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1.
Org Lett ; 23(15): 6158-6163, 2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34313448

RESUMO

A novel annulation of 2-cyanoaryl acrylamides via C═C double bond cleavage has been developed for facile and efficient access to a broad spectrum of functionalized 4-amino-2-quinolones, which are important N-heterocycles. In this transformation, the solvent THF is demonstrated to play a crucial role, and the addition of alkyl radicals to nitrile, 1,5-hydride shift, and cleavage of the C-C bond are involved in the mechanism.

2.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(3): 763-771, 2021 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-34105470

RESUMO

OBJECTIVE: To analyze the influence of bone marrow involvement (BMI) in patients with malignant lymphoma (ML) on laboratory indexes, and evaluate the laboratory markers that can be used to predict/diagnose BMI. METHODS: The clinical characteristics and laboratory indexes of 137 ML patients were analyzed retrospectively, from which the indexes of BMI in ML patients was studied. The logistic regression analysis and receiver operating curve (ROC) were used to evaluate independent risk factors and predictors of BMI diagnosis in ML patients. RESULTS: Compared with non-BMI group, the red blood cell distribution width, C-reactive protein, erythrocyte sedimentation rate, D-dimer, lactate dehydrogenase, alkaline phosphatase, ß2-microglobulin, transferrin, CA153, CA125, and soluble interleukin-2 receptor (sIL-2R) levels were increased while platelet (PLT) count was decreased in BMI group, and the difference was statistically significant (P<0.05). The blood indexes related to BMI and the statistically significant indexes in the univariate regression analysis were corrected by multivariate logistic regression analysis. The corrected results showed that T cell-related non-Hodgkin lymphoma (adjusted OR=2.18, 95%CI: 1.48-4.90, P<0.001), clinical stage Ⅲ-Ⅳ (adjusted OR=3.32, 95%CI: 2.16-5.83, P<0.001), sIL-2R (adjusted OR=4.26, 95%CI: 2.95-12.85, P<0.001) were the risk factors for ML patients with BMI, while PLT (adjusted OR=0.89, 95%CI: 0.55-0.96, P= 0.003) was a protective factor. ROC analysis showed that the areas under the ROC curve of PLT and sIL-2R predicting BMI in ML patients was 0.712 (95%CI: 0.646-0.776, P<0.001) and 0.796 (95%CI: 0.739-0.853, P<0.001), respectively. The best cut-off point of PLT and sIL-2R was 160×109/L and 2 568 U/ml, respectively. The diagnostic specificities of the two indexes here were both greater than 80%. CONCLUSION: PLT and sIL2R show good diagnostic value for ML patients with BMI.


Assuntos
Laboratórios , Linfoma , Medula Óssea , Humanos , Prognóstico , Estudos Retrospectivos
3.
Biomed Pharmacother ; 140: 111733, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34029950

RESUMO

AIMS: This study aimed to investigate the therapeutic effect of Cordyceps sinensis-derived fungus Isaria felina on experimental autoimmune thyroiditis (EAT). METHODS: A NaI-induced EAT mouse model was established. The mice received oral administration of vehicle, low-dose Isaria felina (300 mg/kg), or high-dose Isaria felina (600 mg/kg) once a day for four weeks before euthanasia. Enzyme-linked immunosorbent assays (ELISA) was performed to measure serum thyroid-stimulating hormone (TSH) levels, thyroid antibodies, and cytokines. Hematoxylin and eosin (H&E) staining was conducted to assess histopathological changes in the thyroid tissue samples of mice. TUNEL and Bcl-2 immunohistochemistry (IHC) were performed to evaluate cell apoptosis, and cleaved caspase-3 IHC was performed to detect the relative expression in the thyroid tissue samples. RESULTS: Compared with KIO3 and KI water, NaI water consumption successfully induced EAT in mice, as evidenced by significantly increased circulating TSH and thyroid antibody levels, along with typical histopathological abnormalities of autoimmune thyroiditis (AIT) in the thyroid tissue samples. Compared with vehicle or low-dose Isaria felina, high-dose Isaria felina treatment resulted in significant reductions in white cell counts and circulating TSH, thyroid antibody, and cytokine levels of EAT mice. High-dose Isaria felina also alleviated histopathological abnormalities and attenuated TUNEL staining, Bcl-2 protein expression, and cleaved caspase-3 expression in the thyroid tissue samples. CONCLUSION: High-dose Isaria felina treatment alleviates thyroid inflammation and cell apoptosis in EAT, serving as a novel, promising therapeutic agent for AIT.


