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1.
Dev Comp Immunol ; 126: 104244, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34450127

RESUMO

The mechanism by which infection by Bombyx mori cytoplasmic nucleopolyhedrosis virus (BmCPV) causes autophagy has not been studied in detail. Herein we have observed by electron microscopy that infection with BmCPV causes autophagosome and mitochondrial structure damage in Bombyx mori midgut. In BmN cells infected with BmCPV and expressing eGFP-LC3, fluorescence spots and LC3-II levels increased, suggesting that BmCPV infection causes autophagy. Autophagy inducer rapamycin (Rap) and autophagy inhibitor 3-methyladenine (3-MA) were used to monitor the effects of mitophagy on BmCPV proliferation. It was found BmCPV proliferation to be promoted by mitophagy. Transient transfection experiments in cultured BmN cells showed that mitophagy can be triggered by expression of BmCPV structural protein VP4. Moreover, VP4 caused upregulation of p-Drp1, PINK1 and Parkin proteins in the mitophagy pathway and downregulation of mitochondrial membrane protein Tom20. Furthermore, interaction between VP4 with Tom40 was confirmed by Co-IP, western blot and colocalization experiment, and overexpression of Tom40 reduce the level of mitochondrial autophagy induced by VP4. These results suggested that VP4 induced PINK1-Parkin-mediated mitophagy interacting with Tom40. These findings deepen our understanding of the interaction between BmCPV and silkworm and also provide a molecular target for screening anti-BmCPV drugs.

2.
Microbiol Spectr ; : e0191821, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34851181

RESUMO

This study aimed to compare the fecal microbiome and antimicrobial resistance between captive and free-range sika deer with the same exposure to antibiotic anthelmintics. The taxonomic differences mainly involved significant changes in the dominant phyla, genera, and species. Linear discriminant analysis effect size (LEfSe) analysis revealed that 22 taxa were significantly different between the two groups. The KEGG analysis showed that the fecal microbiome metabolic function, and all level 2 categories in metabolism had higher abundance in the free-range deer. Based on the carbohydrate-active enzyme (CAZy) database analysis, glycoside hydrolases and carbohydrate-binding modules showed remarkable differences between the two groups. Regarding antibiotic resistance, tetQ and lnuC dominated the antibiotic resistance ontology (ARO) terms, and tetracycline and lincosamide resistance dominated the antimicrobial resistance patterns. Furthermore, the lnuC, ErmF, and tetW/N/W AROs and lincosamide resistance showed higher abundance in the captive deer, suggesting that captivity may yield more serious resistance issues because of the differences in greenfeed diet, breeding density, and/or housing environment. The results also revealed important associations between the phylum Proteobacteria, genus Prevotella, and major antibiotic resistance genes. Although the present study was a pilot study with a limited sample size that was insufficient control for some potential factors, it serves as the metagenomic study on the microbial communities and antimicrobial resistance in sika deer. IMPORTANCE We used a metagenomic approach to investigate whether and how captive and free-range impact the microbial communities and antimicrobial resistance in sika deer. The results provide solid evidence of the significant impacts on the microbial composition and function in captive and free-range sika deer. Interestingly, although the sika deer had the same exposure to antibiotic anthelmintics, the antimicrobial resistances were affected by the breeding environment.

3.
Appl Opt ; 60(30): 9347-9351, 2021 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-34807070

RESUMO

At various temperatures, ranging from 25°C to 50°C, we characterized two types of photodetectors based on surface-state absorption in silicon: (1) contactless integrated photonic probes (CLIPPs) and (2) normal-incidence photoconductors. Both types of photodetectors exhibited temperature-dependent AC admittance without illumination. With illumination at telecommunication wavelengths near 1550 nm, in the temperature range we measured, the photoresponse of CLIPPs, i.e., the variance of admittance due to illumination, was relatively insensitive to temperature changes; in comparison, the temperature dependence of the photoresponse of normal-incidence photoconductors was more pronounced-their responsivity increased as temperature raised.

