Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 46
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Org Lett ; 2022 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-35005977

RESUMO

The catalytic asymmetric synthesis of borylated 3-hydroxyoxindoles by addition of gem-diborylalkanes to isatins is disclosed. Chiral 3-hydroxyoxindoles bearing two contiguous stereogenic centers were produced in up to >20:1 dr and 99% ee. The synthetic utility of the corresponding products is presented through several transformations of the boryl moiety. This report provides an efficient strategy to incorporate a boryl functional group toward the synthesis of 3-hydroxyoxindoles.

2.
Microbiol Spectr ; : e0082621, 2022 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-35019693

RESUMO

Infection of Cryptococcus neoformans is one of the leading causes of morbidity and mortality, particularly among immunocompromised patients. However, currently available drugs for the treatment of C. neoformans infection are minimal. Here, we report SP1, a peptide derived from glyceraldehyde-3-phosphate dehydrogenase (GAPDH) of Saccharomyces cerevisiae, efficiently kills C. neoformans and Cryptococcus gattii. SP1 causes damages to the capsule. Unlike many antimicrobial peptides, SP1 does not form pores on the cell membrane of C. neoformans. It interacts with membrane ergosterol and enters vacuole possibly through membrane trafficking. C. neoformans treated with SP1 show the apoptotic phenotypes such as imbalance of calcium ion homeostasis, reactive oxygen increment, phosphatidylserine exposure, and nuclear fragmentation. Our data imply that SP1 has the potential to be developed into a treatment option for cryptococcosis. IMPORTANCE Cryptococcus neoformans and Cryptococcus gattii can cause cryptococcosis, which has a high mortality rate. To treat the disease, amphotericin B and fluconazole are often used in clinic. However, amphotericin B has rather high renal toxicity, and tolerance to these drugs are quicky developed. The peptide SP1 derived from baker's yeast GAPDH shows antifungal function to kill Cryptococcus neoformans and Cryptococcus gattii efficiently with a high specificity, even for the drug-resistant strains. Our data demonstrate that SP1 induces the apoptosis-like death of Cryptococcus neoformans at low concentrations. The finding of this peptide may shed light on a new direction to treat cryptococcosis.

3.
Biochim Biophys Acta Mol Cell Res ; 1869(1): 119147, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34600918

RESUMO

Fragment size distribution, the important biological properties of cell-free DNA (cfDNA), provides useful information required for diagnostic assay development. However, besides methodological discrepancies, it varies due to the complicated origins and occurrences of in vivo cfDNA. In addition, limited data are available concerning the cfDNA associated with autophagy and distributional difference between cf-mitochondrial DNA (cf-mtDNA) and cf-nuclear DNA (cf-nDNA) fragments. Here we developed an in vitro model of mouse microglial cell (BV-2) with starvation-induced autophagy, in which cfDNA was isolated from the cell supernatant by ultrafiltration (UF) and column-based commercial kit (CC), respectively. Using Agilent 2100 Bioanalyzer, a DNA ladder pattern as the presence of peaks corresponding to mono-, di- and tri-nucleosomes was clearly visualized both in isolation products of UF and CC. However, we also detected shorter fragments than mono-nucleosome by UF. In comparing the UF and CC, we found that the former produced the higher recovery efficiency for spiked-in DNA of shorter fragments than mono-nucleosome in both water and medium, but the latter was superior for spiked-in DNA fragments which were longer than or equal to mono-nucleosome in medium. Combined with these two isolation methods, we have observed that autophagy-associated cf-mtDNA and cf-nDNA were both highly enriched in

Assuntos
Autofagia , Ácidos Nucleicos Livres/química , Fragmentação do DNA , DNA Mitocondrial/química , Nucleossomos/química , Animais , Linhagem Celular , Ácidos Nucleicos Livres/genética , DNA Mitocondrial/genética , Camundongos , Microglia/metabolismo , Nucleossomos/genética , Inanição/metabolismo
4.
Appl Environ Microbiol ; : aem0219421, 2021 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-34936834