Assuntos
Beauveria , Tireoidite Autoimune/terapia , Animais , Autoanticorpos/sangue , Cordyceps , Modelos Animais de Doenças , Feminino , Iodeto Peroxidase/imunologia , Camundongos , Proteínas Proto-Oncogênicas c-bcl-2/imunologia , Glândula Tireoide/imunologia , Glândula Tireoide/patologia , Tireoidite Autoimune/sangue , Tireoidite Autoimune/imunologia , Tireotropina/sangue
4.
Chem Biol Drug Des ; 97(2): 200-209, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32915501

RESUMO

In an effort to discover new agents with high anti-inflammatory activity, 22 new 4-sulfonyloxy/alkoxy benzoxazolone derivatives were synthesized, characterized, and evaluated for their anti-inflammatory activities against lipopolysaccharide (LPS)-induced nitric oxide (NO) production and TNF-α expression in RAW 264.7 cells in vitro. Most of these compounds displayed greater inhibitory ability against NO production than the lead compound 4-o-methyl-benzenesulfonyl benzoxazolone, and the most active compound 2h exhibited the strongest inhibitory activity against NO, IL-1ß, and IL-6 production with IC50 values 17.67, 20.07, and 8.61 µΜ, respectively. The effects of 2h were comparable or stronger than those of the positive control celecoxib. Compound 2h also displayed higher activity in vivo than celecoxib in a mouse model of xylene-induced ear edema, based on their inhibitory rates of 42.69% and 30.87%, respectively. Further molecular analysis revealed that compound 2h significantly reduced the iNOS levels in cell supernatant and suppressed the protein expression of iNOS, p-p38, p-ERK, and nuclear NF-κB. The results indicated that the anti-inflammatory effect of 2h might be realized through the regulation of ERK- and p38-mediated mitogen-activated protein kinase (MAPK)-NF-κB/iNOS signaling, thereby reducing the excessive release of NO, IL-1ß, and IL-6. Our findings demonstrated that compound 2h, a new benzoxazolone derivative, could inhibit activation of the MAPK-NF-κB/iNOS pathway, supporting its potential as a novel anti-inflammatory agent.


Assuntos
Anti-Inflamatórios/farmacologia , Benzoxazóis/química , Transdução de Sinais/efeitos dos fármacos , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/uso terapêutico , Benzoxazóis/farmacologia , Benzoxazóis/uso terapêutico , Sítios de Ligação , Regulação para Baixo/efeitos dos fármacos , Edema/induzido quimicamente , Edema/tratamento farmacológico , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Simulação de Acoplamento Molecular , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/química , Óxido Nítrico Sintase Tipo II/metabolismo , Células RAW 264.7 , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
5.
J Ethnopharmacol ; 238: 111839, 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-30928501

