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1.
Front Public Health ; 9: 575315, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34595146

RESUMO

Objective: The aim of this study is to analyze the latent class of basic reproduction number (R 0) trends of the 2019 novel coronavirus disease (COVID-19) in the major endemic areas of China. Methods: The provinces that reported more than 500 cases of COVID-19 till February 18, 2020 were selected as the major endemic areas. The Verhulst model was used to fit the growth rate of cumulative confirmed cases. The R 0 of COVID-19 was calculated using the parameters of severe acute respiratory syndrome (SARS) and COVID-19. The latent class of R 0 was analyzed using the latent profile analysis (LPA) model. Results: The median R 0 calculated from the SARS and COVID-19 parameters were 1.84-3.18 and 1.74-2.91, respectively. The R 0 calculated from the SARS parameters was greater than that calculated from the COVID-19 parameters (Z = -4.782 to -4.623, p < 0.01). Both R 0 can be divided into three latent classes. The initial value of R 0 in class 1 (Shandong Province, Sichuan Province, and Chongqing Municipality) was relatively low and decreased slowly. The initial value of R 0 in class 2 (Anhui Province, Hunan Province, Jiangxi Province, Henan Province, Zhejiang Province, Guangdong Province, and Jiangsu Province) was relatively high and decreased rapidly. Moreover, the initial R 0 value of class 3 (Hubei Province) was in the range between that of classes 1 and 2, but the higher R 0 level lasted longer and decreased slowly. Conclusion: The results indicated that the overall R 0 trend is decreased with the strengthening of comprehensive prevention and control measures of China for COVID-19, however, there are regional differences.


Assuntos
COVID-19 , SARS-CoV-2 , Número Básico de Reprodução , China/epidemiologia , Humanos , Incidência
2.
J Int Med Res ; 49(9): 3000605211047712, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34586928

RESUMO

Although direct-acting oral anticoagulants (DOACs) decrease the bleeding risk compared with vitamin K antagonists (VKAs), DOACs might cause spontaneous hemothorax in very elderly patients, even at a very low dose. Interactions between drugs might increase the risk of bleeding. In this article, we report a case of a 95-year-old man who developed spontaneous hemothorax while taking rivaroxaban 2.5 mg twice daily, 3 days after concomitant use of itraconazole. Rivaroxaban was discontinued, and thoracentesis was performed to drain grossly bloody pleural effusion. To our knowledge, this is the first case report of spontaneous hemothorax that might have been caused by concomitant low-dose rivaroxaban and azole anti-fungal agents. This case highlights the potential risk of spontaneous hemothorax in very elderly patients while taking rivaroxaban and azole anti-fungal agents simultaneously. Special attention should be paid to interactions between drugs that might increase the risk of bleeding. Drugs that have competing metabolic pathways should be avoided. Closer monitoring, including testing for anti-Xa and additional reassessment, should be considered in high-risk patients.


Assuntos
Fibrilação Atrial , Rivaroxabana , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/uso terapêutico , Inibidores do Fator Xa/efeitos adversos , Hemorragia , Hemotórax/tratamento farmacológico , Humanos , Itraconazol/uso terapêutico , Masculino , Rivaroxabana/efeitos adversos
3.
Clin Transl Med ; 11(9): e517, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34586745

