Association between antihypertensive drugs and oral cancer: a drug target Mendelian randomization study.

Background: Recent reports have suggested that antihypertensive drugs may play an oncogenic role in common cancers, but it is still uncertain whether this could influence the risk of oral cancer. Through two-sample Mendelian randomization (MR), we sought to assess the causal effect of antihypertensive drugs on oral cancer outcomes. Methods: To proxy the exposure of antihypertensive drugs, we utilized two genetic instruments, including expression quantitative trait loci of drug target genes and genetic variants within or around drug target genes related to blood pressure from genome-wide association studies. Inverse-variance-weighted MR (IVW-MR) and summary-data-based MR (SMR) were employed to compute the instrument effect estimates. Results: It was observed through IVW-MR analysis that there is a positive relationship between KCNH2 (target of beta-adrenoceptor blockers)-mediated blood pressure and oral cancer (odds ratio [OR] = 1.197, 95% confidence interval [CI] = 1.028-1.394). Similarly, SMR analysis demonstrated that a higher expression of KCNH2 (target of beta-adrenoceptor blockers) was linked to a greater risk of oral cancer (OR = 2.223, 95% CI = 1.094-4.516). Both analyses yielded no consistent evidence of other associations. Conclusion: This two-sample MR study proposed a latent causal association between KCNH2 (target of beta-adrenoceptor blockers) inhibition and diminished risk of oral cancer.

A nucleic acid dye-enhanced electrochemical biosensor for the label-free detection of Hg2+ based on a gold nanoparticle-modified disposable screen-printed electrode.

In this paper, a nucleic acid dye-enhanced electrochemical biosensor based on a screen-printed carbon electrode (SPCE) modified with Au nanoparticles (AuNPs) was designed for the detection of Hg2+ in water. AuNPs were modified on the surface of the disposable SPCE through the electrodeposition of HAuCl4. Subsequently, thiolated DNA probes were immobilized on the AuNP-modified electrode surface by Au-S reaction. After Hg2+ was bound with a DNA probe by thymine (T)-Hg2+-thymine (T) mismatch, the DNA probe was folded into a hairpin structure where positively charged GelRed molecules were embedded into the double-stranded part of the hairpin. Thus, the current of [Fe(CN)6]3-/4- increased significantly on account of the decreased electrostatic repulsion at the electrode surface. Under the optimized experimental conditions, the peak current of [Fe(CN)6]3-/4- exhibited a good linear relationship with lgCHg2+ in the concentration of Hg2+ linear range of 0.1 nM to 500 nM, and the limit of detection (S/N = 3) was calculated as 0.04 nM. The electrochemical sensor also exhibited excellent selectivity for Hg2+ in the presence of nine interfering ions, including Na+, Fe3+, Ni2+, Mg2+, Co2+, Pb2+, K+, Al3+ and Cu2+. Meanwhile, the developed electrochemical sensor was tested in the analysis of Hg2+ in tap water and river water samples, and the recoveries ranged from 81.0 to 114%. Therefore, this nucleic acid dye-enhanced electrochemical biosensor provided the advantages of simplicity, sensitivity, and specificity and is expected to be an alternative for Hg2+ detection in actual environmental samples.

Novel role of CAP1 in regulation RNA polymerase II-mediated transcription elongation depends on its actin-depolymerization activity in nucleoplasm.

Lung cancer is one of the most intractable diseases with high incidence and mortality worldwide. Adenylate cyclase-associated protein 1 (CAP1), a well-known actin depolymerization factor, is recently reported to be an oncogene accelerating cancer cell proliferation. However, the physiological significance of CAP1 in lung cancer is incompletely understood and the novel functions of CAP1 in transcriptional regulation remain unknown. Here we found that CAP1 was highly expressed in lung cancer tissues and cells, which was also negatively associated with prognosis in lung cancer patients. Moreover, CAP1 promoted A549 cells proliferation by promoting protein synthesis to accelerate cell cycle progression. Mechanistically, we revealed that CAP1 facilitated cyclin-dependent kinase 9 (CDK9)-mediated RNA polymerases (Pol) II-Ser2 phosphorylation and subsequent transcription elongation, and CAP1 performed its function in this progress depending on its actin-depolymerization activity in nucleoplasm. Furthermore, our in vivo findings confirmed that CAP1-promoted A549 xenograft tumor growth was associated with CDK9-mediated Pol II-Ser2 phosphorylation. Our study elucidates a novel role of CAP1 in modulating transcription by promoting polymerase II phosphorylation and suggests that CAP1 is a newly identified biomarker for lung cancer treatment and prognosis prediction.

