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1.
Exp Cell Res ; 387(2): 111774, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31838061

RESUMO

BACKGROUND: The lncRNA NKILA has been reported to interact with NF-κB and has an important role in various human diseases. However, the role of NKILA in myocardial ischaemic injury is still unknown. METHODS: We established cell and animal models of myocardial ischaemic injury. We confirmed our findings by overexpressing NKILA, silencing myocardin and using an NF-κB pathway inhibitor in a hypoxia/reoxygenation (H/R) model of H9c2 cells. An animal model of ischaemia-reperfusion (I/R) injury was established by LAD ligation. Overexpression of NKILA was achieved by adeno-associated virus (AAV) injection through the tail vein. Annexin-V/PI staining and flow cytometric analysis were performed to test cell apoptosis. ELISAs were used to determine the secretion of inflammatory factors. TTC, HE and TUNEL staining were performed to study myocardial pathological injury. qRT-PCR or Western blotting were used to test the expression levels of NKILA, myocardin, the NF-κB pathway and apoptosis-related proteins. RESULTS: H/R and I/R treatment significantly suppressed the expression of NKILA and activated the NF-κB pathway, resulting in the loss of myocardin. Overexpressing NKILA led to the suppression of the NF-κB pathway and successfully prevented the cell apoptosis and inflammatory responses caused by H/R stimulation in H9c2 cells. Silencing myocardin reversed the protective effect of NKILA and led to severe injury in the H9c2 cells that underwent H/R. Furthermore, the NF-κB pathway inhibitor BAY11-7028 reduced the H/R injury in H9c2 cells with little effect on NKILA expression. Similar results were confirmed in an animal model of myocardial I/R injury and showed that overexpression of NKILA inhibited I/R-triggered myocardial injury in vivo. CONCLUSION: NKILA enhanced the expression of myocardin via inhibiting the NF-κB signalling pathway and preventing cell apoptosis and the inflammatory response of cardiomyocytes, thus ameliorating myocardial I/R injury.

2.
Huan Jing Ke Xue ; 40(11): 5098-5106, 2019 Nov 08.
Artigo em Chinês | MEDLINE | ID: mdl-31854579

RESUMO

Four soil conditioners, SAMMNS, CCT01, Mineral, and Tebeigai were selected for this study. The effects of the four conditioners on soil pH, bulk density, organic matter, available nutrients, texture, microaggregates, Cd available in soil, and Cd content in brown rice were investigated using field-controlled cadmium tests conducted in cadmium-contaminated paddy fields in Pingxiang. The results showed that compared to the control, soil conditioners could increase pH, bulk density, and cation exchange capacity in soil. SAMMNS and CCT01 soil conditioners increased the amount of silt and clay, but that of sand decreased, whereas the Mineral and Tebeigai soil conditioners decreased silt and clay, and sand increased. In addition to the CCT01 soil conditioner, the application of soil conditioners increased large-scale agglomerates and reduced small-scale microaggregates. The effects of soil conditioners on soil physical and chemical properties promoted the conversion of Cd from contaminated soil from high activity to low activity, which reduced available Cd content in soil (5.21%-34.78%) and Cd content in brown rice (51.39%-68.06%). Correlation analysis showed that Cd content in brown rice was significantly positively correlated with available Cd and available phosphorus in soil, whereas it was negatively correlated with pH and bulk density in soil. Considering the effects of soil and brown rice on cadmium reduction and physicochemical properties, Tebeigai soil conditioner exhibited the best repair effects, followed by SENMES and Mineral soil conditioner.

3.
Sheng Li Xue Bao ; 71(6): 883-893, 2019 Dec 25.
Artigo em Chinês | MEDLINE | ID: mdl-31879744

RESUMO

In this study, we improved the culture method of mouse hippocampal primary microglia to obtain hippocampal ramified microglia with high activity and purity, which were resemble to the resting status of normal microglia in healthy brain in vivo. Hippocampal tissue was excised from 2-4-week-old SPF C57BL/6J mice and cut into pieces after PBS perfusion, and then manually dissociated into the single-cell suspension by using Miltenyi Biotec's Adult Brain Dissociation Kit. The tissue fragments such as myelin in the supernatant were removed by debris removal solution in the kit. The cell suspension was incubated with CD11b immunomagnetic beads for 15 min at 4 °C. To obtain high-purity microglia, we used two consecutive cell-sorting steps by magnetic activated cell sorting (MACS). After centrifugation, the cells were resuspended and seeded in a 24-well culture plate. The primary microglia were cultured with complete medium (CM) or TIC medium (a serum-free medium with TGF-ß, IL-34 and cholesterol as the main nutritional components) for 4 days, and then were used for further experiments. The results showed that: (1) The cell viability was (56.03 ± 2.10)% by manual dissociation of hippocampus; (2) Compared with immunopanning, two-step MACS sorting allowed for efficient enrichment of microglia with higher purity of (86.20 ± 0.68)%; (3) After being incubated in TIC medium for 4 d, microglia exhibited branching, quiescent morphology; (4) The results from qRT-PCR assay showed that the levels of TNF-α, IL-1ß and CCL2 mRNA in TIC cultured-microglia were similar to freshly isolated microglia, while those were much higher in CM cultured-microglia after incubation for 4 d and 7 d (P < 0.05). Taken together, compared to the conventional approaches, this modified protocol of mouse hippocampal primary microglia culture by using MACS and TIC medium enables the increased yield and purity of microglia in the quiescent state, which is similar to normal ramified microglia in healthy brain in vivo.


