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1.
Carbohydr Polym ; 278: 118920, 2022 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-34973739

RESUMO

Gas detection in flexible electronics demands novel materials with superior sensing performance that have high mechanically strength, are flexible, low-cost, and sustainable. We explore a composite sensing nanopaper based on lignocellulosic cellulose nanofibrils (LCNF) as a renewable and mechanically strong substrate that enables the fabrication of flexible, and highly sensitive gas sensors. In the system the hydrophobic lignin covalently bonds to cellulose in the nanofibrils, increasing the nanopaper water-resistance and limiting sensing materials response to humidity. The sensor is composed of polyaniline (PANI) grown on flexible LCNF and reduced graphene oxide (rGO) nanosheets. The proposed structure, at 10 wt% rGO, demonstrated a 10-fold improvement in sensitivity to volatile amines (i.e. ammonia detection down to 1 ppm) while maintaining an acceptable selectivity. Furthermore, we demonstrated the application of the sensing nanopaper in a microwave sensor that paves the path toward flexible, wireless, and high-performance sensing devices.

2.
Commun Biol ; 5(1): 36, 2022 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-35017643

RESUMO

Chinese wild rice (Zizania latifolia; family: Gramineae) is a valuable medicinal homologous grain in East and Southeast Asia. Here, using Nanopore sequencing and Hi-C scaffolding, we generated a 547.38 Mb chromosome-level genome assembly comprising 332 contigs and 164 scaffolds (contig N50 = 4.48 Mb; scaffold N50 = 32.79 Mb). The genome harbors 38,852 genes, with 52.89% of the genome comprising repetitive sequences. Phylogenetic analyses revealed close relation of Z. latifolia to Leersia perrieri and Oryza species, with a divergence time of 19.7-31.0 million years. Collinearity and transcriptome analyses revealed candidate genes related to seed shattering, providing basic information on abscission layer formation and degradation in Z. latifolia. Moreover, two genomic blocks in the Z. latifolia genome showed good synteny with the rice phytocassane biosynthetic gene cluster. The updated genome will support future studies on the genetic improvement of Chinese wild rice and comparative analyses between Z. latifolia and other plants.

3.
PLoS One ; 17(1): e0262401, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34995321

RESUMO

BACKGROUND: Exclusive breastfeeding rate in Malaysia is low despite its known health benefits. This study aims to determine the prevalence of intention to breastfeed among pregnant mothers, the prevalence of exclusive breastfeeding practice after delivery, and factors associated with exclusive breastfeeding practice. METHODS: This was a prospective cohort study. All pregnant women at 36 weeks gestation or above from 17 antenatal health clinics in an urban district were invited to participate in the study. A self-administered questionnaire was used, encompassing sociodemographic, breastfeeding knowledge, attitude, and intention towards the practice of breastfeeding. The participants were followed up one month post-natal for their practice of breastfeeding via telephone or during their post-natal follow-up appointment. RESULTS: 483 pregnant mothers participated in the study initially. 462 (95.7%) were contactable after one month. 99.4% (459/462) of participants intended to breastfeed. 65.4% (302/462) of participants practiced exclusive breastfeeding. There was no significant association between intention and practice of exclusive breastfeeding. Multiple logistic regression analysis shows, pregnant mothers with high breastfeeding knowledge (AOR = 1.138; 95% CI 1.008-1.284) and Malay ethnicity (AOR = 2.031; 95% CI 1.066-3.868) were more likely to breastfeed their infant exclusively. CONCLUSIONS: Prevalence of exclusive breastfeeding practice at one month in the studied district was 65.4%. Malay mothers and mothers with high breastfeeding knowledge were more likely to breastfeed exclusively. Thus, we recommend targeted intervention towards non-Malay mothers and increasing breastfeeding knowledge to all pregnant mothers.