4.
Opt Express ; 29(24): 40643-40651, 2021 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-34809399

RESUMO

Plasmonic devices can modulate light beyond the diffraction limit and thus have unique advantages in realizing an ultracompact feature size. However, in most cases, external light coupling systems are needed, resulting in a prohibitively bulky footprint. In this paper, we propose an integrated plasmonic biosensor on a vertical cavity surface emitting laser (VCSEL) platform. The plasmonic resonant wavelength of the nanohole array was designed to match (detune) with the emission peak wavelength of the VCSEL before (after) binding the molecules, thus the refractive index that represents the concentration of the molecule could be measured by monitoring the light output intensity. It shows that high contrast with relative intensity difference of 98.8% can be achieved for molecular detection at conventional concentrations. The size of the device chip could be the same as a VCSEL chip with regular specification of hundreds of micrometers in length and width. These results suggest that the proposed integrated sensor device offers great potential in realistic applications.

5.
Bioorg Med Chem Lett ; : 128480, 2021 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-34843914

RESUMO

The present study aims to determine the major metabolites of amentoflavone (AMF) and further evaluate their inhibitory effects on PARP-1. First, different fractions (Frs. 1-9), which were collected according to retention time of AMF metabolites based on UHPLC-QTOF-MS/MS qualitative analysis, were evaluated on their inhibitory effects against PARP-1. Then, two mono-sulfate metabolites in the fractions with potent PARP-1 inhibitory effect were targetedly semi-synthesized. Moreover, three mono-sulfate conjugates (compound 8, 9 and 10), including one disulfate conjugate (compound 10), were isolated and their structures were fully elucidated by UHPLC-QTOF-MS/MS and NMR. Finally, the binding mode of compound 8 (amentoflavone-4‴-O-sulfate) toward PARP-1 and its potentiation on carboplatin (CBP) in A549 cells were investigated. This study was the first report on bioactivity evaluation of AMF metabolites in rat bile on PARP-1 and the potentiation of compound 8 on carboplatin (CBP) in A549 cells in vitro. This paper also provided scientific basis for the AMF metabolites on PARP-1 inhibition and chemosensitization.

6.
Chin J Nat Med ; 19(11): 844-855, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34844723

RESUMO

The fruits of Eucalyptus globulus Labill. are known to have a plenty of medicinal properties, such as anti-tumor, anti-inflammatory, and immunosuppressive activity. Our previous study found that the phloroglucinol-sesquiterpene adducts in the fruits of E. globulus were immunosuppressive active constituents, especially Eucalyptin C (EuC). Phosphoinositide 3-kinases-γ (PI3Kγ) plays a pivotal role in T cell mediated excessive immune responses. In this study, EuC was first discovered to be a novel selective PI3Kγ inhibitor with an IC50 value of 0.9 µmol·L-1 and selectivity over 40-fold towards the other PI3K isoforms. Molecular docking, molecular dynamics simulation, and cellular thermal shift assay showed that EuC bound to PI3Kγ. Furthermore, EuC suppressed the downstream of PI3Kγ to induce the apoptosis and inhibit the activation of primary spleen cells derived from allergic contact dermatitis mice. This work highlights the role of the fruits of E. globulus as a source of bioactive plant with immunosuppressive activity.