RESUMO

Social behaviors do not only exist in higher organisms but are also present in microbes that interact for the common good. Here, we report that budding yeast cells interact with their neighboring cells after exposure to DNA damage. Yeast cells irradiated with DNA-damaging ultraviolet light secrete signal peptides that can increase the survival of yeast cells exposed to DNA-damaging stress. The secreted peptide is derived from glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and it induced cell death of a fraction of yeast cells in the group. The data suggest that the GAPDH-derived peptide serves in budding yeast's social interaction in response to DNA-damaging stress. Importance Many studies have shown that microorganisms, including bacteria and yeast, display increased tolerance to stress after exposure to the same stressor. However, the mechanism remains unknown. In this manuscript, we report a striking finding that S. cerevisiae cells respond to DNA damage by secreting a peptide that facilitates resistance to DNA-damaging stress. Although it has been shown that GAPDH possesses many key functions in cells aside from its well-established role in glycolysis, this study demonstrated that GAPDH is also involved in the social behaviors response to DNA-damaging stress. The study opens the gate to an interesting research field about microbial social activity for adaptation to a harsh environment.

5.
Blood Coagul Fibrinolysis ; 32(7): 513-518, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34102654

RESUMO

To explore the causative mutation for autosomal recessive inheritance factor V (FV) deficiency in a Chinese family. Relative coagulation indexes and the FV antigen were tested by the one-stage clotting method and ELISA, respectively. At the same time, the calibrated automated thrombogram (CAT) was used to analyze the mutant protein function. All 25 exons, flanking sequences, 5' and 3' untranslated regions of the F5 were amplified by PCR and sequenced directly, while each suspected variant was verified by reverse sequencing. The possible impact of the mutant was analyzed by the corresponding bioinformatics software. The phenotypic tests showed that the proband's FV activity has decreased to 24%, whereas the FV antigen has also reduced to 28%. The genetic analysis revealed that she was a compound heterozygote for a frameshift variant from small deletion in the exon 13 (c.2390_2390delC, p.Pro798Leufs∗13) and a missense mutation in the exon 25 (c.6665A>G, p.Asp2222Gly). Meanwhile, the online bioinformatics software indicated that the frameshift variant was disease-causing. The pathogenic variant p.Pro798Leufs∗13 and the benign variant p.Asp2222Gly largely account for the decrease of the FV deficiency in this Chinese family, of which the pathogenic variant is firstly reported in the world.


Assuntos
Deficiência do Fator V/genética , Fator V/genética , Adulto , Coagulação Sanguínea , Deficiência do Fator V/sangue , Deficiência do Fator V/congênito , Feminino , Mutação da Fase de Leitura , Heterozigoto , Humanos , Masculino , Mutação de Sentido Incorreto , Linhagem , Mutação Puntual
6.
Nat Commun ; 12(1): 1566, 2021 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-33692347

RESUMO

The Kondo effect offers an important paradigm to understand strongly correlated many-body physics. Although under intensive study, some of the important properties of the Kondo effect, in systems where both itinerant coupling and localized coupling play significant roles, are still elusive. Here we report the evolution and universality of the two-stage Kondo effect, the simplest form where both couplings are important using single molecule transistor devices incorporating Manganese phthalocyanine molecules. The Kondo temperature T* of the two-stage Kondo effect evolves linearly against effective interaction of involved two spins. Observed Kondo resonance shows universal quadratic dependence with all adjustable parameters: temperature, magnetic field and biased voltages. The difference in nonequilibrium conductance of two-stage Kondo effect to spin 1/2 Kondo effect is also identified. Messages learned in this study fill in directive experimental evidence of the evolution of two-stage Kondo resonance near a quantum phase transition point, and help in understanding sophisticated molecular electron spectroscopy in a strong correlation regime.