Sequence Braiding: Visual Overviews of Temporal Event Sequences and Attributes.

Temporal event sequence alignment has been used in many domains to visualize nuanced changes and interactions over time. Existing approaches align one or two sentinel events. Overview tasks require examining all alignments of interest using interaction and time or juxtaposition of many visualizations. Furthermore, any event attribute overviews are not closely tied to sequence visualizations. We present Sequence Braiding, a novel overview visualization for temporal event sequences and attributes using a layered directed acyclic network. Sequence Braiding visually aligns many temporal events and attribute groups simultaneously and supports arbitrary ordering, absence, and duplication of events. In a controlled experiment we compare Sequence Braiding and IDMVis on user task completion time, correctness, error, and confidence. Our results provide good evidence that users of Sequence Braiding can understand high-level patterns and trends faster and with similar error. A full version of this paper with all appendices; the evaluation stimuli, data, and analysis code; and source code are available at [Formula: see text].

CBX4 promotes the proliferation and metastasis via regulating BMI-1 in lung cancer.

Proliferation and metastasis are significantly malignant characteristics of human lung cancer, but the underlying molecular mechanisms are poorly understood. Chromobox 4 (CBX4), a member of the Polycomb group (PcG) family of epigenetic regulatory factors, enhances cellular proliferation and promotes cancer cell migration. However, the effect of CBX4 in the progression of lung cancer is not fully understood. We found that CBX4 is highly expressed in lung tumours compared with adjacent normal tissues. Overexpression of CBX4 significantly promotes cell proliferation and migration in human lung cancer cell lines. The knockdown of CBX4 obviously suppresses the cell growth and migration of human lung cancer cells in vitro. Also, the proliferation and metastasis in vivo are blocked by CBX4 knockdown. Furthermore, CBX4 knockdown effectively arrests cell cycle at the G0/G1 phase through suppressing the expression of CDK2 and Cyclin E and decreases the formation of filopodia through suppressing MMP2, MMP9 and CXCR4. Additionally, CBX4 promotes proliferation and metastasis via regulating the expression of BMI-1 which is a significant regulator of proliferation and migration in lung cancer cells. Taken together, these data suggest that CBX4 is not only a novel prognostic marker but also may be a potential therapeutic target in lung cancer.

ROCK1 induces dopaminergic nerve cell apoptosis via the activation of Drp1-mediated aberrant mitochondrial fission in Parkinson's disease.

Dopamine deficiency is mainly caused by apoptosis of dopaminergic nerve cells in the substantia nigra of the midbrain and the striatum and is an important pathologic basis of Parkinson's disease (PD). Recent research has shown that dynamin-related protein 1 (Drp1)-mediated aberrant mitochondrial fission plays a crucial role in dopaminergic nerve cell apoptosis. However, the upstream regulatory mechanism remains unclear. Our study showed that Drp1 knockdown inhibited aberrant mitochondrial fission and apoptosis. Importantly, we found that ROCK1 was activated in an MPP+-induced PD cell model and that ROCK1 knockdown and the specific ROCK1 activation inhibitor Y-27632 blocked Drp1-mediated aberrant mitochondrial fission and apoptosis of dopaminergic nerve cells by suppressing Drp1 dephosphorylation/activation. Our in vivo study confirmed that Y-27632 significantly improved symptoms in a PD mouse model by inhibiting Drp1-mediated aberrant mitochondrial fission and apoptosis. Collectively, our findings suggest an important molecular mechanism of PD pathogenesis involving ROCK1-regulated dopaminergic nerve cell apoptosis via the activation of Drp1-induced aberrant mitochondrial fission.

