Chemotherapy-induced neurotoxicity is a common adverse effect of cancer treatment. No medication has been shown to be effective in the prevention or treatment of chemotherapy-induced neurotoxicity. ...Using minoxidil as an initial template for structural modifications in conjunction with an in vitro neurite outgrowth assay, an image-based high-content screening platform, and mouse behavior models, an effective neuroprotective agent CN016 was discovered. Our results showed that CN016 could inhibit paclitaxel-induced inflammatory responses and infiltration of immune cells into sensory neurons significantly. Thus, the suppression of proinflammatory factors elucidates, in part, the mechanism of action of CN016 on alleviating paclitaxel-induced peripheral neuropathy. Based on excellent efficacy in improving behavioral functions, high safety profiles (MTD > 500 mg/kg), and a large therapeutic window (MTD/MED > 50) in mice, CN016 might have great potential to become a peripherally neuroprotective agent to prevent neurotoxicity caused by chemotherapeutics as typified by paclitaxel.
Dendritic cells (DCs) play a critical role in initiating immune responses; however, DCs also induce Th2-related allergic sensitivities. Thus, DCs become a target for therapeutic design in allergic ...diseases. In this study, we aim to investigate the anti-allergic effect of pure compounds from a medicinal mushroom
(Ac) on DC-induced allergic responses. We identified a benzenoid compound 4,7-dimethoxy-5-methyl-l,3-benzodioxole (DMB) which may modulate Th2 polarization in bone marrow-derived DCs (BMDCs) and in a murine food allergy model. DMB effectively reduced the Th2 adjuvant cholera toxin (CT)-induced BMDC maturation and cytokine production. In studying the mechanism, DMB blocked the molecular processes involved in Th2 induction, including cAMP activation, IL-33 production, and IRF4/Tim4 upregulation, in CT-activated BMDCs. Furthermore, DMB treatment attenuated the symptoms, clinical scores, and Th2 responses of CT-induced ovalbumin (OVA)-specific food allergy in mice at sensitization stage. These results indicated that DMB could suppress DC function for Th2 polarization and mitigate allergic responses. Thus, DMB may have potential to be a novel agent for preventing or treating food allergy.
Fertilizer plays an important role in agricultural development. However, the soil environment of tea gardens has been deteriorated and the growth of tea trees has been hindered by the long-term ...excessive chemical fertilizer used in tea gardens. To study effects of reducing chemical fertilizer on the quality components of Tieguanyin tea leaves, Tieguanyin tea garden located in yellow-red soil was treated with three consecutive times and five recipes of chemical fertilizer. The results showed that appropriate reduction of chemical fertilizer applied in tea gardens can increase the contents of potassium and organic matter in soil, polyphenols and water extract in tea leaves. Most of the contents reach their peaks in T3 treatment, which compound fertilizer that the contents of NPK are all 15% was 412.50 kg/ha and urea was 206.25 kg/ha applied in the tea gardens, that 55% of the conventional usage by local farmers. At the same time, with the reducing chemical fertilizer applied in tea gardens, the caffeine in tea leaves was significantly decreased. Therefore, T3 treatment can improve the soil environment of tea gardens and the concentration of Oolong tea soup. Besides, it infers that the amount of chemical fertilizer in T3 treatment is a key control point for the quality of tea. The indirect influence coefficients that the chemical fertilizer effects on the contents of tea water extract, free amino acid and caffeine are all at their peaks of 5.249, 4.245 and 8.594 respectively through the changing of the soil nutrient contents. It is benefit for improving the overall quality of Oolong tea.
Purpose
To evaluate the clinical outcomes of preventive covered stent placement at the gastroduodenal artery stump in patients with angiogram-negative sentinel hemorrhage after ...pancreaticoduodenectomy.
Methods
Between July 2006 and September 2018, patients undergoing computed tomography angiography or diagnostic angiography for sentinel hemorrhage after pancreaticoduodenectomy were retrospectively reviewed. Patients having angiogram-negative angiography and undergoing preventive covered stent placement or conservative treatment were included. Clinical outcomes, technique success, and complications were evaluated.
Results
A total of 25 patients (mean age 62.5 years) were evaluated, including 15 patients underwent preventive covered stent placement at the gastroduodenal artery stump and 10 patients received conservative treatments. The clinical success rates were 50% (5/10) and 86.7% (13/15) for conservative treatments and covered stent groups, respectively (
p
= 0.07). In the conservative treatment group, delayed massive hemorrhage occurred in five patients, two of whom died of recurrent bleeding due to gastroduodenal artery pseudoaneurysm within 16 days, and two had intraluminal hemorrhage within 5 days. In the covered stent group, one patient had inferior pancreaticoduodenal artery pseudoaneurysm 1 day after the placement of the covered stent, and one had recurrent bleeding due to duodenal ulcer within 14 days. The 30-day mortality was 40% (4/10) and 0 in the conservative treatment and covered stent groups, respectively (
p
= 0.02). The difference in the overall survival was nonsignificant between the two groups (
p
= 0.23).
