides or proteins in a sequence-independent manner.
Hepatoma-derived growth factor (HDGF) is an acidic heparin-binding protein involved in tumor progression and poor prognosis of kinds of cancers. Aimed at investigating the functions of HDGF in intrahepatic cholangiocarcinoma (IHCC), we detected the expression of HDGF by immunohistochemistry in 83 patients. Associations of HDGF with clinicopathologic features, microvascular density (MVD), and overall survival rates were further analyzed by Chi-square method, univariate or multivariate analysis. HDGF functions in IHCC proliferation, invasion, and angiogenesis were detected by MTT, transwell, and tube formation assays, respectively. As a result, we found that HDGF-positive expression rate in IHCC was 51.8 % (43/83) in IHCC. HDGF expression was significantly correlated to MVD (P?=?0.031), lymphatic invasion (P?=?0.030), distant metastasis (P?=?0.002), and TNM stage (P?=?0.037). HDGF was further identified as an independent prognostic factor in IHCC with Kaplan-Meier method (P?=?0.003) and Cox-regression model (P?=?0.008). Moreover, both intracellular and extracellular HDGF were proved to promote the proliferation, invasion, and angiogenesis of IHCC cell lines. In conclusion, HDGF was identified as an independent prognostic biomarker in IHCC. HDGF can promote IHCC cells progression, including proliferation, invasion, and angiogenesis, indicating HDGF could become a new promising and potential drug target of IHCC.
Receptor-mediated mitophagy is one of the major mechanisms of mitochondrial quality control essential for cell survival. We previously have identified FUNDC1 as a mitophagy receptor for selectively removing damaged mitochondria in mammalian systems. A critical unanswered question is how receptor-mediated mitophagy is regulated in response to cellular and environmental cues. Here, we report the striking finding that BCL2L1/Bcl-xL, but not BCL2, suppresses mitophagy mediated by FUNDC1 through its BH3 domain. Mechanistically, we demonstrate that BCL2L1, but not BCL2, interacts with and inhibits PGAM5, a mitochondrially localized phosphatase, to prevent the dephosphorylation of FUNDC1 at serine 13 (Ser13), which activates hypoxia-induced mitophagy. Our results showed that the BCL2L1-PGAM5-FUNDC1 axis is critical for receptor-mediated mitophagy in response to hypoxia and that BCL2L1 possesses unique functions distinct from BCL2.
High risk human papillomavirus (HPV) is a well recognized causative agent of cervical cancer. Suberoylanilide hydroxamic acid (SAHA) is a potential anti-cervical cancer drug; however, its effect on the expression of HPV E6 and E7 genes remains unclear. Here, we show that, in SAHA treated HeLa cells, HPV18 E6 and E7 mRNA and protein levels were reduced, HPV18 promoter activity was decreased, and the association of RNP II with HPV18 promoter was diminished, suggesting that SAHA inhibited the transcription initiation of HPV18 E6 and E7 genes. In SAHA-treated HeLa, although the level of lysine 9-acetylated histone H3 in the whole cell extracts increased obviously, its enrichment on HPV18 promoter was significantly reduced which is correlated with the down-regulation of HPV E6 and E7.
A trityl ion mediated C?H functionalization of ethers with a wide range of nucleophiles at ambient temperature has been developed. The reaction displays high chemoselectivity and good functional group tolerance. The protocol also exhibits excellent regio- and diastereoselectivities for the unsymmetric ethers, thus stereoselectively generating highly functionalized disubstituted 2,5-trans tetrahydrofurans (THF), 2,6-trans tetrahydropyrans (THP), 2,6-trans dihydropyrans (DHP), and 1,3-trans isochromans, and highlighting the capacity of the protocol in complex molecule synthesis.
The pathological mechanism of Alzheimer's disease (AD) needs to be elucidated. The Bcl-2 associated athanogene 5 (Bag5) is an important member in the Bag family. However, the role of Bag5 in AD has not yet been elucidated. In this study, we found that expression of Bag5 is elevated in the brains of AD transgenic Tg2576 mice at both mRNA levels and proteins. In vitro experiments indicated that A?1-42 treatment led to the upregulation of Bag5 in a dose-dependent manner. In addition, our results indicated that inhibition of Bag5 using small RNA interferences exacerbated A?1-42-induced neurotoxicity. On one hand, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assay demonstrated that inhibition of Bag5 exacerbated A?1-42-related cell death. On the other hand, silence of endogenous Bag5 promotes the generation of reactive oxygen species (ROS) and malondialdehyde (MDA) induced by A?1-42. Finally and importantly, it was shown that knockdown of Bag5 exacerbated A?1-42-induced apoptosis and caspase-3 cleavage. These data suggest that induction of Bag5 might have a neuroprotective effect in AD.
