ABSTRACT
BACKGROUND: The aim was to identify the nutritional indexes, construct a prognostic model, and develop a nomogram for predicting individual survival probability in pan-cancers. METHODS: Nutritional indicators, clinicopathological characteristics, and previous major treatment details of the patients were collected. The enrolled patients were randomly divided into training and validation cohorts. Least absolute shrinkage and selection operator (Lasso) regression cross-validation was used to determine the variables to include in the cox regression model. The training cohort was used to build the prediction model, and the validation cohort was used to further verify the discrimination, calibration, and clinical effectiveness of the model. RESULTS: A total of 2020 patients were included. The median OS was 56.50 months (95% CI, 50.36-62.65 months). In the training cohort of 1425 patients, through Lasso regression cross-validation, 13 characteristics were included in the model. Cox proportional hazards model was developed and visualized as a nomogram. The C-indexes of the model for predicting 1-, 3-, 5-, and 10-year OS were 0.848, 0.826, 0.814, and 0.799 in the training cohort and 0.851, 0.819, 0.814, and 0.801 in the validation cohort. The model showed great calibration in the two cohorts. Patients with a score of less than 274.29 had a better prognosis (training cohort: HR, 6.932; 95% CI, 5.723-8.397; log-rank p < 0.001; validation cohort: HR, 8.429; 95% CI, 6.180-11.497; log-rank p < 0.001). CONCLUSION: The prognostic model based on the nutritional indexes of pan-cancer can divide patients into different survival risk groups and performed well in the validation cohort.
Subject(s)
Neoplasms , Nomograms , Nutrition Assessment , Nutritional Status , Humans , Female , Male , Prognosis , Middle Aged , Neoplasms/mortality , Aged , Proportional Hazards Models , Cohort Studies , Retrospective Studies , Adult , Survival RateABSTRACT
Autophagy impairment is a key factor in Alzheimer's disease (AD) pathogenesis. TFEB (transcription factor EB) and TFE3 (transcription factor binding to IGHM enhancer 3) are nuclear transcription factors that regulate autophagy and lysosomal biogenesis. We previously showed that corynoxine (Cory), a Chinese medicine compound, protects neurons from Parkinson's disease (PD) by activating autophagy. In this study, we investigated the effect of Cory on AD models in vivo and in vitro. We found that Cory improved learning and memory function, increased neuronal autophagy and lysosomal biogenesis, and reduced pathogenic APP-CTFs levels in 5xFAD mice model. Cory activated TFEB/TFE3 by inhibiting AKT/mTOR signaling and stimulating lysosomal calcium release via transient receptor potential mucolipin 1 (TRPML1). Moreover, we demonstrated that TFEB/TFE3 knockdown abolished Cory-induced APP-CTFs degradation in N2aSwedAPP cells. Our findings suggest that Cory promotes TFEB/TFE3-mediated autophagy and alleviates Aß pathology in AD models.
Subject(s)
Alzheimer Disease , Autophagy , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors , Disease Models, Animal , Transient Receptor Potential Channels , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism , Animals , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Autophagy/drug effects , Mice , Lysosomes/metabolism , Lysosomes/drug effects , Humans , Mice, Transgenic , Amyloid beta-Peptides/metabolism , Mice, Inbred C57BL , TOR Serine-Threonine Kinases/metabolism , Male , Proto-Oncogene Proteins c-akt/metabolism , Neurons/drug effects , Neurons/metabolism , Neurons/pathology , Signal Transduction/drug effects , Amyloid beta-Protein Precursor/metabolism , Amyloid beta-Protein Precursor/geneticsABSTRACT
Additives were widely investigated to retain the nutrients and mitigate the greenhouse gas emissions (GHGs) during manure composting. However, the sustained effects of additives on the GHGs emissions following incorporation of composts to soil were scarcely explored. This study evaluated the effects of bentonite added at the beginning of pig manure composting on the GHGs emissions during two successive processes, i.e., composting and soil incubation amended with composting products. Addition of bentonite did not hinder the composting process and alter the total CO2 emission. On the other hand, reduction by about 17% and 29% for CH4 and N2O emission, respectively, was achieved in the presence of bentonite during composting. Incorporation of the final composting products to soil enhanced significantly the soil C and N of various forms, and gas emissions of CO2 and N2O. However, no significant differences were observed between bentonite-manure co-compost and manure-only compost application except for the N2O emission. Compared to the manure-only compost, compost amended with bentonite reduced N2O loss by around 6.8%, but not statistically significant. This study confirmed that addition of bentonite at the composting stage can mitigate the GHGs emission considering both composting and compost application stages, with all reductions occurring at the composting stage.