Assuntos
Técnicas de Cultura de Células , Separação Celular , Hipocampo , Magnetismo , Microglia , Animais , Técnicas de Cultura de Células/métodos , Separação Celular/métodos , Células Cultivadas , Camundongos , Camundongos Endogâmicos C57BL , Microglia/citologia
4.
Ecotoxicol Environ Saf ; 183: 109511, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31386941

RESUMO

Antibiotics have become a global public concern because of their extensively usage and high toxicity on aquatic organisms, especially leading to the widespread of antibiotic resistance genes. The objective of this study was to evaluate the occurrence, spatial distribution and ecological risks of multi-classes commonly used human and veterinary antibiotics in both aqueous and sedimentary phases of 65 shallow lakes in the lower-middle reaches of the Yangtze River, China. In the target area, antibiotic concentrations in most of lakes (<20 ng/L in the water of 22 lakes and <20 ng/g in the sediments of 43 lakes) were generally lower than those documented in previous studies in China and other countries, and these differences were probably due to less pollutant sources, high temperatures and heavy rainfall in summer. The concentrations of antibiotics in water (>100 ng/L) or sediments (>100 ng/g) of nine lakes, such as Dianshan Lake, Ge Lake and Ce Lake, were comparable to those in rivers and lakes that were seriously polluted by urban and livestock wastewater in China. The Taihu lakes showed relatively higher antibiotic concentrations, followed by the Huaihe River lakes, Poyang lakes and Dongting lakes. The composition of antibiotics showed that agricultural source might be the main source of antibiotics in most of the lakes in the lower-middle reaches of the Yangtze River basin, China. The pseudo distribution coefficient (P-Kd) and significant relationship between antibiotics and environmental factors in the present study suggested the spatial of antibiotics in the lakes might be affected by antibiotics' physiochemical properties and environmental factors. The environmental risk assessment results showed that in general, sulfamethoxazole (SMX), erythromycin (ETM) and ofloxacin (OFX) in the surface water could pose medium risks to algae or bacteria in the aquatic ecosystem, while antibiotics ETM, roxithromycin (RTM), enrofloxacin (EFX) and sulfadiazine (SDZ) in the sediment might pose medium risks to algae or bacteria populations. High potential risk might occur in winter in most lakes due to lower water storage and less degradation. Overall, our study reveals the pollution trends and potential sources of antibiotics in shallow lakes in the lower-middle reaches of the Yangtze River basin.


Assuntos
Antibacterianos/análise , Monitoramento Ambiental/métodos , Sedimentos Geológicos/química , Lagos/química , Rios/química , Poluentes Químicos da Água/análise , Organismos Aquáticos , China , Ecossistema , Humanos , Medição de Risco , Estações do Ano
5.
Cell Rep ; 27(13): 3844-3859.e6, 2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-31242418

RESUMO

Spinal long-term potentiation (LTP) at C-fiber synapses is hypothesized to underlie chronic pain. However, a causal link between spinal LTP and chronic pain is still lacking. Here, we report that high-frequency stimulation (HFS; 100 Hz, 10 V) of the mouse sciatic nerve reliably induces spinal LTP without causing nerve injury. LTP-inducible stimulation triggers chronic pain lasting for more than 35 days and increases the number of calcitonin gene-related peptide (CGRP) terminals in the spinal dorsal horn. The behavioral and morphological changes can be prevented by blocking NMDA receptors, ablating spinal microglia, or conditionally deleting microglial brain-derived neurotrophic factor (BDNF). HFS-induced spinal LTP, microglial activation, and upregulation of BDNF are inhibited by antibodies against colony-stimulating factor 1 (CSF-1). Together, our results show that microglial CSF1 and BDNF signaling are indispensable for spinal LTP and chronic pain. The microglia-dependent transition of synaptic potentiation to structural alterations in pain pathways may underlie pain chronicity.