4.
J Environ Manage ; 301: 113887, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34610559

RESUMO

Biodegradation of pyridine starts with two mono-oxygenation reactions, and 2-hydroxyl pyridine (2-HP) accumulates as pyridine is mono-oxygenated in the first reaction. The accumulation of 2-HP inhibits both initial reactions. Therefore, selective acceleration of the second mono-oxygenation reaction should significantly enhance pyridine transformation and mineralization. Activated-sludge biomass was separately acclimated with pyridine or 2-HP to produce pyridine- and 2-HP-acclimated biomasses. The pyridine-acclimated biomass was superior for pyridine biodegradation, but the 2-HP-acclimated biomass was superior for 2-HP biodegradation. As a consequence, the pyridine-acclimated biomass by itself achieved faster mono-oxygenation of pyridine to 2-HP, but 2-HP accumulated, which limited mineralization to 60%. In contrast, mineralization reached 90% when one-third of the pyridine-acclimated was replaced with 2-HP-acclimated biomass, because 2-HP did not accumulate during pyridine biodegradation. The lack of 2-HP accumulation relieved its inhibition: e.g., the pyridine removal rates, normalized to the mass of pyridine-acclimated biomass, increased from 0.52 to 0.57 mM0.5⋅h-1 when one-third of the pyridine-acclimated biomass was replaced by 2-HP-acclimated biomass. Phylogenetic analysis showed that microbiological communities of pyridine-acclimated biomass and 2-HP-acclimated biomass differed in important ways. On the one hand, the 2-HP-acclimated biomass was richer and dominated by a rare biosphere, or genera having <0.1% of total reads. On the other hand, the most-enriched genus in the pyridine-acclimated community (Methylibium) is associated with the first mono-oxygenation of pyridine, while enriched genera in the 2-HP-acclimated community (Sediminibacterium and Dokdonella) are associated with the second mono-oxygenation of pyridine.


Assuntos
Piridinas , Esgotos , Aceleração , Biomassa , Filogenia
5.
Microvasc Res ; 139: 104263, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34655603

RESUMO

Cannabinoids are reported to regulate cardiovascular functions. Cannabinoid receptors 1 (CB1Rs) are widely expressed in both the neuronal system and vascular system, but the contribution of CB1Rs in vascular smooth muscle (CB1RSM) to cardiovascular functions is not clear yet. In this research, we analyzed the effects of CB1RSM on blood pressure, vasoconstriction, and vasodilation abilities by using conditionally CB1R knockout mice (CB1RSMKO). The results show no significant difference in basal blood pressure between the conscious CB1RSMKO and control mice, indicating that CB1RSM is not essential for basal blood pressure maintenance. The constriction of the CB1RSMKO mesenteric artery in vitro was not significantly altered compared with that of the control mice. In contrast, the relaxation to CB1R agonist 2-AG or WIN55212-2 was decreased in CB1RSMKO vessels, suggesting that activation of CB1RSM mediates the vasodilation effect of cannabinoids. Ischemia stroke mouse model was used to further identify the potential function of CB1RSM in pathological conditions, and the results showed that the infarct volume in CB1RSMKO mice is significantly increased compared with the control littermates. These results suggest that vascular CB1R may not play a central role in basal vascular health maintenance but is protective in ischemia states, such as stroke. The protection function may be mediated, at least partly, by the relaxation effect of CB1RSM-dependent activities of endocannabinoids.

6.
Org Biomol Chem ; 2021 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-34877952

RESUMO

Nitrogen-containing heterocycles are ubiquitous fragments of numerous natural products, pharmaceuticals, designed bioactive drug candidates and agrochemicals. During the past few decades, these compounds have received considerable attention from the synthetic chemistry community, and great efforts have been focused on the development of concise and efficient methods for the synthesis of these heterocyclic skeletons. In this review, we summarize a diverse range of synthetic methods employing ß-aminovinyl esters(ketones) as key CC-N-synthons to furnish useful bioactive heterocyclic frameworks, such as quinolines, pyridines, pyrazines, pyrroles, indoles, oxazoles, imidazoles, thiazoles, isothiazoles, pyrazoles, triazoles, and azepines, thus offering new opportunities and expanding the toolbox of synthetic chemistry reactions.

