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1.
Exp Brain Res ; 2020 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-32146503

RESUMO

Fitts' Law is a well-studied principle in psychology which holds that movement time (MT) varies with the size and distance of a target across a wide range of tasks. In a recent study, the authors demonstrated that performance on a current trial in a Fitts' Law paradigm is affected by what happens during the previous trial (Tang et al. in Psychon Bull Rev 25(5):1833-1839, 2018). The aim of the present study was to explore how long this trial-to-trial transfer might last and whether or not the transfer would occur between the left and right hands. A series of experiments was carried out using discrete trials, a paradigm in which the current authors and others have previously established that Fitts' Law operates (Fitts and Peterson in J Exp Psychol 67(2):103-112, 1964; Tang et al. 2018). Three inter-trial intervals (3 s, 4 s, and 5 s) were used in separate testing sessions, the order of which was counterbalanced across participants. In addition, trial-to-trial transfer was tested within a single hand and between hands. The results demonstrate that transfer from one trial to the next could bridge 4 s when either the right or the left hand was used and would disappear by 5 s. Moreover, the effect transferred between the two hands. The endpoint accuracy of the current trial was not affected by the previous trial. These findings suggest that the trial-to-trial effect reduces over time and that the transfer of sensorimotor memory or the task set is independent of the particular hand used.

2.
J Clin Lab Anal ; : e23276, 2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-32141648

RESUMO

BACKGROUND: Tuberculosis (TB) is an infectious disease, caused by mycobacterium tuberculosis infection, which is associated with oxidative stress and the induction of host antioxidants to counteract this response. The heme oxygenase-1 (HO-1) single nucleotide polymorphisms have been reported to be associated with many critical diseases. Our purpose was to investigate the association of HO-1 single nucleotide polymorphisms with the susceptibility to tuberculosis in Chinese Han population. METHODS: A case-control study was performed on Chinese Han population, and a group of 638 TB patients was compared to 610 healthy controls. Three single nucleotide polymorphisms (SNPs) including rs2071746, rs5995098, and rs8140669 were genotyped using the MassARRAY platform. The genotype frequency was compared between TB patients and healthy controls. The association between the three genetic models of the three SNPs and TB risk was further investigated. RESULTS: The results showed that, in the case of additive model, there was significant difference of the genotype frequencies of SNP rs8140669 between the TB patients and control groups (P = .038). In the case of dominant model, the genotype frequencies of SNP rs8140669 may have difference between the two cohorts (P = .051), while the allele frequency and genotype distribution for other two SNPs showed no significant difference between the two groups (P > .05). CONCLUSION: HO-1 polymorphism was associated with TB susceptibility in Chinese Han population.

3.
J Neurol ; 2020 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-32130498

RESUMO

OBJECTIVE: This study aimed to identify to resting-state cerebral blood flow (CBF) connectivity alterations in patients with anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis. METHODS: Three-dimensional pseudo-continuous arterial spin labeling (pcASL) imaging was performed to measure the resting-state CBF in 23 patients with anti-NMDAR encephalitis at the peak stage of the disease and 32 healthy subjects. CBF was normalized to reduce variations among subjects. CBF was compared between the groups, and the correlations between the CBF alterations and clinical parameters were assessed. Differences in CBF connectivity in specific brain regions were also compared between groups. RESULTS: Compared with the healthy subjects, the patients with anti-NMDAR encephalitis exhibited increased CBF in the left insula (L_insula), left superior temporal lobe (L_STL), L_hippocampus, L_pallidum, bilateral putamen (Bi_putamen), and Bi_caudate, and decreased CBF in the bilateral precuneus (Bi_Pc) and bilateral occipital lobe (Bi_OL) (P < 0.05, FEW corrected). Compared with healthy subjects, the patients with anti-NMDAR encephalitis exhibited increased negative CBF connectivity between the Bi_Pc, Bi_OL and L_TL, L_insula (P < 0.05, FEW corrected). Anti-NMDAR encephalitis patients with behavioral changes exhibited higher CBF in the L_insula and lower CBF in the R_Pc, Bi_calcarine, Bi_cuneus, and Bi_lingual than patients without behavioral changes and health controls. The ROC curve shows changed CBF in the L_insula, and R_Pc, Bi_calcarine, Bi_cuneus, and Bi_lingual served as a predictor of behavioral changes in patients with anti-NMDAR encephalitis. CONCLUSIONS: Our results suggest that patients with anti-NMDAR encephalitis may exhibit both regional CBF abnormalities and deficits in CBF connectivity, which may underlie the clinical symptoms of anti-NMDAR encephalitis.

