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1.
Org Lett ; 22(4): 1504-1509, 2020 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-32043889

RESUMO

An unprecedented copper-catalyzed reaction of sulfoxonium ylides and anthranils is reported that enables an easy access to 2,3-diaroylquinolines through a [4+1+1] annulation. Copper-catalyzed homocoupling of sulfoxonium ylides provided α,α,ß-tricarbonyl sulfoxonium ylides, which provides a strategy to extend the carbon chain through C-C bond formation. The utility of the products as well as the mechanistic details of the process are presented.

2.
Acta Pharmacol Sin ; 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31911637

RESUMO

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common life-threatening monogenetic diseases characterized by progressive enlargement of fluid-filled renal cysts. Our previous study has shown that Ganoderma triterpenes (GT) retards PKD renal cyst development. In the present study we identified the effective ingredient of GT in suppression of kidney cyst development. Using an in vitro MDCK cystogenesis model, we identified ganoderic acid A (GA-A) as the most promising candidate among the 12 ganoderic acid (GA) monomers. We further showed that GA-A (6.25-100 µM) significantly inhibited cyst growth in MDCK cyst model and embryonic kidney cyst model in vitro, and the inhibitory effect was reversible. In kidney-specific Pkd1 knockout (kPKD) mice displaying severe cystic kidney disease, administration of GA-A (50 mg· kg-1 ·d-1, sc) significantly attenuated renal cyst development. In both MDCK cells and kidney of kPKD mice, we revealed that GA-A dose-dependently downregulated the Ras/MAPK signaling pathway. The expression of proliferating cell nuclear antigen (PCNA) was also suppressed, suggesting a possible effect of GA-A on cell proliferation. These experimental data suggest that GA-A may be the main ingredient of GT as a potential therapeutic reagent for treating ADPKD.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31990992

RESUMO

MicroRNAs (miRNAs) have emerged as critical regulators of neuronal survival during cerebral ischaemia/reperfusion injury. Accumulating evidence has shown that miR-199a-5p plays a crucial role in regulating apoptosis and survival in various cell types. However, whether miR-199a is involved in regulating neuronal survival during cerebral ischaemia/reperfusion injury remains unknown. In this study, we aimed to explore the biological role of miR-199a-5p in regulating neuronal injury induced by oxygen-glucose deprivation/reoxygenation (OGD/R), an in vitro cellular model of cerebral ischaemia and reperfusion injury. We found that miR-199a-5p expression was significantly altered in neurons in response to OGD/R treatment. Overexpression of miR-199a-5p facilitated OGD/R-induced apoptosis and reactive oxygen species (ROS) production, whereas miR-199a-5p inhibition alleviated OGD/R-induced apoptosis and ROS production. Notably, our results identified Brahma-related gene 1 (Brg1) as a target gene of miR-199a-5p. Moreover, inhibition of miR-199a-5p promoted the activation of nuclear factor-erythroid-2-related factor-2 (Nrf2)/heme oxygenase-1 (HO-1) signalling via targeting Brg1. However, silencing of Brg1 markedly reversed the miR-199a-5p inhibition-mediated neuroprotective effect. Taken together, our results suggest that downregulation of miR-199a-5p protects neurons from OGD/R-induced neuronal injury through upregulating Brg1 to activate Nrf2/HO-1 signalling. The miR-199a-5p/Brg1/Nrf2/HO-1 regulation axis may play an important role in regulating neuronal survival during cerebral ischaemic/reperfusion injury in vivo.

4.
Chemosphere ; 247: 125855, 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31935577

RESUMO

To preliminarily investigate the occurrence, spatial distributions, homolog compositions, and ecological risks of chlorinated paraffins (CPs) in Yunnan, China, 110 soil samples were collected from an area part of Yunnan, representative of the whole Yunnan area, where had similar characteristics to most parts of Yunnan and 22 pooled soil samples were analyzed for 50 CP congener groups (C9-17Cl5-10). The chlorinated nonane paraffin (C9-CP), short chain (SCCP), and medium chain chlorinated paraffin (MCCP) concentrations in soil samples were 8-109 ng/g (average 39 ng/g), 79-948 ng/g (average 348 ng/g), and 20-1206 ng/g (average 229 ng/g), respectively. The C9-CP homologs contributed 5%-16% of the C9-13-CP concentrations in soils. No significant correlation was found between CP concentrations and the total organic carbon content (P > 0.05). The CP levels in soils from Yunnan were at a medium level compared with those in other areas worldwide. Human activity and atmosphere deposition would influence the levels and spatial distributions of CPs in this area. The concentrations of CPs in east area were higher than those in west area. C10Cl6-7 were the major SCCP congeners and C14Cl6-7 were the major MCCP congeners. Principal component analysis indicated that SCCPs and MCCPs came from different sources. A preliminary risk assessment indicated that these concentrations of CPs in soil from Yunnan do not pose a significant ecological risk for soil organisms.

