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In this study, the novel conservative representation of chemical explosive mode analysis is augmented to analyze the key flame features in the Burrows-Kurkov flames simulated by both Reynolds-Averaged Navier-Stokes (RANS) and large eddy simulation (LES). Subtle difference are revealed in flame stabilization mechanisms resulting from the difference in modeling and spatial resolution. RANS shows that, ahead of the flame onset location, the composition diffusion and shock wave compression play dominant roles in chemical explosion indicating that the flame is stabilized by the assisted-ignition combustion mode. In contrast, LES shows that the flame is stabilized by the auto-ignition mode since the nonchemical contribution counteracts chemical reaction during the development of ignited flame kernels. For RANS, the radical pool builds up through the unphysical back diffusion near the flame stabilization front, which reveals the limitation of RANS method in the resolution and characterization of the key flame features in Burrows-Kurkov flames. • The novel CCEMA method is improved in the aspect of EI definition. • The impacts of high-speed source terms on CEMs are rigorously quantified. • CCEMA is applied to the Burrows-Kurkov flames simulated by both RANS and LES. • The subtle difference in flame features between RANS and LES results are detected. • The limitation of RANS in characterization of Burrows-Kurkov flame is revealed. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a multifactorial neurodegenerative disease with damages to mitochondria and endoplasmic reticulum (ER), followed by neuroinflammation. We previously reported that a triple herbal extract DA-9805 in experimental PD toxin-models had neuroprotective effects by alleviating mitochondrial damage and oxidative stress. In the present study, we investigated whether DA-9805 could suppress ER stress and neuroinflammation in vitro and/or in vivo. Pre-treatment with DA-9805 (1 μg/ml) attenuated upregulation of glucose-regulated protein 78 (GRP78), C/EBP homologous protein (CHOP) and cleaved caspase-3 in SH-SY5Y neuroblastoma cells treated with thapsigargin (1 µg/ml) or tunicamycin (2 µg/ml). In addition, DA-9805 prevented the production of IL-1β, IL-6, TNF-α and nitric oxide through inhibition of NF-κB activation in BV2 microglial cells stimulated with lipopolysaccharides (LPS). Intraperitoneal injection of LPS (10 mg/kg) into mice can induce acute neuroinflammation and dopaminergic neuronal cell death. Oral administration of DA-9805 (10 or 30 mg/kg/day for 3 days before LPS injection) prevented loss of dopaminergic neurons and activation of microglia and astrocytes in the substantia nigra in LPS-injected mouse models. Taken together, these results indicate that DA-9805 can effectively prevent ER stress and neuroinflammation, suggesting that DA-9805 is a multitargeting and disease-modifying therapeutic candidate for PD. [Display omitted] • DA-9805 is a triple mixed herbal ethanol extract. • DA-9805 prevented ER-stress-induced apoptosis and mitochondrial damage in neurons. • DA-9805 blocked LPS-induced cytokine production by inhibiting NF-κB. • DA-9805 prevented neuroinflammation and dopaminergic neuronal death in the brain. • DA-9805 is a promising candidate drug for multitargeting and disease-modifying PD. [ABSTRACT FROM AUTHOR]

Abstract: Emerging evidences from preclinical and clinical studies have shown that epidermal growth factor (EGF) has some effectiveness against endogenously arising carcinogenesis. Functional +61A>G polymorphism (rs4444903 A>G) in the promoter region of the EGF gene was observed to modulate EGF levels, thus affecting the susceptibility to gastrointestinal cancer; but individually published studies showed inconclusive results. The aim of this Human Genome Epidemiology (HuGE) review and meta-analysis was to derive a more precise estimation of the association between EGF +61A>G polymorphism and gastrointestinal cancer risk. A literature search of Pubmed, Embase, Web of Science and Chinese BioMedical databases from inception through July 2012 was conducted. Twelve studies were assessed with a total of 2868 gastrointestinal cancer cases and 4278 healthy controls. When all the eligible studies were pooled into the meta-analysis, the results showed that the G allele and GG genotype of EGF +61A>G polymorphism might increase the risk of gastrointestinal cancer. In the stratified analysis by cancer types, the G allele and GG genotype of EGF +61A>G polymorphism showed displayed significant correlations with increased risk of esophageal cancer. We also found significant correlations between the G carrier (GG+AG) and GG genotype of EGF +61A>G polymorphism and colorectal cancer risk. However, EGF +61A>G polymorphism did not appear to have an influence on gastric cancer susceptibility. Results from the current meta-analysis indicate that EGF +61A>G polymorphism might increase the risk of esophageal and colorectal cancers. Nevertheless, further studies are needed to determine whether genetic associations between EGF +61A>G polymorphism and susceptibility to gastric cancer are significant. [Copyright &y& Elsevier]