7.
Front Neurol ; 12: 701929, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34899554

RESUMO

Background and purpose: The causes of the higher incidence of intracerebral hemorrhage (ICH) on a given day are unclear. Previous studies have shown that it may vary by region and population. The purpose of this study was to detect weekly variations in ICH occurrence in southwest China and to assess differences in ICH occurrence among different populations. Methods: This hospital-based study included patients with first-onset ICH that occurred from January 1, 2012, to December 31, 2019. The weekly variation in ICH occurrence was analyzed and stratified by sex, age, comorbidities, living habits, and residence. Results: A total of 5,038 patients with first-onset ICH were enrolled. ICH occurrence was higher on Monday [odds ratio (OR), 1.22; 95% CI, 1.09-1.36; P < 0.001] and Friday (OR, 1.15; 95% CI, 1.03-1.28; P < 0.001) among all patients, and this pattern was consistent with that of men, whereas women showed a higher incidence on Mondays, Saturdays, and Sundays. The increase in the number of ICH events on Monday and Friday was pronounced in the age range of 41-60 years; however, no significant weekly variation in ICH occurrence was observed among other age groups. After stratifying by comorbidities, a significant weekly variation in ICH occurrence was observed in patients with hypertension or diabetes. Smoking and alcohol consumption was associated with a higher incidence of ICH on Friday; otherwise, a Monday excess was observed. The urban population demonstrated a significant weekly variation in ICH occurrence, whereas the rural population did not. Conclusions: Intracerebral hemorrhage occurrence showed weekly variations in southwest China and was significantly affected by sex, age, comorbidities, living habits, and residence. This suggests that weekly variations in ICH occurrence maybe dependent on the region and population.

8.
Front Cell Dev Biol ; 9: 799123, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34950664

RESUMO

Focal adhesions (FAs) are adhesive organelles that attach cells to the extracellular matrix and can mediate various biological functions in response to different environmental cues. Reduced FAs are often associated with enhanced cell migration and cancer metastasis. In addition, because FAs are essential for preserving vascular integrity, the loss of FAs leads to hemorrhages and is frequently observed in many vascular diseases such as intracranial aneurysms. For these reasons, FAs are an attractive therapeutic target for treating cancer or vascular diseases, two leading causes of death world-wide. FAs are controlled by both their formation and turnover. In comparison to the large body of literature detailing FA formation, the mechanisms of FA turnover are poorly understood. Recently, autophagy has emerged as a major mechanism to degrade FAs and stabilizing FAs by inhibiting autophagy has a beneficial effect on breast cancer metastasis, suggesting autophagy-mediated FA turnover is a promising drug target. Intriguingly, autophagy-mediated FA turnover is a selective process and the cargo receptors for recognizing FAs in this process are context-dependent, which ensures the degradation of specific cargo. This paper mainly reviews the cargo recognition mechanisms of FA-phagy (selective autophagy-mediated FA turnover) and its disease relevance. We seek to outline some new points of understanding that will facilitate further study of FA-phagy and precise therapeutic strategies for related diseases associated with aberrant FA functions.

10.
Org Biomol Chem ; 19(47): 10296-10313, 2021 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-34812834

RESUMO

Phosphoramide, as an important framework of many biologically active molecules, has attracted widespread attention in recent decades. It is not only widely used in pharmaceuticals because of its excellent biological activities, but it also shows good performance in organic dyes, flame retardants and extractors. Thus, it is of great significance to develop effective and convenient methods for the synthesis of phosphoramides. In this review, the recent advancements made in the synthesis routes and applications of phosphoramides are discussed. The synthetic strategies of phosphoramides can be separated into five categories: phosphorus halides as the substrate, phosphates as the substrate, phosphorus hydrogen as the substrate, azides as the substrate and other methods. The latest examples of these methods are provided and some representative mechanisms are also described.