6.
Front Plant Sci ; 10: 677, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31178885

RESUMO

The protective role of melatonin in plants against various abiotic stresses have been widely demonstrated, but poorly explored in organ-specific responses and the transmission of melatonin signals across organs. In this study, the effects of melatonin with the root-irrigation method and the leaf-spraying method on the antioxidant system and photosynthetic machinery in maize seedlings under drought stress were investigated. The results showed that drought stress led to the rise in reactive oxygen species (ROS), severe cell death, and degradation of D1 protein, which were mitigated by the melatonin application. The application of melatonin improved the photosynthetic activities and alleviated the oxidative damages of maize seedlings under the drought stress. Compared with the leaf-spraying method, the root-irrigation method was more effective on enhancing drought tolerance. Moreover, maize seedlings made organ-specific physiological responses to the drought stress, and the physiological effects of melatonin varied with the dosage, application methods and plant organs. The signals of exogenous melatonin received by roots could affect the stress responses of leaves, and the melatonin signals perceived by leaves also led to changes in physiological metabolisms in roots under the stress. Consequently, the whole seedlings coordinated the different parts and made a systemic acclimation against the drought stress. Melatonin as a protective agent against abiotic stresses has a potential application prospect in the agricultural industry.

7.
Water Res ; 159: 444-453, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31125804

RESUMO

The abilities of three phylogenetically distant ammonia oxidizers, Nitrososphaera gargensis, an ammonia-oxidizing archaeon (AOA); Nitrosomomas nitrosa Nm90, an ammonia-oxidizing bacterium (AOB); and Nitrospira inopinata, the only complete ammonia oxidizer (comammox) available as a pure culture, to biotransform seven sulfonamides (SAs) were investigated. The removals and protein-normalized biotransformation rate constants indicated that the AOA strain N. gargensis exhibited the highest SA biotransformation rates, followed by N. inopinata and N. nitrosa Nm90. The transformation products (TPs) of sulfadiazine (SDZ), sulfamethazine (SMZ) and sulfamethoxazole (SMX) and the biotransformation mechanisms were evaluated. Based on the analysis of the TP formulas and approximate structures, it was found that during biotransformation, i) the AOA strain carried out SA deamination, hydroxylation, and nitration; ii) the AOB strain mainly performed SA deamination; and iii) the comammox isolate participated only in deamination reactions. It is proposed that deamination was catalyzed by deaminases while hydroxylation and nitration were mediated by nonspecific activities of the ammonia monooxygenase (AMO). Additionally, it was demonstrated that among the three ammonia oxidizers, only AOB contributed to the formation of pterin-SA conjugates. The biotransformation of SDZ, SMZ and SMX occurred only when ammonia oxidation was active, suggesting a cometabolic transformation mechanism. Interestingly, SAs could also be transformed by hydroxylamine, an intermediate of ammonia oxidation, suggesting that in addition to enzymatic conversions, a microbially induced abiotic mechanism contributes to SA transformation during ammonia oxidation. Overall, using experiments with pure cultures, this study provides important insights into the roles played by ammonia oxidizers in SA biotransformation.


Assuntos
Amônia , Nitrificação , Archaea , Biotransformação , Oxirredução , Filogenia , Microbiologia do Solo , Sulfonamidas
8.
Ecotoxicol Environ Saf ; 173: 45-53, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-30763810

RESUMO

Herein we investigated the multi-phase distribution and estrogenic effects of endocrine disrupting chemicals (EDCs) in suspended particulate matter (SPM), colloids, and soluble phases from the Shaying River to assess the composition of estrogenic compounds and associated estrogenic risk. The yeast two hybrid (YES) method, cross-flow ultrafiltration (CFUF), and LC-MS/MS were employed. Risk quotient (RQ) values ranged from 0.72 to 3.88, revealing that the Shaying River posed high estrogenic risk to aquatic organisms. The contribution ratios of the target EDCs to the EEQYES ranged from 62.7% to 92.5%, indicating that these chemicals were major contributors of estrogenic effects in the Shaying River. Further, 54.0-77.8% of the detected EDCs were distributed in the soluble phase, 15.1-31.7% were bound to colloidal substances, and 3.90-19.4% EDCs were associated with SPM. Significant correlation between total EDC abundance and COD contents was detected, and the concentrations of endogenous estrogens (E1, E2, and E3) were positively correlated with total nitrogen (TN) and total phosphorus (TP). In addition, the in-situ SPM-soluble (Kpoc) and colloid-soluble partition (Kcoc) coefficients were calculated. The log Kpoc values of target compounds varied from 4.10 to 5.19, while log Kcoc values ranged from 4.25 to 5.56. Their Kcoc values were larger than the Kpoc values, indicating that organic colloids were the most important carriers of EDCs in the aquatic environment.