7.
Intern Med J ; 51(5): 732-738, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-32149434

RESUMO

BACKGROUND: Primary insomnia is a worldwide problem and it has a considerable negative impact on one's physical and mental health. Studies have shown that non-synonymous Single-nucleotide polymorphisms in 5-hydroxytryptamine (serotonin or 5-HT) are related to primary insomnia. Previous studies have shown that 5-HT polymorphism (rs140700) is related to depression, and insomnia is often accompanied by depression and anxiety. The relationship between this site and primary insomnia is unknown. We speculated that this site may be related to primary insomnia, so we investigated the relationship between rs140700 and primary insomnia. AIMS: To explore the relationship between the 5-HT gene polymorphism rs140700 and primary insomnia. METHODS: In this study, we included 57 patients with primary insomnia and 54 age- and gender-matched normal controls. The subjects who belonged to the Chinese population were subjected to polysomnography for three consecutive nights. Their sleep quality was assessed, and the genotypes of the 5-hydroxytryptamine (5-HT) gene polymorphism rs140700 were determined by the flight mass spectrometry. RESULTS: The genotype distributions of the 5-HT gene polymorphism rs140700 were in Hardy-Weinberg equilibrium in both patients and controls (P > 0.05). The allele and genotype distributions of this variant were comparable between the patients and controls in all subjects and between genders (all P > 0.05). The influence of rs140700 on percentage of stage 1 (P = 0.015) change and arousal index (P = 0.028) of primary insomnia was statistically significant. The logistic multi-factor regression analysis results revealed that 5-HT gene polymorphism rs140700 was not a risk factor for primary insomnia in the Chinese population (P = 0.589). CONCLUSIONS: The 5-HT gene polymorphism rs140700 may not be a susceptibility locus for primary insomnia in the Chinese population.


Assuntos
Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Serotonina , Distúrbios do Início e da Manutenção do Sono , Alelos , Estudos de Casos e Controles , China/epidemiologia , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Distúrbios do Início e da Manutenção do Sono/epidemiologia , Distúrbios do Início e da Manutenção do Sono/genética
8.
Nat Commun ; 11(1): 5596, 2020 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-33154378

RESUMO

Age-related osteoporosis is characterized by the deterioration in bone volume and strength, partly due to the dysfunction of bone marrow mesenchymal stromal/stem cells (MSCs) during aging. Alpha-ketoglutarate (αKG) is an essential intermediate in the tricarboxylic acid (TCA) cycle. Studies have revealed that αKG extends the lifespan of worms and maintains the pluripotency of embryonic stem cells (ESCs). Here, we show that the administration of αKG increases the bone mass of aged mice, attenuates age-related bone loss, and accelerates bone regeneration of aged rodents. αKG ameliorates the senescence-associated (SA) phenotypes of bone marrow MSCs derived from aged mice, as well as promoting their proliferation, colony formation, migration, and osteogenic potential. Mechanistically, αKG decreases the accumulations of H3K9me3 and H3K27me3, and subsequently upregulates BMP signaling and Nanog expression. Collectively, our findings illuminate the role of αKG in rejuvenating MSCs and ameliorating age-related osteoporosis, with a promising therapeutic potential in age-related diseases.


Assuntos
Envelhecimento , Histonas/metabolismo , Ácidos Cetoglutáricos/uso terapêutico , Osteoporose/tratamento farmacológico , Envelhecimento/metabolismo , Envelhecimento/patologia , Animais , Biomarcadores/metabolismo , Proteínas Morfogenéticas Ósseas/metabolismo , Regeneração Óssea/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Senescência Celular/efeitos dos fármacos , Feminino , Ácidos Cetoglutáricos/sangue , Masculino , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia , Metilação/efeitos dos fármacos , Camundongos , Osteogênese/efeitos dos fármacos , Osteoporose/metabolismo , Osteoporose/patologia , Transdução de Sinais/efeitos dos fármacos
9.
Diabetes ; 69(10): 2144-2156, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32801140