11.
Nano Lett ; 21(20): 8664-8670, 2021 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-34618467

RESUMO

Rechargeable batteries with metallic lithium (Li) anodes are attracting ever-increasing interests because of their high theoretical specific capacity and energy density. However, the dendrite growth of the Li anode during cycling leads to poor stability and severe safety issues. Here, Li3Bi alloy coated carbon cloth is rationally chosen as the substrate of the Li anode to suppress the dendrite growth from a thermodynamic aspect. The adsorption energy of a Li atom on Li3Bi is larger than the cohesive energy of bulk Li, enabling uniform Li nucleation and deposition, while the high diffusion barrier of the Li atom on Li3Bi blocks the migration of adatoms from adsorption sites to the regions of fast growth, which further ensures uniform Li deposition. With the dendrite-free Li deposition, the composite Li/Li3Bi anode enables over 250 cycles at an ultrahigh current density of 20 mA cm-2 in a symmetrical cell and delivers superior electrochemical performance in full batteries.

12.
J Vet Intern Med ; 2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34642962

RESUMO

BACKGROUND: Pituitary pars intermedia dysfunction (PPID) is a common endocrinopathy of horses diagnosed with a thyrotropin-releasing hormone (TRH) stimulation test. HYPOTHESIS/OBJECTIVES: Describe the repeatability of TRH stimulation in horses with and without PPID in winter and autumn. ANIMALS: Twenty adult horses; 6 controls and 6 with PPID tested in autumn, 8 controls and 6 with PPID tested in winter with 3 controls and 3 with PPID tested in both seasons. METHODS: Thyrotropin-releasing hormone stimulation was performed on 2 consecutive occasions, 1 week before and 1 week after the winter solstice and the autumn equinox. Blood was collected before and 30 minutes after IV injection of 1 mg of TRH. ACTH concentration was determined by a chemiluminescent assay. Repeatability and test-retest reliability were assessed by repeated measures analysis of variance, intraclass correlation coefficient and within-horse coefficients of variation (CV). Bland-Altman plots were generated to visualize agreement between repetitions. RESULTS: In winter, no week effect was detected on the results of the TRH simulation and the test had an excellent test-retest reliability. In autumn, after-TRH ACTH concentrations were significantly lower on week 2 (P = .02) and the test only had a good test-retest reliability. There were significantly larger within-horse CV during autumn (P = .04) and after TRH stimulation (P = .04). There were 2 misclassifications in winter and 4 in autumn. CONCLUSIONS AND CLINICAL IMPORTANCE: The TRH stimulation test was repeatable when performed 2 weeks apart in winter; however, in autumn, more variability in after-TRH ACTH concentrations resulted in decreased repeatability.

13.
IEEE Trans Image Process ; 30: 8939-8954, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34699359

RESUMO

We address the requirement of image coding for joint human-machine vision, i.e., the decoded image serves both human observation and machine analysis/understanding. Previously, human vision and machine vision have been extensively studied by image (signal) compression and (image) feature compression, respectively. Recently, for joint human-machine vision, several studies have been devoted to joint compression of images and features, but the correlation between images and features is still unclear. We identify the deep network as a powerful toolkit for generating structural image representations. From the perspective of information theory, the deep features of an image naturally form an entropy decreasing series: a scalable bitstream is achieved by compressing the features backward from a deeper layer to a shallower layer until culminating with the image signal. Moreover, we can obtain learned representations by training the deep network for a given semantic analysis task or multiple tasks and acquire deep features that are related to semantics. With the learned structural representations, we propose SSSIC, a framework to obtain an embedded bitstream that can be either partially decoded for semantic analysis or fully decoded for human vision. We implement an exemplar SSSIC scheme using coarse-to-fine image classification as the driven semantic analysis task. We also extend the scheme for object detection and instance segmentation tasks. The experimental results demonstrate the effectiveness of the proposed SSSIC framework and establish that the exemplar scheme achieves higher compression efficiency than separate compression of images and features.

