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1.
Eur J Med Chem ; 222: 113564, 2021 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-34091208

RESUMO

COX-2 and STAT3 are two key culprits in the glioma microenvironment. Herein, to inhibit COX-2 and block STAT3 signaling, we disclosed 27 N-anthraniloyl tryptamine compounds based on the combination of melatonin derivatives and N-substituted anthranilic acid derivatives. Among them, NP16 showed the best antiproliferative activity and moderate COX-2 inhibition. Of note, NP16 decreased the level of p-JAK2 and p-STAT3, and blocked the nuclear translocation of STAT3 in GBM cell lines. Moreover, NP16 downregulated the MMP-9 expression of BV2 cells in a co-culture system of BV2 and C6 glioma cells, abrogated the proliferative/invasive/migratory abilities of GBM cells, induced apoptosis by ROS and the Bcl-2-regulated apoptotic pathway, and induced obvious G2/M arrest in glioma cells in vitro. Furthermore, NP16 displayed favorable pharmacokinetic profiles covering long half-life (11.43 ± 0.43 h) and high blood-brain barrier permeability. Finally, NP16 effectively inhibited tumor growth, promoted the survival rate, increased the expression of E-cadherin and reduced overproduction of PGE2, MMP-9, VEGF-A and the level of p-STAT3 in tumor tissue, and improved the anxiety-like behavior in C6 glioma model. All these evidences demonstrated N-anthraniloyl tryptamine derivatives as multifunctional anti-glioma agents with high potency could drain the swamp to beat glioma.

2.
Brain ; 2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34114611

RESUMO

Variants in KCNT1, encoding a sodium-gated potassium channel (subfamily T member 1), have been associated with a spectrum of epilepsies and neurodevelopmental disorders. These range from familial autosomal dominant or sporadic sleep-related hypermotor epilepsy ((AD)SHE) to epilepsy of infancy with migrating focal seizures (EIMFS) and include developmental and epileptic encephalopathies (DEE). This study aims to provide a comprehensive overview of the phenotypic and genotypic spectrum of KCNT1 mutation-related epileptic disorders in 248 individuals, including 66 unpreviously published and 182 published cases, the largest cohort reported so far. Four phenotypic groups emerged from our analysis: i) EIMFS (152 individuals, 33 previously unpublished); ii) DEE other than EIMFS (non-EIMFS DEE) (37 individuals, 17 unpublished); iii) (AD)SHE (53 patients, 14 unpublished); iv) other phenotypes (6 individuals, 2 unpublished). In our cohort of 66 new cases, the most common phenotypic features were: a) in EIMFS, heterogeneity of seizure types, including epileptic spasms, epilepsy improvement over time, no epilepsy-related deaths; b) in non-EIMFS DEE, possible onset with West syndrome, occurrence of atypical absences, possible evolution to DEE with SHE features; one case of sudden unexplained death in epilepsy (SUDEP); c) in (AD)SHE, we observed a high prevalence of drug-resistance, although seizure frequency improved with age in some individuals, appearance of cognitive regression after seizure onset in all patients, no reported severe psychiatric disorders, although behavioural/psychiatric comorbidities were reported in about 50% of the patients, SUDEP in one individual; d) other phenotypes in individuals with mutation of KCNT1 included temporal lobe epilepsy, and epilepsy with tonic-clonic seizures and cognitive regression. Genotypic analysis of the whole cohort of 248 individuals showed only missense mutations and one inframe deletion in KCNT1. Although the KCNT1 mutations in affected individuals were seen to be distributed among the different domains of the KCNT1 protein, genotype-phenotype considerations showed many of the (AD)SHE-associated mutations to be clustered around the RCK2 domain in the C-terminus, distal to the NADP domain. Mutations associated with EIMFS/non-EIMFS DEE did not show a particular pattern of distribution in the KCNT1 protein. Recurrent KCNT1 mutations were seen to be associated with both severe and less severe phenotypes. Our study further defines and broadens the phenotypic and genotypic spectrums of KCNT1-related epileptic conditions and emphasizes the increasingly important role of this gene in the pathogenesis of early onset DEEs as well as in focal epilepsies, namely (AD)SHE.