RESUMO

Impaired wound healing is one of the main causes of diabetic foot ulcerations. However, the exact mechanism of delayed wound healing in diabetes is not fully understood. Long noncoding RNAs (lncRNAs) are widely involved in a variety of biological processes and diseases, including diabetes and its associated complications. In this study, we identified a novel lncRNA, MRAK052872, named lncRNA UpRegulated in Diabetic Skin (lnc-URIDS), which regulates wound healing in diabetes. lnc-URIDS was highly expressed in diabetic skin and dermal fibroblasts treated with advanced glycation end products (AGEs). lnc-URIDS knockdown promoted migration of dermal fibroblasts under AGEs treatment in vitro and accelerated diabetic wound healing in vivo. Mechanistically, lnc-URIDS interacts with procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1 (Plod1), a critical enzyme responsible for collagen cross-linking. The binding of lnc-URIDS to Plod1 results in a decreased protein stability of Plod1, which ultimately leads to the dysregulation of collagen production and deposition and delays wound healing. Collectively, this study identifies a novel lncRNA that regulates diabetic wound healing by targeting Plod1. The findings of the current study offer some insight into the potential mechanism for the delayed wound healing in diabetes and provide a potential therapeutic target for diabetic foot.


Assuntos
RNA Longo não Codificante/metabolismo , Pele/metabolismo , Animais , Western Blotting , Ensaio de Imunoadsorção Enzimática , Produtos Finais de Glicação Avançada/genética , Produtos Finais de Glicação Avançada/metabolismo , Hibridização In Situ , Masculino , Pró-Colágeno-Lisina 2-Oxoglutarato 5-Dioxigenase/genética , Pró-Colágeno-Lisina 2-Oxoglutarato 5-Dioxigenase/metabolismo , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Pele/patologia , Cicatrização/genética , Cicatrização/fisiologia
10.
Sci Rep ; 10(1): 9482, 2020 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-32514042

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

11.
Zhongguo Zhen Jiu ; 40(4): 379-83, 2020 Apr 12.
Artigo em Chinês | MEDLINE | ID: mdl-32275366

RESUMO

OBJECTIVE: To explore the therapeutic effect and partial mechanism of electroacupuncture (EA) for patients with insulin resistance (IR) polycystic ovary syndrome (PCOS). METHODS: Seventy patients with IR-PCOS were randomly divided into an EA group (36 cases, 5 cases dropped off) and a medication group (34 cases, 4 cases dropped off). The patients in the medication group were treated with oral administration of metformin hydrochloride, 500 mg each time, twice a day. The patients in the EA group were treated with EA (continuous wave, 2 Hz of frequency) at Zusanli (ST 36), Zhongwan (CV 12), Qihai (CV 6), Yishu (EX-B 3), Shenshu (BL 23), Pishu (BL 20), Ciliao (BL 32) for 30 min, three times a week. One menstrual cycle or 4 weeks were taken as a course of treatment, and 3 continuous courses were given. The follow-up was 3 months. The lipid metabolism indexes of triacylglycerol (TG), total cholesterol (TC), high-density lipoprotein (HDL) and low-density lipoprotein (LDL), homeostasis model assessment-insulin resistance index (HOMA-IR) and testosterone (T) in serum were compared before and after treatment, and the clinical effects of the two groups were evaluated during the follow-up. RESULTS: The total effective rate was 67.7% (21/31) in the EA group and 60.0% (18/30) in the medication group, with no significant difference between the two groups (P>0.05). After treatment, the levels of serum T, HOMA-IR, LDL, TG and TC were decreased significantly in the two groups (P<0.01, P<0.05), and HDL was increased significantly (P<0.01); the levels of TC in the EA group after treatment was lower than that in the medication group (P<0.05). CONCLUSION: EA may adjust some dyslipidemia in patients to correct IR and improve endocrine disorder of PCOS, which had superior/similar effects to metformin.


Assuntos
Eletroacupuntura , Resistência à Insulina , Síndrome do Ovário Policístico/terapia , Pontos de Acupuntura , Feminino , Humanos
12.
J Periodontol ; 91(9): 1203-1212, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-31983062