Subject(s)
Composting , Greenhouse Gases , Animals , Swine , Greenhouse Gases/analysis , Bentonite , Manure , Carbon Dioxide/analysis , Nitrogen/analysis , Methane/analysis , Soil , Nitrous Oxide/analysisABSTRACT
Secondary water supply systems (SWSSs) are characterized by long water stagnation and low levels of chlorine residuals, which may pose a high microbial risk to terminal users. In this study, the SWSSs of 12 residential neighborhoods in a metropolitan area of 5 million people in southeastern China were seasonally investigated to assess their microbial risks by determining more than 30 physicochemical and biological parameters. Although the microbiological quality of SWSS water met the requirements of the standards for drinking water quality of China, it did deteriorate in various aspects. The heterotrophic plate counts with R2A media were high (> 100 CFU/mL) in some SWSS tank and tap water samples. Propidium monoazide (PMA)-qPCR revealed a one magnitude higher abundance of viable bacteria in the tank and tap water samples (average 103.63±1.10 and 103.65±1.25 gene copies/mL, respectively) compared with the input water samples, and Enterococcus, Acanthamoeba, and Hartmannella vermiformis were only detected in the tanks. In particular, the high detection frequency of Legionella in 35% tank and 21% tap water samples suggested it is a supplementary microbial safety indicator in SWSSs. The microbial regrowth potential was more obvious in summer, and Illumina sequencing also demonstrated distinct seasonal changes in the relative abundance of bacterial gene sequences at the genus level. Turbidity and residual chlorine were closely connected with total bacterial biomass, and the latter seemed responsible for microbial community structure alteration. The extremely low chlorine residuals associated with a high abundance of total bacteria (as high as 106.48 gene copies/mL) and Legionella (as high as 106.71 gene copies/100 mL) in the closed valve tanks highlighted the high microbial risk increased by mishandling the operation of SWSSs. This study found that SWSSs possessed a higher microbial risk than the drinking water network, which suggested that the frequency and scope of monitoring the microbial risk of SWSSs in megacities should be strengthened for the purpose of waterborne epidemic disease prevention and control.
Subject(s)
Legionella , Water Supply , Cities , Humans , Legionella/genetics , Water , Water MicrobiologyABSTRACT
Epistasis plays an important role in manipulating rice tiller number, but epistatic mechanism still remains a challenge. Here we showed the process of epistatic analysis between tillering QTLs. A half diallel mating scheme was conducted based on 6 single segment substitution lines and 9 dual segment pyramiding lines to allow the analysis of 4 epistatic components. Additive-additive, additive-dominance, dominance-additive, and dominance-dominance epistatic effects were estimated at 9 stages of development via unconditional QTL analysis simultaneously. Unconditional QTL effect (QTL cumulative effect before a certain stage) was then divided into several conditional QTL components (QTL net effect in a certain time interval). The results indicated that epistatic interaction was prevalent, all QTL pairs harboring epistasis and one QTL always interacting with other QTLs in various component ways. Epistatic effects were dynamic, occurring mostly within 14d and 21-35d after transplant and exhibited mainly negative effects. The genetic and developmental mechanism on several tillering QTLs was further realized and perhaps was useful for molecular pyramiding breeding and heterosis utilization for improving plant architecture.