Abstract: Background: Mitochondrial dysfunction is a prominent feature of neurodegenerative diseases including Parkinson''s disease (PD), in which insulin signaling pathway may also be implicated because 50–80% of PD patients exhibited metabolic syndrome and insulin resistance. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its toxic metabolite, 1-methyl-4-phenyl-2,3-dihydropyridinium ion (MPP+), inhibit complex I in mitochondrial respiratory chain and are used widely to construct the PD models. But the precise molecular link between mitochondrial damage and insulin signaling remains unclear. Methods and results: Using cell-based mitochondrial activity profiling system, we systemically demonstrated that MPP+ suppressed mitochondrial activity and mitochondrial gene expressions mediated by nuclear respiratory factor-1 (NRF-1) and mitochondrial transcription factor A (TFAM) in SH-SY5Y cells. MPP+ fragmented mitochondrial networks and repressed phosphorylation of AKT. Similarly, the expressions of mitochondrial genes and tyrosine hydroxylase and AKT phosphorylation were reduced in substantia nigra and striatum of MPTP-injected mice. Transient transfection of TFAM, NRF-1, or myr-AKT reversed all aspects of the MPP+-mediated changes. Conclusions: Mitochondrial activation by TFAM, NRF-1, and myr-AKT abrogated MPP+-mediated damages on mitochondria and insulin signaling, leading to recovery of nigrostriatal neurodegeneration. General significance: We suggest that TFAM, NRF-1, and AKT may be the critical points of therapeutic intervention for PD. This article is part of a Special Issue entitled Biochemistry of Mitochondria. [Copyright &y& Elsevier]

Background & Aims: The activation of Wnt/β-catenin signaling causes the development of gastric and colon cancers. Sox17 represses Wnt/β-catenin signaling and is down-regulated in colon cancer. This study was designed to elucidate the role of Sox17 during the course of gastrointestinal tumorigenesis. Methods: Sox17 expression was examined in gastrointestinal tumors of mouse models and humans. The roles of Sox17 in gastric tumorigenesis were examined by cell culture experiments and by construction of Sox17 transgenic mice. Results: Sox17 was induced in K19-Wnt1/C2mE mouse gastric tumors and K19-Wnt1 preneoplastic lesions, where Wnt/β-catenin signaling was activated. Consistently, Wnt activation induced Sox17 expression in gastric cancer cells. In contrast, Sox17 was rarely detected by immunohistochemistry in gastric and colon cancers, whereas strong nuclear staining of Sox17 was found in >70% of benign gastric and intestinal tumors. Treatment with a demethylating agent induced Sox17 expression in gastric cancer cells, thus indicating the down-regulation of Sox17 by methylation. Moreover, transfection of Sox17 in gastric cancer cells suppressed both the Wnt activity and colony formation efficiency. Finally, transgenic expression of Sox17 suppressed dysplastic tumor development in K19-Wnt1/C2mE mouse stomach. Conclusions: Sox17 plays a tumor suppressor role through suppression of Wnt signaling. However, Sox17 is induced by Wnt activation in the early stage of gastrointestinal tumorigenesis, and Sox17 is down-regulated by methylation during malignant progression. It is therefore conceivable that Sox17 protects benign tumors from malignant progression at an early stage of tumorigenesis, and down-regulation of Sox17 contributes to malignant progression through promotion of Wnt activity. [Copyright &y& Elsevier]