3.
Phys Rev Lett ; 126(21): 211101, 2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34114858

RESUMO

Experiments measuring the Newtonian gravitational constant G can offer uniquely sensitive probes of the test of the gravitational inverse-square law. An analysis of the non-Newtonian effect in two independent experiments measuring G is presented, which permits a test of the 1/r^{2} law at the centimeter range. This work establishes the strongest bound on the magnitude α of Yukawa-type deviations from Newtonian gravity in the range of 5-500 mm and improves the previous bounds by up to a factor of 7 at the length range of 60-100 mm.

4.
J Affect Disord ; 290: 219-226, 2021 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-34004404

RESUMO

BACKGROUND: Physical inactivity exacerbates poorer sleep quality, but potential underlying mechanisms of this association remain unknown. The present study aims to disentangle the pathways linking psychical activity to sleep quality through the serial mediation effect of anxiety and depression in a Chinese population. METHODS: Data analyzed were from Guangdong Sleep and Psychosomatic Health Survey, a cross-sectional population-based study with a representative sample of adult inhabitants aged 18-85 years living in Guangdong province, China. A total of 13,768 participants were included with the response rate of 80.4%. Singe and serial mediation analyses were conducted to examine whether anxiety and depression mediated the relationship between physical activity and sleep quality, independently and jointly. RESULTS: Both direct and indirect effects of physical activity on sleep quality were found. As predicted, anxiety and depression mediated the relationship between physical activity and sleep quality (B Anxiety = -0.17, 95% bootstrap CI: -0.20 to -0.15; B Depression= -0.25, 95% bootstrap CI: -0.28 to -0.21), respectively. In addition, serial mediation analyses indicated that the association of physical activity and sleep quality is mediated by anxiety and depression in a sequential manner (B = -0.13, 95% bootstrap CI: -0.15 to -0.11). LIMITATIONS: The primary limitation of the study is the cross-sectional design, which limits the causal inference ability. CONCLUSIONS: These findings highlight the role of anxiety and depression as serial mediators of the relationship between physical activity and sleep quality. Thus, exercise-based programs focusing on improving sleep could benefit from a multi-faceted approach therapeutically targeting psychiatric disorders.

5.
Appl Microbiol Biotechnol ; 105(10): 4285-4295, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33990857

RESUMO

Natural killer-92 cells (NK-92 cells) need to be efficiently expanded by serum-free culture in vitro to meet clinical requirements. Fatty acids mainly provide substrates for energy production, which is of crucial importance to meet the energy demands of highly proliferating cells. This study optimized the medium (EM) for NK-92 cells by designing an experiment to expand cells efficiently. EM, an in-house designed chemically defined serum-free medium, was used as the basal medium. Fatty acids as additive ingredients were screened and optimized by the experimental design method. Three additives, arachidonic acid, myristic acid and palmitoleic acid, were screened; therefore, the optimized medium was named EM-FA. The total cell expansion of NK-92 cells in EM-FA was 72.61±11.95-fold on day 8, which was significantly higher than the 28.55±8.67-fold expansion in EM. To explore the mechanism by which fatty acids promote NK-92 cell expansion, the cell growth kinetics and metabolic characteristics in EM-FA were analyzed. The results showed that NK-92 cells in EM-FA were rapidly expanded while maintaining their cell phenotype and cytotoxicity and enhancing the oxygen consumption rate and mitochondrial function. Fatty acids promoted ATP production to elevate the energy flux for better cell expansion. This study developed an expansion strategy of NK-92 cells in vitro to facilitate their clinical application. KEY POINTS: • Arachidonic acid, myristic acid and palmitoleic acid in serum-free medium were optimized by experimental design to enable the rapid expansion of NK-92 cells in vitro. • Fatty acids upregulated oxidative phosphorylation levels and improved the energy metabolism of NK-92 cells.


Assuntos
Ácidos Graxos , Células Matadoras Naturais , Proliferação de Células , Meios de Cultura , Metabolismo Energético
6.
Front Immunol ; 12: 653803, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33936076

RESUMO

Acute respiratory distress syndrome (ARDS) triggered mostly by infection, is a syndrome that involves respiratory failure. ARDS induces strong local infiltration of regulatory T cells (Treg cells) in the lungs, and Treg cells were recently highlighted as being related to the repair of various tissue. However, at present, there is still a lack of adequate evidence showing the impact of Treg cells on pulmonary regeneration during ARDS. Here, we verified that Treg cells are strongly induced in ARDS mice and Treg depletion results in impaired lung repair. Moreover, Treg cells show high expression of ST2, a cellular receptor for the tissue alarmin IL-33, which is strongly upregulated in the lung during ARDS. In addition, we demonstrated that IL-33 signaling is crucial for Treg cell accumulation, and ST2-blocked mice show a decrease in the Treg cell population. Critically, transfer of exogenous IL-33 into Treg depleted mice restored Treg cells and facilitated lung regeneration by promoting alveolar type II cell (AEC2) recovery in ARDS, with elevated neutrophils infiltration and upregulated TGF-ß1 release. These results emphasized the importance of IL-33 in accelerating the expansion of pulmonary Treg cells and promoting their activity to mediate pulmonary epithelial regeneration during ARDS in a TGF-ß1-dependent manner.