Subject(s)
Chromosomes, Plant , Epistasis, Genetic , Oryza/genetics , Phenotype , Quantitative Trait LociABSTRACT
No genomic sequence of Mycobacterium isolated from orchids has been reported yet; therefore, this study intends to analyze the complete genomic sequence of a growth-promoting Mycobacterium from orchid Doritaenopsis. Mycobacterium strain Mya-zh01 was isolated from the flower stalk of Doritaenopsis Jiuhbao Red Rose. Our results show that Mya-zh01 can effectively produce and secrete the plant growth hormone indole-3-acetic acid (IAA). Inoculation of Mya-zh01 increased root number and length, plant height, leaf number, and leaf length in Doritaenopsis. Furthermore, inoculation of Mya-zh01 promotes seed germination in Doritaenopsis. We sequenced and assembled chromosome for Mya-zh01 (5,027,704 bp with 68.48% GC content), which was predicted to encode 4968 proteins with functions in oxidation reduction, growth, plasma membrane, ATP and DNA binding, carbon metabolism and biosynthesis of amino acids pathways. Mya-zh01 may trap iron from nature or host cells to facilitate the growth of the orchids by producing two siderophores (Mycobactin and Nocobactin NA). Four pathways (tryptamine, indole-3-acetamide, indole-3-pyruvate, and flavin monooxygenase) and seven enzymes [tryptophan synthase alpha chain, tryptophan synthase beta chain, amidase, monoamine oxidase, indole-3-pyruvate monooxygenase, indole-3-pyruvate decarboxylase and aldehyde dehydrogenase (NAD +)] involved in IAA biosynthesis were predicted in Mya-zh01 genome. In conclusion, this study demonstrated the significance of Mya-zh01 in facilitating plant growth and seed germination in Doritaenopsis by IAA biosynthesis, which provides a new insight into the mechanism of plant-bacteria interaction in Doritaenopsis.
Subject(s)
Mycobacterium/genetics , Orchidaceae/microbiology , Plant Development , Seeds/microbiology , Flowers/microbiology , Germination , Mycobacterium/isolation & purification , Mycobacterium/metabolismABSTRACT
Objective To analyze the genetic characteristics of the hemagglutinin (HA) and neuraminidase (NA) genes of influenza B viruses isolated in Yancheng City from 2015 to 2017. Methods The throat swab specimens of influenza-like illness( ILI) from sentinel surveillance hospital and outbreak sites were collected and sent to Yancheng CDC for virus nucleic acids and virus isolation testing. After validation with serological tests, eighteen strains of influenza B virus isolates were selected to amplify their HA1 and NA genes through RT-PCR assay. Their molecular characteristics of the obtained viral HA1 and NA gene sequences were analyzed using bioinformation software from three aspects, including nucleic acid level, amino acid level and molecular evolution level. Results Basically, the clustering relationships and the branche patterns between HA1 and NA genes from the 18 Yancheng influenza B virus strains were similar. The Yamagata lineage strains in 2015 were distributed in the Yamagata Clade 3 branch, belonging to Phuket/3073 strains. The Victoria lineage strains in 2016-2017 were distributed in the Victoria Clade 1A branch, belonging to Brisbane/60 strains. D196N substitution was detected on HA1 protein in all of Yamagata lineage strains at 190-helix epitope; Amino acid substitutions of victoria lineage strains involved two antigenic epitopes, 117 and 129 sites of 120-loop epitope and 197 and 199 sites of 190-helix epitope. No Intra-lineage or inter-lineage rearrangements occurred in Yancheng strains. Eighteen influenza B strains had no mutations in catalytic residues and drug resistant sites of NA genes. Conclusion The Yamagata strains well matched with vaccine strain B/Phuket/3073/2013. The HA1 and NA genes of victoria lineage strains circulated in Yancheng City during 2016 to 2017 are changing gradually. The accumulation of these mutations will result in antigenic drift of victoria lineage strains and increase the mismatch of the IFV field stains with the available vaccine strains, which may reduce the protective effect of flu vaccine.