Summary: Fungal sinusitis is an opportunistic fungal infection. Candida albicans, Aspergillus spp, and Mucorales, the most common pathogenic fungi, differ in both prognosis and therapy. Early diagnosis and differentiation between the subtypes therefore are pivotal for adequate treatment. This report describes a diagnostic immunohistochemical method that is able to distinguish these types of fungi. Formalin-fixed paraffin-embedded blocks of 89 fungal sinusitis specimens (12 C albicans, 52 Aspergillus spp, and 25 Mucorales) and 21 cultures (5 C albicans, 11 Aspergillus spp, and 5 Mucorales) were stained with MUC2, MUC5AC, and MUC5B antibodies. The immunohistochemical staining results of paraffin-embedded samples for MUC5B were successful in 100% and 92.3% of the C albicans and Aspergillus spp samples, respectively. Only 4.0% of the Mucorales parafin sections were found positive, demonstrating a significant difference in detection from C albicans and Aspergillus spp (P < .001). MUC5B expressions for cultures showed that it stained 100% and 90.9% for C albicans and Aspergillus spp, respectively, but negative for Mucorales. The expressions of MUC2 and MUC5AC for both paraffin-embedded samples and cultures were negative. The present study demonstrates the ability of an MUC5B antibody to distinguish C albicans and Aspergillus spp from Mucorales and its use as a diagnostic tool in fungal sinusitis. [Copyright &y& Elsevier]

Abstract: Using two-site enzyme immunoassays, we measured protein levels of epidermal growth factor (EGF), transforming growth factor alpha (TGFα), and heparin-binding epidermal growth factor (HB-EGF) in adult rat brain, and compared them with the phosphorylation levels of their receptor (ErbB1). There were significant variations in the brain distributions of each ErbB1 ligand. Among these ErbB1 ligands, HB-EGF protein levels were higher than those of TGFα and those of EGF were the lowest. TGFα protein was relatively enriched in the midbrain regions, while HB-EGF levels were most abundant in the cerebellum. Protein distributions of the EGF family members were discordant with previously reported mRNA distributions. In addition, there was significant basal ErbB1 phosphorylation detected with the largest amount of activation in the midbrain. These observations suggest that the activation of brain ErbB1 involves post-translational regulation of multiple EGF family members in a region-specific manner. [Copyright &y& Elsevier]

A comprehensive review is conducted on the investigations of the forced single-phase convective heat transfer in non-circular microchannels. The observations and results available in the open literature are inspected and compared for better understanding of the physical nature of the heat transfer performance and providing some lines of future research. There seems to be no unequivocal agreement in the understanding on the relative phenomena and the determination of the heat transfer coefficients in microchannels. The study on the interfacial phenomena and interaction at the interface will be the frontier in this area. Appropriate data reduction and the correlating parameters will be the cornerstone of comparability and evaluation for comprehensive investigations. The selection of correlating parameters will actually be the basis for the better understanding and description of new phenomena. [ABSTRACT FROM AUTHOR]