RESUMO

BACKGROUND: Platinum-based chemotherapy is effective in inducing shrinkage of primary lung cancer lesions; however, it shows finite therapeutic efficacy in patients suffering from brain metastasis (BM). The intrinsic changes of BM cells, which contribute to the poor results remain unknown. METHODS: Platinum drug-sensitivity was assessed by utilizing a preclinical BM model of PC9 lung adenocarcinoma cells in vitro and in vivo. High consumption of glutathione (GSH) and two associated upregulated proteins (GPX4 and GSTM1) in BM were identified by integrated metabolomics and proteomics in cell lines and verified by clinical serum sample. Gain-of-function and rescue experiments were implemented to reveal the impact and mechanism of GPX4 and GSTM1 on the chemosensitivity in BM. The interaction between GPX4 and GSTM1 was examined by immunoblotting and immunoprecipitation. The mechanism of upregulation of GPX4 was further uncovered by luciferase reporter assay, immunoprecipitation, and electrophoretic mobility shift assay. RESULTS: The derivative brain metastatic subpopulations (PC9-BrMs) of parental cells PC9 developed obvious resistance to platinum. Radically altered profiles of BM metabolism and protein expression compared with primary lung cancer cells were described and GPX4 and GSTM1 were identified as being responsible for the high consumption of GSH, leading to decreased chemosensitivity by negatively regulating ferroptosis. Besides, GSTM1 was found regulated by GPX4, which was transcriptionally activated by the Wnt/NR2F2 signaling axis in BM. CONCLUSIONS: Collectively, our findings demonstrated that Wnt/NR2F2/GPX4 promoted acquired chemoresistance by suppressing ferroptosis with high consumption of GSH. GPX4 inhibitor was found to augment the anticancer effect of platinum drugs in lung cancer BM, providing novel strategies for lung cancer patients with BM.

4.
Artigo em Inglês | MEDLINE | ID: mdl-34585354

RESUMO

The objective of this study is to investigate the mediating effect of placental inflammatory biomarkers on the relationship between prenatal phthalate coexposure and cognitive development in preschoolers. A subgroup of 1660 mother-child pairs from the Ma'anshan Birth Cohort study were included. We measured the levels of phthalate metabolites of dibutyl phthalate (DBP), butyl benzyl phthalate (BBzP), and di (2-ethylhexyl) phthalate (DEHP) in all the women included in the study from three urine samples collected in each of the trimesters. A potency-weighted sum of coexposure to DBP, BBzP, and DEHP (indicator: ∑PAE) was calculated. The mRNA of the proinflammatory cytokine IL-6 and the classically activated macrophage (M1) biomarker CD68 was analyzed using placental tissues. The Wechsler Preschool and Primary Scale of Intelligence-Fourth Edition-Chinese was used to evaluate the full-scale intelligence quotient (FSIQ) of children aged 2.5-6 years. Average ∑PAEs and ∑PAEs in each trimester were associated with IL-6 and CD68. ∑PAE in the first trimester was positively associated with IL-6 (ß = 0.11, 95% CIs = 0.03-0.19) and CD68 (ß = 0.16, 95% CIs = 0.04-0.28), and negatively associated with FSIQ (ß =-0.06, 95% CIs = -0.11 to -0.02), verbal comprehension (ß =-0.06, 95% CIs = -0.11 to -0.01), and processing speed (ß =-0.07, 95% CIs = -0.12 to -0.01). Additionally, sex discrepancies were observed for the mediating effects of placental inflammation on the relationships between ∑PAE and children's cognitive development. For instance, the association between ∑PAE in early pregnancy and FSIQ was partially mediated by IL-6 (estimated proportion mediated: 21.85%) and CD68 (estimated proportion mediated: 16.2%). Gender-specific associations and trimester-specific relationships of prenatal multiple phthalate coexposure were revealed. ∑PAE in the first trimester of pregnancy was associated with increased of placental inflammation, and a decrease in preschoolers' cognitive development. In boys, placental IL-6 and CD68 elevation resulting from phthalates might be potential mechanisms of poor cognitive development.