Assuntos
Disruptores Endócrinos/análise , Estrogênios/análise , Rios/química , Poluentes Químicos da Água/análise , Organismos Aquáticos , China , Coloides/química , Disruptores Endócrinos/química , Monitoramento Ambiental , Estrogênios/química , Material Particulado/química , Medição de Risco , Poluentes Químicos da Água/química
9.
Int J Mol Med ; 43(4): 1866-1878, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30720049

RESUMO

Beclin1, a key regulator of autophagy, has been demonstrated to be associated with cancer cell resistance to chemotherapy. Paclitaxel is a conventional chemotherapeutic drug used in the clinical treatment of breast cancer. However, the function and mechanism of Beclin1 in paclitaxel­mediated cytotoxicity in breast cancer are not well defined. The present study demonstrated that paclitaxel suppressed cell viability and Beclin1 expression levels in BT­474 breast cancer cells in a dose­ and time­dependent fashion. Compared with the control, the knockdown of Beclin1 significantly enhanced breast cancer cell death via the induction of caspase­dependent apoptosis following paclitaxel treatment in vitro (P<0.05). In a BT­474 xenograft model, paclitaxel achieved substantial inhibition of tumor growth in the Beclin1 knockdown group compared with the control group. Furthermore, analysis of the publicly available Gene Expression Omnibus datasets revealed a clinical correlation between Beclin1 levels and the response to paclitaxel therapy in patients with breast cancer. Collectively, the present results suggest that Beclin1 protects breast cancer cells from apoptotic death. Thus, the inhibition of Beclin1 may be a novel way to improve the effect of paclitaxel. Additionally, Beclin1 may function as a favorable prognostic biomarker for paclitaxel treatment in patients with breast cancer.


Assuntos
Apoptose/efeitos dos fármacos , Proteína Beclina-1/antagonistas & inibidores , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Paclitaxel/farmacologia , Proteína Beclina-1/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Feminino , Técnicas de Silenciamento de Genes , Humanos , Ensaio Tumoral de Célula-Tronco , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Mol Pain ; 15: 1744806919826789, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30632435

RESUMO

Accumulating evidence shows that inhibition of glycogen synthase kinase-3beta (GSK-3ß) ameliorates cognitive impairments caused by a diverse array of diseases. Our previous work showed that spared nerve injury (SNI) that induces neuropathic pain causes short-term memory deficits. Here, we reported that GSK-3ß activity was enhanced in hippocampus and reduced in spinal dorsal horn following SNI, and the changes persisted for at least 45 days. Repetitive applications of selective GSK-3ß inhibitors (SB216763, 5 mg/kg, intraperitoneally, three times or AR-A014418, 400 ng/kg, intrathecally, seven times) prevented short-term memory deficits but did not affect neuropathic pain induced by SNI. Surprisingly, we found that the repetitive SB216763 or AR-A014418 induced a persistent pain hypersensitivity in sham animals. Mechanistically, both ß-catenin and brain-derived neurotrophic factor (BDNF) were upregulated in spinal dorsal horn but downregulated in hippocampus following SNI. Injections of SB216763 prevented the BDNF downregulation in hippocampus but enhanced its upregulation in spinal dorsal horn in SNI rats. In sham rats, SB216763 upregulated both ß-catenin and BDNF in spinal dorsal horn but affect neither of them in hippocampus. Finally, intravenous injection of interleukin-1beta that induces pain hypersensitivity and memory deficits mimicked the SNI-induced the differential regulation of GSK-3ß/ß-catenin/BDNF in spinal dorsal horn and in hippocampus. Accordingly, the prolonged opposite changes of GSK-3ß activity in hippocampus and in spinal dorsal horn induced by SNI may contribute to memory deficits and neuropathic pain by differential regulation of BDNF in the two regions. GSK-3ß inhibitors that treat cognitive disorders may result in a long-lasting pain hypersensitivity.