Nonviral gene delivery vectors are promising alternatives to viral vectors, but their low transfection efficiency limits their applications. Mimicking virus transfection process has been attempted to enhance the nonviral gene delivery efficiency. Herein, we present a virus-mimicking polymeric vector capable of sticking onto the cell membrane and ejecting DNA into the cytoplasm for efficient gene transfection. This DNA-ejecting vector is advantageous in bypassing endo-/lysosomal DNA degradation, leading to high gene expression efficiency and avoiding the safety concerns of the internalized carrier materials. Linear polyethyleneimine is quaternized to carry N -[(p -acyloxybenzyloxycarbonyl)ethyl]- N -methyl ammonium, which is susceptible to esterase hydrolysis to water-soluble zwitterion. Optimizing the acyl chain lengths gives the polymer, L4 (acyl = octanoyl), which packs DNA into the nano-sized polyplex with pendant octanoyl chains. On contacting a cell, the octanoyl chains can insert into the lipid-bilayer and anchor the polyplex onto the cell membrane. The part of the polyplexes facing the cytoplasm exposes to cytosolic esterases, which hydrolyze the octanoyl esters and turn the polymer zwitterionic, thereby liberalizing the DNA to squeeze into the cytoplasm driven by free DNA's strong electrostatic repulsion. The polyplex coated with a poly(γ-glutamic acid) layer maintains the DNA-injection ability and has high efficiency for in vivo gene transfection. We present a virus-mimicking vector capable of sticking onto the cell membrane and ejecting DNA into cytosol without entering the cells. The esterase-catalyzed charge-reversal polymer with long acyl chains, N -[ p -octanoyloxybenzyloxycarbonyl]ethyl- N -methyl ammonium of linear polyethyleneimine (L4), can pack DNA into nano-sized polyplex and can be coated with poly(γ-glutamic acid (γPGA) for improved serum stability. On contacting a cell, γPGA comes off and releases the L4/DNA, whose long acyl chains insert into the cell membrane and make part of L4 expose to the cytosolic esterase, turning cationic L4 neutral and liberalizing the DNA to squeeze into the cytosol for efficient gene expression. Therefore, γPGA/L4/DNA has enhanced gene expression in tumors and enhanced tumor gene therapeutic efficiency. [Display omitted] • The first nonviral vector capable of anchoring cytomembrane and ejecting DNA into the cytoplasm without entering the cells. • The right long alkyl chains enable cytomembrane anchoring and esterase-catalyzed charge-reversal for DNA-ejection. • The vector avoids lysosome-trapping caused DNA degradation and endocytosed carrier materials-caused toxicity. • The poly(γ-glutamic acid)-coating retains the DNA-ejecting ability in in vivo application. [ABSTRACT FROM AUTHOR]

Leptomeningeal metastasis (LM) is thought to be a devastating and increasingly frequent neurological complication of cancer characterized by infiltration of malignant cells into the leptomeninges and the subarachnoid space. Intracranial hypertension and hydrocephalus are observed in about half of patients with LM. They are responsible for rapidly declining neurological status and eventual poor outcome in many patients with LM. Impediment of CSF circulation is considered the pathophysiological basis of increased intracranial pressure and hydrocephalus related to LM, which makes ventriculoperitoneal shunt (VP shunt) an acceptable palliative approach for LM now. It is noteworthy that LM generally causes communicating hydrocephalus. Lumboperitoneal shunt (LP shunt) has been demonstrated to be effective in the treatment of communicating hydrocephalus secondary to hemorrhage or infection, idiopathic intracranial hypertension and normal pressure hydrocephalus. And LP shunt has several advantages over VP shunt. Therefore we hypothesize that LP shunt can be used in the treatment of intracranial hypertension and hydrocephalus related to LM and should be given greater priority over VP shunt. [ABSTRACT FROM AUTHOR]

Albumin is a serum transport protein, which has been utilized as a carrier for a variety of drugs to improve their delivery efficiency and to obtain favorable pharmacokinetic profiles. However, natural albumin possesses only a few high-affinity binding sites for a limited number of drugs. This results in deficiencies in drug-loading and serum stability, and consequently, in impaired therapeutic efficacy. Herein, BSA was modified with different isothiocyanate conjugates (BSA-ITCs), which self-assembled with paclitaxel (PTX) to produce BSA-ITCs/PTX nanoparticles. Among these BSA-ITCs, phenethyl isothiocyanate (PEITC)-modified BSA (BSA-PEITC35) conjugates effectively loaded PTX and formed highly stable BSA-PEITC35/PTX nanoparticles. Molecular modeling studies suggested that PEITC groups in BSA-PEITC35 can significantly lower the PTX binding free energy. BSA-PEITC35/PTX showed enhanced stability, prolonged blood circulation and increased tumor accumulation than unmodified BSA/PTX, and exerted more potent antitumor activity than both BSA/PTX and Abraxane in subcutaneous mouse tumor models after intravenous administration. Here, we designed phenethyl isothiocyanate (PEITC)-modified BSA (BSA-PEITC35) which self-assembled with paclitaxel (PTX) to form well-stabilized nanoparticles for effective cancer drug delivery. The introduction of PEITC moieties greatly lowered the binding energies of albumin and PTX, and led to greater drug loading and enhanced serum stability. BSA-PEITC35/PTX exhibited more efficient antitumor activity than both BSA/PTX and Abraxane, a clinically used albumin-stabilized PTX nanoparticle formulation. Thus, this strategy to introduce drug binding ligands in albumin is feasible and promising to develop effective albumin-based drug delivery system. Unlabelled Image [ABSTRACT FROM AUTHOR]