Conclusions
The preventive covered stent placement at the gastroduodenal artery stump is safe and reduces delayed massive hemorrhage and short-term mortality in patients with angiogram-negative sentinel hemorrhage after pancreaticoduodenectomy.
Graphic Abstract
Today, women are concerned with health promotion but also with improvements in body weight and shape. The purpose of this study was to investigate the effects of aerobic exercise training (AET) ...combined with isolated soy protein (ISP) supplementation on the body composition, anthropometric characteristics, and cardiopulmonary endurance of women. The qualified subjects were randomly assigned to AET or AET + ISP groups. Women in the AET + ISP group were given an ISP-rich supplement (40 g/day) 5 days a week for 8 weeks; those in the AET group were given the same amount of water in an identical manner. All women received 60 min of AET twice a week for 8 weeks at an intensity of 40–65% heart rate reserve (HRR) and their body composition, anthropometric characteristics, and physical fitness were measured one week before and after the 8-week AET class. A total of 16 subjects (age: 36.13 ± 5.76 years) completed the study and were included in the dataset. The results of this study show that the AET + ISP group obtained greater reductions in body weight (effect size = 0.99), body mass index (BMI, effect size = 1.04), percentage body fat (PBF, effect size = 1.18), circumferences (waist and hip, all effect sizes > 0.8), and greater gains in the percentage lean body mass (PLBM, effect size = 0.89), compared with the AET group, without significant differences in 20 m multi-stage shuttle run test (20 m MST). We conclude that there is a trend for the consumption of ISP following AET to improve the body composition and anthropometric characteristics in women, compared with those who received the same AET without ISP supplementation.
Bone morphogenetic protein receptor I B (BMPR1B) is a transmembrane receptor mediating TGF-β signal transduction. Recent studies indicate a tumor suppressor role for BMPR1B in ovarian cancer. ...Polymorphism at BMPR1B 3'UTR within the miR-125b binding site alters its binding affinity toward the miRNA, which may result in insufficient post-transcriptional repression.
Single-nucleotide polymorphisms rs1970801, rs1434536, and rs11097457 near the miR-125b binding site in BMPR1B were genotyped by Taqman assay on 193 endometriosis patients and 202 healthy controls. BMPR1B and CA125 levels in ectopic endometrial tissues were evaluated by quantitative PCR and immunohistochemistry. Luciferase reporter assay was utilized to verify regulatory roles of BMPR1B 3'UTR with allelic variants of rs1434536 in a cell line model. Cell proliferation and migration were recorded, while expression of BMPR1B, CA125, glucocorticoid receptor (GCCR) and IL-1β were measured by quantitative PCR in endometrial cells transfected with wild-type or mutated miR-125b.
This study found two endometriosis-associated SNPs, rs1434536 (P = 0.010) and rs1970801 (P = 0.0087), located within and next to a miR-125b binding site on BMPR1B. Interestingly, patients with homozygous variant alleles at rs1434536 showed significantly lower serum CA125 levels. Immunohistochemistry staining further confirmed inverse correlation between BMPR1B and CA125 levels in three rs1434536 genotypes. Cell assays demonstrated the variant allele of rs1434536 up-regulating BMPR1B at both mRNA and protein levels, which negatively correlated with CA125 and IL-1β levels. Disruption of the binding between miR-125b and BMPR1B hampered abnormal cell proliferation.
SNPs of BMPR1B within and next to the miR-125b binding site manifested strong correlation with endometriosis development in a Taiwanese cohort. Disrupting the binding of miR-125b toward BMPR1B would increase protein expression, diminishing abnormal cell proliferation as well as serum and cellular CA125 levels. Genetic variation at the miR-125b binding site may play functional roles to protect against endometriosis progression.