Glutamate transport is a critical process in the brain that maintains low extracellular levels of glutamate to allow for efficient neurotransmission and prevent excitotoxicity. Loss of glutamate transport function is implicated in epilepsy, traumatic brain injury, and amyotrophic lateral sclerosis. It remains unclear whether or not glutamate transport can be modulated in these disease conditions to improve outcome. Here, we show that sirtuin (SIRT)4, a mitochondrial sirtuin, is up-regulated in response to treatment with the potent excitotoxin kainic acid. Loss of SIRT4 leads to a more severe reaction to kainic acid and decreased glutamate transporter expression and function in the brain. Together, these results indicate a critical and novel stress response role for SIRT4 in promoting proper glutamate transport capacity and protecting against excitotoxicity. Loss of sirtuin 4 (SIRT4) in mice leads to decreased glutamate transporter expression and function in the brain, which can ultimately cause increased excitotoxic effects. SIRT4 is up-regulated in response to treatment with the potent excitotoxin kainic acid. These results indicate a critical and novel stress response role for SIRT4 in promoting proper glutamate transport capacity and protecting against excitotoxicity. GLT-1, Glutamate Transporter 1, same as excitatory amino acid transporter 2; Glu, glutamate.
Purpose. To evaluate the pooled prevalence rate and risk factors of dry eye symptoms (DES) in mainland China. Methods. All the published population-based studies investigating the prevalence of DES in China were searched and evaluated against inclusion criteria. A systematic review and meta-analysis were performed. Results. Twelve out of the 119 identified studies were included in the meta-analysis. The pooled prevalence of DES in China was 17.0%. Female individuals, subjects living in the Northern and Western China, and over 60 years of age had significantly higher prevalent rates (21.6%, 17.9%, 31.3%, and 34.4%, resp.) compared with their counterparts. Patients with diabetes were also found to be more vulnerable to DES. Conclusions. The pooled prevalence rate of DES in mainland China was lower than that in other Asian regions and countries. A remarkable discrepancy in the prevalence in different geographic regions was noted. Aging, female gender, and diabetes were found to be risk factors for DES in China.
Chong-Myung-Tang (CMT) is a multi-herbal formula that has been used to improve memory. However, the potential mechanism remains unknown. The present study investigated the effects of CMT (50, 100, and 200 mg/kg) on spatial memory of aged mice. The behavioral training tests indicated that 200 mg/kg CMT treatment can significantly improve spatial memory of aged mice in the Morris water maze. Moreover, cell survival was examined by injecting bromodeoxyuridine (BrdU) on the first three days. The result showed that 200 mg/kg CMT treatment significantly increased cell survival in the dentate gyrus. Cell proliferation was determined by injecting BrdU 2 h before the mice were killed. The result suggested that CMT treatments had no influence on cell proliferation in the dentate gyrus. Thus, an increase in cell survival in the dentate gyrus stimulated by CMT may be involved in the effect of CMT on spatial memory improvement.
BackgroundMicroRNA-200c (miR-200c) is one of the short noncoding RNAs that play crucial roles in tumorigenesis and tumor progression. It also acts as considerable modulator in the process of epithelial-to-mesenchymal transition (EMT), a cell development regulating process that affects tumor development and metastasis. However, the role of miR-200c in bladder cancer cells and its mechanism has not been well studied. The purpose of this study was to determine the potential role of miR-200c in regulating EMT and how it contributed to bladder cancer cells in invasion, migration and proliferation.MethodsReal-time reverse transcription-PCR was used to identify and validate the differential expression of MiR-200c involved in EMT in 4 bladder cancer cell lines and clinical specimens. A list of potential miR-200 direct targets was identified through the TargetScan database. The precursor of miR-200c was over-expressed in UMUC-3 and T24 cells using a lentivirus construct, respectively. Protein expression and signaling pathway modulation were validated through Western blot analysis and confocal microscopy, whereas BMI-1 and E2F3, direct target of miR-200c, were validated by using the wild-type and mutant 3¿-untranslated region BMI-1/E2F3 luciferase reporters.ResultsWe demonstrate that MiR-200c is down-regulated in bladder cancer specimens compared with adjacent ones in the same patient. Luciferase assays showed that the direct down-regulation of BMI-1 and E2F3 were miR-200c-dependent because mutations in the two putative miR-200c-binding sites have rescued the inhibitory effect. Over-expression of miR-200c in bladder cancer cells resulted in significantly decreased the capacities of cell invasion, migration and proliferation. miR-200c over-expression resulted in conspicuous down-regulation of BMI-1and E2F3 expression and in a concomitant increase in E-cadherin levels.ConclusionsmiR-200c appears to control the EMT process through BMI-1 in bladder cancer cells, and it inhibits their proliferation through down-regulating E2F3. The targets of miR-200c include BMI-1 and E2F3, which are a novel regulator of EMT and a regulator of proliferation, respectively.