5.
Ecotoxicol Environ Saf ; 223: 112569, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34352582

RESUMO

Transgenic-Bacillus thuringiensis (Bt) crops express insecticidal proteins, which can accumulate in plants and soil where they may influence microbial populations. The impact of Bt crops on bacterial communities has only been assessed under short-term, and results have been contradictory. Here, we analyzed the bacterial communities in three niches, rhizosphere soil (RS), root endosphere (RE) and leaf endosphere (LE), of three Bt rice and their non-Bt parental lines for three consecutive years by high-throughput sequencing. In principal coordinate analysis (PCoA) and PERMANOVA (Adonis) analysis, operational taxonomic units (OTUs) were clustered primarily by niche type and differed significantly in the RE and LE but not in the RS between each of three Bt lines compared with the non-Bt rice line, and not in each respective niche among the three Bt rice lines. The bacterial communities in the RS of different rice lines over the 3 years were clustered mainly by year rather than by lines. The differential bacterial taxa among the lines did not overlap between years, presumably because Cry proteins are rapidly degraded in the soil. A network analysis of RS bacterial communities showed that the network complexity and density for the three Bt rice lines did not decrease compared with those for the non-Bt line. In conclusion, our results demonstrated that bacterial communities differed significantly in RE and LE between Bt and non-Bt rice lines, but the differences were mild and transient, and had no adverse impact on RS over the 3 years. This study provides favorable evidence in support of the commercialization of Bt rice.


Assuntos
Bacillus thuringiensis , Oryza , Bacillus thuringiensis/genética , Proteínas de Bactérias/genética , Endotoxinas/genética , Proteínas Hemolisinas/genética , Oryza/genética , Plantas Geneticamente Modificadas , Rizosfera
6.
Mol Plant Pathol ; 22(10): 1256-1270, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34390118

RESUMO

Vesicular trafficking is an important dynamic process that facilitates intracellular transport of biological macromolecules and their release into the extracellular environment. However, little is known about whether or how plant viruses utilize intracellular vesicles to their advantage. Here, we report that southern rice black-streaked dwarf virus (SRBSDV) enters intracellular vesicles in epithelial cells of its insect vector by engaging VAMP7 and Vti1a proteins in the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex. The major outer capsid protein P10 of SRBSDV was shown to interact with VAMP7 and Vti1a of the white-backed planthopper and promote the fusion of vesicles into a large vesicle, which finally fused with the plasma membrane to release virions from midgut epithelial cells. Downregulation of the expression of either VAMP7 or Vti1a did not affect viral entry and accumulation in the gut, but significantly reduced viral accumulation in the haemolymph. It also did not affect virus acquisition, but significantly reduced the virus transmission efficiency to rice. Our data reveal a critical mechanism by which a plant reovirus hijacks the vesicle transport system to overcome the midgut escape barrier in vector insects and provide new insights into the role of the SNARE complex in viral transmission and the potential for developing novel strategies of viral disease control.

7.
Oxid Med Cell Longev ; 2021: 9942090, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34413931

RESUMO

The roots of Vicatia thibetica de Boiss are a kind of Chinese herb with homology of medicine and food. This is the first report showing the property of the extract of Vicatia thibetica de Boiss roots (HLB01) to extend the lifespan as well as promote the healthy parameters in Caenorhabditis elegans (C. elegans). For doxorubicin- (Doxo-) induced premature aging in adult mice, HLB01 counteracted the senescence-associated biomarkers, including P21 and γH2AX. Interestingly, HLB01 promoted the expression of collagen in C. elegans and mammalian cell systemically, which might be one of the essential factors to exert the antiaging effects. In addition, HLB01 was also found as a scavenger of free radicals, thereby performing the antioxidant ability. Lifespan extension by HLB01 was also dependent on DAF-16 and HSF-1 via oxidative stress resistance and heat stress resistance. Taken together, overall data suggested that HLB01 could extend the lifespan and healthspan of C. elegans and resist Doxo-induced senescence in mice via promoting the expression of collagen, antioxidant potential, and stress resistance.

8.
Environ Health Prev Med ; 26(1): 80, 2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34388980

RESUMO

High levels (> 100 ug/L) of arsenic are known to cause lung cancer; however, whether low (≤ 10 ug/L) and medium (10 to 100 ug/L) doses of arsenic will cause lung cancer or other lung diseases, and whether arsenic has dose-dependent or threshold effects, remains unknown. Summarizing the results of previous studies, we infer that low- and medium-concentration arsenic cause lung diseases in a dose-dependent manner. Arsenic trioxide (ATO) is recognized as a chemotherapeutic drug for acute promyelocytic leukemia (APL), also having a significant effect on lung cancer. The anti-lung cancer mechanisms of ATO include inhibition of proliferation, promotion of apoptosis, anti-angiogenesis, and inhibition of tumor metastasis. In this review, we summarized the role of arsenic in lung disease from both pathogenic and therapeutic perspectives. Understanding the paradoxical effects of arsenic in the lungs may provide some ideas for further research on the occurrence and treatment of lung diseases.