14.
Antioxidants (Basel) ; 10(10)2021 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-34679723

RESUMO

Burmannic acid (BURA) is a new apocarotenoid bioactive compound derived from Indonesian cinnamon; however, its anticancer effect has rarely been investigated in oral cancer cells. In this investigation, the consequences of the antiproliferation of oral cancer cells effected by BURA were evaluated. BURA selectively suppressed cell proliferation of oral cancer cells (Ca9-22 and CAL 27) but showed little cytotoxicity to normal oral cells (HGF-1). In terms of mechanism, BURA perturbed cell cycle distribution, upregulated mitochondrial superoxide, induced mitochondrial depolarization, triggered γH2AX and 8-hydroxy-2-deoxyguanosine DNA damage, and induced apoptosis and caspase 3/8/9 activation in oral cancer cells. Application of N-acetylcysteine confirmed oxidative stress as the critical factor in promoting antiproliferation, apoptosis, and DNA damage in oral cancer cells.

15.
Polymers (Basel) ; 13(17)2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34502931

RESUMO

In order to reduce the dependency of resin synthesis on petroleum resources, vanillyl alcohol which is a renewable material that can be produced from lignin has been used to synthesize bioepoxy resin. Although it has been widely reported that the curing reaction and properties of the cured epoxies can be greatly affected by the molecular structure of the curing agents, the exact influence remains unknown for bioepoxies. In this study, four aliphatic amines with different molecular structures and amine functionalities, namely triethylenetetramine (TETA), Tris(2-aminoethyl)amine (TREN), diethylenetriamine (DETA), and ethylenediamine (EDA), were used to cure the synthesized vanillyl alcohol-based bioepoxy resin (VE). The curing reaction of VE and the physicochemical properties, especially the thermomechanical performance of the cured bioepoxies with different amine functionalities, were systematically investigated and compared using different characterization methods, such as DSC, ATR-FTIR, TGA, DMA, and tensile testing, etc. Despite a higher curing temperature needed in the VE-TETA resin system, the cured VE-TETA epoxy showed a better chemical resistance, particularly acidic resistance, as well as a lower swelling ratio than the others. The higher thermal decomposition temperature, storage modulus, and relaxation temperature of VE-TETA epoxy indicated its superior thermal stability and thermomechanical properties. Moreover, the tensile strength of VE cured by TETA was 1.4~2.6 times higher than those of other curing systems. In conclusion, TETA was shown to be the optimum epoxy curing agent for vanillyl alcohol-based bioepoxy resin.

16.
Atherosclerosis ; 334: 39-47, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34478920

RESUMO

BACKGROUND AND AIMS: Hyperhomocysteinemia (HHcy) is an independent risk factor for atherosclerosis and plaque vulnerability. Macrophage apoptosis mediated by endoplasmic reticulum (ER) stress plays an important role in the pathogenesis of HHcy-aggravated atherosclerosis. Endoplasmic reticulum oxidoreductase 1α (Ero1α) is critical for ER stress-induced apoptosis. We hypothesized that Ero1α may contribute to ER-stress induced macrophage apoptosis and plaque stability in advanced atherosclerotic lesions by HHcy. METHODS: Apoe-/- mice were maintained on drinking water containing homocysteine (Hcy, 1.8 g/L) to establish HHcy atherosclerotic models. The role of Ero1α in atherosclerotic plaque stability, macrophage apoptosis and ER stress were monitored in the plaque of aortic roots in HHcy Apoe-/- mice with or without silence or overexpression of Ero1α through lentivirus. Mouse peritoneal macrophages were used to confirm the regulation of Ero1α on ER stress dependent apoptosis in the presence of HHcy. RESULTS: Atherosclerotic plaque vulnerability and macrophage apoptosis were promoted in Apoe-/- mice by high Hcy diet, accompanied by the upregulation of Ero1α expression and ER stress. Inhibition of Ero1α prevented macrophage apoptosis and atherosclerotic plaque vulnerability, and vice versa. Consistently, in mouse peritoneal macrophages, ER stress and apoptosis were attenuated by Ero1α deficiency, but enhanced by Ero1α overexpression. CONCLUSIONS: Hcy, via upregulation of Ero1α expression, activates ER stress-dependent macrophage apoptosis to promote vulnerable plaque formation in atherosclerosis. Ero1α may be a potential therapeutic target for atherosclerosis induced by Hcy.


