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1.
Spectrochim Acta A Mol Biomol Spectrosc ; 246: 119000, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-33032113

RESUMO

Sulfonamides are a kind of antibiotics which have been widely used as feed additives for livestock and poultry. However, sulfa drugs have raised worldwide concerns because of their adverse impact on human health. In this study, two sulfonamides, sulfametoxydiazine (SMD) and sulfamonomethoxine (SMM), were selected to explore the binding modes with human serum albumin (HSA). The spectroscopic approaches revealed that SMD or SMM could spontaneously enter into the binding site I of HSA through hydrogen bond interactions and van der Waals forces, and that SMD exhibited much stronger binding affinity toward HSA than SMM at different temperatures (p < 0.01, n = 3). The binding constants for SMD-HSA and SMM-HSA were determined to be (8.297 ± 0.010) × 104 L·mol-1 and (1.178 ± 0.008) × 104 L·mol-1 at 298 K, respectively. The interaction of SMD or SMM to HSA induced microenvironmental and conformational changes in HSA, where SMD had a greater effect on the α-helix content of HSA. Results from molecular docking implied that the amino acid residues of HSA, such as Arg222, Ala291 and Leu238, played key roles in the sulfonamide-HSA binding process. Meanwhile, hydrogen bonds might be a key factor contributing to the binding affinity of sulfa drugs and HSA. Additionally, the combined use of SMD and SMM led to an obvious variation in Ka values of binary systems (p < 0.01, n = 3). These findings might be helpful to understand the biological effects of sulfonamides in humans.

2.
Nat Commun ; 11(1): 4773, 2020 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-32963236

RESUMO

In situ tuning of the electronic structure of active sites is a long-standing challenge. Herein, we propose a strategy by controlling the hydrogen spillover distance to in situ tune the electronic structure. The strategy is demonstrated to be feasible with the assistance of CoOx/Al2O3/Pt catalysts prepared by atomic layer deposition in which CoOx and Pt nanoparticles are separated by hollow Al2O3 nanotubes. The strength of hydrogen spillover from Pt to CoOx can be precisely tailored by varying the Al2O3 thickness. Using CoOx/Al2O3 catalyzed styrene epoxidation as an example, the CoOx/Al2O3/Pt with 7 nm Al2O3 layer exhibits greatly enhanced selectivity (from 74.3% to 94.8%) when H2 is added. The enhanced selectivity is attributed to the introduction of controllable hydrogen spillover, resulting in the reduction of CoOx during the reaction. Our method is also effective for the epoxidation of styrene derivatives. We anticipate this method is a general strategy for other reactions.

3.
J Ethnopharmacol ; 264: 113380, 2020 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-32918994

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Sea buckthorn is popularly used as a herbal medicine and food additive in the world. Sea buckthorn flavonoids (SF) is reported to have an ameliorative effect on obesity and hyperlipidemia (HLP). AIM: To identify the major bioactive compounds and the lipid-lowering mechanism of SF. METHODS: We used network pharmacology analysis and in vitro experiments to identify the major bioactive compounds and the lipid-lowering mechanism of SF. RESULTS: A total of 12 bioactive compounds, 60 targets related to SF and HLP were identified, and a component-target-disease network was constructed. The KEGG analysis revealed that SF regulated cholesterol metabolism, fat digestion and absorption, and PPAR signaling pathways in HLP. The experimental validation indicated that sea buckthorn flavonoids extract (SFE) and 4 bioactive compounds reduced lipid droplet accumulation, up-regulated the mRNA expression of PPAR-γ, PPAR-α, ABCA1 and CPT1A, etc, down-regulated SREBP-2 and its target gene LDLR, which are closely related to cholesterol conversion into bile acids, de novo synthesis and fatty acids oxidation. The major bioactive flavonoid isorhamnetin (ISOR) also increased the protein expression of PPAR-γ, LXRα and CYP7A1. CONCLUSION: SF might promote cholesterol transformation into bile acids and cholesterol efflux, inhibit cholesterol de novo synthesis and accelerate fatty acids oxidation for ameliorating HLP.