RESUMO

BACKGROUND: Growth differentiation factor 11 (GDF11), a secreted member of the transforming growth factor-ß superfamily, has recently been suggested as an anti-aging factor that declines with age in the bloodstream, and restoration of the youthful level by administration of its recombinant protein could reverse age-related dysfunctions. However, its effects on titanium implant osseointegration and mandibular bone during aging remain unknown. METHODS: Two-month-old and 18-month-old C57BL male mice were given daily intraperitoneal injections of recombinant GDF11 (rGDF11) or vehicle for 6 weeks. Experimental titanium implants were inserted into femurs on the fourth week. Inhibition of GDF11 function was achieved by GDF11 antibody. Implant-bearing femurs were subjected to histomorphometric analysis and biomechanical evaluation. Mandibles were scanned with micro-CT and decalcified for histological measurements. RESULTS: In both young adult and aged mice, supraphysiologic GDF11 leads to a significantly decreased bone-to-implant contact ratio (BIC) and peri-implant bone volume/total volume (BV/TV) at the histologic level and reduced resistance at the biomechanical level, indicating weakened implant fixation. Moreover, rGDF11 administration resulted in less trabecular bone volume and thinner cortical thickness in the mandible, which was further compromised in the old animals. In contrast, inhibition of GDF11 improved peri-implant bone healing in old mice. CONCLUSIONS: Rather than functioning as a rejuvenating factor, exogenous GDF11 negatively affects not only titanium implant healing but also mandibular bone in both young and old mice. In contrast, neutralization of endogenous GDF11 has positive effects on implant fixation in aged mice.


Assuntos
Implantes Dentários , Titânio , Animais , Proteínas Morfogenéticas Ósseas , Fêmur/diagnóstico por imagem , Fêmur/cirurgia , Fatores de Diferenciação de Crescimento , Masculino , Mandíbula/diagnóstico por imagem , Mandíbula/cirurgia , Camundongos , Camundongos Endogâmicos C57BL , Osseointegração
13.
Acta Biomater ; 102: 298-314, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31751808

RESUMO

The anomalous high expression of matrix metalloproteinase 9 (MMP-9) is one important factor that impedes diabetic wound healing. Therefore, inhibition of MMP-9 expression in a diabetic wound could be a feasible method to promote wound healing. In this study, we studied the possibility of self-therapy using wound dressings that contain bacterial cellulose-hyperbranched cationic polysaccharide (BC-HCP) derivatives that encapsulate siRNA (BC-HCP/siMMP-9) and have controlled release properties. Herein, we used four HCPs (Gly-DMAPA, Gly-D4, Amyp-DMAPA, Amyp-D4) as gene carriers. Our results showed that all HCP derivatives were minimally toxic to cells in vitro, while the cationic properties of HCP could be used as a complexation agent for MMP-9 siRNA (siMMP-9). Upon exposure to bacterial cellulose (BC), the BC slowly released HCP/siMMP-9. The released siMMP-9 effectively reduced the gene expression and protein levels of MMP-9 in a human immortalized epithelial cell line (HaCAT) and in diabetic rat wounds. Inhibition of MMP-9 in the wounds of diabetic rats resulted in a significant enhancement of wound healing, suggesting that the BC-HCP/siMMP-9 composite dressing could be used as a safe and effective dressing to promote wound healing in diabetic rats. STATEMENT OF SIGNIFICANCE: In this work, we evaluated the possibility of using bacterial cellulose-hyperbranched cationic polysaccharide derivatives (BC-HCP) as a self-therapeutic wound dressing with siRNA encapsulated and controlled release properties. Our results showed that the BC-HCP/siMMP-9 composite dressing slowly released HCP/siMMP-9. The released siMMP-9 effectively reduced the gene expression and protein level of MMP-9 in human immortalized epithelial cell line and in the wound of diabetic rats. The BC-HCP/siMMP-9 composite dressing promoted diabetic wound healing by the unique nanostructure of BC and by releasing siMMP-9 for specific MMP-9 inhibition. Therefore, it could be used as a safe and effective dressing to promote wound healing in diabetic rats. This is the first evidence on the study of using BC as a dressing composite by encapsulating HCP/siRNA complexes for efficient RNAi gene silencing for better wound healing in diabetic rats.