7.
Food Res Int ; 148: 110626, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34507770

RESUMO

Fermented grain (FG), a complex and unique ecosystem, is the main microbial habitats, biochemical reaction system and direct source of flavor compounds for the Chinese strong-flavor Baijiu (CSFB) production. However, the dynamics of physicochemical properties, prokaryotic community and flavor compounds of FGs during the long-term fermentation process are still not completely clear. Here, the above topics on FGs in the actual production process were comprehensively studied by using a combination of physicochemical analysis, GC-MS detection and Illumina HiSeq sequencing methods. The whole fermentation process could be divided into two stages including early (0-25d) and the later stage (25-60d) based on the dynamics of FG physicochemical properties and the changes of prokaryotic community diversity. A total of 41phyla and 364 genera were detected, and 9 of them were dominant genera in FG complex ecosystem, including Lactobacillus, Pediococcus, Ochrobactrum, Bacillus etc. Among them, the dynamics of 29 top10 genera in FGs were mainly influenced by the starch and total acid, followed by NH4+ and ethanol, and 7 genera (hubs, e.g., Clostridium, Methanosaeta, Bacillus, etc.) of them may play important roles in FG ecosystem stability. A total of 71 volatiles including 33 esters, 14 alcohols, 9 fatty acids, 5 phenols, and 10 other compounds were detected in the FGs, and most of them formed in the early stage. Some important flavor substances (e.g., ethyl octanoate, 3-methylbutanol, hexanoate, etc.) increased in the later stage. Moreover, the formation of some flavor compound might require multiple microbes involved. For instance, ten of the top10 genera, including Lactobacillus, Clostridium, Methanosarcina, Sedimentibacter, Bacillus, etc., were significantly and positively correlated with four important esters. This study may help to clarify the complex correlations among prokaryotic community, physicochemical properties and flavors, allow the improvement of CSFB quality by using bioaugmentation and/or controlling environmental factors, and shed more light on the ecological rules guiding community assembly in FGs.


Assuntos
Microbiota , China , Fermentação , Aromatizantes/análise , Paladar
8.
Mol Ther Nucleic Acids ; 25: 668-682, 2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34589285

RESUMO

Hepatitis B virus (HBV) produces circular RNA (circRNA), whose functions have not yet been clearly elucidated. In this study, a novel circRNA HBV_circ_1 produced by HBV was identified in HBV-positive HepG2.2.15 cells and HBV-related hepatocellular carcinoma (HCC) tissue (HCCT). Microarray analysis of 68 HCCT samples showed that HBV_circ_1 abundance was significantly higher than that in paracancerous tissues. In addition, survival rate of HBV_circ_1-positive patients was significantly lower compared with HBV_circ_1-negative patients. Transient expression indicated that HBV_circ_1 enhanced cell proliferation, migration, and invasion and inhibited apoptosis in vitro. Furthermore, ectopical HBV_circ_1 expression increased tumor size in vivo. HBV_circ_1 was confirmed to interact with cyclin-dependent kinase 1 (CDK1) to regulate cell proliferation. These results suggest that HCC progression may be promoted by interaction of HBV_circ_1 with CDK1. Our data not only showed a novel clue to understand carcinogenesis and progress of HBV-related HCC but also provided a new target for the development of therapeutic drugs.

9.
Anim Sci J ; 92(1): e13638, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34585472

RESUMO

The aim of this study was to compare the meat quality and evaluate the chemical composition of Chinese Ningdu yellow chicken of different weights once they have reached market age. Thirty hens at the day of age 118 were selected and divided into three groups according to their weight: light weight (1288.00 ± 69.78 g, n = 10), medium weight (1407.17 ± 39.40 g, n = 10), heavy weight (1581.6 ± 46.59 g, n = 10), and the differences in weight among these three groups are significant. Biochemical, histological, and metabonomic approaches were used to obtain index values of meat quality and chemical composition. Compared with meat from lighter chickens, muscle fiber density was significantly lower in heavier chickens, and meat pH was positively correlated with chicken weight. Though the amount of all measured amino acids were not different among three weight groups of chicken, the levels of several kinds of fatty acids exhibited significant differences or correlations, including linolenic acid, arachidonic acid, myristic acid, oleic acid, and docosahexaenoic acid (DHA). These results contribute to help customers choose the optimal chicken weight depending upon the food to be cooked.