5.
Oncogene ; 39(4): 922-934, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31576013

RESUMO

Multiple myeloma (MM) is still incurable despite the successful application of proteasome inhibitors in clinic. Bortezomib represents the most common chemotherapy for MM, whereas acquired drug resistance and eventually developed relapse remain the major obstruction. In the current study, we established bortezomib-resistant myeloma cell lines and screened gene expression profiles using single cell RNA-sequencing. Resistant MM cells exhibited increased clonogenic potential, specific metabolic, and epigenetic signatures, along with the self-renewal signaling characteristic of MM stem-like cells. Aberrant activation of hedgehog (Hh) signaling was correlated with drug resistance and stem cell-like transcriptional program. The key transcriptional factor GLI2 of the Hh pathway was restricted in the high acetylation and low ubiquitination states in bortezomib-resistant myeloma cells. Further investigation revealed that SIRT1 deacetylates and stabilizes GLI2 protein at lysine 757 and consequentially activates the Hh signaling, and itself serves as a direct target of Hh signaling to format a positive regulating loop. Using combination screening with an epigenetic compound library, we identified the SIRT1 specific inhibitor S1541 and S2804 had very obvious synergetic antimyeloma effect. Sirt1 inhibition could partially impeded the Hh pathway and conferred bortezomib sensitivity in vitro and in vivo. Notably, elevated SIRT1 level was also a prominent hallmark for the resistant myeloma cells, and this expression pattern was confirmed in myeloma patients, but independent of RAS/RAF mutations. Clinically, SIRT1 expression in patients with complete response was suppressed but elevated in relapsed patients, and retrospective analysis showed patients with higher SIRT1 expression had poorer outcomes. In conclusion, the cooperation of SIRT1 and Hh is an important mechanism of drug resistance in myeloma, and therapeutics combining SIRT1 inhibitors will sensitize myeloma cells to proteasome inhibitors.

6.
J Invest Surg ; 33(3): 211-217, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30909770

RESUMO

Background: Acute aorta dissection (AD) is a fatal emergency, however, studies addressing the clinical characteristics, management, and outcome of acute AD in young adult patients aged under 45 years in China are very few.Methods: A retrospective study including 490 patients with acute AD as the final diagnosis was conducted. Patients' demographics, clinical characteristics, medical history, and laboratory and diagnostic imaging findings were retrieved from medical records. Results: The median age of young adult patients with acute AD was 38 years old with an interquartile range from 33 to 41. Male and smoker constituted 84.49% and 50.61% of the cohort, respectively. Hypertension was found in 54.49%, while Marfan syndrome was seen in 4.29% of the patients. Abrupt onset of chest or back pain was the most common symptoms (85.31%), while altered consciousness, coma and oliguria were less reported. Most patients (89.39%) were managed with surgical interventions. Typical complications (central nervous system complications, spinal cord ischemia, myocardial ischemia/infarction, mesenteric ischemia/infarction and acute renal failure) were seen in a small portion of treated patients during perioperative period. For in-hospital mortality there were 24 (∼5%) cases recorded. Correlation analysis indicated that perioperative complications were associated with the length of cardiopulmonary bypass (CPB) (P < 0.0001), and mortality after surgery correlated history of prior cardiac surgery (P = 0.043). Conclusion: CPB and prior cardiac surgery were associated with perioperative complications and mortality after surgery, respectively. The findings are valuable to the further refinement of diagnosis and surgical management of patients with acute aortic dissection.

7.
Braz J Med Biol Res ; 52(12): e8786, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31778439

RESUMO

Exercise-based training decreases hospitalizations in heart failure patients but such patients have exercise intolerance. The objectives of the study were to evaluate the effect of 12 weeks of Tai Chi exercise and lower limb muscles' functional electrical stimulation in older chronic heart failure adults. A total of 1,084 older adults with chronic systolic heart failure were included in a non-randomized clinical trial (n=271 per group). The control group did not receive any kind of intervention, one group received functional electrical stimulation of lower limb muscles (FES group), another group practiced Tai Chi exercise (TCE group), and another received functional electrical stimulation of lower limb muscles and practiced Tai Chi exercise (FES & TCE group). Quality of life and cardiorespiratory functions of all patients were evaluated. Compared to the control group, only FES group had increased Kansas City Cardiomyopathy Questionnaire (KCCQ) score (P<0.0001, q=9.06), only the TCE group had decreased heart rate (P<0.0001, q=5.72), and decreased peak oxygen consumption was reported in the TCE group (P<0.0001, q=9.15) and FES & TCE group (P<0.0001, q=10.69). FES of lower limb muscles and Tai Chi exercise can recover the quality of life and cardiorespiratory functions of older chronic heart failure adults (trial registration: Research Registry 4474, January 1, 2015).