Plaque assays of human respiratory syncytial virus (HRSV) are time-consuming, requiring 4 to 7 days for plaque formation and several hours for dye staining. Here, we describe a simple method by which RSV plaques can be visualized and counted with the naked eye only 2 days after infection of HEp-2 cells. In this assay, the infected cells are stained with monoclonal antibodies and the plaques are developed using diaminobenzidine (DAB). We tested the accuracy of this new plaque assay by comparing the results obtained on days 1, 2, 3, 4, 5, and 6 post-infection. The whole procedure is significantly simpler than the traditional method, with an immunostaining process of around 1.5 h. Our method is rapid, accurate, and simple; thus, it has the potential to significantly contribute to studies related to RSV disease. [ABSTRACT FROM AUTHOR]

Asteroids are the remnants of the process by which planets formed from the protoplanetary disk. Laboratory analyses of materials originating from asteroids give us the unique opportunity to reveal the formation history of our Solar System about 4.6 billion years ago. To obtain surface regolith in the low-gravity and vacuum environment, a gas-driven sampling strategy has been proposed, but the relation between the collected mass and the gas ejection remains to be explored, which is important for the development of efficient sampling mechanism designs. In this paper, we simulate the gas–particle two-phase flow in the gas-driven sampling process by using the coupled Computational Fluid Dynamics and Discrete Element Method (CFD–DEM) method. The results show that the sampling process can be divided into three stages according to the mass of particles that are sampled. Initially, the impact ejection of the pressurized gas on the regolith layer dominates, during which the sampling speed increases to a maximum value rapidly. After that, the gas flow transports the ejected particles to the collection chamber. In this stage, the conveyance effect of gas plays a primary role. As grains accumulate near the entrance of the collecting tube, jamming state happens and obstructs the particle flow, making the sampling rate drop to a stable value. By varying the inlet gas velocity, we show that higher gas velocity increases the collected mass rate greatly at the first stage while no significant differences are found after the development of jamming state inside the chamber. The position of the inlets affects the flow field and thus could be used to prevent the unfavorable aggregation of particles near the collecting tube, which facilitates the sampling. The influence of the inlet gas angle is also explored. We find two inward tilting gas inlets could increase the sampling efficiency considerably through striking a balance between ejected mass and ejecting velocity. The results presented in this article are expected to provide important information on the optimal designs of gas-driven sampling devices for future asteroid space mission. • CFD–DEM method is used to study the gas-driven sampling on asteroid regolith. • The impact ejection of pressurized gas and its conveyance effect dominate at different stages. • The gas inlet velocity affects the sampling efficiency only at the initial stage. • The inlet position and angle can be used to prevent the unfavorable jamming of particles. [ABSTRACT FROM AUTHOR]