Assuntos
Glicogênio Sintase Quinase 3 beta/metabolismo , Hipocampo/metabolismo , Hiperalgesia/patologia , Interleucina-1beta/farmacologia , Transtornos da Memória/patologia , Corno Dorsal da Medula Espinal/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Modelos Animais de Doenças , Inibidores Enzimáticos/uso terapêutico , Regulação da Expressão Gênica/efeitos dos fármacos , Hiperalgesia/etiologia , Indóis/uso terapêutico , Masculino , Maleimidas/uso terapêutico , Transtornos da Memória/etiologia , Transtornos da Memória/prevenção & controle , Proteínas do Tecido Nervoso/metabolismo , Medição da Dor , Traumatismos dos Nervos Periféricos/complicações , Ratos , Ratos Sprague-Dawley , Tiazóis/uso terapêutico , Fatores de Tempo , Ureia/análogos & derivados , Ureia/uso terapêutico , beta Catenina/metabolismo
11.
PeerJ ; 6: e5693, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30479882

RESUMO

Background: In our previous study, Melaleuca alternifolia essential oil (EO) was considered to have an insecticidal effect by acting on the mitochondrial respiratory chain in insects. However, the mode of action is not fully understood. Methods: In this study, we investigated the insecticidal efficacy of the M. alternifolia EO against another major stored-product pest, Tribolium confusum Jacquelin du Val. Rarefaction and vacuolization of the mitochondrial matrix were evident in oil-fumigated T. confusum adults. Results: Alterations to the mitochondria confirmed the insecticidal effect of the M. alternifolia EO. Furthermore, comparative transcriptome analysis of T. confusum using RNA-seq indicated that most of the differentially expressed genes were involved in insecticide detoxification and mitochondrial function. The biochemical analysis showed that the intracellular NAD+/NADH ratio is involved in the differential effect of the M. alternifolia EO. Discussion: These results led us to conclude that NAD+/NADH dehydrogenase may be the prime target site for the M. alternifolia EO in insects, leading to blocking of the mitochondrial respiratory chain.

12.
Int J Ophthalmol ; 11(9): 1463-1466, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30225219

RESUMO

AIM: To reveal the expression of multidrug-resistance associated proteins: glutathione-S-transferase π (GSTπ), P-glycoprotein (P-gp) and vault protein lung resistance protein (LRP) in retinoblastoma (RB) without any conservative treatment before primary enucleation and to correlate this expression with histopathological tumor features. METHODS: A total of 42 specimens of RB undergone primary enucleation were selected for the research. Sections from the formalin-fixed, paraffin-embedded specimens were stained with HE and immunohistochemistry to detect the expression of GSTπ, P-gp and LRP. RESULTS: GSTπ was expressed in 39/42 (92.86%) RBs and in 9/9 (100%) well-differentiated RBs. P-gp/GSTπ was found in 30 (71.42%) of 42 RBs. Totally 9 (21.43%) tumors were well differentiated and 33 (78.57%) were poorly differentiated. Totally 15 (35.71%) eyes had optic nerve (ON) tumor invasion, 36 (85.71%) had choroidal tumor invasion, and 14 (33.33%) had simultaneous choroidal and ON invasion. There was no statistically significant relationship between P-gp, GSTπ, LRP positivity and the degree of ocular layer tumor invasion and ON tumor invasion (P>0.05). CONCLUSION: RB intrinsically expresses GSTπ, P-gp and LRP. GSTπ expression is positive in 100% well-differentiation ones, so in which way it is correlated with differentiation. But the other two proteins expressions are not related to tumor differentiation and to the degree of tumor invasion. GSTπ may be a new target of chemotherapy in RB.

13.
Mol Pain ; 14: 1744806918798406, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30105926

RESUMO

Spinal nociceptive transmission receives biphasic modulation from supraspinal structures. Recent studies demonstrate that the anterior cingulate cortex facilitates spinal excitatory synaptic transmission and nociceptive reflex. However, whether the top-down descending facilitation can cause long-term synaptic changes in spinal cord remains unclear. In the present study, we recorded C-fiber-evoked field potentials in spinal dorsal horn and found that the anterior cingulate cortex stimulation caused enhancement of C-fiber-mediated responses. The enhancement lasted for more than a few hours. Spinal application of N-methyl-D-aspartate (NMDA) receptor antagonist D-AP5 abolished this enhancement, suggesting that the activation of the NMDA receptor is required. Furthermore, spinal application of methysergide, a serotonin receptor antagonist, also blocked the anterior cingulate cortex-induced spinal long-term potentiation. Our results suggest that the anterior cingulate cortex stimulation can produce heterosynaptic form of long-term potentiation at the spinal cord dorsal horn, and this novel form of long-term potentiation may contribute to top-down long-term facilitation in chronic pain conditions.