Assuntos
Arsênio , Neoplasias Pulmonares , Pulmão , Animais , Arsênio/efeitos adversos , Arsênio/uso terapêutico , Arsênio/toxicidade , Relação Dose-Resposta a Droga , Humanos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/tratamento farmacológico , Camundongos
9.
Tissue Eng Part C Methods ; 27(9): 497-511, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34445889

RESUMO

Skeletal muscle tissue engineering (SMTE) is of great significance in the study of skeletal muscle physiology and pathology, which could be used in skeletal muscle graft. The scientometric analysis of SMTE can help researchers to quickly understand the evolutive history, status, novelties, and trend of this field. In this study, we performed a scientometric study that can be used to construct and visualize networks of SMTE using VOSviewer. A total of 1384 documents published between 1994 and 2020 were retrieved and analyzed. Our results showed that number of publications in SMTE has increased slowly from 1994 to 2014 and has increased rapidly from 2015 to 2020. The geographical distribution of publications in terms of total publications about SMTE is concentrated in Europe and the United States. The most productive institution was University of Michigan, while Harvard University and the University of Pittsburgh were ranked the second and third places. SMTE influenced a wide spectrum of disciplines, including Biology and Medicine and Physical Sciences. In addition, the research hotspot of SMTE was expanding from seed cells to the combination with advanced strategies (electrostatic spinning, bioprinting, and materials) for emulating the highly bionic engineered skeletal muscle tissues. This study provided a unique perspective for understanding the history and trends of SMTE, which could help to promote the rapid development of the field. Impact statement Skeletal muscle tissue engineering (SMTE), which acts as an important branch of tissue engineering, hold a great promise in the study of skeletal muscle physiology and pathology. The field of SMTE has developed rapidly in recent decades while still lacking studies based on scientometric methods. This article provided the first scientometric study of SMTE from development trends and evolution of the field. The results indicated that the field of SMTE was experiencing rapid growth and had a significant impact on multiple fields, particularly in Biology and Medicine and Physical Sciences.

10.
Plant Sci ; 310: 110988, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34315602

RESUMO

Alternative pathway (AP) plays essential roles in plant adaptation to environmental stress. However, the exact role of AP in response to aluminum (Al) toxicity remains elusive. We here provide solid evidences that the activated AP capacity in root tips of soybean alleviated Al toxicity. Furthermore, inhibition of AP by pharmacological or transgenic approach aggravated Al-induced programmed cell death (PCD) occurrence mediated through reactive oxygen species (ROS)-dependent mitochondrial pathway. Our results also demonstrated that nitric oxide (NO) plays a negative role in PCD occurrence caused by Al in soybean root tips. Interestingly, the alleviating effect of NO on Al-induced PCD could be blocked by AP inhibition. Further investigation showed that NO mediates the induction of AP resulting from the upregulation of AOX expression and pyruvate content in Al-treated root tips of soybean. Taken together, our results clearly suggest that AP participates in the alleviation of Al toxicity and also plays a critical role in the alleviating effect of NO on Al-induced PCD occurrence, which will open up new avenues for the improvement of plant growth in acidic soils.


Assuntos
Alumínio/toxicidade , Óxido Nítrico/metabolismo , Soja/metabolismo , Apoptose/efeitos dos fármacos , Proteínas de Plantas/efeitos dos fármacos , Proteínas de Plantas/metabolismo , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Soja/efeitos dos fármacos
11.
Steroids ; 174: 108887, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34237315