Assuntos
Aterosclerose , Homocisteína , Animais , Apolipoproteínas E/genética , Apoptose , Aterosclerose/genética , Estresse do Retículo Endoplasmático , Macrófagos Peritoneais , Camundongos
17.
J Med Chem ; 64(19): 14513-14525, 2021 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-34558909

RESUMO

Autophagy is upregulated in response to metabolic stress, a hypoxic tumor microenvironment, and therapeutic stress in various cancers and mediates tumor progression and resistance to cancer therapy. Herein, we identified a cinchona alkaloid derivative containing urea (C1), which exhibited potential cytotoxicity and inhibited autophagy in hepatocellular carcinoma (HCC) cells. We showed that C1 not only induced apoptosis but also blocked autophagy in HCC cells, as indicated by the increased expression of LC3-II and p62, inhibition of autophagosome-lysosome fusion, and suppression of the Akt/mTOR/S6k pathway in the HCC cells. Finally, to improve its solubility and efficacy, we encapsulated C1 into PEGylated lipid-poly(lactic-co-glycolic acid) (PLGA) nanoscale drug carriers. Systemic administration of nanoscale C1 significantly suppressed primary tumor growth and prevented distant metastasis while maintaining a desirable safety profile. Our findings demonstrate that C1 combines autophagy modulation and apoptosis induction in a single molecule, making it a promising therapeutic option for HCC.

18.
J Pers Med ; 11(9)2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34575651

RESUMO

Ethyl acetate Nepenthes extract (EANT) from Nepenthes thorellii × (ventricosa × maxima) shows antiproliferation and apoptosis but not necrosis in breast cancer cells, but this has not been investigated in oral cancer cells. In the present study, EANT shows no cytotoxicity to normal oral cells but exhibits selective killing to six oral cancer cell lines. They were suppressed by pretreatment of the antioxidant inhibitor N-acetylcysteine (NAC), demonstrating that EANT-induced cell death was mediated by oxidative stress. Concerning high sensitivity to EANT, Ca9-22 and CAL 27 oral cancer cells were chosen for exploring detailed selective killing mechanisms. EANT triggers a mixture of necrosis and apoptosis as determined by annexin V/7-aminoactinmycin D analysis. Still, they show differential switches from necrosis at a low (10 µg/mL) concentration to apoptosis at high (25 µg/mL) concentration of EANT in oral cancer cells. NAC induces necrosis but suppresses annexin V-detected apoptosis in oral cancer cells. Necrostatin 1 (NEC1), a necroptosis inhibitor, moderately suppresses necrosis but induces apoptosis at 10 µg/mL EANT. In contrast, Z-VAD-FMK, a pancaspase inhibitor, slightly causes necrosis but suppresses apoptosis at 10 µg/mL EANT. Furthermore, the flow cytometry-detected pancaspase activity is dose-responsively increased but is suppressed by NAC and ZVAD, although not for NEC1 in oral cancer cells. EANT causes several oxidative stress events such as reactive oxygen species, mitochondrial superoxide, and mitochondrial membrane depolarization. In response to oxidative stresses, the mRNA for antioxidant signaling, such as nuclear factor erythroid 2-like 2 (NFE2L2), catalase (CAT), heme oxygenase 1 (HMOX1), and thioredoxin (TXN), are overexpressed in oral cancer cells. Moreover, EANT also triggers DNA damage, as detected by γH2AX and 8-oxo-2'-deoxyguanosine adducts. The dependence of oxidative stress is validated by the evidence that NAC pretreatment reverts the changes of cellular and mitochondrial stress and DNA damage. Therefore, EANT exhibits antiproliferation involving an oxidative stress-dependent necrosis/apoptosis switch and DNA damage in oral cancer cells.