Assuntos
Giro do Cíngulo/fisiologia , Potenciação de Longa Duração/fisiologia , Medula Espinal/fisiologia , Sinapses/fisiologia , Animais , Masculino , Células do Corno Posterior/fisiologia , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de Serotonina/metabolismo
14.
Environ Sci Technol ; 52(16): 9196-9205, 2018 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-30004677

RESUMO

Biotransformation of various micropollutants (MPs) has been found to be positively correlated with nitrification in activated sludge communities. To further elucidate the roles played by ammonia-oxidizing bacteria (AOB) and nitrite-oxidizing bacteria (NOB), we investigated the biotransformation capabilities of an NOB pure culture ( Nitrobacter sp.) and an AOB ( Nitrosomonas europaea)/NOB ( Nitrobacter sp.) coculture for 15 MPs, whose biotransformation was reported previously to be associated with nitrification. The NOB pure culture did not biotransform any investigated MP, whereas the AOB/NOB coculture was capable of biotransforming six MPs (i.e., asulam, bezafibrate, fenhexamid, furosemide, indomethacin, and rufinamide). Transformation products (TPs) were identified, and tentative structures were proposed. Inhibition studies with octyne, an ammonia monooxygenase (AMO) inhibitor, suggested that AMO was the responsible enzyme for MP transformation that occurred cometabolically. For the first time, hydroxylamine, a key intermediate of all aerobic ammonia oxidizers, was found to react with several MPs at concentrations typically occurring in AOB batch cultures. All of these MPs were also biotransformed by the AOB/NOB coculture. Moreover, the same asulam TPs were detected in both biotransformation and hydroxylamine-treated abiotic transformation experiments, whereas rufinamide TPs formed from biological transformation were not detected during hydroxylamine-mediated abiotic transformation, which was consistent with the inability of rufinamide abiotic transformation by hydroxylamine. Thus, in addition to cometabolism likely carried out by AMO, an abiotic transformation route indirectly mediated by AMO might also contribute to MP biotransformation by AOB.


Assuntos
Amônia , Nitritos , Reatores Biológicos , Biotransformação , Técnicas de Cocultura , Hidroxilamina , Hidroxilaminas , Oxirredução , Oxirredutases
15.
Int J Oncol ; 53(3): 1301-1312, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30015871

RESUMO

Beclin1 (BECN1), which directly interacts with B­cell lymphoma 2, serves an important role in autophagy and is involved in the tumorigenesis of various types of cancer. However, the definite role of BECN1 in breast cancer remains controversial. Bi-allelic knockout of Becn1 in a mouse model leads to an embryonic lethal phenotype, which hampers further investigation. To generate cell lines with knockout of BECN1, the CRISPR/Cas9 technique was used to disrupt BECN1 in human triple-negative breast cancer (TNBC) MDA­MB­231 cells. To the best of our knowledge, the present study was the first to successfully disrupt BECN1 in MDA­MB­231 cells and to screen three stable monoclonal BECN1­knockout cell lines, suggesting that BECN1­knockout is not lethal in TNBC cells. Functional analysis revealed that complete loss of BECN1 suppressed MDA­MB­231 proliferation and colony formation via inducing G0/G1 cell cycle arrest, not apoptosis, in vitro. On the other hand, BECN1­knockout inhibited the migratory and invasive ability of MDA­MB­231 cells by partially reversing signals of epithelial-mesenchymal transition. Finally, analysis of publicly available gene expression datasets revealed increased expression of BECN1 in TNBC samples. Taken together, the results of the present study identified BECN1 as an oncogene, providing a novel potential target for the treatment of TNBC.


Assuntos
Proteína Beclina-1/genética , Transição Epitelial-Mesenquimal/genética , Pontos de Checagem da Fase G1 do Ciclo Celular/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias de Mama Triplo Negativas/genética , Apoptose/genética , Autofagia/genética , Proteína Beclina-1/metabolismo , Sistemas CRISPR-Cas , Divisão Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Conjuntos de Dados como Assunto , Feminino , Perfilação da Expressão Gênica , Técnicas de Inativação de Genes , Humanos , Oncogenes/genética , Neoplasias de Mama Triplo Negativas/patologia
16.
Chem Biol Interact ; 284: 69-79, 2018 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-29458014

RESUMO

l-theanine, the most abundant free amino acid in tea, has been documented to possess many different bioactive properties through oral or intragastrical delivery. However, little is known about the effect of topical delivery of l-theanine on acute inflammation. In the present study, by using 12-O-tetradecanoylphorbol-13-acetate (TPA, 2.5 µg/ear)-induced ear edema model in mice, we first found that single-dose local pretreatment of l-theanine 30 min before TPA time- and dose-dependently suppressed the increases in both skin thickness and weight. Subsequently l-theanine ameliorated TPA-induced erythema, vascular permeability increase, epidermal and dermal hyperplasia, neutrophil infiltration and activation via downregulating the expression of PECAM-1 (a platelet endothelial adhesion molecule-1) in blood vessels and the production of pro-inflammatory cytokines IL-1ß, TNF-α, and mediator cyclooxygenase-2 (COX-2), which is mainly expressed in neutrophils. It highlighted the potential of l-theanine as a locally administrable therapeutic agent for acute cutaneous inflammation.