ABSTRACT
PURPOSE: Vitamin C (VC) is a kind of essential nutrient in the body regarded as a canonical antioxidant during the past hundred years. However, the anti-cancer effect of VC is controversial. Our study is trying to clarify the relationship between VC dosage and breast cancer metastasis. METHODS: Human breast cancer cell lines Bcap37 and MDA-MB-453 were treated with VC at three different concentrations (low-dose, 0.01 mM; medium-dose, 0.1 mM; high-dose, 2 mM). Wound healing assays were conducted for migration assay; transwell tests were performed to detect the ability of cell invasion. The protein levels were evaluated by Western blot analysis or immunohistochemistry. Tumor xenografts in nude mice were built to test the effects of VC on breast cancer cell proliferation and metastasis. RESULTS: 0.01 and 0.1 mM VC promoted cell migration and invasion when compared with the control group, but 2 mM VC significantly suppressed cell migration and invasion of breast cancer cell lines. High-dose VC increased E-cadherin and reduced Vimentin, indicating that high-dose VC suppressed epithelial-mesenchymal transition (EMT) in breast cancer cells. Besides, high-dose VC inhibited cell invasion promoted by TGF-ß1 in breast cancer cells. Meanwhile, high-dose VC reversed the suppression of E-cadherin and enhancement of Vimentin induced by TGF-ß1 in breast cancer cells. Furthermore, high-dose VC significantly inhibited breast cancer metastasis in vivo. CONCLUSION: High-dose VC inhibits cell migration and invasion of breast cancer cell lines through suppressing EMT. Thus, it may be considered as an anticancer drug candidate for breast cancer patients.
ABSTRACT
AIM: To evaluate the protective effects of lipoic acid-niacin (N2L) dimers against blue light (BL)-induced oxidative damage to human retinal pigment epithelium (hRPE) cells in vitro. METHODS: hRPE cells were divided into a control group (CG), a BL group, an N2L plus BL irradiation group, an α-lipoic acid (ALA) plus BL group, an ALA-only group, and an N2L-only group. hRPE cellular viability was detected by performing 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) bromide assays, and apoptosis was evaluated by annexin-V-PE/7-AAD staining followed by flow cytometry. Ultrastructural changes in subcellular organelles were observed by transmission electron microscopy. Reactive oxygen species formation was assayed by flow cytometry. The expression levels of the apoptosis-related proteins BCL-2 associated X protein (BAX), B-cell leukmia/lymphoma 2 (BCL-2), and caspase-3 were quantified by Western blot analysis. RESULTS: BL exposure with a light density of 4±0.5 mW/cm2 exceeding 6h caused hRPE toxicity, whereas treatment with a high dose of N2L (100 mol/L) or ALA (150 mol/L) maintained cell viability at control levels. BL exposure caused vacuole-like degeneration, mitochondrial swelling, and reduced microvillus formation; however, a high dose of N2L or ALA maintained the ultrastructure of hRPE cells and their organelles. High doses of N2L and ALA also protected hRPE cells from BL-induced apoptosis, which was confirmed by Western blot analysis: BCL-2 expression significantly increased, while BAX and caspase-3 expression slightly decreased compared to the CG. CONCLUSION: High-dose N2L treatment (>100 mol/L) can reduce oxidative damage in degenerating hRPE cells exposed to BL with an efficacy similar to ALA.
ABSTRACT
Herein, a simple and efficient fluorescence analysis method for L-Cysteine (L-Cys) was established. The method was based on the fluorescent "off-on" mode of nitrogen doped carbon dots (NCDs). The NCDs were prepared via a facile one-step solvothermal method. In the process of exploring the bio-functional application of these newly synthesized NCDs, we found these NCDs with rich functional groups exhibited excellent optical properties. In addition, these newly synthesized NCDs showed an excitation-dependent emissions photolumine-scent (PL) property and exhibited good performance in the detection of Fe3+ ions by quenching the blue emission fluorescence. Interestingly, the quenched fluorescence of NCDs was recovered with the addition of L-Cys, which provided a novel approach for L-Cys detection. The NCDs-based fluorescent "off-on" sensor has a wide linear detection range (0-100 µM), and a relatively low detection limits (0.35 µM) for L-Cys. This simple fluorescent "off-on" approach is, very sensitive and selective for L-Cys detection, which also provides a new insight on NCDs biosensor application.