RESUMO

BACKGROUND: Activin A has been reported to play important roles in the pathogenesis of atherosclerosis. The purpose of this study is to investigate the effects of activin A on oxidized low-density lipoprotein (ox-LDL)-induced foam cell formation and explore the underlying molecular mechanisms in murine macrophage-like cell line RAW 264.7. METHODS: The effects of activin A on Dil-labeled ox-LDL uptake were examined by confocal microscopy and flow cytometry analysis. The mRNA and protein levels of cholesterol receptors were analyzed by RT-qPCR and western blot analysis, respectively. To investigate whether activin receptor-like kinase 4 (Alk4) is required for activin A-mediated cellular effects, cells were pre-treated with SB-431542. The involvement of Smad2, Smad3 and Smad4 was confirmed by transfection with specific small interfering RNAs (siRNAs). RESULTS: Activin A inhibits ox-ldl-induced foam cell formation and class A scavenger receptors (SR-A) expression, while up-regulates ATP-binding cassette transporter A1 (ABCA1) and ABCG1 expression in RAW 264.7 macrophages. Pre-treatment with SB-431542 abolished activin A-mediated anti-atherogenic effect. Knockdown of Smad2 reversed activin A-induced inhibition of ox-LDL uptake and SR-A expression. However, knockdown of Smad3 or Smad4 did not have such effect. Meanwhile, knockdown of either Smad2, Smad3 or Smad4 reversed the activin A-induced up-regulation of ABCA1 and ABCG1. CONCLUSIONS: Our study provides novel evidence that activin A may exert anti-atherogenic effects through Alk4-Smad signaling pathway in RAW 264.7 macrophages.

12.
Phytomedicine ; 91: 153650, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34332282

RESUMO

BACKGROUND: Diabetic nephropathy (DN) is associated with renal interstitial injury and fibrosis. Our previous study showed that andrographolide protected against the progression of DN and high glucose (HG)-induced mesangial dysfunction. However, the protective effects of andrographolide on renal tubular epithelial cells have not been fully elucidated. PURPOSE: To determine the protective effects of andrographolide on renal tubular damage and explore the underlying mechanism. STUDY DESIGN: Human tubular epithelial cells (HK-2 cells) were treated with andrographolide (5 and 10 µM) under HG conditions. Diabetic mice were treated with andrographolide (i.p. 2 and 4 mg/kg, twice per week). METHODS: Western blotting, reverse transcription-polymerase chain reaction (RT-PCR), immunofluorescence and flow cytometry were used to analyze the effects of andrographolide on renal tubular injury and fibrotic mechanisms in HK-2 cells. The protective effects of andrographolide against renal tubulointerstitial injury and fibrosis were investigated in diabetic mice fed a high-fat diet (HFD). Renal interstitial tissue was collected at sacrifice for immunohistochemistry, immunofluorescence analysis, RT-PCR and Western blotting to analyze the effects of andrographolide on renal tubular injury and fibrosis. RESULTS: In vitro assay results indicated that andrographolide (5 and 10 µM) effectively inhibited HG-induced apoptosis, epithelial-mesenchymal transition (EMT) and collagen deposition in HK-2 cells. Mechanistically, HG stimulated mitochondrial reactive oxygen species (mtROS)-mediated NOD-like receptor family and pyrin domain-containing protein 3 (NLRP3) inflammasome activation and EMT in tubular epithelial cells, and andrographolide (5 and 10 µM) inhibited these effects by ameliorating mitochondrial dysfunction. In vivo, treatment with andrographolide (2 and 4 mg/kg) inhibited renal tubular cell apoptosis, EMT and tubulointerstitial fibrosis, mitochondrial dysfunction and NLRP3 inflammasome activation in diabetic mice. CONCLUSION: Andrographolide (5 and 10 µM) prevents HG-induced renal tubular cell damage, and andrographolide (2 and 4 mg/kg) protects against the progression of diabetic tubular injury and fibrosis in mice by suppressing mitochondrial dysfunction and NLRP3 inflammasome activation.