4.
Spectrochim Acta A Mol Biomol Spectrosc ; 245: 118929, 2020 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-32961448

RESUMO

Levamlodipine (LEE) is a drug commonly used for antihypertensive treatment in clinical therapy. The overlapping fluorescence spectra of LEE and human serum albumin (HSA) cause some trouble in analysis of interactions between them by using the classic fluorescence method. Here, the multivariate curve resolution-alternating least squares (MCR-ALS) approach was used to overcome this disadvantage. Meanwhile, the binding properties of LEE-HSA complex were then explored through computer modeling. The MCR-ALS results suggested that LEE-HSA complex was present in the mixture solution of LEE and HSA. This conclusion was then confirmed by the Stern-Volmer equation and time-resolved fluorescence experiment. The binding constant (Ka) was 2.139 × 104 L·mol-1 at 298 K. LEE was located close to the Trp-214 residue of HSA, with van der Waals forces and hydrogen bonding as main driving forces for this interaction. LEE can alter the conformation of HSA, in which the content of α-helix reduced from 57.2% to 52.3%. The Pi-Alkyl interactions contributed to maintaining the stability of the LEE-HSA complex. The results of molecular dynamics simulations showed that LEE-HSA complex was formed within 5 ns, and the particle size (Rg) of HSA was altered by the binding reaction. This study would promote better understanding of the transportation and distribution mechanisms of LEE in the human body.

5.
Eur J Med Chem ; 207: 112734, 2020 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-32866756

RESUMO

Nuclear factor erythroid 2-related factor 2 (NRF2) is a pleiotropic transcription factor which regulates the constitutive and inducible transcription of a wide array of genes and confers protection against a variety of pathologies. Directly disrupting Kelch-like ECH-associated protein 1 (KEAP1)-NRF2 protein-protein interaction (PPI) has been explored as a promising strategy to activate NRF2. We reported here the first identification of a series of 2-oxy-2-phenylacetic acid substituted naphthalene sulfonamide derivatives as potent KEAP1-NRF2 inhibitors. Our efforts led to the potent small molecule KEAP1-NRF2 inhibitor, 20c, which exhibited a Kd of 24 nM to KEAP1 and an IC50 of 75 nM in disrupting KEAP1-NRF2 interaction. Subsequent biological studies provided consistent evidence across mouse macrophage cell-based and in vivo models that 20c induced NRF2 target gene expression and enhanced downstream antioxidant and anti-inflammatory activities. Our study not only demonstrated that small molecule KEAP1-NRF2 PPI inhibitors can be potential preventive and therapeutic agents for diseases and conditions involving oxidative stress and inflammation but also enriched the chemical diversity of the KEAP1-NRF2 inhibitors.

6.
J Med Chem ; 63(19): 11149-11168, 2020 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-32902980

RESUMO

The Keap1 (Kelch-like ECH-associated protein 1)-Nrf2 (nuclear factor erythroid 2-related factor 2)-ARE (antioxidant response element) pathway is the major defending mechanism against oxidative stresses, and directly disrupting the Keap1-Nrf2 protein-protein interaction (PPI) has been an attractive strategy to target oxidative stress-related diseases, including cardiovascular diseases. Here, we describe the design, synthesis, and structure-activity relationships (SARs) of indoline-based compounds as potent Keap1-Nrf2 PPI inhibitors. Comprehensive SAR analysis and thermodynamics-guided optimization identified 19a as the most potent inhibitor in this series, with an IC50 of 22 nM in a competitive fluorescence polarization assay. Further evaluation indicated the proper drug-like properties of 19a. Compound 19a dose-dependently upregulated genes and protein level of Nrf2 as well as its downstream markers and showed protective effects against lipopolysaccharide-induced injury in both H9c2 cardiac cells and mouse models. Collectively, we reported here a novel indoline-based Keap1-Nrf2 PPI inhibitor as a potential cardioprotective agent.

8.
Eur J Surg Oncol ; 46(10 Pt B): e55-e61, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32782201

RESUMO

BACKGROUND: The aim of this study was to evaluate the safety of natural orifice specimen extraction surgery (NOSES) and to compare the short- and long-term outcomes of three techniques of NOSES for rectal cancer (RC). MATERIALS AND METHODS: A consecutive series of RC patients in stage I-III who underwent laparoscopic NOSES were enrolled. Three main techniques of NOSES included specimen eversion and extra-abdominal resection (EVER), specimen extraction and extra-abdominal resection (EXER) and intra-abdominal resection and specimen extraction (IREX). The postoperative complications, 5-year disease free survival (DFS), 5-year local recurrence rate (LRR) and 5-year distant metastasis rate (DMR) were compared in three techniques. RESULTS: 268 RC patients met inclusion criteria, including 83 patients treated with EVER, 75 patients treated with EXER and 110 patients treated with IREX. Tumor location was the most critical factor associated with technique selection, with P < 0.001. Postoperative complication rate was 12.3% for all patients, and it was 18.1% for EVER, 13.3% for EXER and 7.3% for IREX. There were no significant differences for anastomotic leakage, anastomotic bleeding and intraabdominal abscess among three technique groups, with P > 0.05. For long-term outcomes, the 5-year DFS, 5-year LRR and 5-year DMR were 85.03%, 4.22% and 11.00% for all patients. Patients in advanced tumor stage have worse long-term survival compared with patients in early stage, but no significant survival differences were observed among three technique groups. CONCLUSION: Three techniques of NOSES for RC had acceptable short- and long-term outcomes, and tumor location was a determinant of technique selection.