ABSTRACT
A 41 year old man presented with a familial history of multiple endocrine neoplasia type 2A (MEN2A) and severe hypertension. Rearranged during transfection (RET) gene sequencing confirmed a Cys634Tyr mutation of TGC to TAC. Total thyroidectomy and bilateral neck dissection were performed and the pathological assessment revealed a medullary thyroid carcinoma (MTC), 0.6 cm in size on the right side (number of lymph nodes: 0/2, 0/15, 0/12, and 0/8 in areas VI, II, III, and IV, respectively) and a papillary thyroid carcinoma (PTC), 0.2 cm in size on the left side (numbers of lymph nodes: 2/6, 0/3, 0/10, and 0/6 in areas VI, II, III, and IV, respectively). There were no pathological changes in the MTC observed in the thyroid tissues on the left side. We believe that the follow-up of patients with both MTC and PTC should utilize a combination of the respective principles for rational disease reassessment.
Subject(s)
Carcinoma, Neuroendocrine/genetics , Multiple Endocrine Neoplasia Type 2a/genetics , Proto-Oncogene Proteins c-ret/genetics , Thyroid Cancer, Papillary/genetics , Thyroid Neoplasms/genetics , Adult , Carcinoma, Neuroendocrine/pathology , Germ-Line Mutation , Humans , Lymph Nodes/pathology , Male , Multiple Endocrine Neoplasia Type 2a/pathology , Mutation , Pedigree , Polymorphism, Single Nucleotide/genetics , Proto-Oncogene Mas , Thyroid Cancer, Papillary/pathology , Thyroid Neoplasms/pathologyABSTRACT
Methylene blue (MB) can ameliorate behavioral, neurochemical, and neuropathological impairments in animal models of acute and chronic neurodegenerative disorders, but the underlying mechanism remains unclear. Myocyte enhancer factor 2 (MEF2D) is known to promote neuronal survival in several models, and several survival and death signals converge on MEF2D and regulate its activity. Here, we investigated the role of MEF2D in the neuroprotective effect of MB against glutamate-induced toxicity in HT22 neuronal cells. Our results showed that MB, event at less than 100 nM, improved the viability of HT22 cells exposed to 2 mM glutamate. MB attenuated the mitochondrial impairment and quenches the reactive oxygen species (ROS) induced by glutamate. Surprisingly, MB at 50-200 nM did not affect the Nrf2/HO-1 pathway, an important endogenous anti-oxidative system. Further study showed that MB increased the transcription and translation of MEF2D. In addition, MB upregulated the expression of mitochondrial NADH dehydrogenase 6 (ND6) in a MEF2D-dependent manner. Knockdown of MEF2D abolished both MB-medicated increase of ND6 and MB-induced neuroprotection against glutamate-induced toxicity. Moreover, we showed that MB promoted Akt function activity, suppressed GSK-3ß activity, and increased MEF2D level in hippocampus of mice and HT22 cells. These findings for the first time demonstrate that MB protects HT22 neuronal cells against glutamate-induced cell death partially via the regulation of MEF2D-associated survival pathway.