Assuntos
Diabetes Mellitus Experimental , Nefropatias Diabéticas , Diterpenos/farmacologia , Animais , Células Cultivadas , Diabetes Mellitus Experimental/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Fibrose , Humanos , Inflamassomos , Rim/efeitos dos fármacos , Rim/patologia , Camundongos , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR
13.
Viruses ; 13(6)2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200968

RESUMO

Plant viruses transmitted by hemipteran vectors commonly cause losses to crop production. Rice stripe virus (RSV) and rice black streaked dwarf virus (RBSDV) are transmitted to rice plants by the same vector, the small brown planthopper (SBPH), Laodelphax striatellus Fallén, in a persistent propagative manner. However, rarely do the respective diseases they cause occur simultaneously in a field. Here, we determined the acquisition efficiency of RSV and RBSDV when acquired in succession or simultaneously by SBPH. When RBSDV was acquired first, RSV acquisition efficiency was significantly lower than when only acquiring RSV. However, RBSDV acquisition efficiency from insects that acquired RSV first was not significantly different between the insects only acquiring RBSDV. Immunofluorescence assays showed that the acquisition of RBSDV first might inhibit RSV entry into midgut epithelial cells, but RSV did not affect RBSDV entry. SBPHs were more likely to acquire RBSDV when they were feeding on plants coinfected with the two viruses. When RBSDV was acquired before RSV, RBSDV titer was significantly higher and RSV titer first declined, then increased compared to when only acquiring RBSDV or RSV. Only 5% of the SBPHs acquired both viruses when feeding on plants coinfected with RSV and RBSDV. These results provide a better understanding of the interaction between two persistent viruses when present in the same vector insect and explain why RSV and RBSDV occur in intermittent epidemics.


Assuntos
Insetos Vetores/virologia , Interações Microbianas , Vírus de Plantas/fisiologia , Animais , Mucosa Intestinal/virologia
14.
Autophagy ; : 1-18, 2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34229552

RESUMO

There is increasing evidence that mitophagy, a specialized form of autophagy to degrade and clear long-lived or damaged mitochondria, is impaired in aging and age-related disease. Previous study has demonstrated the obesity-exposed oocytes accumulate and transmit damaged mitochondria due to an inability to activate mitophagy. However, it remains unknown whether mitophagy functions in oocyte and what's the regulatory mechanism in oocyte aging. In the study, when fully grown oocytes were treated with CCCP, an uncoupling agent to induce mitophagy, we found the activation of the PRKN-mediated mitophagy pathway accompanied the blockage of meiosis at metaphase I stage. Our result then demonstrated its association with the decreased activity of RAB7 and all the observed defects in CCCP treated oocytes could be effectively rescued by microinjection of mRNA encoding active RAB7Q67L or treatment with the RAB7 activator ML098. Further study indicated PRKN protein level as a rate-limiting factor to facilitate degradation of RAB7 and its GEF (guanine nucleotide exchange factor) complex CCZ1-MON1 through the ubiquitin-proteasome system. In GV oocytes collected during ovarian aging, we found the age-related increase of PINK1 and PRKN proteins and a significant decrease of RAB7 which resulted in defects of mitophagosome formation and the accumulation of damaged mitochondria. The age-related retardation of female fertility was improved after in vivo treatment of ML098. Thus, RAB7 activity is required to maintain the balance between mitophagy and chromosome stability and RAB7 activator is a good candidate to ameliorate age-related deterioration of oocyte quality.Abbreviations: ATG9: autophagy related 9A; ATP: adenosine triphosphate; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CCCP: carbonyl cyanide 3-chlorophenylhydrazone; CCZ1: CCZ1 vacuolar protein trafficking and biogenesis associated; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GAPs: GTPase-activating proteins; GEF: guanine nucleotide exchange factor; GV: germinal vesicle; GVBD: germinal vesicle breakdown; LAMP1: lysosomal-associated membrane protein 1; MI: metaphase I stage of meiosis; MII: metaphase II stage of meiosis; Mito: MitoTracker; mtDNA: mitochondrial DNA; MON1: MON1 homolog, secretory trafficking associated; OPTN: optineurin; PINK1: PTEN induced putative kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; RAB7: RAB7, member RAS oncogene family; ROS: reactive oxygen species; TEM: transmission electron microscopy; TOMM20/TOM20: translocase of outer mitochondrial membrane 20; TUBB: tubulin, beta; UB: ubiquitin.