Assuntos
Terapia por Estimulação Elétrica/métodos , Insuficiência Cardíaca Sistólica/reabilitação , Extremidade Inferior/fisiopatologia , Músculo Esquelético/fisiopatologia , Tai Ji/métodos , Idoso , Doença Crônica , Insuficiência Cardíaca Sistólica/fisiopatologia , Humanos , Qualidade de Vida , Resultado do Tratamento
8.
J Am Soc Nephrol ; 30(11): 2073-2090, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31653783

RESUMO

BACKGROUND: Necroptosis is a newly discovered cell death pathway that plays a critical role in AKI. The involvement of integrin-linked kinase (ILK) in necroptosis has not been studied. METHODS: We performed experiments in mice with an Ilk deletion in collecting duct (CD) principal cells (PCs), and cultured tubular epithelial cells treated with an ILK inhibitor or ILK siRNA knockdown. RESULTS: Ilk deletion in CD PCs resulted in acute tubular injury and early mortality in mice. Progressive interstitial fibrosis and inflammation associated with the activation of the canonical TGF-ß signaling cascade were detected in the kidneys of the mice lacking ILK in the CD PCs. In contrast to the minimal apoptosis detected in the animals' injured CDs, widespread necroptosis was present in ILK-deficient PCs, characterized by cell swelling, deformed mitochondria, and rupture of plasma membrane. In addition, ILK deficiency resulted in increased expression and activation of necroptotic proteins MLKL and RIPK3, and membrane translocation of MLKL in CD PCs. ILK inhibition and siRNA knockdown reduced cell survival in cultured tubular cells, concomitant with increased membrane accumulation of MLKL and/or phospho-MLKL. Administration of a necroptosis inhibitor, necrostatin-1, blocked cell death in vitro and significantly attenuated inflammation, interstitial fibrosis, and renal failure in ILK-deficient mice. CONCLUSIONS: The study demonstrates the critical involvement of ILK in necroptosis through modulation of the RIPK3 and MLKL pathway and highlights the contribution of CD PC injury to the development of inflammation and interstitial fibrosis of the kidney.

9.
EBioMedicine ; 48: 478-490, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31628020

RESUMO

BACKGROUND: Urea, the end product of protein metabolism, has been considered to have negligible toxicity for a long time. Our previous study showed a depression phenotype in urea transporter (UT) B knockout mice, which suggests that abnormal urea metabolism may cause depression. The purpose of this study was to determine if urea accumulation in brain is a key factor causing depression using clinical data and animal models. METHODS: A meta-analysis was used to identify the relationship between depression and chronic diseases. Functional Magnetic Resonance Imaging (fMRI) brain scans and common biochemical indexes were compared between the patients and healthy controls. We used behavioural tests, electrophysiology, and molecular profiling techniques to investigate the functional role and molecular basis in mouse models. FINDINGS: After performing a meta-analysis, we targeted the relevance between chronic kidney disease (CKD) and depression. In a CKD mouse model and a patient cohort, depression was induced by impairing the medial prefrontal cortex. The enlarged cohort suggested that urea was responsible for depression. In mice, urea was sufficient to induce depression, interrupt long-term potentiation (LTP) and cause loss of synapses in several models. The mTORC1-S6K pathway inhibition was necessary for the effect of urea. Lastly, we identified that the hydrolysate of urea, cyanate, was also involved in this pathophysiology. INTERPRETATION: These data indicate that urea accumulation in brain is an independent factor causing depression, bypassing the psychosocial stress. Urea or cyanate carbamylates mTOR to inhibit the mTORC1-S6K dependent dendritic protein synthesis, inducing impairment of synaptic plasticity in mPFC and depression-like behaviour. CKD patients may be able to attenuate depression only by strict management of blood urea.