Assuntos
Edema/prevenção & controle , Glutamatos/farmacologia , Inflamação/prevenção & controle , Infiltração de Neutrófilos/efeitos dos fármacos , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Pele/efeitos dos fármacos , Acetato de Tetradecanoilforbol/farmacologia , Administração Tópica , Animais , Proliferação de Células/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Regulação para Baixo/efeitos dos fármacos , Orelha/patologia , Feminino , Interleucina-1beta/metabolismo , Camundongos , Neutrófilos/citologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Permeabilidade/efeitos dos fármacos , Pele/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
17.
Huan Jing Ke Xue ; 39(11): 5198-5206, 2018 Nov 08.
Artigo em Chinês | MEDLINE | ID: mdl-30628245

RESUMO

Field experiments were conducted on the heavy metal contents (Cd, Pb, Cr, inorganic As, and total Hg) of the 129 main cultivated rice varieties in southern China. We analyzed the effects of different varieties and types of rice on the absorption capacities of these heavy metals. The results showed that the Cd content in 35 brown rice of early rice was 0.35-0.60 mg·kg-1, exceeding the standard rate of 100%. The Pb content in brown rice was 0.08-0.30 mg·kg-1, exceeding the rate of 14.29%. The Cd content in 54 brown rice of medium rice was 0.03-0.45 mg·kg-1, exceeding the rate of 33.33%. The Cd content in 40 brown rice of late rice was 0.08-0.20 mg·kg-1, which did not exceed the national standard. Early, middle, and late rice all showed that the Cd content of three-line hybrid rice was higher than that of two-line hybrid rice, but the difference was not obvious. The contents of Cr and total Hg in brown rice of three-line hybrid rice in early rice were significantly higher than that of two-line hybrid rice. There was a significant positive correlation between Cd content in brown rice and Pb and total Hg content in medium rice, and there was a significant negative correlation between inorganic Cd content and inorganic As content, whereas there was no significant correlation between Cd and Cr content. In short, rice's absorption and accumulation of heavy metals is greatly affected by genetic background, species types, and heavy metal interactions.


Assuntos
Metais Pesados/metabolismo , Oryza/metabolismo , Poluentes do Solo/metabolismo , China , Oryza/classificação , Solo
18.
J Neurosci ; 37(33): 7878-7892, 2017 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-28716963

RESUMO

Elevated levels of chemokine C-C motif ligand 2 (CCL2) and its receptor CCR2 have been reported in patients with temporal lobe epilepsy and in experimental seizures. However, the functional significance and molecular mechanism underlying CCL2-CCR2 signaling in epileptic brain remains largely unknown. In this study, we found that the upregulated CCL2 was mainly expressed in hippocampal neurons and activated microglia from mice 1 d after kainic acid (KA)-induced seizures. Taking advantage of CX3CR1GFP/+:CCR2RFP/+ double-transgenic mice, we demonstrated that CCL2-CCR2 signaling has a role in resident microglial activation and blood-derived monocyte infiltration. Moreover, seizure-induced degeneration of neurons in the hippocampal CA3 region was attenuated in mice lacking CCL2 or CCR2. We further showed that CCR2 activation induced STAT3 (signal transducer and activator of transcription 3) phosphorylation and IL-1ß production, which are critical for promoting neuronal cell death after status epilepticus. Consistently, pharmacological inhibition of STAT3 by WP1066 reduced seizure-induced IL-1ß production and subsequent neuronal death. Two weeks after KA-induced seizures, CCR2 deficiency not only reduced neuronal loss, but also attenuated seizure-induced behavioral impairments, including anxiety, memory decline, and recurrent seizure severity. Together, we demonstrated that CCL2-CCR2 signaling contributes to neurodegeneration via STAT3 activation and IL-1ß production after status epilepticus, providing potential therapeutic targets for the treatment of epilepsy.SIGNIFICANCE STATEMENT Epilepsy is a global concern and epileptic seizures occur in many neurological conditions. Neuroinflammation associated with microglial activation and monocyte infiltration are characteristic of epileptic brains. However, molecular mechanisms underlying neuroinflammation in neuronal death following epilepsy remain to be elucidated. Here we demonstrate that CCL2-CCR2 signaling is required for monocyte infiltration, which in turn contributes to kainic acid (KA)-induced neuronal cell death. The downstream of CCR2 activation involves STAT3 (signal transducer and activator of transcription 3) phosphorylation and IL-1ß production. Two weeks after KA-induced seizures, CCR2 deficiency not only reduced neuronal loss, but also attenuated seizure-induced behavioral impairments, including anxiety, memory decline, and recurrent seizure severity. The current study provides a novel insight on the function and mechanisms of CCL2-CCR2 signaling in KA-induced neurodegeneration and behavioral deficits.