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Guilingji (GLJ), a famous and classical traditional Chinese medicine (TCM) prescription, has been used to extend the lifespan and improve the life qualities of the elderly for hundreds of years in China. AIM OF THE STUDY: We aimed to explore the protective effects of GLJ on the testicular dysfunction of aging rats, as well as the regulating effects of GLJ on the metabolic disturbance and metabolite changes in natural aging rats. MATERIALS AND METHODS: Forty 23-month-old rats were divided randomly into four groups, including the old control group and three groups of GLJ treatment at 37.5, 75, and 150 mg/kg doses, respectively. Additionally, 10 four-month rats were included as the youth control group. Testicular dysfunction was first evaluated by measuring the changes in the wet weights of the testicles, concentration of serum testosterone (T), and morphologic changes of the testis. Subsequently, an 1H NMR-based metabolomics approach coupled with multivariate analysis, including partial least squares discriminant analysis (PLS-DA) and orthogonal partial least squares-discriminant analysis (OPLS-DA) was applied to monitor the metabolite changes. RESULTS: Compared with the old control group, the wet weights of the testicles and T concentration were significantly increased, while the morphologic abnormality of testicular tissues was improved by a 4-week treatment course with GLJ. Furthermore, compared with the old control group, the urinary levels of alanine, pantothenate, phenylalanine, ß-hydroxybutyrate and pyruvate were significantly decreased after a 4-week treatment course with GLJ. Additionally, we found that amino acid metabolism and pyruvate metabolism were significantly involved in the regulatory effect of GLJ. CONCLUSIONS: The current findings provided, for the first time, sound evidence of the protective effects of GLJ on testicular dysfunction from both biochemical and metabolomics perspectives. The mechanisms of GLJ could be related to regulating amino acid metabolism and pyruvate metabolism. The current study lays an important foundation for further research and for the broad clinical application of GLJ.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Substâncias Protetoras/farmacologia , Testículo/efeitos dos fármacos , Envelhecimento , Aminoácidos/metabolismo , Animais , Masculino , Metabolômica , Espectroscopia de Prótons por Ressonância Magnética , Ácido Pirúvico/metabolismo , Ratos , Ratos Sprague-Dawley , Testículo/patologia , Testosterona/sangue
6.
Nature ; 565(7739): E8, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30568306

RESUMO

Change history: In this Letter, owing to a production error, all the data points (except the two points for O-2 and N-2, respectively) were missing in Fig. 1b. The figure has been corrected online.

7.
Nature ; 563(7732): 546-550, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30429610

RESUMO

Oxygen, one of the most abundant elements on Earth, often forms an undesired interstitial impurity or ceramic phase (such as an oxide particle) in metallic materials. Even when it adds strength, oxygen doping renders metals brittle1-3. Here we show that oxygen can take the form of ordered oxygen complexes, a state in between oxide particles and frequently occurring random interstitials. Unlike traditional interstitial strengthening4,5, such ordered interstitial complexes lead to unprecedented enhancement in both strength and ductility in compositionally complex solid solutions, the so-called high-entropy alloys (HEAs)6-10. The tensile strength is enhanced (by 48.5 ± 1.8 per cent) and ductility is substantially improved (by 95.2 ± 8.1 per cent) when doping a model TiZrHfNb HEA with 2.0 atomic per cent oxygen, thus breaking the long-standing strength-ductility trade-off11. The oxygen complexes are ordered nanoscale regions within the HEA characterized by (O, Zr, Ti)-rich atomic complexes whose formation is promoted by the existence of chemical short-range ordering among some of the substitutional matrix elements in the HEAs. Carbon has been reported to improve strength and ductility simultaneously in face-centred cubic HEAs12, by lowering the stacking fault energy and increasing the lattice friction stress. By contrast, the ordered interstitial complexes described here change the dislocation shear mode from planar slip to wavy slip, and promote double cross-slip and thus dislocation multiplication through the formation of Frank-Read sources (a mechanism explaining the generation of multiple dislocations) during deformation. This ordered interstitial complex-mediated strain-hardening mechanism should be particularly useful in Ti-, Zr- and Hf-containing alloys, in which interstitial elements are highly undesirable owing to their embrittlement effects, and in alloys where tuning the stacking fault energy and exploiting athermal transformations13 do not lead to property enhancement. These results provide insight into the role of interstitial solid solutions and associated ordering strengthening mechanisms in metallic materials.