Assuntos
Bandagens , Celulose/farmacologia , Dendrímeros/farmacologia , Diabetes Mellitus Experimental/fisiopatologia , RNA Interferente Pequeno/farmacologia , Cicatrização/efeitos dos fármacos , Animais , Celulose/toxicidade , Dendrímeros/toxicidade , Células HaCaT , Humanos , Masculino , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , RNA Interferente Pequeno/toxicidade , Ratos Sprague-Dawley
14.
Cell Death Dis ; 10(11): 813, 2019 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-31653825

RESUMO

Wound healing in diabetic skin is impaired by excessive activation of matrix metalloproteinase-9 (MMP-9). MMP-9 transcription is activated by Ten-eleven translocation 2 (TET2), a well-known DNA demethylation protein that induces MMP-9 promoter demethylation in diabetic skin tissues. However, how TET2 is targeted to specific loci in the MMP-9 promoter is unknown. Here, we identified a TET2-interacting long noncoding RNA (TETILA) that is upregulated in human diabetic skin tissues. TETILA regulates TET2 subcellular localization and enzymatic activity, indirectly activating MMP-9 promoter demethylation. TETILA also recruits thymine-DNA glycosylase (TDG), which simultaneously interacts with TET2, for base excision repair-mediated MMP-9 promoter demethylation. Together, our results suggest that the TETILA serves as a genomic homing signal for TET2-mediated demethylation specific loci in MMP-9 promoter, thereby disrupting the process of diabetic skin wound healing.


Assuntos
Proteínas de Ligação a DNA/genética , Diabetes Mellitus/genética , Metaloproteinase 9 da Matriz/genética , Proteínas Proto-Oncogênicas/genética , RNA Longo não Codificante/genética , Cicatrização/genética , Desmetilação do DNA , Metilação de DNA/genética , Diabetes Mellitus/patologia , Dioxigenases , Humanos , Regiões Promotoras Genéticas/genética , Translocação Genética
15.
J Environ Sci (China) ; 80: 186-196, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30952336

RESUMO

Ground-basedMulti-AXis Differential Optical Absorption Spectroscopy (MAX-DOAS) measurements were performed at Shangdianzi (SDZ) regional atmospheric background station in northern China from March 2009 to February 2011. The tropospheric NO2 vertical column densities (VCDs) were retrieved to investigate the background condition of the Beijing-Tianjin-Hebei developed economic circle in China. The seasonal variation of mean NO2 tropospheric VCDs (VCDTrop) at SDZ is apparent, with the maximum (1.3 × 1016 molec/cm2) in February and the minimum (3.5 × 1015 molec/cm2) in August, much lower than those observed at the Beijing city center. The average daytime diurnal variations of NO2 VCDTrop are rather consistent for all four seasons, presenting the minimum at noon and the higher values in the morning and evening. The largest and lowest amplitudes of NO2 VCDTrop diurnal variation appear in winter and in summer, respectively. The diurnal pattern at SDZ station is similar to those at other less polluted stations, but distinct from the ones at the urban or polluted stations. Tropospheric NO2 VCDs at SDZ are strongly dependent on the wind, with the higher values being associated with the pollution plumes from Beijing city. Tropospheric NO2 VCDs derived from ground-based MAX-DOAS at SDZ show to be well correlated with corresponding OMI (Ozone Monitoring Instrument) satellite products with a correlation coefficient R = 0.88. However, the OMI observations are on average higher than MAX-DOAS NO2 VCDs by a factor of 28%, probably due to the OMI grid cell partly covering the south of SDZ which is influenced more by the pollution plumes from the urban areas.


Assuntos
Poluentes Atmosféricos/análise , Monitoramento Ambiental/métodos , Dióxido de Nitrogênio/análise , Atmosfera/química , Pequim , Cidades , Ozônio/análise , Estações do Ano
16.
Sci Rep ; 9(1): 1357, 2019 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-30718549