7.
Schizophr Bull ; 2021 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-33837780

RESUMO

Exosomes are involved in the pathophysiology of neuropsychiatric diseases, but the role of exosomes in schizophrenia (SCZ) is unclear. Here, we demonstrate that transplantation of serum exosomes from SCZ patients into mice caused behavioral abnormalities such as deficits in prepulse inhibition and sociability, hyperactivity, and anxiogenesis. A comparative bioinformatics analysis suggested shared and distinct differentially expressed genes (DEGs) and enriched molecular pathways in the brains of SCZ exosome-recipient mice, methylazoxymethanol acetate-treated rats, and SCZ patients, which correlates evidence of altered prefrontal-hippocampal functional coherence in SCZ. A large proportion of SCZ-relevant DEGs in the exosome-recipient mice were targets of DE exosomal miRNAs in SCZ patients. Furthermore, we identified 20 hub genes for SCZ risk genes, including BDNF and NRG1, which were DE miRNA targets in SCZ. Collectively, our study suggests that SCZ exosome transplantation caused SCZ-relevant behaviors in mice, and epigenetic regulation may contribute to the phenotypes in the SCZ exosome-recipient mice. Our results may provide a potential animal model and novel therapeutic targets for SCZ.

8.
Hum Mutat ; 42(6): 762-776, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33847017

RESUMO

Bi-allelic TECPR2 variants have been associated with a complex syndrome with features of both a neurodevelopmental and neurodegenerative disorder. Here, we provide a comprehensive clinical description and variant interpretation framework for this genetic locus. Through international collaboration, we identified 17 individuals from 15 families with bi-allelic TECPR2-variants. We systemically reviewed clinical and molecular data from this cohort and 11 cases previously reported. Phenotypes were standardized using Human Phenotype Ontology terms. A cross-sectional analysis revealed global developmental delay/intellectual disability, muscular hypotonia, ataxia, hyporeflexia, respiratory infections, and central/nocturnal hypopnea as core manifestations. A review of brain magnetic resonance imaging scans demonstrated a thin corpus callosum in 52%. We evaluated 17 distinct variants. Missense variants in TECPR2 are predominantly located in the N- and C-terminal regions containing ß-propeller repeats. Despite constituting nearly half of disease-associated TECPR2 variants, classifying missense variants as (likely) pathogenic according to ACMG criteria remains challenging. We estimate a pathogenic variant carrier frequency of 1/1221 in the general and 1/155 in the Jewish Ashkenazi populations. Based on clinical, neuroimaging, and genetic data, we provide recommendations for variant reporting, clinical assessment, and surveillance/treatment of individuals with TECPR2-associated disorder. This sets the stage for future prospective natural history studies.