ROCK1 promotes migration and invasion of non­small­cell lung cancer cells through the PTEN/PI3K/FAK pathway.

Rho­associated protein kinase 1 (ROCK1), a member of the ROCK family, serves an important function in cell migration and invasion in neoplasms. ROCK1 has been found to be overexpressed in several types of cancers. However, the role of ROCK1 in non­small­cell lung cancer (NSCLC) is poorly understood. In the present study, ROCK1 was found to be overexpressed in NSCLC cells and tissues, and it was associated with poor survival of NSCLC patients. Subsequently, ROCK1 knockdown NSCLC cell lines were established using shRNA. ROCK1 knockdown significantly reduced the migration and invasion ability in the cell monolayer scratching and Transwell assays. ROCK1 knockdown was also found to markedly inhibit cell adhesion ability. Moreover, the phosphorylation of focal adhesion kinase (FAK) was inhibited by ROCK1 knockdown, reducing NSCLC cell migration and invasion ability. This mechanistic study revealed that ROCK1 significantly enhanced cell migration and invasion by inhibiting the phosphatase and tensin homolog (PTEN)/phosphoinositide 3­kinase (PI3K)/FAK pathway. More importantly, the interruption of the PTEN/PI3K/FAK pathway markedly rescued the inhibition of cell migration and invasion mediated by ROCK1 knockdown. Taken together, these results suggest a novel role for ROCK1 in cell migration and invasion by inhibiting cell adhesion ability, and indicate that ROCK1 may be of value as a therapeutic target for the treatment of NSCLC.

Lycorine Induces Mitochondria-Dependent Apoptosis in Hepatoblastoma HepG2 Cells Through ROCK1 Activation.

Lycorine, a naturally occurring compound extracted from the Amaryllidaceae plant family, has been reported to exhibit antitumor activity in various cancer cell types. In the present study, we investigated the molecular mechanisms underlying lycorine-induced apoptosis in hepatoblastoma HepG2 cells. We found that lycorine induced mitochondria-dependent apoptosis in HepG2 cells accompanied by mitochondrial permeability transition pore (mPTP) opening, mitochondrial membrane potential (MMP) loss, adenosine triphosphate (ATP) depletion, Ca2+ and cytochrome c (Cyto C) release, as well as caspase activation. Furthermore, we found Rho associated coiled-coil containing protein kinase 1 (ROCK1) cleavage/activation played a critical role in lycorine-induced mitochondrial apoptosis. In addition, the ROCK inhibitor Y-27632 was employed, and we found that co-treatment with Y-27632 attenuated lycorine-induced mitochondrial injury and cell apoptosis. Meanwhile, an in vivo study revealed that lycorine inhibited tumor growth and induced apoptosis in a HepG2 xenograft mouse model in association with ROCK1 activation. Taken together, all these findings suggested that lycorine induced mitochondria-dependent apoptosis through ROCK1 activation in HepG2 cells, and this may be a theoretical basis for lycorine's anticancer effects.

IR-783 inhibits breast cancer cell proliferation and migration by inducing mitochondrial fission.

IR­783, a near­infrared heptamethine cyanine dye, has been reported to possess cancer targeting and anticancer effects; Ηowever, the molecular mechanism by which IR­783 exhibits anti­breast cancer activity is unclear. In the present study, the inhibitory effects of IR­783 on the proliferation and migration of breast cancer cells were investigated. Our results revealed that IR­783 inhibited MDA­MB­231 and MCF­7 cell proliferation in a dose­ and time­dependent manner by inducing cell cycle arrest at the G0/G1 phase. In addition, a Transwell assay demonstrated that IR­783 treatment suppressed the migratory ability of MDA­MB­231 and MCF­7 cells. Furthermore, IR­783 treatment decreased the expression levels of matrix metalloproteinase (MMP)­2 and MMP­9 in MDA­MB­231 cells. Furthermore, IR­783 induced MDA­MB­231 and MCF­7 cell mitochondrial fission, and also decreased the levels of ATP. This was accompanied with a decrease in polymerized filamentous actin, which is the fundamental component of filopodia at the cell surface. Collectively, the results of the present study demonstrated that IR­783 inhibited the proliferation and migration of MDA­MB­231 and MCF­7 cells by inducing mitochondrial fission and subsequently decreasing ATP levels, resulting in cell cycle arrest and filopodia formation suppression. These findings suggest that IR­783 may be developed into an effective novel drug for treating breast cancer.