Assuntos
Quimiocina CCL2/metabolismo , Interleucina-1beta/biossíntese , Neurônios/metabolismo , Receptores CCR2/metabolismo , Fator de Transcrição STAT3/metabolismo , Estado Epiléptico/metabolismo , Animais , Morte Celular/fisiologia , Feminino , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Camundongos , Camundongos Knockout , Neurônios/patologia , Receptores CCR2/deficiência , Estado Epiléptico/patologia , Estado Epiléptico/prevenção & controle
19.
J Am Heart Assoc ; 6(8)2017 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-28751541

RESUMO

BACKGROUND: Percutaneous coronary intervention has been widely used in the treatment of ischemic heart disease, but vascular restenosis is a main limitation of percutaneous coronary intervention. Our previous work reported that caveolin-1 had a key functional role in intimal hyperplasia, whereas whether Cavin-1 (another important caveolae-related protein) was involved is still unknown. Therefore, we will investigate the effect of Cavin-1 on neointimal formation. METHODS AND RESULTS: Balloon injury markedly reduced Cavin-1 protein and enhanced ubiquitin protein expression accompanied with neointimal hyperplasia in injured carotid arteries, whereas Cavin-1 mRNA had no change. In cultured vascular smooth muscle cells (VSMCs), Cavin-1 was downregulated after inhibition of protein synthesis by cycloheximide, which was distinctly prevented by pretreatment with proteasome inhibitor MG132 but not by lysosomal inhibitor chloroquine, suggesting that proteasomal degradation resulted in Cavin-1 downregulation. Knockdown of Cavin-1 by local injection of Cavin-1 short hairpin RNA (shRNA) into balloon-injured carotid arteries in vivo promoted neointimal formation. In addition, inhibition or overexpression of Cavin-1 in cultured VSMCs in vitro prompted or suppressed VSMC proliferation and migration via increasing or decreasing extracellular signal-regulated kinase phosphorylation and matrix-degrading metalloproteinases-9 activity, respectively. However, under basic conditions, the effect of Cavin-1 on VSMC migration was stronger than on proliferation. Moreover, our results indicated that Cavin-1 regulated caveolin-1 expression via lysosomal degradation pathway. CONCLUSIONS: Our study revealed the role and the mechanisms of Cavin-1 downregulation in neointimal formation by promoting VSMC proliferation, migration, and synchronously enhancing caveolin-1 lysosomal degradation. Cavin-1 may be a potential therapeutic target for the treatment of postinjury vascular remodeling.


Assuntos
Angioplastia com Balão/efeitos adversos , Lesões das Artérias Carótidas/metabolismo , Caveolina 1/metabolismo , Movimento Celular , Proliferação de Células , Proteínas de Membrana/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Neointima , Proteínas de Ligação a RNA/metabolismo , Animais , Lesões das Artérias Carótidas/etiologia , Lesões das Artérias Carótidas/genética , Lesões das Artérias Carótidas/patologia , Artéria Carótida Externa/metabolismo , Artéria Carótida Externa/patologia , Células Cultivadas , Modelos Animais de Doenças , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Lisossomos/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Proteínas de Membrana/genética , Músculo Liso Vascular/lesões , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise , Interferência de RNA , RNA Interferente Pequeno/administração & dosagem , Proteínas de Ligação a RNA/genética , Ratos Sprague-Dawley , Transdução de Sinais , Fatores de Tempo , Transfecção , Remodelação Vascular
20.
Front Plant Sci ; 8: 785, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28553310

RESUMO

Melatonin (N-acetyl-5-methoxytryptamine) plays important role in multiple plant developmental processes and stress responses. We investigated the possible mediatory role of melatonin in growth, photosynthesis, and the response to cold stress in rice by using three different experiments: soaking seed; immersing roots, and spraying to leaves with 0, 20, or 100 µM melatonin. After 6 days of cold stress, the growth of rice seedlings was significantly inhibited, but this inhibition was alleviated by exogenous melatonin. Furthermore, exogenous melatonin pretreatment alleviated the accumulation of reactive oxygen species, malondialdehyde and cell death induced by cold stress. Melatonin pretreatment also relieved the stress-induced inhibitions to photosynthesis and photosystem II activities. Further investigations showed that, antioxidant enzyme activities and non-enzymatic antioxidant levels were increased by melatonin pretreatments. The treatment methods of seed soaking and root immersion were more effective in improving cold stress resistance than the spraying method. The results also indicated the dose-dependent response of melatonin on rice physiological, biochemical, and photosynthetic parameters.

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