10.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 44(8): 864-870, 2019 Aug 28.
Artigo em Chinês | MEDLINE | ID: mdl-31570672

RESUMO

OBJECTIVE: To explore roles of expressions of EHD2 and E-cadherin in clear cell renal cell carcinoma (ccRCC).
 Methods: Four couples of fresh ccRCC tissues and adjacent non-cancerous tissues were collected to evaluate the expression of EHD2 and E-cadherin protein by Western blotting. A total of 65 paraffin-embedded renal ccRCC tissues were collected, and immunohistochemical assay was used to detect the expression of EHD2 and E-cadherin in the samples. The correlation between their expression and clinical and pathological indicators of ccRCC was analyzed, and the relationship between EHD2 and E-cadherin proteins and prognosis for patients with ccRCC was also explored.
 Results: The results of Western blotting showed that the expression levels of EHD2 and E-cadherin were low in 4 ccRCC tissues compared with the adjacent noncancerous tissues. Immunohistochemical results revealed that the expressions of EHD2 and E-cadherin were higher in the localized ccRCC tissues than those in the metastatic ccRCC tissues; the expression levels of EHD2 and E-cadherin were decreased, while the TNM staging and Fuhrman grade were increased (P<0.05 or P<0.01). There was positive correlation between the expressions of EHD2 and E-cadherin in ccRCC (r=0.390, P<0.01). The progression-free survival in ccRCC patients with lower expression of both EHD2 and E-cadherin was better than that in ccRCC patients with higher expressions of EHD2 and E-cadherin (P<0.05). 
 Conclusion: The low expressions of EHD2 and E-cadherin are the potential indicators for the ccRCC patients with poor prognosis.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Caderinas , Proteínas de Transporte , Humanos , Estadiamento de Neoplasias , Prognóstico
11.
Nat Commun ; 10(1): 4268, 2019 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-31537811

RESUMO

Atropisomeric biaryl motifs are ubiquitous in chiral catalysts and ligands. Numerous efficient strategies have been developed for the synthesis of axially chiral biaryls. In contrast, the asymmetric construction of o-quinone-aryl atropisomers has yet to be realized. Inspired by the rapid progress of the chemistry of biaryls, here we present our initial investigations about the atroposelective construction of axially chiral arylquinones by a bifunctional chiral phosphoric acid-catalyzed asymmetric conjugate addition and central-to-axial chirality conversion. With o-naphthoquinone as both the electrophile and the oxidant, three types of arylation counterparts, namely 2-naphthylamines, 2-naphthols and indoles, are utilized to assemble a series of atropisomeric scaffolds in good yields and excellent enantioselectivities. This approach not only expands the axially chiral library but also offers a route to a class of potential, chiral biomimetic catalysts.

12.
J Org Chem ; 84(19): 12301-12313, 2019 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-31482711

RESUMO

A copper-catalyzed protocol for the construction of various 2-aryl(alkyl)-3-acylquinolines or 3-arylquinolines using readily available anthranils and 1,3-diketones or aldehydes as starting materials is reported herein. Dioxygen as the sole oxidant and hexafluoroisopropanol as the solvent play an important role in both procedures. This ring-opening/reconstruction strategy involving N-O bond cleavage and C-N/C-C bond formation features high yields and broad substrate scope.

13.
ACS Omega ; 4(6): 9680-9685, 2019 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-31460058

RESUMO

Three modified 1,2,4-trizaole derivatives were synthesized and compounded in pairs. Their structures were confirmed by 1H NMR and ESI-MS. Antibacterial tests were proceeded to evaluate the fungicidal activity of synthesized compounds. The results of antibacterial tests showed that the synthesized compounds exhibited good antibacterial activities against Coriolus versicolor, Gloeophyllum trabeum, Trichoderma viride, and Aspergillus niger at a ratio of 5:5. In order to improve the water solubility of target products, emulsification experiments were carried out and beta-cypermethrin was added as a pesticide. The appropriate emulsifier types and dosage ratios for the synthesized compounds were finally screened out.

15.
Molecules ; 24(14)2019 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-31330777

RESUMO

The electro-peroxone (E-peroxone) process is an emerging electrocatalytic ozonation process that is enabled by in situ producing hydrogen peroxide (H2O2) from cathodic oxygen reduction during ozonation. The in situ-generated H2O2 can then promote ozone (O3) transformation to hydroxyl radicals (•OH), and thus enhance the abatement of ozone-refractory pollutants compared to conventional ozonation. In this study, a chemical kinetic model was employed to simulate micropollutant abatement during the E-peroxone treatment of various water matrices (surface water, secondary wastewater effluent, and groundwater). Results show that by following the O3 and •OH exposures during the E-peroxone process, the abatement kinetics of a variety of model micropollutants could be well predicted using the model. In addition, the effect of specific ozone doses on micropollutant abatement efficiencies could be quantitatively evaluated using the model. Therefore, the chemical kinetic model can be used to reveal important information for the design and optimization of the treatment time and ozone doses of the E-peroxone process for cost-effective micropollutant abatement in water and wastewater treatment.