4.
J Exp Clin Cancer Res ; 39(1): 54, 2020 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-32209115

RESUMO

BACKGROUND: Exosomes are vesicles of endocytic origin released by various cell types and emerging as important mediators in tumor cells. Human metastases-associated lung adenocarcinoma transcript 1 (MALAT1) is a long non-coding RNA known to promote cell proliferation, metastasis, and invasion in colorectal cancer (CRC). METHODS: The expression of MALAT1 was analyzed in CRC using qRT-PCR. FUT4 and fucosylation levels were detected in CRC clinical samples and CRC cell lines by immunofluorescent staining, western blot and lectin blot analysis. CRC derived exosomes were isolated and used to examine their tumor-promoting effects in vitro and in vivo. RESULTS: The invasive and metastatic abilities of primary CRC cells were enhanced after exposure to exosomes derived from highly metastatic CRC cells, which increased the fucosyltransferase 4 (FUT4) levels and fucosylation not by directly transmitting FUT4 mRNA. Exosomal MALAT1 increased FUT4 expresssion via sponging miR-26a/26b. Furthermore, MALAT1/miR-26a/26b/FUT4 axis played an important role in exosome-mediated CRC progression. Exosomal MALAT1 also mediated FUT4-associated fucosylation and activated the PI3K/AKT/mTOR pathway. CONCLUSIONS: These data indicated that exosomal MALAT1 promoted the malignant behavior of CRC cells by sponging miR-26a/26b via regulating FUT4 and activating PI3K/Akt/mTOR pathway.

5.
J Nanobiotechnology ; 18(1): 44, 2020 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-32169061

RESUMO

BACKGROUND: Traditional sandwich enzyme-linked immunosorbent assay (ELISA) using polyclonal and monoclonal antibodies as reagents presents several drawbacks, including limited amounts, difficulty in permanent storage, and required use of a secondary antibody. Nanobodies can be easily expressed with different systems and fused with several tags in their tertiary structure by recombinant technology, thus offering an effective detection method for diagnostic purposes. Recently, the fenobody (ferritin-fused nanobody) and RANbody (nanobody-fused reporter) have been designed and derived from the nanobody for developing the diagnostic immunoassays. However, there was no report about developing the sandwich ELISA using the fenobody and RANbody as pairing reagents. RESULTS: A platform for developing a sandwich ELISA utilizing fenobody as the capture antibody and RANbody as the detection antibody was firstly designed in the study. Newcastle disease virus (NDV) was selected as the antigen, from which 13 NDV-specific nanobodies were screened from an immunized Bactrian camel. Then, 5 nanobodies were selected to produce fenobodies and RANbodies. The best pairing of fenobodies (NDV-fenobody-4, 800 ng/well) and RANbodies (NDV-RANbody-49, 1:10) was determined to develop the sandwich ELISA for detecting NDV. The detection limits of the assay were determined to be 22 of hemagglutination (HA) titers and 10 ng of purified NDV particles. Compared with two commercial assays, the developed assay shows higher sensitivity and specificity. Meanwhile, it exhibits 98.7% agreement with the HA test and can detect the reference NDV strains belonging to Class II but not Class I. CONCLUSIONS: In the presented study, the 13 anti-NDV nanobodies binding the NDV particles were first produced. Then, for the first time, the sandwich ELISA to detect the NDV in the different samples has been developed using the fenobody and RANbody as reagents derived from the nanobodies. Considering the rapidly increasing generation of nanobodies, the platform can reduce the cost of production for the sandwich ELISA and be universally used to develop assays for detecting other antigens.