Lung cancer is the leading cause of cancer deaths worldwide. Given that the major threat of cancer is metastasis, delineation of the molecular mechanism underlying it would help devise therapeutic ...strategies. Transglutaminase 2 (TG2), belonging to the transglutaminase superfamily, is
a versatile protein with enzymatic and nonenzymatic functions. It mainly localizes inside the cell, but also appears extracellularly. Recent findings have demonstrated the involvement of TG2 in cancer development. Here we examine the role of TG2 in metastasis of lung cancer using a lung cancer
cell line CL1-0, which exhibits low invasiveness, and its invasive subline CL1-5. Our results show that CL1-5 cells express a higher amount of TG2 than CL1-0 cells. Overexpression of TG2 in CL1-0 enhances cell migration and invasion, and lowering TG2 expression in CL1-5 cells reduces their
ability to do so. The transamidase activity of TG2 is not required since cells expressing the inactive TG2 mutant or treated with a TG2 inhibitor are still able to migrate and invade. TG2-stimulated migration and invasion are, at least in part, mediated by Rac, as inhibition of Rac activity
suppresses cell migration and invasion. Lastly, exogenous application of recombinant TG2 protein to CL1-0 cells substantially augments cell migration and invasion, suggesting the significance of extracellular TG2 in promoting these events. Collectively, our results show that TG2 plays a positive role in cell migration and invasion, and this might help metastasis of lung cancer cells.
•Effects of Cu and Co on porous low-dielectric-constant (low-k) films are compared•Less degradation in electrical characteristics and reliability for Co/porous low-k integration.•Barrier-free or ...barrier-less Co interconnect processing can be achieved.
Continuous scaling in back-end-of-line interconnects brings about a significant increase in the line resistance for advanced integrated circuits. To alleviate this issue, cobalt (Co) is proposed to replace copper (Cu) as an interconnect conductor. Effects of different metals (Cu and Co) on the electrical characteristics and reliability of the porous carbon-doping low-dielectric-constant (low-k) films were evaluated in this study. Compared with Cu/porous low-k integration, Co/porous low-k integration exhibited less degradation in the electrical characteristics and reliability under thermal or electrical stress. This study suggests that Co interconnects can provide barrier-free or barrier-less processing, which is a promising strategy for advanced semiconductor technology nodes.
Cardiovascular Diseases (CVDs) such as atherosclerosis, where inflammation occurs in the blood vessel wall, are one of the major causes of death worldwide. Mesenchymal Stem Cells (MSCs)-based ...treatment coupled with nanoparticles is considered to be a potential and promising therapeutic strategy for vascular regeneration. Thus, angiogenesis enhanced by nanoparticles is of critical concern. In this study, Polyethylene Glycol (PEG) incorporated with 43.5 ppm of gold (Au) nanoparticles was prepared for the evaluation of biological effects through in vitro and in vivo assessments. The physicochemical properties of PEG and PEG–Au nanocomposites were first characterized by UV-Vis spectrophotometry (UV-Vis), Fourier-transform infrared spectroscopy (FTIR), and Atomic Force Microscopy (AFMs). Furthermore, the reactive oxygen species scavenger ability as well as the hydrophilic property of the nanocomposites were also investigated. Afterwards, the biocompatibility and biological functions of the PEG–Au nanocomposites were evaluated through in vitro assays. The thin coating of PEG containing 43.5 ppm of Au nanoparticles induced the least platelet and monocyte activation. Additionally, the cell behavior of MSCs on PEG–Au 43.5 ppm coating demonstrated better cell proliferation, low ROS generation, and enhancement of cell migration, as well as protein expression of the endothelialization marker CD31, which is associated with angiogenesis capacity. Furthermore, anti-inflammatory and endothelial differentiation ability were both evaluated through in vivo assessments. The evidence demonstrated that PEG–Au 43.5 ppm implantation inhibited capsule formation and facilitated the expression of CD31 in rat models. TUNEL assay also indicated that PEG–Au nanocomposites would not induce significant cell apoptosis. The above results elucidate that the surface modification of PEG–Au nanomaterials may enable them to serve as efficient tools for vascular regeneration grafts.
In this paper, we present a copper(I)-catalyzed nitrile-addition/
-arylation ring-closure cascade for the synthesis of 5,11-dihydro-6
-indolo3,2-
quinolin-6-ones from 2-(2-bromophenyl)-
...-(2-cyanophenyl)acetamides. Using CuBr and
-BuONa in dimethylformamide (DMF) as the optimal reaction conditions, the cascade reaction gave the target products, in high yields, with a good substrate scope. Application of the cascade reaction was demonstrated on the concise total syntheses of alkaloid isocryptolepine. Further optimization of the products from the cascade reaction led to 3-chloro-5,12-bis2-(dimethylamino)ethyl-5,12-dihydro-6
-1,3dioxolo4',5':5,6indolo3,2-
quinolin-6-one (
), which exhibited the characteristic DNA topoisomerase-I inhibitory mechanism of action with potent in vitro anticancer activity. Compound
actively inhibited ARC-111- and SN-38-resistant HCT-116 cells and showed in vivo activity in mice bearing human HCT-116 and SJCRH30 xenografts. The interaction of
with the Top-DNA cleavable complex was revealed by docking simulations to guide the future optimization of 5,11-dihydro-6
-indolo3,2-
quinolin-6-ones as topoisomerase-I inhibitors.
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