Cu2-x Se nanoparticles (Cu2-x Se NPs) mediated neurotoxicity via oxidative stress damage in PC-12 cells and BALB/c mice.

Cu2-x Se nanoparticles (Cu2-x Se NPs) are widely used for optical diagnostic imaging and photothermal therapy due to their strong near-infrared (NIR) optical absorption. With the continuous expansion of applications using Cu2-x Se NPs, their biosafety has received increasing attention in recent years. Cu2-x Se NPs can enter the brain by crossing the blood-brain barrier, but the neurotoxicity of NPs remains unclear. The present investigation provides direct evidence that the toxicity of Cu2-x Se NPs can be specifically exploited to kill rat pheochromocytoma PC-12 cells (a cell line used as an in vitro model for brain neuron research) in dose- and time-dependent manners. These cytotoxicity events were accompanied by mitochondrial damage, adenosine triphosphate (ATP) depletion, production of oxidizing species (including reactive oxygen species (ROS), malondialdehyde (MDA) and hydrogen peroxide (H2O2)), as well as reductions in antioxidant defense systems (glutathione (GSH) and superoxide dismutase (SOD)). Moreover, our in vivo study also confirmed that Cu2-x Se NPs markedly induced neurotoxicity and oxidative stress damage in the striatum and hippocampal tissues of BALB/c mice. These findings suggest that Cu2-x Se NPs induce neurotoxicity in PC-12 cells and BALB/c mice via oxidative stress damage, which provides useful information for understanding the neurotoxicity of Cu2-x Se NPs.

Dynamin-related protein 1-mediated mitochondrial fission contributes to IR-783-induced apoptosis in human breast cancer cells.

IR-783 is a kind of heptamethine cyanine dye that exhibits imaging, cancer targeting and anticancer properties. A previous study reported that its imaging and targeting properties were related to mitochondria. However, the molecular mechanism behind the anticancer activity of IR-783 has not been well demonstrated. In this study, we showed that IR-783 inhibits cell viability and induces mitochondrial apoptosis in human breast cancer cells. Exposure of MDA-MB-231 cells to IR-783 resulted in the loss of mitochondrial membrane potential (MMP), adenosine triphosphate (ATP) depletion, mitochondrial permeability transition pore (mPTP) opening and cytochrome c (Cyto C) release. Furthermore, we found that IR-783 induced dynamin-related protein 1 (Drp1) translocation from the cytosol to the mitochondria, increased the expression of mitochondrial fission proteins mitochondrial fission factor (MFF) and fission-1 (Fis1), and decreased the expression of mitochondrial fusion proteins mitofusin1 (Mfn1) and optic atrophy 1 (OPA1). Moreover, knockdown of Drp1 markedly blocked IR-783-mediated mitochondrial fission, loss of MMP, ATP depletion, mPTP opening and apoptosis. Our in vivo study confirmed that IR-783 markedly inhibited tumour growth and induced apoptosis in an MDA-MB-231 xenograft model in association with the mitochondrial translocation of Drp1. Taken together, these findings suggest that IR-783 induces apoptosis in human breast cancer cells by increasing Drp1-mediated mitochondrial fission. Our study uncovered the molecular mechanism of the anti-breast cancer effects of IR-783 and provided novel perspectives for the application of IR-783 in the treatment of breast cancer.

Zinc oxide/silver bimetallic nanoencapsulated in PVP/PCL nanofibres for improved antibacterial activity.