10.
PLoS One ; 16(9): e0257013, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34492064

RESUMO

The cardinal symptoms of some ophthalmic diseases observed through exceptional retinal blood vessels, such as retinal vein occlusion, diabetic retinopathy, etc. The advanced deep learning models used to obtain morphological and structural information of blood vessels automatically are conducive to the early treatment and initiative prevention of ophthalmic diseases. In our work, we propose a hierarchical dilation convolutional network (HDC-Net) to extract retinal vessels in a pixel-to-pixel manner. It utilizes the hierarchical dilation convolution (HDC) module to capture the fragile retinal blood vessels usually neglected by other methods. An improved residual dual efficient channel attention (RDECA) module can infer more delicate channel information to reinforce the discriminative capability of the model. The structured Dropblock can help our HDC-Net model to solve the network overfitting effectively. From a holistic perspective, the segmentation results obtained by HDC-Net are superior to other deep learning methods on three acknowledged datasets (DRIVE, CHASE-DB1, STARE), the sensitivity, specificity, accuracy, f1-score and AUC score are {0.8252, 0.9829, 0.9692, 0.8239, 0.9871}, {0.8227, 0.9853, 0.9745, 0.8113, 0.9884}, and {0.8369, 0.9866, 0.9751, 0.8385, 0.9913}, respectively. It surpasses most other advanced retinal vessel segmentation models. Qualitative and quantitative analysis demonstrates that HDC-Net can fulfill the task of retinal vessel segmentation efficiently and accurately.


Assuntos
Retinopatia Diabética/diagnóstico por imagem , Processamento de Imagem Assistida por Computador , Retina/diagnóstico por imagem , Oclusão da Veia Retiniana/diagnóstico por imagem , Vasos Retinianos/diagnóstico por imagem , Aprendizado Profundo , Retinopatia Diabética/diagnóstico , Retinopatia Diabética/patologia , Dilatação , Humanos , Redes Neurais de Computação , Retina/patologia , Oclusão da Veia Retiniana/diagnóstico , Oclusão da Veia Retiniana/patologia , Vasos Retinianos/patologia
11.
Dev Comp Immunol ; 125: 104227, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34363835

RESUMO

The diversity of microbiota and metabolites in the digestive tract gut is important in physiology and homeostasis, nutrient uptake and virus infection. In lepidopteran insect model silkworms, little is known about how microbiota and metabolites are altered after oral infection with BmNPV. Herein, we used 16S rDNA sequencing and metabolomics to show that the gut microbiota and metabolites of silkworm midgut are significantly altered after BmNPV infection. Kyoto Encyclopedia of Genes and Genomes analysis revealed enrichment of flavone and flavonol biosynthesis, glycosyltransferases, and electron transfer carriers signaling pathways, suggesting potential roles in viral infection. Infection also changed the abundance of metabolites in the digestive tract gut, where most pathways were related to metabolism of amino acids, fatty acids and other pathways (e.g., citrate cycle). In addition, a correlation was observed between digestive tract gut microbiota and metabolites. These results shed light on the interaction between digestive tract gut microbiota, metabolites and host-virus interaction, and enhance our understanding of viral infection links to midgut microbiota and metabolic activity in the silkworm.

12.
J Med Chem ; 64(16): 12089-12108, 2021 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-34404206

RESUMO

Poly (ADP-ribose) polymerase-1 (PARP-1) is a potential target for the discovery of chemosensitizers and anticancer drugs. Amentoflavone (AMF) is reported to be a selective PARP-1 inhibitor. Here, structural modifications and trimming of AMF have led to a series of AMF derivatives (9a-h) and apigenin-piperazine/piperidine hybrids (14a-p, 15a-p, 17a-h, and 19a-f), respectively. Among these compounds, 15l exhibited a potent PARP-1 inhibitory effect (IC50 = 14.7 nM) and possessed high selectivity to PARP-1 over PARP-2 (61.2-fold). Molecular dynamics simulation and the cellular thermal shift assay revealed that 15l directly bound to the PARP-1 structure. In in vitro and in vivo studies, 15l showed a potent chemotherapy sensitizing effect against A549 cells and a selective cytotoxic effect toward SK-OV-3 cells through PARP-1 inhibition. 15l·2HCl also displayed good ADME characteristics, pharmacokinetic parameters, and a desirable safety margin. These findings demonstrated that 15l·2HCl may serve as a lead compound for chemosensitizers and the (BRCA-1)-deficient cancer therapy.