Subject(s)
Hippocampus/drug effects , Methylene Blue/pharmacology , Neuroprotective Agents/pharmacology , Oxidative Stress/drug effects , Animals , Apoptosis/drug effects , Glutamic Acid/metabolism , Glutamic Acid/pharmacology , Hippocampus/metabolism , MEF2 Transcription Factors/metabolism , Mice , Mitochondria/drug effects , Mitochondria/metabolism , Neurons/drug effects , Neurons/metabolism , Reactive Oxygen Species/metabolism , Signal Transduction/drug effectsABSTRACT
In this study, a series of novel ferulic and caffeic acid dimers was designed and synthesised, and their multifunctional properties against Alzheimer's disease (AD) were evaluated. Results showed that our multifunctional strategy was great supported by enhancing the inhibition of Aß1-42 self-induced aggregation. Moreover, 7b also had potent protective effects against glutamate-induced cell death without significant cell toxicity in mouse hippocampal neuronal HT22 cells and 10c effectively scavenged diphenylpicrylhydrazyl free radicals. Collectively, these data strongly encourage further optimisation of 7b as a new hit to develop multifunctional agents for the treatment of AD.
Subject(s)
Alzheimer Disease/drug therapy , Caffeic Acids/chemical synthesis , Caffeic Acids/therapeutic use , Coumaric Acids/chemical synthesis , Coumaric Acids/therapeutic use , Amyloid beta-Peptides/antagonists & inhibitors , Animals , Antioxidants/pharmacology , Biphenyl Compounds/chemistry , Cell Death/drug effects , Cell Line , Free Radical Scavengers/chemistry , Free Radical Scavengers/pharmacology , Glutamic Acid/toxicity , Humans , Mice , Neurons/drug effects , Peptide Fragments/antagonists & inhibitors , Picrates/chemistryABSTRACT
Colibactin is an as-yet-uncharacterized genotoxic secondary metabolite produced by human gut bacteria. Here we report the biosynthetic discovery of two new precolibactin molecules from Escherichia coli, including precolibactin-886, which uniquely incorporates the highly sought genotoxicity-associated aminomalonate building block into its unprecedented macrocyclic structure. This work provides new insights into the biosynthetic logic and mode of action of this colorectal-cancer-linked microbial chemical.
Subject(s)
Malonates/metabolism , Peptides/metabolism , Polyketides/metabolism , Escherichia coli/metabolism , Humans , Malonates/chemistry , Molecular Conformation , Peptides/chemistry , Polyketides/chemistryABSTRACT
Oxidative stress mediates the pathogenesis of neurodegenerative disorders. Gartanin, a natural xanthone of mangosteen, possesses multipharmacological activities. Herein, the neuroprotection capacity of gartanin against glutamate-induced damage in HT22 cells and its possible mechanism(s) were investigated for the first time. Glutamate resulted in cell death in a dose-dependent manner and supplementation of 1-10 µM gartanin prevented the detrimental effects of glutamate on cell survival. Additional investigations on the underlying mechanisms suggested that gartanin could effectively reduce glutamate-induced intracellular ROS generation and mitochondrial depolarization. We further found that gartanin induced HO-1 expression independent of nuclear factor erythroid-derived 2-like 2 (Nrf2). Subsequent studies revealed that the inhibitory effects of gartanin on glutamate-induced apoptosis were partially blocked by small interfering RNA-mediated knockdown of HO-1. Finally, the protein expression of phosphorylation of AMP-activated protein kinase (AMPK) and its downstream signal molecules, Sirtuin activator (SIRT1) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), increased after gartanin treatment. Taken together, these findings suggest gartanin is a potential neuroprotective agent against glutamate-induced oxidative injury partially through increasing Nrf-2-independed HO-1 and AMPK/SIRT1/PGC-1α signaling pathways.