RESUMO

Tungsten Disulfide (WS2) is considered to be a promising Hydrogen Evolution Reaction (HER) catalyst to replace noble metals (such as Pt and Pd). However, progress in WS2 research has been impeded by the inertness of the in-plane atoms during HER. Although it is known that microstructure and defects strongly affect the electrocatalytic performance of catalysts, the understanding of such related catalytic origin still remains a challenge. Here, we combined a one-pot synthesis method with wet chemical etching to realize controlled cobalt doping and tunable morphology in WS2. The etched products, which composed of porous WS2, CoS2 and a spot of WOx, show a low overpotential and small Tafel slope in 0.5 M H2SO4 solution. The overpotential could be optimized to -134 mV (at 10 mA/cm2) with a Tafel slope of 76 mV/dec at high loadings (5.1 mg/cm2). Under N2 adsorption analysis, the treated WS2 sample shows an increase in macropore (>50 nm) distributions, which may explain the increase inefficiency of HER activity. We applied electron holography to analyze the catalytic origin and found a low surface electrostatic potential in Co-doped region. This work may provide further understanding of the HER mechanism at the nanometer scale, and open up new avenues for designing catalysts based on other transition metal dichalcogenides for highly efficient HER.

17.
CNS Neurosci Ther ; 25(4): 452-464, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30294901

RESUMO

Autophagy is an essential cellular process concern with cellular homeostasis down-regulated by mTOR, whose activity can be modulated by rapamycin, a kind of lipophilic macrolide antibiotic, through forming a complex with immunophilin FKBP12 essential for mTOR regulation to induce autophagy. Therefore, rapamycin is normally used as a neuron protective agent. The immunophilin FKBP12 binding ligand FK506 is well known as an immunosuppressive agent by inhibiting the calcineurin expression. In this study, we synthesized a series of modified compounds based on the FKBP12 binding moiety to as same as the binding structure of rapamycin and FK506 particularly. We removed the other binding regions of the complex that has the property of immunosuppression. We found that a novel small molecule named TH2849 from these derivative compounds has a significant binding connection with mTOR by comparing to calcineurin. The effects of TH2849 on calcineurin/NFAT were not as significant as FK506, and weak effects on IL2/p34cdc2 /cyclin signaling pathway were also found. Moreover, TH2849 also shows mitochondrial protective effect through stabilizing the mitochondrial structure and transmembrane potential (ΔΨm) and could rescue dopaminergic neurons in MPTP-treated zebrafishes as well as mice models with less immunosuppressive effect. Our present study shows that TH2849 works as a neuroprotective agent possibly by inducing autophagy and low immunosuppressive effect.


Assuntos
Autofagia/efeitos dos fármacos , Imunossupressores/farmacologia , Intoxicação por MPTP/tratamento farmacológico , Sirolimo/farmacologia , Tacrolimo/análogos & derivados , Tacrolimo/farmacologia , Animais , Autofagia/imunologia , Imunossupressores/química , Imunossupressores/uso terapêutico , Intoxicação por MPTP/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/imunologia , Células PC12 , Ratos , Sirolimo/uso terapêutico , Peixe-Zebra
18.
Org Lett ; 20(20): 6502-6505, 2018 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-30336673

RESUMO

Different site selectivities have been reported for indoles with different directing groups in copper-catalyzed site-selective C-H arylations. Computational and mass spectrometric studies have been conducted in an effort to understand the origin of site selectivity and the effects of the directing groups. A Heck-like mechanism involving a four-membered ring is found in all three of the cases studied. For N-acetyl indole with a weak directing group, a neutral Heck-like mechanism is controlled by an electronic effect resulting in C2 site selectivity. In contrast, indole with a N-P(O) tBu2 group and N-benzyl-3-pivaloyl indole prefer a cationic Heck-like reaction in which a favorable six-membered chelation between the directing group and the CuIII center determines the C6 and C5 site selectivities.