Assuntos
Antineoplásicos/uso terapêutico , Flavonas/uso terapêutico , Neoplasias/tratamento farmacológico , Piperazinas/uso terapêutico , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Descoberta de Drogas , Feminino , Flavonas/síntese química , Flavonas/metabolismo , Flavonas/farmacocinética , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Piperazinas/síntese química , Piperazinas/metabolismo , Piperazinas/farmacocinética , Poli(ADP-Ribose) Polimerase-1/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/síntese química , Inibidores de Poli(ADP-Ribose) Polimerases/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/farmacocinética , Ligação Proteica , Ratos Sprague-Dawley , Relação Estrutura-Atividade
13.
Phys Rev Lett ; 126(25): 250502, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34241519

RESUMO

Quantum key distribution endows people with information-theoretical security in communications. Twin-field quantum key distribution (TF-QKD) has attracted considerable attention because of its outstanding key rates over long distances. Recently, several demonstrations of TF-QKD have been realized. Nevertheless, those experiments are implemented in the laboratory, and therefore a critical question remains about whether the TF-QKD is feasible in real-world circumstances. Here, by adopting the sending-or-not-sending twin-field QKD (SNS-TF-QKD) with the method of actively odd parity pairing (AOPP), we demonstrate a field-test QKD over 428 km of deployed commercial fiber and two users are physically separated by about 300 km in a straight line. To this end, we explicitly measure the relevant properties of the deployed fiber and develop a carefully designed system with high stability. The secure key rate we achieved breaks the absolute key rate limit of repeaterless QKD. The result provides a new distance record for the field test of both TF-QKD and all types of fiber-based QKD systems. Our work bridges the gap of QKD between laboratory demonstrations and practical applications and paves the way for an intercity QKD network with measurement-device-independent security.

14.
Appl Microbiol Biotechnol ; 105(14-15): 6019-6031, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34324010

RESUMO

Claudin-2 is a major component of tight junctions (TJs), which play an important role in reovirus entry into host cells. The Bombyx mori cytoplasmic polyhedosis virus (BmCPV) relates to the cypovirus strain of the reovirus family. So far, the role of claudin-2 in the process of BmCPV infection is not known. In the present study, it was observed that increasing expression of the claudin-2 gene (CLDN2) may concomitantly elevate BmCPV infection. Contrarily, knockdown of CLDN2 expression by siRNAs can reduce BmCPV infection. Similarly, antibody-based blockage of claudin-2 could also decrease BmCPV cell entry. These results suggest that claudin-2 can promote BmCPV infection in vitro. Moreover, immunofluorescence (IF) assays showed that claudin-2 can interact with BmCPV during viral infection. Specifically, co-immunoprecipitation experiments indicated that claudin-2 binds the BmCPV VP7 (instead of VP3 proteins). The interaction between VP7 and claudin-2 was further confirmed by bimolecular fluorescence complementation (BIFC). Altogether, our results suggest that BmCPV cell entry can be promoted upon interaction of VP7 with claudin-2. These findings provide new mechanistic insights related to BmCPV infection. KEY POINTS: •Claudin-2 could promote BmCPV infection of cells. •Claudin-2 interacted with BmCPV during BmCPV infection. •Claudin-2 could interact with BmCPV VP7 protein, but not with VP3 proteins.


Assuntos
Bombyx , Reoviridae , Animais , Claudina-2 , Claudinas/genética , Interações Hospedeiro-Patógeno , Proteínas de Insetos , Internalização do Vírus , Proteína da Zônula de Oclusão-2
15.
Phytomedicine ; 88: 153604, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34130054