Subject(s)
AMP-Activated Protein Kinases/metabolism , Apoptosis/drug effects , Heme Oxygenase-1/metabolism , Membrane Proteins/metabolism , NF-E2-Related Factor 2/metabolism , Neurons/drug effects , Xanthones/pharmacology , Animals , Cell Line , Cell Survival/drug effects , Glutamic Acid/pharmacology , Mice , Neurons/cytology , Neurons/metabolism , Neuroprotective Agents/pharmacology , Oxidative Stress/drug effects , Reactive Oxygen Species/metabolism , Signal Transduction/drug effects , Xanthones/chemistryABSTRACT
Natural xanthones have diversity pharmacological activities. Here, a series of xanthones isolated from the pericarps of Garcinia mangostana Linn, named α-Mangostin, 8-Deoxygartanin, Gartanin, Garciniafuran, Garcinone C, Garcinone D, and γ-Mangostin were investigated. Biological screening performed in vitro and in Escherichia coli cells indicated that most of the xanthones exhibited significant inhibition of self-induced ß-amyloid (Aß) aggregation and also ß-site amyloid precursor protein-cleaving enzyme 1, acted as potential antioxidants and biometal chelators. Among these compounds, α-Mangostin, Gartanin, Garcinone C and γ-Mangostin showed better antioxidant properties to scavenge Diphenyl-1-(2,4,6-trinitrophenyl) hydrazyl (DPPH) free radical than Trolox, and potent neuroprotective effects against glutamate-induced HT22 cell death partly by up-regulating HO-1 protein level and then scavenging reactive oxygen species. Moreover, Gartanin, Garcinone C and γ-Mangostin could be able to penetrate the blood-brain barrier (BBB) in vitro. These findings suggest that the natural xanthones have multifunctional activities against Alzheimer's disease (AD) and could be promising compounds for the therapy of AD.
Subject(s)
Alzheimer Disease/metabolism , Garcinia mangostana , Plant Extracts/therapeutic use , Xanthones/therapeutic use , Alzheimer Disease/drug therapy , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Animals , Aspartic Acid Endopeptidases/antagonists & inhibitors , Aspartic Acid Endopeptidases/metabolism , Cell Line , Mice , Plant Extracts/isolation & purification , Plant Extracts/pharmacology , Xanthones/isolation & purification , Xanthones/pharmacologyABSTRACT
PURPOSE: To explore the effects and mechanisms of GSK126, a novel inhibitor of histone methyltransferase enhancer of zeste homologue 2, on cancer cell migration. METHODS: Gastric cancer cell line MGC803 and human lung adenocarcinoma cell line A549 were treated with GSK126 at three doses. Transwell and wound healing assays were conducted to detect cell migration. Human umbilical vein endothelial cells tube formation assay and chick embryo chorioallantoic membrane assay were performed to assess the effects of GSK126 on angiogenesis in vitro and in vivo, respectively. The mRNA level of VEGF-A was detected by quantitative PCR, and the protein levels of VEGF-A were detected both by western blot analysis and immunohistochemistry. Epi-fluorescent intensity was obtained by in vivo imaging. RESULTS: GSK126 inhibited cell migration in both MGC803 and A549 in a dose-dependent manner, as revealed by transwell and wound healing assays. The effects of GSK 126 were similar to those of gefitinib at the same doses. Moreover, GSK126 at doses of 20 and 50 µM inhibited angiogenesis both in vitro and in vivo. GSK126 reduced both the mRNA and protein expression of VEGF-A in a dose-dependent manner. Finally, in vivo imaging assay revealed that GSK126 at 200 mg/kg significantly inhibited cancer cell migration. CONCLUSIONS: GSK126 inhibits cell migration and angiogenesis in solid tumor cell lines through down-regulation of VEGF-A expression. Thus, it may be considered as a novel anticancer drug candidate for solid tumor.