19.
Int J Mol Med ; 42(1): 435-442, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29620153

RESUMO

Histone deacetylase inhibitors (HDACis) are able to suppress breast cancer cells in vitro and in vivo by altering the expression of estrogen receptor (ER), progesterone receptor (PR) or human epidermal growth factor receptor 2 (Her2/neu). Since HDACis can alter the expression of various microRNAs (miRNAs/miRs), the present study aimed to examine the role of miRNAs in the effects of HDACis on breast cancer cells. We first examined the mRNA expression of ER, PR, and Her2/neu using RT-PCR and the protein levels of ER, PR, and Her2/neu using western blot analysis in MDA-MB-231 and BT474 cells, after trichostatin A (TSA) or vorinostat (SAHA) treatment. We then conducted miRNA expression profiling using microarrays after BT474 cells were treated with TSA or SAHA. Finally, we examined the effects of synthetic miR-762 and miR-642a-3p inhibitors on SAHA-induced downregulation of Her2/neu and SAHA-induced apoptosis and PARP cleavage in BT474 cells. The results indicated that TSA and SAHA dose­dependently enhanced the mRNA and protein expression levels of ER and PR in MDA­MB­231 and BT474 cells. In addition, the mRNA expression levels of Her2/neu were reduced in MDA­MB­231 cells, and the mRNA and protein expression levels of Her2/neu were reduced in BT474 cells in response to SAHA and TSA. Furthermore, treatment with TSA (0.2 µM) or SAHA (5.0 µM) induced a marked alteration in the expression of various miRNAs in BT474 cells. Notably, when cells were cotransfected with miR­762 and miR­642a­3p inhibitors, SAHA­induced downregulation of Her2/neu was inhibited, and SAHA­induced apoptosis and poly (ADP­ribose) polymerase cleavage were significantly reduced in BT474 cells. These results indicated that numerous HDACi­induced miRNAs are required to downregulate Her2/neu levels and promote apoptosis of Her2­overexpressing breast cancer cells.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , MicroRNAs/genética , Apoptose/efeitos dos fármacos , Apoptose/genética , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Feminino , Humanos , Ácidos Hidroxâmicos/farmacologia , MicroRNAs/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transfecção , Vorinostat
20.
Endocrinology ; 159(2): 1172-1186, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29244109

RESUMO

Diabetes elevates matrix metalloproteinase (MMP)-9 levels in the skin and its keratinocytes, and activated MMP-9 impairs skin wound healing. Epigenetic regulation of the DNA methylation status within the MMP-9 promoter plays an important role in the alteration of MMP-9 expression. Our aim was to investigate the role and mechanism of growth arrest and DNA damage-inducible 45a (GADD45a), a well-known DNA demethylation regulatory protein that mediates DNA methylation, in the regulation of MMP-9 expression. In this study, we showed that GADD45a was markedly upregulated in skin tissues from patients with diabetic foot ulcers, in diabetic rats, and in human keratinocyte (HaCaT) cells exposed to advanced glycation end products. We observed a substantial positive correlation between the levels of GADD45a and MMP-9 expression. Knockdown of GADD45a ameliorated the increase in MMP-9 transcription induced by a diabetic condition by inhibiting demethylation in the MMP-9 promoter and promoted diabetic HaCaT cell migration, but GADD45a knockdown did not affect HaCaT cell proliferation or apoptosis. Additionally, we demonstrated that overexpression of GADD45a activated MMP-9 expression by inducing promoter demethylation. Moreover, we found that GADD45a binds to the promoter of MMP-9 and recruits thymine-DNA glycosylase for base excision repair-mediated demethylation in diabetic HaCaT cells and diabetic rat skin. Our results reveal a mechanism in which GADD45a is required for demethylation of the MMP-9 promoter and the induction of diabetic wound healing. The inhibition of GADD45a might be a therapeutic strategy for diabetic foot ulcers.


Assuntos
Proteínas de Ciclo Celular/fisiologia , Reparo do DNA/genética , Diabetes Mellitus Experimental/patologia , Produtos Finais de Glicação Avançada/farmacologia , Queratinócitos/patologia , Metaloproteinase 9 da Matriz/genética , Proteínas Nucleares/fisiologia , Pele/patologia , Animais , Células Cultivadas , Desmetilação do DNA , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Pé Diabético/genética , Pé Diabético/metabolismo , Pé Diabético/patologia , Epigênese Genética , Regulação Enzimológica da Expressão Gênica , Produtos Finais de Glicação Avançada/metabolismo , Humanos , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Regiões Promotoras Genéticas , Ratos , Ratos Sprague-Dawley , Pele/efeitos dos fármacos , Pele/metabolismo , Cicatrização/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...