6.
Behav Brain Res ; 383: 112539, 2020 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-32032741

RESUMO

Parthenolide (PTL) is a natural compound with anti-inflammatory and antioxidant properties and is an active ingredient extracted from the medicinal plant Tanacetum parthenium. ACT001 is derived from parthenolide and is a fumarate form of dimethylaminomylide (DMAMCL). Its effect is equivalent to that of PTL, but it is more stable in plasma and has lower acquisition costs. Related reports indicate that NLRP3-mediated neuroinflammation is involved in the progression of Parkinson's disease (PD). In our research, we explored whether ACT001 alleviates NLRP3-mediated neuroinflammation in PD mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Our results revealed that ACT001 reduces movement impairment and cognitive deficit in PD mice. In addition, it alleviates dopaminergic neurodegeneration in the nigrostriatal pathway and inhibits oxidative stress, the inflammatory response and activation of the NLRP3 inflammasome in the midbrain of MPTP-induced PD mice. Moreover, it attenuates microglial activation in the nigrostriatal pathway. Overall, our study showed that ACT001 alleviates NLRP3-mediated neuroinflammation in PD mice induced by MPTP.

7.
Cell Death Dis ; 11(2): 122, 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32051397

RESUMO

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

8.
Artigo em Inglês | MEDLINE | ID: mdl-32081591

RESUMO

BACKGROUND: Previously, we have found that IL-22 could be not only secreted outside of cells, but also highly expressed on the T cells membrane in HIV-1 negative patients with tuberculosis (TB). However, the study on membrane-bound IL-22+ cells of HIV-1 infected patients is rare. Therefore, we investigated antigen-specific membrane-bound IL-22+ T cell subsets in Mycobacterium tuberculosis (M.tb) coinfection of HIV-1 infected individuals. METHODS: A case-control study that enrolled 74 HIV-1 infected participants was carried out, including HIV-1 monoinfection (HIV+TB-, n = 43), HIV-1 infected patients with latent TB (HIV+LTB, n = 18) and HIV-1 coinfected patients with active TB (HIV+TB+, n = 13). We made use of an IFN-γ release assay (IGRA) to screen LTB individuals. Purified protein derivative (PPD) and phosphoantigen (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) were used as specific-stimulators to detect the levels of peripheral blood membrane-bound IL-22+ T cell subsets via cell surface staining and flow cytometry among three groups. RESULTS: An approximate rate of 24.3% (n = 18 out of 74) of latent M.tb infection among HIV-1 positive population in Eastern China. Interestingly, HMBPP-specific CD3+Vγ2+ T cells were impaired in HIV+TB+patients compared with HIV+LTB patients (P < 0.05). Furthermore, increases of PPD-specific and HMBPP-specific membrane-bound IL-22+ T cell subsets including CD3+, CD3+CD4+ and CD3+Vγ2+ T cells were observed in HIV+TB+group rather than HIV+LTB groups (all P < 0.05). CONCLUSION: Antigen-specific membrane-bound IL-22+ T cells were highly expressed in M.tb coinfection of HIV-1 infected individuals, and may play an important role in anti-TB immune response during coinfection with HIV-1.

9.
Mikrochim Acta ; 187(2): 122, 2020 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-31932902

RESUMO

Terbium(III)-functionalized zirconium-based MOFs (Tb3+@UIO-67) were synthesized by doping Tb3+ into UIO-67 using a post-synthetic modification. The Tb3+@UIO-67 (solid or aqueous dispersion) shows only blue fluorescence (emission peaks at 420 nm) under an ultraviolet lamp (254 nm). Upon addition of 2,6-pyridinedicarboxylic acid (DPA; an anthrax biomarker), the color of the Tb3+@UIO-67 aqueous dispersion under an ultraviolet lamp changes from blue to green. This is mainly because DPA has a good sensitization effect on Tb3+. DPA can be determined by measurement of the ratio of the fluorescence intensities at 544 nm and 420 nm (excitation at 278 nm). The method allows DPA to be detected in the 0.3 to 6 µM concentration range, with a detection limit of 36 nM. Graphical abstract Schematic representation of a ratiometric fluorescent probe synthesized by doping terbium ions into a zirconium-based MOF (UIO-67) for determination of an anthrax biomarker.