To investigate the effect and mechanism of the CXC chemokine receptor 4 (CXCR4) in the proliferation and migration of breast cancer, a short-hairpin RNA (shRNA) eukaryotic expression vector targeting CXCR4 was constructed, and the impact of such on the proliferation, adhesion and migration of human breast cancer MDA-MB-231 cells was observed. The fragments of CXCR4-shRNA were synthesized and cloned into a pGCsi-U6-Neo-green fluorescent protein vector. The recombinant plasmids were transfected into 293T cells and the most efficacious interfering vector was selected. MDA-MB-231 cells were transfected by liposome assay. The effects of silencing CXCR4 expression by shRNA on the growth, adhesion and migration of MDA-MB-231 cells were determined by Cell Counting Kit-8, cell-matrix adhesion and wound-healing assays. The shRNA eukaryotic expression vectors targeting CXCR4 (CXCR4-shRNA) were successfully constructed and transfected into 293T cells. Quantitative polymerase chain reaction and western blot analysis revealed that the maximum inhibitory rate of CXCR4 expression was 81.3%. CXCR4-shRNA transfection significantly inhibited the proliferation of MDA-MB-231 cells (P<0.05), as well as the adhesion between MDA-MB-231 cells and the extracellular matrix (P<0.05). Furthermore, wound-healing assays demonstrated that the migration distance of MDA-MB-231 cells in the CXCR4-shRNA transfection group was significantly smaller than that in the control plasmid and blank control groups (P<0.01). The CXCR4-shRNA interfering vector specifically inhibited CXCR4 expression, as well as the proliferation, adhesion and migration of MDA-MB-231 cells.
Two-dimensional interfaces between crystalline materials have been shown to generate unusual interfacial electronic states in complex oxides. Recently, a one-dimensional interface has been realized in hexagonal boron nitride and graphene planar heterostructures, where a polar-on-nonpolar one-dimensional boundary is expected to possess peculiar electronic states associated with edge states of graphene and the polarity of boron nitride. Here we present a combined scanning tunnelling microscopy and first-principles theory study of the graphene-boron nitride boundary to provide a first glimpse into the spatial and energetic distributions of the one-dimensional boundary states down to atomic resolution. The revealed boundary states are about 0.6?eV below or above the Fermi level depending on the termination of the boron nitride at the boundary, and are extended along but localized at the boundary. These results suggest that unconventional physical effects similar to those observed at two-dimensional interfaces can also exist in lower dimensions.
As microbial drug-resistance increases, there is a critical need for new classes of compounds to combat infectious diseases. The Ixodes scapularis tick antifreeze glycoprotein, IAFGP, functions as an antivirulence agent against diverse bacteria, including methicillin-resistant Staphylococcus aureus. Recombinant IAFGP and a peptide, P1, derived from this protein bind to microbes and alter biofilm formation. Transgenic iafgp-expressing flies and mice challenged with bacteria, as well as wild-type animals administered P1, were resistant to infection, septic shock, or biofilm development on implanted catheter tubing. These data show that an antifreeze protein facilitates host control of bacterial infections and suggest therapeutic strategies for countering pathogens.
There is currently no standard first-line regimen for patients with extranodal natural killer (NK)/T-cell lymphoma (ENKTCL). In this study, we investigated the efficacy and toxicity of gemcitabine (GEM) combined with oxaliplatin (L-OHP), L-asparaginase (L-ASP) and dexamethasone (DXM) (GOLD regimen) as a systemic treatment scheme for newly-diagnosed ENKTCL cases. A total of 55 patients were recruited at the Henan Province Cancer Hospital and the Cancer Center of Sun Yat-sen University between May, 2008 and August, 2012. The GOLD regimen included a 14-day treatment cycle with GEM (1,000 mg/m(2)) on day 1, L-OHP (100 mg/m(2)) on day 1, L-ASP (10,000 U/m(2)) on days 1-5 and DXM (20 mg b.i.d.) on days 1-4. The response rate, survival rate and treatment toxicity were analyzed. The overall response rate was 91% (48/55) with a complete response in 62% (34/55) and a partial response in 29% (15/55) of the patients. For all patients, the 1-, 2- and 3-year progression-free survival (PFS) rate was 86, 64 and 57% and the overall survival (OS) 91, 80 and 74%, respectively. The 1-year PFS in patients with stage I/II vs. those with III/IV disease was 87 vs. 66% (P<0.001) and the 1-year OS was 98 vs. 75%, respectively (P<0.001). No chemotherapy-related mortality or severe complications were recorded. In conclusion, the GOLD regimen was found to be highly effective and safe for the treatment of patients with newly-diagnosed ENKTCL.