The anti-infection ability and skin regeneration are important aspects on the progress of wound healing, which needs an ideal wound dressing that not only resists bacteria but also promotes skin regeneration. In this study, zinc oxide/silver/polyvinylpyrrolidone/polycaprolactone (ZnO/Ag/PVP/PCL) nanofibres were prepared through electrospinning. Firstly, zinc oxide nanoparticles (ZnONPs) and silver nanoparticle (AgNPs) were synthesized respectively. Secondly, the two nanoparticles were mixed with polyvinylpyrrolidone (PVP) and polycaprolactone (PCL) to obtain the nanofibres. The results of scanning electron microscopy (SEM) showed that ZnONPs and AgNPs were 40.07 ± 9.70 nm and 37.46 ± 12.02 nm, respectively. After electrospinning, the nanofibres were 368.22 ± 123.96 nm in diameter. Infrared spectroscopy revealed that ZnONPs/AgNPs bimetallic nanomaterials were physically embedded in the nanofibres. The antibacterial effects against Staphylococcus aureus and Escherichia coli of ZnO/Ag/PVP/PCL nanofibres were significantly better than these of the single metal material-loaded nanofibres. More importantly, the combination of ZnO and Ag reduced the cytotoxicity of ZnO/Ag/PVP/PCL bimetallic nanofibres toward fibroblasts. These findings demonstrated that ZnO/Ag/PVP/PCL bimetallic nanofibres should be of greater interest than the single metal nanomaterial-loaded nanofibres in inhibiting growth of bacteria.

Synergistic active targeting of dually integrin αvß3/CD44-targeted nanoparticles to B16F10 tumors located at different sites of mouse bodies.

Conventional enhanced permeation and retention (EPR) mediates the effects of many drugs, including the accumulation of nanocarriers at tumor sites, but its efficiency remains low. In this study, this limitation was overcome by developing a dual-targeting delivery system based on hyaluronan (HA, a major ligand of CD44) and tetraiodothyroacetic acid (tetrac, a specific ligand of αvß3), which was exploited to carry docetaxel (DTX) for the synergistic active targeting to tumors. First, a tetrac-HA (TeHA) conjugate was synthesized and grafted onto the surfaces of solid lipid nanoparticles (SLNs) (TeHA-SLNs/DTX), with a high encapsulation efficiency of >91.6%. The resulting SLNs exhibited an approximately toroid morphology revealed using TEM. The cellular uptake and cytotoxicity of various formulations on CD44/αvß3-enriched B16F10 cells were then assessed, and both results confirmed the selective uptake and high cytotoxicity of the TeHA-SLNs/DTX in a TeHA-dependent manner. In vivo imaging and vessel distribution tests revealed the efficiency of synergistic active targeting was higher than that of EPR-mediated passive targeting by the TeHA-SLNs to αvß3-expressing tumor blood vessels and CD44-expressing tumor cells via selective targeting. Finally, in both xenograft tumor mice and in situ lung metastasis tumor mice, tumor growth was significantly inhibited by TeHA-SLNs/DTX. Therefore, TeHA-SLNs are an efficient system for the dual-targeted delivery of drugs to treat cancer in vivo.

[Studies on screening of matrix and permeation enhancer of sustained-release patches of duliang].

OBJECTIVE: To screen the matrix and permeation enhancer of Duliang Patches. METHODS: Based on L9 (3(4)) orthogonal experimental design, the content of imperatorin of the release rate and transdermal osmolality were regarded as evaluation indexes to optimize the matrix and permeation enhancer of patches suing of Drug dissolution tester and Franz diffusion cell. RESULTS: The best prescriplion of sustained-release patch of Duliang was: the quality percentage content of the starch, sodium carboxymethyl cellulose, glycerin, azone, propylene glycol and PEG400 was 6%, 2%, 30%, 1%, 15% and 2.5% respectively. The release behavior of sustained-release patches of Duliang tallied with Higuchi equation and the effect of sustained-release was apparent. CONCLUSION: The sustained-release patches of Duliang have good property of sustained-release and transdermal in vitro and the stability of patches is also sound while the release in vivo awaits further inspection.