9.
Chin Med J (Engl) ; 134(11): 1289-1298, 2021 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-33928916

RESUMO

BACKGROUND: The significant morbidity and mortality resulted from the infection of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) call for urgent development of effective and safe vaccines. We report the immunogenicity and safety of an inactivated SARS-CoV-2 vaccine, KCONVAC, in healthy adults. METHODS: Phase 1 and phase 2 randomized, double-blind, and placebo-controlled trials of KCONVAC were conducted in healthy Chinese adults aged 18 to 59 years. The participants in the phase 1 trial were randomized to receive two doses, one each on Days 0 and 14, of either KCONVAC (5 or 10 µg/dose) or placebo. The participants in the phase 2 trial were randomized to receive either KCONVAC (at 5 or 10 µg/dose) or placebo on Days 0 and 14 (0/14 regimen) or Days 0 and 28 (0/28 regimen). In the phase 1 trial, the primary safety endpoint was the proportion of participants experiencing adverse reactions/events within 28 days following the administration of each dose. In the phase 2 trial, the primary immunogenicity endpoints were neutralization antibody seroconversion and titer and anti-receptor-binding domain immunoglobulin G seroconversion at 28 days after the second dose. RESULTS: In the phase 1 trial, 60 participants were enrolled and received at least one dose of 5-µg vaccine (n = 24), 10-µg vaccine (n = 24), or placebo (n = 12). In the phase 2 trial, 500 participants were enrolled and received at least one dose of 5-µg vaccine (n = 100 for 0/14 or 0/28 regimens), 10-µg vaccine (n = 100 for each regimen), or placebo (n = 50 for each regimen). In the phase 1 trial, 13 (54%), 11 (46%), and seven (7/12) participants reported at least one adverse event (AE) after receiving 5-, 10-µg vaccine, or placebo, respectively. In the phase 2 trial, 16 (16%), 19 (19%), and nine (18%) 0/14-regimen participants reported at least one AE after receiving 5-, 10-µg vaccine, or placebo, respectively. Similar AE incidences were observed in the three 0/28-regimen treatment groups. No AEs with an intensity of grade 3+ were reported, expect for one vaccine-unrelated serious AE (foot fracture) reported in the phase 1 trial. KCONVAC induced significant antibody responses; 0/28 regimen showed a higher immune responses than that did 0/14 regimen after receiving two vaccine doses. CONCLUSIONS: Both doses of KCONVAC are well tolerated and able to induce robust immune responses in healthy adults. These results support testing 5-µg vaccine in the 0/28 regimen in an upcoming phase 3 efficacy trial. TRIAL REGISTRATION: http://www.chictr.org.cn/index.aspx (No. ChiCTR2000038804, http://www.chictr.org.cn/showproj.aspx?proj=62350; No. ChiCTR2000039462, http://www.chictr.org.cn/showproj.aspx?proj=63353).


Assuntos
Adulto , Método Duplo-Cego , Humanos , Vacinas de Produtos Inativados/efeitos adversos
10.
Huan Jing Ke Xue ; 42(5): 2260-2267, 2021 May 08.
Artigo em Chinês | MEDLINE | ID: mdl-33884795

RESUMO

To understand the effect of nitrogen from runoff during rainfall events for different land uses, sub-catchments A and B in the small Shipanqiu watershed in Zhong County, Chongqing-which were managed using different land use practices-were taken as research objects. Runoff flow and nitrogen levels at the outlet of the catchment were monitored. Sub-catchment A is an agroforestry-water complex and sub-catchment B is the site of traditional agriculture. EMC was used to evaluate the average concentration of runoff nitrogen during rainfall events, and the effect of this runoff nitrogen on the small watershed with different land use systems was analyzed. The results showed that the TN concentration in catchment B (1.37-15.17 mg·L-1) > catchment A (0.84-9.28 mg·L-1); the ratio of the first peak to the second peak in catchment A was 62%, which was far less than the 97% in catchment B; the average DN/TN values were 69% and 75% in catchments A and B, respectively; and the average NN/DN values were 67% and 80% in catchments A and B, respectively. The different land use practices have significant impacts on nitrogen loss. Compared with the catchment where traditional agricultural practices were followed, the agroforestry-water complex catchment effectively reduced the loss of nitrogen and decreased the first TN peak value and DN/TN and NN/DN values. This study provides a scientific basis for the prevention and control of non-point source pollution in small watersheds in the area of the Three Gorges Reservoir.

11.
J Proteome Res ; 20(5): 2643-2650, 2021 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-33780243

RESUMO

Alzheimer's disease (AD) is closely associated with lipid metabolism dysfunction. However, space distribution and metabolism of aberrant lipids in the brain of early-stage AD mouse remain unclear. In our current work, a novel lipidomics method based on mass spectrometry imaging was developed to visually disclose molecular perturbation and characterize space distribution in the brain of double transgenic amyloid precursor protein/presenilin 1 mouse (2 and 3 months old). Significant changes were detected, including phosphatidylethanolamines, phosphatidylcholines, fatty acids, lysophospholipids, and glycerides in AD mouse brain. The results in this study suggest that these significantly altered lipid metabolic pathways (glycerophospholipid metabolism) may be implicated in early-stage AD. Our work deepens the understanding of the physio-pathologic mechanism of early-stage AD.