9.
Drug Discov Today ; 2020 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-32771436

RESUMO

B-cell lymphoma-2 (Bcl-2) family proteins, comprising proapoptotic proteins (Bax and Bak), antiapoptotic proteins (Bcl-2, Bcl-XL, Bcl-w, Mcl-1, and A1) and BCL-2 homology domain 3 (BH3)-only proteins (Bid, Noxa, and Puma), have long been identified as pivotal apoptosis regulators. As an antiapoptotic member, myeloid cell leukemin-1 (Mcl-1) can bind with proapoptotic proteins and inhibit apoptosis. Mcl-1 is frequently overexpressed and closely associated with oncogenesis and poor prognosis in several cancers, posing a tremendous obstacle for cancer therapy. Recently, an increasing number of Mcl-1-selective small-molecule inhibitors have entered preclinical studies and advanced into clinical trials. In this review, we briefly introduce the role of Mcl-1 in apoptosis and highlight the recent development of Mcl-1 small-molecule inhibitors.

10.
J Affect Disord ; 276: 1061-1068, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32768878

RESUMO

OBJECTIVE: A large proportion of patients with atypical parkinsonian syndromes suffer from depression, an antecedent of suicide. This study aimed to explore the prevalence and clinical correlates of suicidal and death ideation (SDI) in patients with Progressive Supranuclear Palsy (PSP) and Corticobasal Syndrome (CBS), as well as compare the differences with patients with Parkinson's disease (PD). METHODS: This was a case-control, cross-sectional study. SDI was diagnosed based on the assessment of the Hamilton Depression Rating Scale (HRDS). The prevalence of SDI among patients with PD, PSP, and CBS (n = 3400, 268, and 65 respectively) were compared before and after propensity score matching (PSM). A forward binary logistic regression model was used to explore the associated factors of SDI. RESULTS: None of the patients reported suicide attempts. The prevalence of SDI in patients with PSP and CBS were 27.2% and 29.2%, respectively, which was significantly higher than that in patients with PD before and after PSM (P < 0.05). The prevalence of SDI was not significantly different among patients with PSP with different subtypes (Richardson syndrome, Parkinsonism, and other), both before and after PSM (P > 0.05). Multivariate analysis indicated that higher gait and midline score and depression were independently associated with an increased risk of SDI in patients with PSP (P < 0.05), while higher non-motor symptoms score and depression were independently associated with the occurrence of SDI in patients with CBS (P < 0.05). CONCLUSIONS: Our study highlights the importance of screening SDI in patients with PSP and CBS.

11.
MedComm (Beijing) ; 2020 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-32838396

RESUMO

Clinicians have been faced with the challenge of differentiating between severe acute respiratory syndrome associated coronavirus 2 (SARS-CoV-2) infected pneumonia (NCP) and influenza A infected pneumonia (IAP), a seasonal disease that coincided with the outbreak. We aim to develop a machine-learning algorithm based on radiomics to distinguish NCP from IAP by texture analysis based on computed tomography (CT) imaging. Forty-one NCP and 37 IAP patients admitted from January to February 6, 2019 admitted to two hospitals in Wenzhou, China. All patients had undergone chest CT examination and blood routine tests prior to receiving medical treatment. NCP was diagnosed by real-time RT-PCR assays. Eight of 56 radiomic features extracted by LIFEx were selected by least absolute shrinkage and selection operator regression to develop a radiomics score and subsequently constructed into a nomogram to predict NCP with area under the operating characteristics curve of 0.87 (95% confidence interval: 0.77-0.93). The nomogram also showed excellent calibration with Hosmer-Lemeshow test yielding a nonsignificant statistic (P = .904). The novel nomogram may efficiently distinguish between NCP and IAP patients. The nomogram may be incorporated to existing diagnostic algorithm to effectively stratify suspected patients for SARS-CoV-2 pneumonia.