15.
Theranostics ; 11(15): 7308-7321, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34158852

RESUMO

Dendritic cells (DCs) can process the antigens of cancer vaccine and thus stimulate the CD8+ T cells to recognize and kill the tumor cells that express these antigens. However, lack of promising carriers for presenting the antigens to DCs is one of the main barriers to the development of clinically effective cancer vaccines. Another limitation is the risk of inflammatory side effects induced by the adjuvants. It is still unclear how we can develop ideal adjuvant-free DC vaccine carriers without adjuvants. Methods: A 12-mer peptide carrier (CBP-12) with high affinity for Clec9a expressed on DCs was developed using an in silico rational optimization method. The therapeutic effects of the adjuvant-free vaccine comprising CBP-12 and exogenous or endogenous antigenic peptides were investigated in terms of antigen cross-presentation efficacy, specific cytotoxic T lymphocyte response, and antitumor activity. We also explored the mechanism involved in the antitumor effects of the adjuvant-free CBP-12 vaccine. Finally, we assessed the effects of the CBP-12 conjugated peptide vaccine combined with radiotherapy. Results: Here, we developed CBP-12 as a vaccine carrier that enhanced the uptake and cross-presentation of the antigens, thus inducing strong CD8+ T cell responses and antitumor effects in both anti-PD-1-responsive (B16-OVA) and -resistant (B16) models, even in adjuvant-free conditions. CBP-12 bound to and activated Clec9a, thereby stimulating Clec9a+ DC to product IL-21, but not IL-12 by activating of Syk. The antitumor effects of the CBP-12 conjugated peptide vaccines could be blocked by an IL-21 neutralizing antibody. We also observed the synergistic antitumor effects of the CBP-12 conjugated peptide vaccine combined with radiotherapy. Conclusions: CBP-12 could serve as an adjuvant-free peptide vaccine carrier for cancer immunotherapy.


Assuntos
Vacinas Anticâncer , Células Dendríticas/imunologia , Sistemas de Liberação de Medicamentos , Interleucinas/imunologia , Lectinas Tipo C/imunologia , Melanoma Experimental/imunologia , Peptídeos , Receptores Imunológicos/imunologia , Transdução de Sinais/efeitos dos fármacos , Quinase Syk/imunologia , Animais , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/farmacologia , Feminino , Interleucinas/genética , Lectinas Tipo C/genética , Melanoma Experimental/genética , Melanoma Experimental/terapia , Camundongos , Camundongos Knockout , Peptídeos/imunologia , Peptídeos/farmacologia , Receptores Imunológicos/genética , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Quinase Syk/genética , Vacinas de Subunidades/imunologia , Vacinas de Subunidades/farmacologia
16.
Cell Prolif ; 54(8): e13080, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34155716

RESUMO

OBJECTIVES: Cell reprogramming has significant impacts on their potential application in regenerative medicine. Chromatin remodelling plays a very important role in cell reprogramming, but its underlying mechanism remains poorly understood. MATERIALS AND METHODS: RNA-seq, quantitative RT-PCR and western blot analysis were applied to study the role of RNF20 and H2B ubiquitination during mouse somatic cell reprogramming. Chromatin structure and the recruitment of transcription factors were analysed by ChIP-seq, micrococcal nuclease sensitivity assays and immunofluorescence staining. RESULTS: We show that RNF20 is highly expressed at the early stage of reprogramming along with the accumulation of H2B ubiquitination at the same stage, and Rnf20 knockout results in the failure of reprogramming at the initial stage but not the maturation and stabilization stages. RNA-seq showed that Rnf20 knockout mainly affects the early stage of cell reprogramming by impairing the transcription of MET-related genes and early pluripotency genes. Importantly, Rnf20 knockout results in a more compacted chromosomes structure in reprogrammable cells, suppressing the recruitment of reprogramming transcription factors to their proper locations on the chromosomes, and finally resulting in the failure of pluripotent gene network establishment. CONCLUSIONS: Histone H2B ubiquitination mediated chromatin relaxation is essential for the induction of somatic cell reprogramming.