12.
Med Sci Monit ; 27: e928478, 2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33686049

RESUMO

BACKGROUND Bifidobacterium is a potentially effective and safe treatment for patients with inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease. However, information on the influence of B. bifidum on gut microbial diversity of treated and pretreated IBD patients is limited. MATERIAL AND METHODS Our study investigated therapeutic and preventive effects of B. bifidum ATCC 29521 on C57BL/6 mice with dextran sulfate sodium (DSS)-induced acute colitis via 16S ribosomal ribonucleic acid (rRNA) gene sequencing. RESULTS Treatment and pretreatment of mice with B. bifidum ATCC 29521 significantly alleviated the severity of acute colitis on the basis of clinical and pathologic indicators. 16S rRNA gene sequencing showed that administration of B. bifidum shifted composition of the gut microbiome in mice with DSS-induced colitis in both treated and pretreated groups. Mice pretreated with B. bifidum ATCC 29521 for 21 days exhibited a significant increase in diversity of the gut microbiome. Principal coordinate analysis showed that gut microbiota structure was shaped by different treatments and time points. On the basis of linear discriminant analysis of effect size, the abundance of the genus Escherichia-Shigella, belonging to the family Enterobacteriaceae, was reduced in the B. bifidum-treated group, indicating that pathogens were inhibited by the B. bifidum treatment. Furthermore, the genera Intestinimonas and Bacteroides were significantly associated with the B. bifidum-pretreated group. CONCLUSIONS 16S rRNA gene sequencing showed that pretreatment with B. bifidum ATCC 29521 reduced intestinal inflammation and altered the gut microbiota to favor the genera Intestinimonas and Bacteroides.


Assuntos
Bifidobacterium bifidum/metabolismo , Colite/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Animais , Bactérias/genética , Colite/microbiologia , Colite Ulcerativa/genética , Colo/patologia , Sulfato de Dextrana/efeitos adversos , Sulfato de Dextrana/farmacologia , Modelos Animais de Doenças , Fezes/microbiologia , Feminino , Microbioma Gastrointestinal/genética , Doenças Inflamatórias Intestinais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Probióticos/uso terapêutico , RNA Ribossômico 16S/genética
13.
Medicine (Baltimore) ; 100(13): e25298, 2021 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-33787619

RESUMO

ABSTRACT: This study was aimed at assessing the impact of the dusk phenomenon on the total glucose exposure in Chinese people with type 2 diabetes.A total of 380 type 2 diabetes who received a retrospective continuous glucose monitoring system (CGMs) for 72 hours were enrolled in our study, 32 of them failed in CGMs. The patients were first divided into 2 groups: dusk phenomenon (n = 95) and non dusk phenomenon group (n = 253). The magnitude of the dusk phenomenon (δDusk) was quantified by pre-dinner glucose minus post-lunch 2 hours glucose. A persistent δDusk ≥ 0 or a once only δDusk < 0 can be diagnosed with the dusk phenomenon. The participants were secondarily matched for the post-lunch 2 hours glucose to assess the impact of the dusk phenomenon on the overall glucose exposure. The impact of the dusk phenomenon was assessed on high-performance liquid chromatography assay (HbA1c) and 24-hour mean glucose.There were 95 of 348 (27.3%) participants with the dusk phenomenon in the overall population, and the median of δDusk level was -0.8 (-1.8, 0.2) mmol/L. The median of glucose differences between the 2 paired groups were 0.4 (-0.4, 1.0)% for HbA1c, 0.9 (0.2, 1.4) mmol/L for 24 hours mean glucose. The correlation analysis showed no relationship between the magnitude of dawn phenomenon and the dusk phenomenon (r = 0.052, P = .472).The incidence of dusk phenomenon is about 27.3% in people with type 2 diabetes. The impacts of dusk phenomenon on HbA1c and 24-hour mean glucose were about 0.4% and 0.9 mmol/L and the dusk phenomenon was not related with the dawn phenomenon.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Hemoglobina A Glicada/metabolismo , Hiperglicemia/sangue , Refeições/fisiologia , Idoso , Automonitorização da Glicemia , Fenômenos Fisiológicos Sanguíneos , China , Diabetes Mellitus Tipo 2/complicações , Feminino , Humanos , Hiperglicemia/etiologia , Masculino , Pessoa de Meia-Idade , Periodicidade
15.
Int J Mol Sci ; 22(4)2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33672018