13.
Food Chem ; 332: 127438, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32645671

RESUMO

ß-N-acetylhexosaminidases have attracted much attention in recent years due to their potential application in oligosaccharide production, in particular lacto-N-triose II (LNT2) and lacto-N-neotetraose (LNnT) synthesis, which can be further used as backbone precursors for human milk oligosaccharides. A novel ß-N-acetylhexosaminidase gene from Tyzzerella nexilis (TnHex189) was heterologously expressed in Bacillus subtilis. The highest ß-N-acetylhexosaminidase activity of 14.5 U mL-1 was obtained in a 5-L fermentor by fed-batch fermentation for 27 h. TnHex189 was optimally active at pH 5.0 and 45 °C. It efficiently synthesized LNT2 with a conversion ratio of 57.2% (4.7 g L-1). The synthesized LNT2 was further converted to LNnT by a reported ß-galactosidase (BgaD-D) in 8 h, with a conversion ratio of 17.3% (6.1 g L-1). These unique synthesis activities may make this enzyme a good candidate for the food industry.


Assuntos
Proteínas de Bactérias/metabolismo , Clostridiales/enzimologia , Trissacarídeos/biossíntese , beta-N-Acetil-Hexosaminidases/metabolismo , Bacillus subtilis/genética , Bacillus subtilis/metabolismo , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Clostridiales/genética , Estabilidade Enzimática , Fermentação , Expressão Gênica , Concentração de Íons de Hidrogênio , Oligossacarídeos/metabolismo , beta-N-Acetil-Hexosaminidases/química , beta-N-Acetil-Hexosaminidases/genética
14.
Diabetes Res Clin Pract ; 166: 108300, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32663490

RESUMO

Coronavirus disease 2019 (COVID-19) is considered to be spread primarily by people who have tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we discuss a patient with severe COVID-19 and a history of type 2 diabetes who had a recurrence of positive SARS-CoV-2 ribonucleic acid (RNA) after recovering. The patient was initially discharged after two consecutive negative SARS-CoV-2 RNA tests and partially absorbed bilateral lesions on chest computed tomography (CT). However, at his first follow-up, reverse transcription-polymerase chain reaction (RT-PCR) assay with an oropharyngeal swab sample was positive for SARS-CoV-2. Despite this, he displayed no obvious clinical symptoms and improved chest CT. The patient was prescribed anti-viral medication. Eight consecutive RT-PCR assays on oropharyngeal swab specimens were conducted after he was re-admitted to our hospital. The results tested positive on the 12th, 14th, 19th, 23rd and 26th of March and negative on the 28th of March, and 6th and 12th of April. After his second discharge, he has tested negative for 5 weeks. This case highlights the importance of active surveillance of SARS-CoV-2 RNA during the follow-up period so that an infectivity assessment can be made.


Assuntos
Betacoronavirus/isolamento & purificação , Glicemia/metabolismo , Infecções por Coronavirus/complicações , Infecções por Coronavirus/diagnóstico , Diabetes Mellitus Tipo 2/fisiopatologia , Pneumonia Viral/complicações , Pneumonia Viral/diagnóstico , RNA Viral/análise , Adulto , Betacoronavirus/genética , Infecções por Coronavirus/transmissão , Infecções por Coronavirus/virologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/virologia , Humanos , Masculino , Pandemias , Pneumonia Viral/transmissão , Pneumonia Viral/virologia , Prognóstico , RNA Viral/genética , Tomografia Computadorizada por Raios X/métodos
15.
Eur J Med Chem ; 202: 112532, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32668381

RESUMO

Therapeutic targeting the protein-protein interaction (PPI) of Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and its main regulator, Kelch-like ECH-Associating protein 1 (Keap1) has been emerged as a feasible way to combat oxidative stress related diseases, due to the key role of Nrf2 in oxidative stress regulation. In recent years, many efforts have been made to develop potent Keap1-Nrf2 inhibitors with new chemical structures. Various molecules with diverse chemical structures have been reported and some compounds exhibit high potency. This review summarizes peptide and small molecule Keap1-Nrf2 inhibitors reported recently. We also highlight the pharmacological effects and discuss the possible therapeutic application of Keap1-Nrf2 inhibitors.