8.
Pharmacol Rep ; 70(3): 558-564, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29677526

RESUMO

BACKGROUND: Great attention has been paid to the development of novel anti-inflammatory drugs to overcome the adverse reactions of traditional drugs. Recently, a new compound 4-o-methyl-benzenesulfonyl benzoxazolone (MBB) we have prepared attracted our attention for its promising anti-inflammatory activity and low toxicity. The present study aimed to further investigate the anti-inflammatory effects of MBB both in vivo and in vitro in order to determine its potential as a novel NSAIDs lead compound. METHODS: The anti-inflammatory effects in vivo were evaluated using acetic acid-induced mice writhing, xylene-induced mice ear edema and collagen-induced rat arthritis. NO, TNF-α, IL-6, IL-1ß and iNOS productions by LPS-stimulated RAW264.7 cells were determined to investigate the basis of anti-inflammatory effects. Finally, the COX inhibition effect was tested in vitro using COX inhibitor screening assay kit. RESULTS: MBB could significantly decrease the writhing and ear swelling in a dose-dependent manner, and it also had a moderate anti-arthritic potential associated with an attenuation of arthritis index score, arthritis swelling, and inhibition of TNF-α and IL-1ß. MBB could inhibit the activity of NO, TNF-α, IL-6, IL-1ß and iNOS to perform its activity in vitro, but it had no effect against COX-1 and COX-2. The anti-inflammation effect may be mediated via the inhibition of iNOS to reduce the production of inflammatory mediators which should be further confirmed. CONCLUSIONS: The compound MBB displayed anti-inflammatory and anti-arthritic effect, and it could be considered as a new NSAIDs lead compound for the further structure modification to develop novel anti-inflammatory drugs.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios/farmacologia , Benzoxazóis/farmacologia , Animais , Artrite Experimental/tratamento farmacológico , Artrite Experimental/metabolismo , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Edema/tratamento farmacológico , Edema/metabolismo , Feminino , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Masculino , Camundongos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Células RAW 264.7 , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/metabolismo
9.
Oxid Med Cell Longev ; 2017: 7028478, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28694915

RESUMO

Increasing evidence has demonstrated that heme oxygenase-1 (HO-1) is a key enzyme triggered by cellular stress, exhibiting cytoprotective, antioxidant, and anti-inflammatory abilities. Previously, we prepared a series of novel active halophenols possessing strong antioxidant activities in vitro and in vivo. In the present study, we demonstrated that these halophenols exhibited significant protective effects against H2O2-induced injury in EA.hy926 cells by inhibition of apoptosis and ROS and TNF-α production, as well as induction of the upregulation of HO-1, the magnitude of which correlated with their cytoprotective actions. Further experiments which aimed to determine the mechanistic basis of these actions indicated that the halophenols induced the activation of Nrf2, Erk1/2, and PI3K/Akt without obvious effects on the phosphorylation of p38, JNK, or the expression of PKC-δ. This was validated with the use of PD98059 and Wortmannin, specific inhibitors of Erk1/2 and PI3K, respectively. Overall, our study is the first to demonstrate that the cytoprotective actions of halophenols involve their antiapoptotic, antioxidant, and anti-inflammatory abilities, which are mediated by the upregulation of Nrf2-dependent HO-1 expression and reductions in ROS and TNF-α generation via the activation of Erk1/2 and PI3K/Akt in EA.hy926 cells. HO-1 may thus be an important potential target for further research into the cytoprotective actions of halophenols.


Assuntos
Heme Oxigenase-1/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Fenóis/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Apoptose/efeitos dos fármacos , Western Blotting , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Citometria de Fluxo , Humanos , Peróxido de Hidrogênio/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
10.
Angew Chem Int Ed Engl ; 56(25): 7205-7208, 2017 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-28508564

RESUMO

The borylation of C-H bonds catalyzed by transition metals has been investigated extensively in the past two decades, but no iridium-catalyzed enantioselective borylation of C-H bonds has been reported. We report a set of iridium-catalyzed enantioselective borylations of aromatic C-H bonds. This reaction relies on a set of newly developed chiral quinolyl oxazoline ligands. This process proceeds under mild conditions with good to excellent enantioselectivity, and the borylated products can be converted to enantioenriched derivatives containing new C-O, C-C, C-Cl, or C-Br bonds.