RESUMO

Hepatitis B is a major global health challenge. In the absence of an effective treatment for the disease, hepatitis B vaccines provide protection against the viral infection. However, some individuals do not have positive immune responses after being vaccinated with the hepatitis B vaccines available in the market. Thus, it is important to develop a more protective vaccine. Previously, we showed that hepatitis B virus (HBV) 'a' determinant (aD) displayed on the prawn nodavirus capsid (Nc) and expressed in Spodoptera frugiperda (Sf9) cells (namely, Nc-aD-Sf9) self-assembled into virus-like particles (VLPs). Immunisation of BALB/c mice with the Nc-aD-Sf9 VLPs showed significant induction of humoral, cellular and memory B-cell immunity. In the present study, the biophysical properties of the Nc-aD-Sf9 VLPs were studied using dynamic light scattering (DLS) and circular dichroism (CD) spectroscopy. Enzyme-linked immunosorbent assay (ELISA) was used to determine the antigenicity of the Nc-aD-Sf9 VLPs, and multiplex ELISA was employed to quantify the cytokine response induced by the VLPs administered intramuscularly into BALB/c mice (n = 8). CD spectroscopy of Nc-aD-Sf9 VLPs showed that the secondary structure of the VLPs predominantly consisted of beta (ß)-sheets (44.8%), and they were thermally stable up to ~52 °C. ELISA revealed that the aD epitope of the VLPs was significantly antigenic to anti-HBV surface antigen (HBsAg) antibodies. In addition, multiplex ELISA of serum samples from the vaccinated mice showed a significant induction (p < 0.001) of IFN-γ, IL-4, IL-5, IL-6, IL-10, and IL-12p70. This cytokine profile is indicative of natural killer cell, macrophage, dendritic cell and cytotoxic T-lymphocyte activities, which suggests a prophylactic innate and adaptive cellular immune response mediated by Nc-aD-Sf9 VLPs. Interestingly, Nc-aD-Sf9 induced a more robust release of the aforementioned cytokines than that of Nc-aD VLPs produced in Escherichia coli and a commercially used hepatitis B vaccine. Overall, Nc-aD-Sf9 VLPs are thermally stable and significantly antigenic, demonstrating their potential as an HBV vaccine candidate.


Assuntos
Proteínas do Capsídeo/imunologia , Citocinas/metabolismo , Vacinas contra Hepatite B/imunologia , Vírus da Hepatite B/imunologia , Epitopos Imunodominantes/imunologia , Nodaviridae/imunologia , Transdução de Sinais/imunologia , Vacinação/métodos , Vacinas de Partículas Semelhantes a Vírus/imunologia , Animais , Anticorpos/imunologia , Antígenos de Superfície da Hepatite B/imunologia , Vacinas contra Hepatite B/administração & dosagem , Temperatura Alta , Camundongos , Camundongos Endogâmicos BALB C , Células Sf9 , Spodoptera , Vacinas de Partículas Semelhantes a Vírus/administração & dosagem
16.
Int J Mol Sci ; 22(5)2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33652577

RESUMO

Gene therapy research has advanced to clinical trials, but it is hampered by unstable nucleic acids packaged inside carriers and there is a lack of specificity towards targeted sites in the body. This study aims to address gene therapy limitations by encapsidating a plasmid synthesizing a short hairpin RNA (shRNA) that targets the anti-apoptotic Bcl-2 gene using truncated hepatitis B core antigen (tHBcAg) virus-like particle (VLP). A shRNA sequence targeting anti-apoptotic Bcl-2 was synthesized and cloned into the pSilencer 2.0-U6 vector. The recombinant plasmid, namely PshRNA, was encapsidated inside tHBcAg VLP and conjugated with folic acid (FA) to produce FA-tHBcAg-PshRNA VLP. Electron microscopy revealed that the FA-tHBcAg-PshRNA VLP has an icosahedral structure that is similar to the unmodified tHBcAg VLP. Delivery of FA-tHBcAg-PshRNA VLP into HeLa cells overexpressing the folate receptor significantly downregulated the expression of anti-apoptotic Bcl-2 at 48 and 72 h post-transfection. The 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay demonstrated that the cells' viability was significantly reduced from 89.46% at 24 h to 64.52% and 60.63%, respectively, at 48 and 72 h post-transfection. As a conclusion, tHBcAg VLP can be used as a carrier for a receptor-mediated targeted delivery of a therapeutic plasmid encoding shRNA for gene silencing in cancer cells.