19.
Antioxidants (Basel) ; 10(9)2021 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-34573042

RESUMO

Several kinds of solvents have been applied to Nepenthes extractions exhibiting antioxidant and anticancer effects. However, they were rarely investigated for Nepenthes ethyl acetate extract (EANT), especially leukemia cells. The purpose of the present study was to evaluate the antioxidant properties and explore the antiproliferation impact and mechanism of EANT in leukemia cells. Five standard assays demonstrated that EANT exhibits antioxidant capability. In the cell line model, EANT dose-responsively inhibited cell viabilities of three leukemia cell lines (HL-60, K-562, and MOLT-4) based on 24 h MTS assays, which were reverted by pretreating oxidative stress and apoptosis inhibitors (N-acetylcysteine and Z-VAD-FMK). Due to similar sensitivities among the three cell lines, leukemia HL-60 cells were chosen for exploring antiproliferation mechanisms. EANT caused subG1 and G1 cumulations, triggered annexin V-detected apoptosis, activated apoptotic caspase 3/7 activity, and induced poly ADP-ribose polymerase expression. Moreover, reactive oxygen species, mitochondrial superoxide, and mitochondrial membrane depolarization were generated by EANT, which was reverted by N-acetylcysteine. The antioxidant response to oxidative stress showed that EANT upregulated mRNA expressions for nuclear factor erythroid 2-like 2 (NFE2L2), catalase (CAT), thioredoxin (TXN), heme oxygenase 1 (HMOX1), and NAD(P)H quinone dehydrogenase 1 (NQO1) genes. Moreover, these oxidative stresses led to DNA damage (γH2AX and 8-hydroxy-2-deoxyguanosine) and were alleviated by N-acetylcysteine. Taken together, EANT demonstrated oxidative stress-dependent anti-leukemia ability to HL-60 cells associated with apoptosis and DNA damage.

20.
Eur J Med Chem ; 225: 113821, 2021 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-34517222

RESUMO

Histone deacetylase 6 (HDAC6) is a potential target for Alzheimer's disease (AD). In this study, a series of novel phenothiazine-, memantine-, and 1,2,3,4-tetrahydro-γ-carboline-based HDAC6 inhibitors with a variety of linker moieties were designed and synthesized. As a hydrochloride salt, the phenothiazine-based hydroxamic acid W5 with a pyridyl-containing linker motif was identified as a high potent and selective HDAC6 inhibitor. It inhibited HDAC6 with an IC50 of 2.54 nM and was more than 290- to 3300-fold selective over other HDAC isoforms. In SH-SY5Y cells, W5 dose-dependently increased the acetylated α-tubulin levels and reduced the hyperphosphorylated tau proteins at Ser396. As an effective metal chelator, W5 inhibited Cu2+-induced Aß1-42 aggregation and disaggregated Cu2+-Aß1-42 oligomers, and showed protective effects on the SH-SY5Y cells against Aß1-42- as well as Cu2+-Aß1-42 induced cell damages, serving as a potential ligand to target AD metal dyshomeostasis. Moreover, W5 promoted the differentiated neuronal neurite outgrowth, increased the mRNA expression of the recognized neurogenesis markers, GAP43, N-myc, and MAP-2. Therefore, W5 might be a good lead for the development of novel HDAC6 inhibitors targeting multi-facets of AD.

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