Assuntos
Compostos de Boro/química , Nitrogênio/química , Catálise , Hidroquinonas/química , Irídio/química , Ligantes , Estrutura Molecular , Oxazóis/química , Estereoisomerismo
11.
Angew Chem Int Ed Engl ; 56(4): 1092-1096, 2017 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-27976482

RESUMO

Iridium catalysts containing dative nitrogen ligands are highly active for the borylation and silylation of C-H bonds, but chiral analogs of these catalysts for enantioselective silylation reactions have not been developed. We report a new chiral pyridinyloxazoline ligand for enantioselective, intramolecular silylation of symmetrical diarylmethoxy diethylsilanes. Regioselective and enantioselective silylation of unsymmetrical substrates was also achieved in the presence of this newly developed system. Preliminary mechanistic studies imply that C-H bond cleavage is irreversible, but not the rate-determining step.


Assuntos
Irídio/química , Nitrogênio/química , Oxazóis/química , Silanos/síntese química , Catálise , Ligantes , Estrutura Molecular , Silanos/química , Estereoisomerismo
12.
Protein Pept Lett ; 19(4): 388-97, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22316305

RESUMO

Computational prediction of protein structural class based on sequence data remains a challenging problem in current protein science. In this paper, a new feature extraction approach based on relative polypeptide composition is introduced. This approach could take into account the background distribution of a given k-mer under a Markov model of order k-2, and avoid the curse of dimensionality with the increase of k by using a T-statistic feature selection strategy. The selected features are then fed to a support vector machine to perform the prediction. To verify the performance of our method, jackknife cross-validation tests are performed on four widely used benchmark datasets. Comparison of our results with existing methods shows that our method provides satisfactory performance for structural class prediction.


Assuntos
Aminoácidos/química , Biologia Computacional , Estrutura Terciária de Proteína , Proteínas/química , Algoritmos , Bases de Dados de Proteínas , Redes Neurais de Computação , Dobramento de Proteína , Proteínas/classificação , Análise de Sequência de Proteína , Máquina de Vetores de Suporte
13.
Colloids Surf B Biointerfaces ; 70(2): 243-7, 2009 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-19185470

RESUMO

Adhesive proteins secreted by the marine mussel could bind strongly to all kinds of surfaces, for instance, ship hulls and petroleum pipelines. Studies indicated that there was an unusual amino acid 3,4-dihydroxy-l-phenylanine (dopa), which was the crucial super adhesive unit in the proteins. The technology of electrolyzing seawater was employed to generate HOCl solution to hinder the adhesion. However, the detailed anti-fouling mechanism of HOCl solution remained unknown to be fully explained. Herein, we theoretically reported a study of single molecular (dopa) reaction under the HOCl solution environment, which would be helpful to reveal the anti-fouling mechanism through electrolyzing seawater. By using the density functional theory (DFT) quantum mechanics procedure, we theoretically studied the reaction mechanism of the adhesive unit dopa in mussel with electrolyzing seawater. Two possible pathways (1 and 2) were obtained (Fig. 6). The transition state for each pathway was determined, the intrinsic reaction coordinate (IRC) was analyzed and the mechanism had been confirmed. The calculations indicated dopa tended to have electrophonic attacking substitution reaction to generate 3-chlorine-4,5-dihydroxyphenylalanine (dopa-Cl) with different pathways, which hindered the formulation of conjuncted dopa-dopa and thus the stickiness among mussel adhesive proteins reduced. The transition states computation showed that pathway (1) had one transition state (TS1-1) with an activation energy of 102.22 kJ mol(-1), while pathway (2) had two transition states (TS2-1, TS2-2) with activation energies of 191.98 kJ mol(-1) and 42.00 kJ mol(-1) respectively and one intermediate (IM2-1). Rate constant value of pathway (1) was much bigger than that of pathway (2) regardless of high or low temperature, which meant that in the reaction process, pathway (1) was the favorable reaction step; but as the temperature rose, the competitiveness of pathway (2) gradually increased. After the theoretical calculation, we found that it was Cl(+) played an important and direct role in the dopa's modification.


Assuntos
Di-Hidroxifenilalanina/química , Água do Mar/química , Animais , Bivalves , Eletroquímica/métodos , Cinética , Modelos Químicos , Conformação Molecular , Estrutura Molecular , Proteínas/química , Propriedades de Superfície , Termodinâmica
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