Assuntos
Inativação Gênica , Técnicas de Transferência de Genes , Vírus da Hepatite B , Plasmídeos , Proteínas Proto-Oncogênicas c-bcl-2 , RNA Interferente Pequeno , Neoplasias do Colo do Útero , Feminino , Células HeLa , Humanos , Plasmídeos/genética , Plasmídeos/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Proteínas Proto-Oncogênicas c-bcl-2/genética , RNA Interferente Pequeno/biossíntese , RNA Interferente Pequeno/genética , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologia
17.
Artigo em Inglês | MEDLINE | ID: mdl-33662568

RESUMO

Cholinesterases act as bio scavengers to clear organophosphorus (OP) compounds and prodrugs. The butyrylcholinesterase (BChE) gene has been found in several types of teleost fish but this gene has yet to be identified in cyprinid fish. Indeed, BChE homologs have not been found in the zebrafish (Danio rerio) genomic database. Here, we demonstrate that BChE activity is present in zebrafish, in line with other groups' findings. Using in-gel native-PAGE enzymatic activity staining and LC-MS/MS technique, an atypical BChE-like protein was identified in zebrafish. The si:ch211-93f2.1 gene was cloned, and His-tagged recombinant protein was expressed using the Pichia yeast system. The purified protein (molecular weight ~ 180 kDa) showed BChE activity, and degraded acetylcholinesterase (ACh) at a higher rate than BCh. However, phylogram analysis shows that this novel cholinesterase shared an evolutionary origin with carboxylic esterase rather than BChE. The zebrafish BChE-like protein shares structural characteristics with cholinesterase and carboxylesterase. The 2-arachidonoylglycerol (2-AG), nicosulfuron, and triacetin exhibited a higher binding affinity to the zebrafish BChE-like protein than BCh and ACh. With the identification of BChE-like protein in zebrafish, this study could shed light on the origin of BChE and may contribute towards the development of a BChE knockout zebrafish model for sensitive drug or toxin screening.

18.
Fitoterapia ; 151: 104879, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33689876

RESUMO

Swertia mileensis, known as Qing-Ye-Dan (QYD), has been documented in Chinese Pharmacopoeia to cure hepatitis. Interestingly, its announced main active component, swertiamarin, could not be detected in the decoction, which indicated that the efficacy of QYD might be attributed to heat-transformed products of swertiamarin (HTPS). Further investigation on HTPS led to the isolation of sweritranslactone D (1), a novel secoiridoid dimer possessing a tetracyclic lactone skeleton, with better hepatoprotective activity than N-acetyl-L-cysteine in vitro.

19.
ISA Trans ; 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33610315

RESUMO

Second-order plus dead-time systems are difficult to tune for a PID controller due to its special structure, especially the underdamped systems that have oscillatory responses. As a control technique with strong disturbance rejection ability, linear active disturbance rejection control is widely used as a substitute for PID controllers. This paper proposes a tuning formula for second-order linear active disturbance rejection control for underdamped second-order plus dead-time systems via internal model control. The formula is derived by minimizing the integral of time squared error index under certain robustness measure condition. Simulation results show that the linear active disturbance rejection controller tuned from the proposed formula can achieve satisfactory control performance for oscillatory systems.

20.
Inorg Chem ; 2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33635076

RESUMO

Zintl phases with nominal 9-4-9 formulas are very interesting for their potential applications as thermoelectric materials. However, the formation of such phases usually requires divalent transition metals, for example, Zn, Mn, and Cd, which are covalently bonded to the pnictogen atoms. In this report, for the first time, two Mg-containing compounds with such structures as Sr9Mg4.45(1)Bi9 and Sr9Mg4.42(1)Sb9 were synthesized and their structures were determined by the single-crystal X-ray diffraction method. Both title compounds crystallize in the orthorhombic space group Pnma and are isostructural with Ca9Mn4.41(1)Sb9, which features complex polyanion structures compared to the classical 9-4-9 phases. For Sr9Mg4.45(1)Bi9, its low thermal conductivity, combined with its high electrical conductivity and moderate Seebeck coefficient, leads to a decent figure of merit of 0.57 at 773 K, which obviously prevails in the unoptimized 9-4-9 phases. The discovery of such Mg-containing 9-4-9 phases is very significant, as the discovery not only enriches the structure map of the well-known 9-4-9 family but also provides very valuable thermoelectric candidates surely deserving of more in-depth investigation.

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