Subject(s)
Angiogenesis Inhibitors/pharmacology , Indoles/pharmacology , Polycomb Repressive Complex 2/antagonists & inhibitors , Pyridones/pharmacology , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Animals , Cell Line, Tumor , Cell Movement/drug effects , Chick Embryo , Enhancer of Zeste Homolog 2 Protein , Humans , Male , Mice , Mice, Inbred BALB C , Neoplasm Metastasis/prevention & controlABSTRACT
PURPOSE: To investigate the effects and mechanisms of fasudil hydrochloride (fasudil) on and in alkali burn-induced corneal neovascularization (CNV) in mice. METHODS: To observe the effect of fasudil, mice with alkali-burned corneas were treated with either fasudil eye drops or phosphate-buffered saline (PBS) four times per day for 14 consecutive days. After injury, CNV and corneal epithelial defects were measured. The production of reactive oxygen species (ROS) and heme oxygenase-1(HO-1) was measured. The infiltration of polymorphonuclear neutrophils (PMNs) and the mRNA expressions of CNV-related genes were analyzed on day 14. RESULTS: The incidence of CNV was significantly lower after treatment with 100 µM and 300 µM fasudil than with PBS, especially with 100 µM fasudil. Meanwhile, the incidences of corneal epithelial defects was lower (n=15, all p<0.01). After treatment with 100 µM fasudil, the intensity of DHE ï¬uorescence was reduced in the corneal epithelium and stroma than with PBS treatment (n=5, all p<0.01), and the number of filtrated PMNs decreased. There were significant differences between the expressions of VEGF, TNF-a, MMP-8, and MMP-9 in the 100 µM fasudil group and the PBS group (n=8, all p<0.05). The production of HO-1 protein in the 100 µM fasudil group was 1.52±0.34 times more than in the PBS group (n=5 sample, p<0.05). CONCLUSIONS: 100 µM fasudil eye drops administered four times daily can significantly inhibit alkali burn-induced CNV and promote the healing of corneal epithelial defects in mice. These effects are attributed to a decrease in inflammatory cell infiltration, reduction of ROS, and upregulation of HO-1 protein after fasudil treatment.
Subject(s)
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/analogs & derivatives , Burns, Chemical/drug therapy , Burns, Chemical/enzymology , Corneal Neovascularization/prevention & control , Eye Burns/drug therapy , Eye Burns/enzymology , rho-Associated Kinases/antagonists & inhibitors , 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/pharmacology , Alkalies/toxicity , Animals , Burns, Chemical/pathology , Corneal Neovascularization/etiology , Corneal Neovascularization/pathology , Disease Models, Animal , Eye Burns/pathology , Female , Heme Oxygenase-1/metabolism , Membrane Proteins/metabolism , Mice , Mice, Inbred BALB C , Protein Kinase Inhibitors/pharmacology , RNA, Messenger/genetics , RNA, Messenger/metabolism , Reactive Oxygen Species/metabolism , Wound Healing/drug effectsABSTRACT
Dynamics of soil organic carbon mineralization affected by long-term fertilizations and temperature in relation to different soil carbon fractions were investigated in paddy soils. Soil samples were collected from the plough layer of 3 long-term national experimental sites in Xinhua, Ningxiang and Taojiang counties of Hunan Province. Mineralization of soil organic C was estimated by 33-day aerobic incubation at different temperatures of 10, 20 and 30 degrees C. The results showed that the rates of CO2 production were higher during the earlier phase (0-13 d) in all treatments, and then decreased according to a logarithm function. Higher incubation temperature strengthened C mineralization in the different treatments. The quantities of cumulative CO2 production in NPK with manure or straw treatments were greater than in inorganic fertilizers treatments. The Q10 values in the different soil treatments ranged from 1.01-1.53. There were significantly positive correlations between the Q10 values and soil total organic carbon (TOC), easy oxidation organic carbon (EOOC), humic acid carbon (C(HA)), fulvic acid carbon (CFA). The cumulative amount of mineralized C was significantly positively correlated with microbial biomass carbon (MBC) at 10 and 20 degrees C, but not significantly at 30 degrees C. Significant correlations were found between the cumulative amount of mineralized C and different soil carbon fractions and C(HA)/C(FA). The correlations of differ- ent soil carbon fractions with the ratio of cumulative mineralized C to TOC were negatively correlated at 10 degrees C, but not significantly at 20 and 30 degrees C. These results suggested that the application of NPK with manure or straw would be helpful to increase the sequestration of C in paddy soils and reduce its contribution of CO2 release in the atmosphere.