10.
Nanoscale ; 12(3): 2063-2070, 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31912846

RESUMO

Bridging S22- moieties have been demonstrated to be highly active sites existing in metal polysulfides for the hydrogen evolution reaction (HER), thus the incorporation of high-density bridging S22- into a Ni3S2 material to improve its electrocatalytic HER performance is highly desirable and challenging. Herein, we report a novel Ni3S2 nanorod array decorated with (020)-oriented VS4 nanocrystals grown on nickel foam (Shig-NS-rod/NF) via a simple and facile solvothermal method. Results show that the in situ incorporation of VS4 not only triggers the formation of such a nanorod array structure, but also contributes to the uniform grafting of high-density and high catalytically active bridging S22- sites on the interface between Ni3S2 and VS4 for enhanced HER activity, and also promotes the absorption ability of OH- radicals and thus accelerates the HER Volmer step in alkaline media. As expected, the resultant Shig-NS-rod/NF material exhibits impressive catalytic performance toward the HER, with a much lower overpotential of 137 mV at 10 mA cm-2 and a long-term durability for at least 22 h, and is superior to Ni3S2 nanorod arrays with low-density bridging S22- (Slow-NS-rod/NF) and NS-film/NF counterparts (without VS4), even outperforming the NF-supported 20% Pt/C at a large current density of over 120 mA cm-2. Our findings put forward fresh insight into the rational design of highly efficient electrocatalysts toward the HER for green hydrogen fuel production.

11.
Sci Total Environ ; 714: 136788, 2020 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-31982766

RESUMO

Acid rain (AR) is a serious issue in China, particularly in the Yangtze River Delta region where the economy has undergone rapid development. Over the last few years, the composition of acid rain in the Yangtze River Delta region has gradually changed from sulfuric acid rain (SAR) to nitric acid rain (NAR) due to controls on SO2 emissions, but increased NOx emissions. These changes have made ecosystems more complex. For this study, we halted AR treatments in Quercus acutissima forest plots that had received simulated AR for one year and monitored them from the following February to November. We investigated their soil resident enzyme and microbial metabolic activities, as well as community functional diversity. The results revealed that AR treatments negatively affected both the soil microbial activity and soil microbial community functional diversity; however, both managed to recover over time, once the AR treatments were stopped. During the AR treatment and recovery periods, four main categories (carbohydrates, carboxylic acids, amino acids, and polymers) were dominantly utilized. The utilization of pyruvic acid, which was affected by the AR treatments, as well as d-mannitol and tween 80, accounted for changes in the peak values of the C substrate groups during the AR treatment recovery period. Finally, changes in the activities of soil enzymes recorded following AR recovery, were closely related to the utilization of six C substrate groups. Our results suggested that the recovery of soils following the cessation of NAR stress was more rapid than from SAR. Further, that short-term NAR could be easily treated during the transformation from SAR to NAR in the Yangtze River Delta region. These results might also enrich the basic data relating to post-AR treatments on the soil environment, while having significance toward guiding further studies on the recovery of ecosystems from AR.


Assuntos
Chuva Ácida , Microbiologia do Solo , China , Microbiota , Ácido Nítrico , Solo
12.
J Invasive Cardiol ; 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31941833

RESUMO

BACKGROUND: Acute kidney injury (AKI) following transcatheter aortic valve replacement (TAVR) is a known complication. The prospective validation of various AKI definitions and estimated baseline renal function equations in the context of TAVR remains an ongoing area of research. This study examined the Valve Academic Research Consortium (VARC) 1 and 2 criteria for AKI, and impact of three estimated glomerular filtration rate (eGFR) equations (CKD-EPI, MDRD, and Cockcroft-Gault) on AKI incidence in TAVR patients. METHODS: Retrospective review of 120 consecutive TAVR procedures over a 4-year period was performed. AKI, including stage, was defined using the VARC 1 and VARC 2 criteria. Univariate and multivariate analyses were performed for association between AKI and known patient, hemodynamic, and procedural variables. Further logistic regression, stepwise logistic regression, and association plots were performed for the three different eGFR calculations. RESULTS: AKI occurred in 22% of VARC 1 patients and 23% of VARC 2 patients. On multivariate analysis, baseline eGFR was predictive of stage 1 AKI by CKD-EPI classification (VARC 1: odds ratio [OR], 0.93; 95% confidence interval [CI], 0.88-0.99; P=.02; VARC 2: OR, 0.93; 95% CI, 0.87-0.99; P=.03) and MDRD (OR, 0.93; 95% CI, 0.88-0.99; P=.03). Non-transfemoral approach was predictive of stage 1 AKI by VARC 2 (OR, 33.33; 95% CI, 1.6-696.41; P=.02). CONCLUSIONS: The incidence and risk factor associations for AKI post TAVR vary by definitions used. Decreased GFR at baseline by both MDRD and CKD-EPI and non-transfemoral approach were associated with an increased risk of AKI post TAVR.