Full engine simulations based on three-dimensional computational fluid dynamics (3-D CFD) allow the visualisation of flow details accompanied by total performances for aeroengine design. In this study, 3-D coupled and uncoupled schemes are performed to simulate the full engine performance of a micro turbojet engine. For the 3-D uncoupled scheme, the general performance map of each core component based on CFD simulation is used as a component model for solving the equations of thermodynamic equilibrium without aerodynamic data crossing the boundary of each component. For the 3-D coupled scheme, a full engine simulation is performed using a Reynolds-averaged Navier-Stokes CFD solver coupled with a power balance iteration, and all components are assembled in one computational domain. The calculation processes of these two schemes are introduced, and the feasibility of using the Regula-Falsi method in the coupled scheme for power balance iteration is verified. Despite some discrepancies, the overall performance results yielded by these two schemes are consistent with the experimental results. A detailed comparison of these two schemes is presented to elucidate the reasons contributing to the discrepancies. The results show that the uncertainty of the boundary conditions limited by the 3-D uncoupled simulation method and the low-dimensional forced mixing at the component's interfaces can result in significant calculation errors. Interactions among core components are demonstrated methodically. Finally, based on a comparative analysis with the 3-D coupled scheme, correction strategies for the component data-based model are proposed to improve the accuracy of uncoupled simulations. With these coupling corrections, the maximum relative error of the thrust between these two schemes reduces by 50% and the result is more close to the experiment. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance The root of Bupleurum falcatum L. (BF) has been used in traditional Korean and Chinese medicines for over 2000 years to treat infections, fever, and chronic liver diseases. Among the many active compounds in BF ethanol extract (BFE), saikosaponins exert pharmacological activities including anti-inflammatory effects. Activated microglial cells release a variety of pro-inflammatory substances, leading to neuronal cell death and neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. The aim of the present study was to investigate the mechanism of the anti-neuroinflammatory effects of BFE using lipopolysaccharide (LPS)-stimulated microglial cells and LPS-intraperitoneal injected C57BL/6 mice. Materials and methods Dried roots of BF were extracted with 70% ethanol (tenfold volume) on a stirring plate for 24 h at room temperature to prepare BFE. Pure saikosaponins (SB3, SB4, and SD) were prepared by solvent extraction and column chromatography fractionation. BV2 murine microglial cells were treated with BFE or saikosaponins for 4 h and stimulated with LPS. Generation of nitric oxide (NO), inflammatory cytokines, and reactive oxygen species (ROS) from activated microglial cells were monitored. The effects of BFE on NF-κB activation were determined using RT-PCR, reporter assay, and immunostaining. The in vivo effects of BFE were also assessed by immunohistochemical staining of tissue sections from LPS-injected mouse brains. Results Treatment with BFE or saikosaponins dose-dependently attenuated LPS-induced production of NO, iNOS mRNA, and ROS by 30–50%. They reduced LPS-mediated increases in the mRNA levels of IL-6, IL-1β, and TNF-α by approximately 30–70% without affecting cell viability, and decreased LPS-mediated NF-κB activity via reducing p65/RELA mRNA, transcriptional activity, and nuclear localization of NF-κB. BFE also reduced LPS-induced activation of microglia and astrocytes in the hippocampus and substantia nigra of LPS-injected mice. Conclusion Our data suggest that BFE may be effective for reducing neuroinflammation-mediated neurodegeneration through suppressing NF-κB-mediated inflammatory pathways. [ABSTRACT FROM AUTHOR]

Highlights: [•] MCE has anti-parkinsonian effect in vivo. [•] MCE rescues movement impairment induced by MPTP. [•] MCE protects against MPTP-induced striatal dopaminergic neurnal loss. [•] MCE inhibits MPTP-induced striatal mitochondrial dysfunction. [ABSTRACT FROM AUTHOR]

Abstract: HRM code for the simulation of N2O/HTPB hybrid rocket motor operation and scale effect analysis has been developed. This code can be used to calculate motor thrust and distributions of physical properties inside the combustion chamber and nozzle during the operational phase by solving the unsteady Navier–Stokes equations using a corrected compressible difference scheme and a two-step, five species combustion model. A dynamic fuel surface regression technique and a two-step calculation method together with the gas–solid coupling are applied in the calculation of fuel regression and the determination of combustion chamber wall profile as fuel regresses. Both the calculated motor thrust from start-up to shut-down mode and the combustion chamber wall profile after motor operation are in good agreements with experimental data. The fuel regression rate equation and the relation between fuel regression rate and axial distance have been derived. Analysis of results suggests improvements in combustion performance to the current hybrid rocket motor design and explains scale effects in the variation of fuel regression rate with combustion chamber diameter. [Copyright &y& Elsevier]