RESUMO

BACKGROUND: Blue light can directly penetrate the lens and reach the retina to induce retinal damage, causing dry age-related macular degeneration (dAMD). Cynaroside (Cyn), a flavonoid glycoside, was proved to alleviate the oxidative damage of retinal cells in vitro. However, whether or not Cyn also exerts protective effect on blue light-induced retinal degeneration and its mechanisms of action are unclear. PURPOSE: This study aims to evaluate the protective effects of Cyn against blue-light induced retinal degeneration and its underlying mechanisms in vitro and in vivo. STUDY DESIGN/METHODS: Blue light-induced N-retinylidene-N-retinylethanolamine (A2E)-laden adult retinal pigment epithelial-19 (ARPE-19) cell damage and retinal damage in SD rats were respectively used to evaluate the protective effects of Cyn on retinal degeneration in vitro and in vivo. MTT assay and AnnexinV-PI double staining assay were used to evaluate the in vitro efficacy. Histological analysis, TUNEL assay, and fundus imaging were conducted to evaluate the in vivo efficacy. ELISA assay, western blot, and immunostaining were performed to investigate the mechanisms of action of Cyn. RESULTS: Cyn decreased the blue light-induced A2E-laden ARPE-19 cell damage and oxidative stress. Intravitreal injection of Cyn (2, 4 µg/eye) reversed the retinal degeneration induced by blue light in SD rats. Furthermore, Cyn inhibited the nuclear translocation of NF-κB and induced autophagy, which led to the clearance of overactivated pyrin domain containing 3 (NLRP3) inflammasome in vitro and in vivo. CONCLUSION: Cyn protects against blue light-induced retinal degeneration by modulating autophagy and decreasing the NLRP3 inflammasome.


Assuntos
Apoptose/efeitos dos fármacos , Glucosídeos/farmacologia , Luteolina/farmacologia , Substâncias Protetoras/farmacologia , Degeneração Retiniana/tratamento farmacológico , Animais , Apoptose/fisiologia , Autofagia/efeitos dos fármacos , Linhagem Celular , Glucosídeos/administração & dosagem , Humanos , Inflamassomos/metabolismo , Injeções Intravítreas , Luz/efeitos adversos , Luteolina/administração & dosagem , Masculino , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/administração & dosagem , Ratos Sprague-Dawley , Degeneração Retiniana/etiologia , Degeneração Retiniana/patologia , Epitélio Pigmentado da Retina/efeitos dos fármacos , Epitélio Pigmentado da Retina/patologia
16.
Biology (Basel) ; 10(6)2021 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-34071147

RESUMO

Hepatopancreas necrosis disease (HPND) of the Chinese mitten crab Eriocheir sinensis causes huge economic loss in China. However, the pathogenic factors and pathogenesis are still a matter of dissension. To search for potential pathogens, the hepatopancreatic flora of diseased crabs with mild symptoms, diseased crabs with severe symptoms, and crabs without visible symptoms were investigated using metatranscriptomics sequencing. The prevalence of Absidia glauca and Candidatus Synechococcus spongiarum decreased, whereas the prevalence of Spiroplasma eriocheiris increased in the hepatopancreatic flora of crabs with HPND. Homologous sequences of 34 viral species and 4 Microsporidian species were found in the crab hepatopancreas without any significant differences between crabs with and without HPND. Moreover, DEGs in the hepatopancreatic flora between crabs with severe symptoms and without visible symptoms were enriched in the ribosome, retinol metabolism, metabolism of xenobiotics by cytochrome P450, drug metabolism-cytochrome P450, biosynthesis of unsaturated fatty acids, and other glycan degradation. Moreover, the relative abundance of functions of DEDs in the hepatopancreatic flora changed with the pathogenesis process. These results suggested that imbalance of hepatopancreatic flora was associated with crab HPND. The identified DEGs were perhaps involved in the pathological mechanism of HPND; nonetheless, HPND did not occur due to virus or microsporidia infection.

17.
J Nat Prod ; 84(7): 1954-1966, 2021 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-34170694

RESUMO

Cdc37 associates kinase clients to Hsp90 and promotes the development of cancers. Celastrol, a natural friedelane triterpenoid, can disrupt the Hsp90-Cdc37 interaction to provide antitumor effects. In this study, 31 new celastrol derivatives, 2a-2d, 3a-3g, and 4a-4t, were designed and synthesized, and their Hsp90-Cdc37 disruption activities and antiproliferative activities against cancer cells were evaluated. Among these compounds, 4f, with the highest tumor cell selectivity (15.4-fold), potent Hsp90-Cdc37 disruption activity (IC50 = 1.9 µM), and antiproliferative activity against MDA-MB-231 cells (IC50 = 0.2 µM), was selected as the lead compound. Further studies demonstrated 4f has strong antitumor activities both in vitro and in vivo through disrupting the Hsp90-Cdc37 interaction and inhibiting angiogenesis. In addition, 4f exhibited less toxicity than celastrol and showed a good pharmacokinetics profile in vivo. These findings suggest that 4f may be a promising candidate for development of new cancer therapies.