Assuntos
Eletroquímica , Modelos Químicos , Oxirredução , Ozônio/química , Poluentes Químicos da Água/química , Eletroquímica/métodos , Cinética , Água/análise , Água/química , Poluentes Químicos da Água/análise
16.
J Hazard Mater ; 380: 120888, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31336267

RESUMO

This study evaluated the prediction of emerging contaminant (EC) removal during heterogeneous catalytic ozonation by chemical kinetic models. Six ECs with differing ozone reactivity were spiked in a synthetic water and a groundwater, then treated by conventional ozonation and heterogeneous catalytic ozonation with α- or ß-MnO2 catalysts. Results show that catalysts did not considerably influence the removal of ECs with high and intermediate ozone reactivity (diclofenac, gemfibrozil, and bezafibrate), but enhanced the removal efficiencies of ECs with low ozone reactivity (2,4-dichlorophenoxyacetic acid, clofibric acid, and ibuprofen) to varied extent (˜10-30%). The removal efficiencies of ECs could be reasonably predicted using chemical kinetic models based on the ozone (O3) and hydroxyl radical (OH) rate constants of ECs, pseudo-first-order rate constants observed for EC adsorption on the MnO2 catalysts, and O3 and OH exposures observed for catalytic ozonation. Furthermore, the model reveals that ECs are removed mainly by O3 and/or •OH oxidation during heterogeneous catalytic ozonation, while adsorption of ECs on catalysts contributes negligibly. Therefore, the removal efficiencies of ECs could be satisfactorily predicted using a simplified model based only on the O3 and OH rate constant and the O3 and OH exposures.

17.
J Environ Manage ; 248: 109232, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31319197

RESUMO

One of the top priorities of the Chinese government's oversight is to address the conflicts between economic growth and resource consumption and between economic development and ecological damage. In this regard, the advocacy and compilation of the natural resources balance sheet can boost the efficiency of the government's oversight and improve the quality of resource management. However, China's natural resources balance sheet is still at an exploratory stage, lacking the theoretical framework of balance sheet preparation, preparatory ideas, and a reporting system, which must be established urgently. First, the study states the purpose of compiling the natural resources balance sheet, and, subsequently, analyzes the theoretical basis, framework system, preparatory ideas, and sample sheet format, thereby offering theoretical and methodological support for its preparation. Moreover, the development, functions, deficits, and future development of the balance sheet are analyzed in the context of the Chinese system, which provides theoretical and methodological support for the preparation of the natural resources balance sheet and government oversight.


Assuntos
Conservação dos Recursos Naturais , Declarações Financeiras , China , Governo , Recursos Naturais
18.
J Org Chem ; 84(13): 8440-8448, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31135154

RESUMO

The scandium-catalyzed redox-neutral cascade [1,5]-hydride transfer/cyclization between C4-amine-substituted isatins and 1,3-dicarbonyl compounds has been developed. This protocol enabled the synthesis of tricyclic [3,4]-fused oxindoles in good to high yields and excellent diastereoselectivities, featuring high atom- and step economy as well as good functional group tolerance.

19.
Environ Technol ; : 1-13, 2019 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-31018776

RESUMO

Many bacteria, including Escherichia coli, are known to enter into a viable but non-culturable (VBNC) state when exposed to harsh environmental stresses. The VBNC cells introduced by chlorination/chloramination have raised increasing concern about biological safety of drinking water. A quantitative relationship between chlorination/chloramination and number of VBNC cells has not been found. In this study, a mathematical model was developed to quantify the effect of chlorination/chloramination on induction of viable but non-culturable (VBNC) Escherichia coli. the model was generated based on a first order kinetics of chlorination/chloramination using the data collected from laboratory disinfection experiments. The disinfection rates of culturable cells (kc) and viable cells (kv) were dose-dependent, and they were also modelled in different initial concentrations by regression analysis to overcome the shortcoming of dose-dependent. In general, the kc and kv values for chlorination (kc, 2.59-29.89 h-1; kv, 19.52-26.74 h-1) was 2-58 times greater than that for chloramination (kc, 0.5446-10.81 h-1; kv, 0.3398-14.57 h-1), suggesting that chlorine was more effective than chloramine in reducing the number of culturable and VBNC cells at same dose of disinfectant. Ultimately, the generated models, which could describe the dynamics of VBNC cells formation in chlorination/chloramination, can provide practical guidance in drinking water treatment and it can also be applied to risk assessment of drinking water management systems.

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