16.
Mod Pathol ; 33(11): 2330-2340, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32514163

RESUMO

Although PD-1/PD-L1 immunotherapy has been used successfully in treating many cancers, metastatic colorectal cancer (CRC) patients are not as responsive. B7-H3 is a promising target for immunotherapy and we found it to have the highest expression among B7-CD28 family members in CRC. Thus, the aim of the present study was to investigate B7-H3 expression in a large CRC cohort. B7-H3, B7-H4, and PD-L1 protein levels and differential lymphocyte infiltration were evaluated in tissue microarrays from 805 primary tumors and matched metastases. The relationships between immune markers, patient characteristics, and survival outcomes were determined. B7-H3 (50.9%) was detected in more primary tumors than B7-H4 (29.1%) or PD-L1 (29.2%), and elevated B7-H3 expression was associated with advanced overall stage. Co-expression of B7-H3 only with B7-H4 or PD-L1 was infrequent in primary tumors (6.3%, 5.7%, respectively). Moreover, B7-H3 in primary tumors was positively correlated with their respective expression at metastatic sites (ρ = 0.631; p < 0.001). No significant relationships between B7-H4 and PD-L1 and survival were observed; however, B7-H3 overexpression in primary tumors was significantly related to decreased disease-free survival. A positive relationship between B7-H3 expression and high density CD45RO T cell was observed in primary tumors, whereas B7-H4 and PD-L1 overexpression were related to CD3 T-cell infiltration. In conclusion, compared with B7-H4 and PD-L1, B7-H3 expression exhibited a higher prevalence and was significantly related to aggressiveness, worse prognosis and CD45RO T-cell infiltration in primary tumors. Further exploration of this potential target of immunotherapy in CRC patients is warranted.

17.
Artigo em Inglês | MEDLINE | ID: mdl-32543082

RESUMO

Electrochemical synthesis based on electrons as reagents provides a broad prospect for commodity chemical manufacturing. A direct one-step route for the electrooxidation of amino C-N bonds to nitrile C≡N bonds offers an alternative pathway for nitrile production. However, this route has not been fully explored with respect to either the chemical bond reforming process or the performance optimization. Proposed here is a model of vacancy-rich Ni(OH)2 atomic layers for studying the performance relationship with respect to structure. Theoretical calculations show the vacancy-induced local electropositive sites chemisorb the N atom with a lone pair of electrons and then attack the corresponding N(sp3 )-H, thus accelerating amino C-N bond activation for dehydrogenation directly into the C≡N bond. Vacancy-rich nanosheets exhibit up to 96.5 % propionitrile selectivity at a moderate potential of 1.38 V. These findings can lead to a new pathway for facilitating catalytic reactions in the chemicals industry.

19.
Appl Biochem Biotechnol ; 192(3): 794-811, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32588207

RESUMO

In this work, an effective hybrid strategy was developed for tandem conversion of biomass to furfurylamine with tin-based solid acid Sn-Maifanitum stone and recombinant Escherichia coli whole cells harboring ω-transaminase. 90.3 mM furfural was obtained from corncob (75 g/L) at 170 °C for 0.5 h over Sn-Maifanitum stone catalyst (3.5 wt%) in the aqueous media (pH 1.0), which could be further bioconverted into furfurylamine at 74.0% yield (based on biomass-derived furfural) within 20.5 h. Finally, an efficient recycling and reuse of Sn-Maifanitum stone catalyst and immobilized Escherichia coli AT2018 whole-cell biocatalyst was developed for the synthesis of furfurylamine from biomass in the one-pot reaction system.

20.
Biomed Res Int ; 2020: 7532514, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32596369

RESUMO

Leptin acts as an adipocytokine functions via the leptin receptor, which stimulates growth, migration, and invasion of cancer cells. This study is aimed at identifying leptin as a prognostic factor in colorectal cancer (CRC). The differentially expressed genes with prognostic value in CRC tissues either with or without liver metastasis were assessed based on The Cancer Genomic Atlas (TCGA). Leptin was considered a candidate gene for further analysis. Its expression features of 206 CRC patients without liver metastasis and 201 patients with metastasis on tissue microarrays were assessed by immunochemical staining, and the effect of leptin on survival was assessed by Kaplan-Meier analyses. Overexpressed leptin indicated a poorer prognosis for CRC patients in overall survival (p < 0.05, log-rank test) based on the TCGA database. The leptin expression significantly correlated with metastasis stage (p < .010) and lymph node involvement (p < .010). Multivariate analysis also indicated that strong leptin expression was an independent adverse prognosticator in CRC (p = .017). Leptin may be valued as a prognostic marker could contribute to predicting a clinical outcome for patients with CRC.

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