18.
Opt Lett ; 46(11): 2577-2580, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34061060

RESUMO

We report on a normal-incidence infrared photoconductor based on surface-state absorption in silicon, featuring broad-spectrum photoresponse, sensitivity of ${-}46\;{\rm dBm} $ enabled by lock-in readouts, CMOS-compatible fabrication process, and near transparency to incident light. Its applications in infrared imaging and measuring the beam profiles are demonstrated and presented. Future extension from this single-pixel element to a many-pixel camera is discussed.

19.
PeerJ ; 9: e11335, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33996283

RESUMO

Background: The Père David's deer (Elaphurus davidianus) population was established from only a small number of individuals. Their genetic diversity is therefore relatively low and transmissible (parasitic) diseases affecting them merit further attention. Parasitic infections can affect the health, survival, and population development of the host. However, few reports have been published on the gastrointestinal parasites of Père David's deer. The aims of this study were: (1) to identify the intestinal parasites groups in Père David's deer; (2) to determine their prevalence and burden and clarify the effects of different seasons and regions on various indicators of Père David's deer intestinal parasites; (3) to evaluate the effects of the Père David's deer reproductive period on these parasites; (4) to reveal the regularity of the parasites in space and time. Methods: In total, 1,345 Père David's deer faecal samples from four regions during four seasons were tested using the flotation (saturated sodium nitrate solution) to identify parasites of different genus or group, and the McMaster technique to count the number of eggs or oocysts. Results: Four groups of gastrointestinal parasites were found, of which strongyles were dominant; their prevalence and burden were significantly higher than other groups. Significant temporal and spatial effects on gastrointestinal parasitic infection were found. Parasite diversity, prevalence, parasite burden, and aggregation were the highest in summer. Among the four regions, parasite diversity, prevalence, and burden were the highest in the Dongting Lake area. In addition, parasite diversity and burden during the reproductive period of Père David's deer was significantly higher than during the post-reproductive period. Conclusions: The summer season and the reproductive period of Père David's deer had great potential for parasite transmission, and there is a high risk of parasite outbreaks in the Dongting Lake area.

20.
J Med Chem ; 64(11): 7760-7777, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34019417

RESUMO

N-Phenylpropenoyl-l-amino acids (NPAs) are inducible nitric oxide synthase (iNOS) inhibitors possessing preventive effects for Parkinson's disease (PD). Here, structural modifications for improving the iNOS inhibitory activity and blood-brain barrier (BBB) permeability of NPAs were conducted, leading to 20 optimized NPA derivatives (1-20). Compound 18, with the most potent activity (IC50 = 74 nM), high BBB permeability (Pe = 19.1 × 10-6 cm/s), and high selectivity over other NOS isoforms, was selected as the lead compound. Further studies demonstrated that 18 directly binds to iNOS. In the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced acute PD model, the oral administration of 18 (1 and 2 mg/kg) exerted preventive effects by alleviating the loss of dopaminergic (DAergic) neurons. Notably, in the MPTP-/probenecid-induced chronic PD model, the same dose of 18 also displayed a therapeutic effect by repairing the damaged DAergic neurons. Finally, good pharmacokinetic properties and low toxicity made 18 a promising candidate for the treatment of PD.


Assuntos
Aminoácidos/química , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Propanóis/química , Aminoácidos/metabolismo , Aminoácidos/farmacologia , Animais , Sítios de Ligação , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Modelos Animais de Doenças , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Desenho de Fármacos , Meia-Vida , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Intoxicação por MPTP/tratamento farmacológico , Intoxicação por MPTP/patologia , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Microglia/citologia , Microglia/efeitos dos fármacos , Microglia/metabolismo , Simulação de Acoplamento Molecular , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Relação Estrutura-Atividade
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