13.
Phys Chem Chem Phys ; 2020 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-31976989

RESUMO

Using ambient-pressure X-ray photoelectron spectroscopy, here we report the real-time monitoring of dynamic surface composition evolution of Cu3Au(100) in response to the imposed environmental stimuli. Segregation of Au to the pristine surface under ultrahigh vacuum annealing leads to the phase separation with pure Au at the surface and alloyed Au in the subsurface. Upon switching to an oxidizing atmosphere, oxygen adsorption drives the surface segregation of Cu along with inward migration of pure Au to the subsurface. Switching to a H2 atmosphere results in oxygen loss from the oxygenated surface, thereby promoting Au surface segregation and reverting the surface to the pristine state with the Au termination. These measurements demonstrated the tunability of the surface composition of the binary alloy by utilizing the interplay between the tendency of segregating a more noble constituent to the surface and the tendency to segregate the more reactive one with the chemical stimuli.

14.
Medicine (Baltimore) ; 99(2): e18367, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31914015

RESUMO

Little is known about the decay kinetics of interferon (IFN)-γ response and its influencing factors in tuberculous pleurisy. We enrolled thirty-two patients with tuberculous pleurisy prospectively and followed up at month 0, 6, and 9, at which time peripheral venous blood was drawn for interferon gamma release assay (IGRA) by means of QuantiFERON-TB Gold In-Tube (QFT-GIT). Demographic and clinical data were captured. To identify significant predictive factors influencing the IFN-γ response, multiple linear regression analyses were performed. Percentage of CD4+, CD8+, Vγ2Vδ2 T cells and Treg cells were measured by flow cytometry. The percentage of QFT-GIT-positive patients at baseline, month 6 and month 9 were 96.9% (30/32), 90.6% (29/32) and 84.4% (27/32), respectively. Quantitative IFN-γ response at baseline were significantly correlated with symptom duration (P = .003, R = 0.261) and age (P = .041, R = 0.132). Besides, the decreases of the IFN-γ response at month 6 and month 9 were positively correlated with the IFN-γ level at baseline. The dynamic tendency of the percentages of Treg cells was similar to the IFN-γ responses at each time-point. Quantitative IFN-γ response could be influenced by host immune status, instead of disease burden and anti-tuberculosis treatment. IGRA is probably not a useful biomarker of treatment efficacy in tuberculous pleurisy.


Assuntos
Testes de Liberação de Interferon-gama/métodos , Interferon gama/imunologia , Tuberculose Pleural/sangue , Adulto , Antituberculosos/administração & dosagem , Antituberculosos/uso terapêutico , Linfócitos T CD4-Positivos/imunologia , Feminino , Citometria de Fluxo/métodos , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Linfócitos T/imunologia , Tuberculose Pleural/diagnóstico , Tuberculose Pleural/tratamento farmacológico , Tuberculose Pleural/metabolismo
15.
Carbohydr Polym ; 231: 115701, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31888799

RESUMO

A facile and rapid approach was designed to extract carboxylated cellulose nanocrystals (CCNCs) through a one-step hydrolysis process by using mixed acid system of sulfuric acid and nitric acid (H2SO4/HNO3). It is found that the surface hydroxyl groups on CNCs could be converted into carboxyl groups efficiently after 0.5 h treatment by introducing HNO3 as oxidant. The degree of oxidation could reach a maximum value of 0.11 at the reaction temperature of 80 °C, which was consistent with those prepared by the conventional TEMPO or APS oxidation method. Meanwhile, the as-prepared CCNCs presented a rod-like morphology with the length and diameter of 186 ±â€¯13 and 9 ±â€¯3 nm, respectively. More importantly, the CCNCs showed excellent dispersibility in water and some organic solvents due to the existence of negative carboxyl groups, which was benefit for their reinforcing applications and developing new applications by further surface functionalization.