Abstract Purpose Gastric cancer is a common malignancy worldwide, and is associated with high morbidity and mortality rates. Cordycepin is a 3′-deoxyadenosine drug with significant anti-cancer effects. The aim of this study was to determine the molecular mechanisms underlying cordycepin action on gastric cancer cell proliferation and migration. Methods The human gastric cancer cell lines MGC-803 and HGC-27 were treated with different concentrations of cordycepin (25 μM, 50 μM, 100 μM and 5 μM, 25 μM and 50 μM) for 48 h. Cell proliferation was assessed by MTT and colony formation assays, and in vitro migration by the wound healing and transwell assays. In addition, Flow Cytometry was used to detect the cell cycle and apoptosis. RT-PCR and Western blotting were used to evaluate the expression levels of key factors. Results Cordycepin significantly inhibited gastric cancer cell proliferation and migration in a dose-dependent manner, in addition to inducing apoptosis and arresting the cell cycle at the G2 phase. Mechanistically, cordycepin targeted the PI3K/Akt signaling pathway by significantly altering the expression levels/activation of several key mediators, and upregulated the anti-metastatic factor CLEC2. Conclusion Cordycepin inhibited the proliferation and migration of gastric cancer cells by upregulating CLEC2 via the Akt signaling pathway. [ABSTRACT FROM AUTHOR]

Cationic polymers are one of the main non-viral vectors for gene therapy, but their applications are hindered by the toxicity and inefficient transfection, particularly in the presence of serum or other biological fluids. While rational design based on the current understanding of gene delivery process has produced various cationic polymers with improved overall transfection, high-throughput parallel synthesis of libraries of cationic polymers seems a more effective strategy to screen out efficacious polymers. Herein, we demonstrate a novel platform for parallel synthesis of low cationic charge-density polyesters for efficient gene delivery. Unsaturated polyester poly(alkylene maleate) (PAM) readily underwent Michael-addition reactions with various mercaptamines to produce polyester backbones with pendant amine groups, poly(alkylene maleate mercaptamine)s (PAMAs). Variations of the alkylenes in the backbone and the mercaptamines on the side chain produced PAMAs with tunable hydrophobicity and DNA-condensation ability, the key parameters dominating transfection efficiency of the resulting polymer/DNA complexes (polyplexes). A semi-library of such PAMAs was exampled from 7 alkylenes and 18 mercaptamines, from which a lead PAMA, G-1, synthesized from poly(1,4-phenylene bis(methylene) maleate) and N,N -dimethylcysteamine, showed remarkable transfection efficiency even in the presence of serum, owing to its efficient lysosome-circumventing cellular uptake. Furthermore, G-1 polyplexes efficiently delivered the suicide gene pTRAIL to intraperitoneal tumors and elicited effective anticancer activity. [ABSTRACT FROM AUTHOR]

[Display omitted] Over the past three decades, the enhanced permeability and retention (EPR) effect has been considered the basis of tumor-targeted drug delivery. Various cancer nanomedicines, including macromolecular drugs, have been designed to utilize this mechanism for preferential extravasation and accumulation in solid tumors. However, such nanomedicines have not yet achieved convincing therapeutic benefits in clinics. Increasing evidence suggests that the EPR effect is over-represented in human tumors, especially in metastatic tumors. This review covers the evolution of the concept, the heterogeneity and limitation of the EPR effect in clinical realities, and prospects for alternative strategies independent of the EPR effect. [ABSTRACT FROM AUTHOR]