Charcot-Marie-Tooth (CMT) disease is a common neurogenetic disorder and its heterogeneity is a challenge for genetic diagnostics. The genetic diagnostic procedures for a CMT patient can be explored according to the electrophysiological criteria: very slow motor nerve conduction velocity (MNCV) (<15 m/s), slow MNCV (15-25 m/s), intermediate MNCV (25-45 m/s), and normal MNCV (>45 m/s). Based on the inheritance pattern, intermediate CMT can be divided into dominant (DI-CMT) and recessive types (RI-CMT). GJB1 is currently considered to be associated with X-linked DI-CMT, and MPZ, INF2, DNM2, YARS, GNB4, NEFL, and MFN2 are associated with autosomal DI-CMT. Moreover, GDAP1, KARS, and PLEKHG5 are associated with RI-CMT. Identification of these genes is not only important for patients and families but also provides new information about pathogenesis. It is hoped that this review will lead to a better understanding of intermediate CMT and provide a detailed diagnostic procedure for intermediate CMT.
This study was conducted to investigate whether dietary Astragalus polysaccharide (APS) could alleviate immunological stress response of chickens after challenge with lipopolysaccharide (LPS). A total of 360 one-day-old commercial Arbor Acres broilers were randomly assigned in a 2×2 factorial design. The main factors were immunological stress (LPS or saline) and dietary APS (0 or 3g APS/kg feed). At 12, 14, 33 and 35 days of age, chickens were injected intramuscularly with either 500?g/kg body weight of LPS or sterile saline. The results showed that the decreased daily feed intake and daily weight gain caused by immunological stress were dramatically attenuated by APS supplementation. The LPS challenge led to an increased mRNA abundance of TLR4, NF-?B, IL-1?, IL-6, avian uncoupling protein, ?1-acid glycoprotein, hemopexin and y(+)LAT2. However, these negative effects of the LPS administration were ameliorated by APS supplementation. Moreover, dietary APS inhibited the LPS-induced depression of amino acid digestibilities. In conclusion, APS is able to alleviate LPS-induced immunological stress response in chickens. The beneficial effect may be attributed to suppressing the expression of pro-inflammatory cytokines through reducing the TLR4 and NF-?B genes transcription, and therewith improving energy and protein metabolism.
Trifloxystrobin (TFS) is the widely used strobilurin fungicide. However, little information is so far available regarding the uptake kinetics and developmental toxicity of TFS to fish. The present study was conducted to investigate the uptake kinetics, potential environment risk and toxicity of TFS on Gobiocypris rarus embryos. Results revealed that increased malformation, decreased body length and heart rate, affected spontaneous movement and swimming speed provide a gradual concentration-dependent manner; values of 144h LC50 (median lethal concentration) and EC50 (median effective concentration) were 1.11 and 0.86?gL(-1). Continuous exposure to TFS resulted in a steady accumulation with no evidence of elimination. Enzyme activities were significantly changed; reactive oxygen species and DNA damage were significantly induced after TFS treatment. Certain genes related to cell apoptosis (p53), metabolism (cyp1a), stress response (hsp70) and blood vessels (vezf1) development were all significantly up-regulated. This is the first study to define uptake kinetics and to focus on behavioral consequences, physiological changes and mRNA expression following TFS exposure in the early life stages of fish. Our results suggest that TFS is highly toxic to fish embryos.
Sonodynamic therapy (SDT), a promising modality for cancer treatment, involves the synergistic interaction of ultrasound and some chemical compounds termed sonosensitizers. However, its effect on pancreatic cancer cells remains unclear. In our study, we sought to identify the cytotoxic effects of ultrasound-activated 5-aminolevulinic acid on human pancreatic cancer Capan-1 cells. Cell viability was determined by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide) analysis; mitochondrial membrane potential was assessed using the fluorescent probe jc-1; apoptosis was evaluated by flow cytometry; cell morphology was investigated by scanning electron microscopy; apoptosis-related protein expression was analyzed by Western blot assay. We found that SDT significantly decreased the survival rate of cells, and this effect increased with 5-aminolevulinic acid concentration and ultrasound exposure time. The mechanism underlying the effect of SDT involves, in part, the induction of a conspicuous loss in mitochondrial membrane potential and, in part, the induction of apoptosis through upregulation of Bax expression, downregulation of Bcl-2 and increased activation of procaspase-3. These results indicate that the ultrasonically induced cell killing effect could be enhanced by 5-ALA and that the mitochondrial pathway might be involved in the cell damage process. We conclude that SDT is a promising new methodology for pancreatic cancer treatment.
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