16.
Biotechnol Lett ; 42(2): 321-328, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31776752

RESUMO

OBJECTIVE: Mesoporous bioactive glass (MBG) has good biocompatibility without immune reaction after implanting into tissue as biomaterial which was used in the treatment of bone defect. Genistein (G), a phytoestrogen, could be used in the treatment of osteoporosis in postmenopausal women. RESULTS: Here, we report that MBG with large pores (MBG-L) and MBG-L adsorbed with G (MBG-L/G) sustained-release G could enhance osteoblast differentiation and matrix mineralization. Interestingly, we observed that MBG-L enhanced the formation of bone-like deposit and Ca deposition in vitro. In the other side, we also found that MBG-L/G substrate could promote osteoblast differentiation and matrix mineralization through Erk activated Runx2 pathway. Interestingly, the expression of osteoblast-specific marker gene Osteopontin (Opn) was also increased in MC3T3-E1 cells cultured on MBG-L/G substrate. CONCLUSIONS: We conclude that MBG-L/G is a potential biomaterial for the treatment of bone defect.

17.
Toxicol Lett ; 320: 19-27, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31778773

RESUMO

The deleterious effects of glucocorticoids on glucose homeostasis limit their clinical use. There is substantial evidence demonstrating that islet function impaired by long-term glucocorticoids exposure is a core defect in the progression of impaired glucose tolerance to diabetes. The activity of heat-shock protein (Hsp) 90 is required to maintain the hormone-binding activity and stability of glucocorticoid receptor (GR). In the present study, Hsp90 inhibition by 17-DMAG counteracted dexamethasone-mediated inhibition of glucose-stimulated insulin secretion in isolated rat islets as well as expressions of neuropeptide Y (NPY) and somatostatin receptor 3 (SSTR3), two negative regulators of insulin secretion. Like 17-DMAG, both the pan-histone deacetylase (HDAC) inhibitor TSA and HDAC6 inhibitor Tubacin exhibited a similar action in protecting islet function against dexamethasone-induced injury, along with the downregulation of NPY and SSTR3 expressions. The hyperacetylation of Hsp90 by TSA and Tubacin disrupted its binding ability to GR and blocked dexamethasone-elicited nuclear translocation of GR in INS-1 ß-cell lines. In addition, Tubacin treatment triggered the GR protein degradation through the ubiquitin-proteasome pathway. These findings suggest that Hsp90 acetylation by inhibiting HDAC6 activity may be a potential strategy to prevent the development of steroid diabetes mellitus via alleviating glucocorticoid-impaired islet function.


Assuntos
Anilidas/farmacologia , Benzoquinonas/farmacologia , Dexametasona/toxicidade , Glucocorticoides/toxicidade , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Insulina/metabolismo , Ilhotas Pancreáticas/efeitos dos fármacos , Lactamas Macrocíclicas/farmacologia , Acetilação , Animais , Linhagem Celular , Proteínas de Choque Térmico HSP90/metabolismo , Desacetilase 6 de Histona/metabolismo , Ilhotas Pancreáticas/metabolismo , Masculino , Complexo de Endopeptidases do Proteassoma/metabolismo , Processamento de Proteína Pós-Traducional , Proteólise , Ratos Sprague-Dawley , Via Secretória , Técnicas de Cultura de Tecidos
18.
Pharmacol Res ; 152: 104595, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31838080

RESUMO

Src homology-2-containing protein tyrosine phosphatase 2 (SHP2) is a major phosphatase involved in several cellular processes. In recent years, SHP2 has been the focus of significant attention in human diseases, particular in cancer. Several studies have shown that SHP2 plays an important role in regulating immune cell functions in tumor microenvironment. A few clinical trials conducted using SHP2 allosteric inhibitors have shown remarkable anti-tumor benefits and good safety profiles. This review focuses on the current understanding of the regulation of SHP2 and highlights the vital roles of SHP2 in T lymphocytes, macrophages and cancer cells. It also summarizes the current development of SHP2 inhibitors as a promising strategy for cancer immunotherapy.