The clinical translation of nanomedicines has been impeded by the unfavorable tumor microenvironment (TME), particularly the tortuous vasculature networks, which significantly influence the transport and distribution of nanomedicines into tumors. In this work, a smart pH-responsive bortezomib (BTZ)-loaded polyhydralazine nanoparticle (PHDZ/BTZ) is presented, which has a great capacity to augment the accumulation of BTZ in tumors by dilating tumor blood vessels via specific release of vasodilator hydralazine (HDZ). The Lewis acid-base coordination effect between the boronic bond of BTZ and amino of HDZ empowered PHDZ/BTZ nanoparticles with great stability and high drug loading contents. Once triggered by the acidic tumor environment, HDZ could be released quickly to remodel TME through tumor vessel dilation, hypoxia attenuation, and lead to an increased intratumoral BTZ accumulation. Additionally, our investigation revealed that this pH-responsive nanoparticle dramatically suppressed tumor growth, inhibited the occurrence of lung metastasis with fewer side effects and induced immunogenic cell death (ICD), thereby eliciting immune activation including massive cytotoxic T lymphocytes (CTLs) infiltration in tumors and efficient serum proinflammatory cytokine secretion compared with free BTZ treatment. Thus, with efficient drug loading capacity and potent immune activation, PHDZ nanoparticles exhibit great potential in the delivery of boronic acid-containing drugs aimed at a wide range of diseases. [ABSTRACT FROM AUTHOR]

Abstract: Background: Atherosclerosis is one of the major complications of diabetes, which may result from insulin resistance via mitochondrial dysfunction. Although a strong association between insulin resistance and cardiovascular disease has been suggested, it is not clear yet whether stress-inducing factors damage mitochondria and insulin signaling pathway in cardiovascular tissues. Methods: We investigated whether stress-induced mitochondrial dysfunction might alter the insulin/Akt signaling pathway in A10 rat vascular smooth muscle cells (VSMC). Results: The treatment of oxidized low density lipoprotein (oxLDL) decreased ATP contents, mitochondrial respiration activity, mRNA expressions of OXPHOS subunits and IRS-1/2 and insulin-mediated phosphorylations of Akt and AMP-activated protein kinase (AMPK). Similarly, dideoxycytidine (ddC), the mtDNA replication inhibitor, or rotenone, OXPHOS complex I inhibitor, inhibited the insulin-mediated pAkt while increased pAMPK regardless of insulin. Reciprocally, an inhibitor of Akt, triciribine (TCN), decreased cellular ATP contents. Overexpression of Akt dominant positive reversed the oxLDL- or ddC-mediated ATP decrease but AMPK activator did not. Akt activation also normalized the aberrant VSMC migration induced by ddC. Conclusions: Defective insulin signaling and mitochondrial function may collectively contribute to developing cardiovascular disease. General significance: Akt may be a possible therapeutic target for treating insulin resistance-associated atherosclerosis. [Copyright &y& Elsevier]

Nanotechnology-based drug delivery platforms have been explored for cancer treatments and resulted in several nanomedicines in clinical uses and many in clinical trials. However, current nanomedicines have not met the expected clinical therapeutic efficacy. Thus, improving therapeutic efficacy is the foremost pressing task of nanomedicine research. An effective nanomedicine must overcome biological barriers to go through at least five steps to deliver an effective drug into the cytosol of all the cancer cells in a tumor. Of these barriers, nanomedicine extravasation into and infiltration throughout the tumor are the two main unsolved blockages. Up to now, almost all the nanomedicines are designed to rely on the high permeability of tumor blood vessels to extravasate into tumor interstitium, i.e., the enhanced permeability and retention (EPR) effect or so-called "passive tumor accumulation"; however, the EPR features are not so characteristic in human tumors as in the animal tumor models. Following extravasation, the large size nanomedicines are almost motionless in the densely packed tumor microenvironment, making them restricted in the periphery of tumor blood vessels rather than infiltrating in the tumors and thus inaccessible to the distal but highly malignant cells. Recently, we demonstrated using nanocarriers to induce transcytosis of endothelial and cancer cells to enable nanomedicines to actively extravasate into and infiltrate in solid tumors, which led to radically increased anticancer activity. In this perspective, we make a brief discussion about how active transcytosis can be employed to overcome the difficulties, as mentioned above, and solve the inherent extravasation and infiltration dilemmas of nanomedicines. [ABSTRACT FROM AUTHOR]