19.
Behav Brain Res ; 379: 112337, 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-31697983

RESUMO

L-3,4-dihydroxyphenylalanine (L-DOPA) is currently the main drug used to treat Parkinson's disease (PD). However, long-term use of l-DOPA causes substantial side effects, and we hope to find a biological active ingredient that synergizes with a low-dose of l-DOPA to achieve the same therapeutic effect as that of a high-dose of l-DOPA. The natural product parthenolide (PTL) is the active ingredient in the medicinal plant feverfew (Tanacetum parthenium) and has antioxidant and anti-inflammatory properties. ACT001, a fumarate salt form of dimethylaminomicheliolide (DMAMCL), is a derivative of parthenolide and has comparable effects to those of PTL but exhibits higher stability in the plasma and is available at a lower cost. In our study, we used ACT001 in combination with l-DOPA to treat 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced Parkinson's disease in mice. Specifically, ACT001 significantly reduced motor dysfunction and dopaminergic neurodegeneration in MPTP-treated mice. Furthermore, ACT001 abolished MPTP-induced α-synuclein overexpression, astrocyte activation and interleukin-1ß (IL-1ß) production in the substantia nigra and striatum of the mouse brain. In addition, ACT001 increased the levels of the anti-apoptotic signalling molecule Bcl-2 and the pAkt/Akt ratio and reduced the levels of the pro-apoptotic signalling molecule Bax and the activation of Caspase3 in the substantia nigra and striatum. We found that the effects of the co-administration of ACT001 and l-DOPA (5 mg/kg) were equivalent to those of the administration of 8 mg/kg l-DOPA in MPTP-induced Parkinson's disease in mice. Then, this evidence suggests that l-DOPA + ACT001 may be used for the treatment of PD.

20.
J Pharm Biomed Anal ; 177: 112875, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31546138

RESUMO

Schisanlactone E (SE) is a bioactive ingredient extracted from the stem of Kadsura heteroclita (Roxb) Craib. SE has various pharmacological activity such as anti-tumor and anti-leukemia effects. However, its absorption, distribution, metabolism, and excretion have rarely been examined. In this study, new quali-quantitative analytical methods were developed for metabolic and pharmacokinetic studies of SE in rats. A UHPLC-MS/MS method was developed to determine SE in rat plasma, urine, and feces. Samples were precipitated with methanol and analyzed in multiple reaction monitoring mode. The established method was validated and applied to the pharmacokinetics, bioavailability, and excretion analysis of SE after oral (6 mg/kg) or intravenous (2 mg/kg) administration. The absolute oral bioavailability of SE was approximately 79.3%. After oral administration, SE was mainly excreted via feces with a rate of 41.7% for 48 h. SE could not be detected in urine. Furthermore, a UHPLC-Q-Orbitrap HRMS method was developed for the metabolite screening of SE in rat plasma, urine, and feces. Metabolites were extracted by solid phase extraction and analyzed with full MS/dd-MS2 scan mode. As a result, 15 metabolites including 11 phase I and 4 phase II metabolites were identified by a three-step analytical strategy. The carboxyl group, the five membered ring, and the six membered α,ß-unsaturated lactone ring of SE could be predicted as the main metabolic sites. This study provides comprehensive insights into the pharmacokinetic and metabolic profiles of SE, and would be valuable for future development and utilization of SE and Kadsura heteroclita.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Kadsura/química , Extração em Fase Sólida/métodos , Triterpenos/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Cromatografia Líquida de Alta Pressão/métodos , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/análise , Fezes/química , Eliminação Intestinal , Masculino , Modelos Animais , Caules de Planta/química , Ratos , Eliminação Renal , Espectrometria de Massas em Tandem/métodos , Triterpenos/administração & dosagem , Triterpenos/análise
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