Assuntos
Cromatina/metabolismo , Histonas/metabolismo , Animais , Células Cultivadas , Reprogramação Celular , Regulação para Baixo , Camundongos , Camundongos Knockout , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Ubiquitina-Proteína Ligases/deficiência , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação , Regulação para Cima
17.
EMBO J ; 40(13): e106864, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33978233

RESUMO

Current understanding holds that Klinefelter syndrome (KS) is not inherited, but arises randomly during meiosis. Whether there is any genetic basis for the origin of KS is unknown. Here, guided by our identification of some USP26 variations apparently associated with KS, we found that knockout of Usp26 in male mice resulted in the production of 41, XXY offspring. USP26 protein is localized at the XY body, and the disruption of Usp26 causes incomplete sex chromosome pairing by destabilizing TEX11. The unpaired sex chromosomes then result in XY aneuploid spermatozoa. Consistent with our mouse results, a clinical study shows that some USP26 variations increase the proportion of XY aneuploid spermatozoa in fertile men, and we identified two families with KS offspring wherein the father of the KS patient harbored a USP26-mutated haplotype, further supporting that paternal USP26 mutation can cause KS offspring production. Thus, some KS should originate from XY spermatozoa, and paternal USP26 mutations increase the risk of producing KS offspring.

18.
J Vis Exp ; (171)2021 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-34057437

RESUMO

Most plant viruses in nature are transmitted from one plant to another by hemipteran insects. A high population density of the vector insects that are highly efficient at virus transmission plays a key role in virus epidemics in fields. Studying virus-insect vector interactions can advance our understanding of virus transmission and epidemics with the aim of designing novel strategies to control plant viruses and their vector insects. Immunofluorescence labeling has been widely used to analyze interactions between pathogens and hosts and is used here in the white-backed planthopper (WBPH, Sogatella furcifera), which efficiently transmits the southern rice black streaked dwarf virus (SRBSDV, genus Fijivirus, family Reoviridae), to locate the virions and insect proteins in the midgut epithelial cells. Using laser scanning confocal microscopy, we studied the morphological characteristics of midgut epithelial cells, cellular localization of insect proteins, and the colocalization of virions and an insect protein. This protocol can be used to study virus activities in insects, functions of insect proteins, and interactions between virus and vector insect.


Assuntos
Hemípteros , Oryza , Vírus de Plantas , Animais , Proteínas de Insetos , Insetos Vetores , Microscopia de Fluorescência , Doenças das Plantas
19.
Planta ; 253(5): 114, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33934247

RESUMO

MAIN CONCLUSION: Genome-wide identification, analysis and functional characterization of an unreported VvBBX gene showed a response to light and positive correlation with anthocyanin content, but also inhibition of light-induced anthocyanin synthesis. B-box (BBX) proteins are a class of zinc (Zn) finger transcription factors or regulators characterized by the presence of one or two BBX domains and play important roles in plant growth and development. However, the BBX genes' potential functions are insufficiently characterized in grape, a globally popular berry with high economic value. Here, 25 BBX family genes including a novel member (assigned VvBBX44) were identified genome widely in grape. The expression level of these VvBBXs were analyzed in 'Cabernet Sauvignon' (V. vinifera) stem, flower, leaf, tendril, petiole, and developing berries. The expression of VvBBX44 increased in developing 'Cabernet Sauvignon' berries. Its expression was inhibited in 'Jingxiu' and 'Muscat Hamburg' berry skin without sunlight. Furthermore, overexpression of VvBBX44 decreased the expression of LONG HYPOCOTYL 5 (VvHY5) and UDP-glucose flavonoid 3-O-glucosyltransferase (VvUFGT), and reduced the anthocyanin content in grape calli. Our results suggest that VvBBX44 may play an important role in grape berry coloring by directly repressing VvHY5 expression. This study provides new insights into the potential role of VvBBXs in berry development and light response and contributes to the understanding on the regulation mechanism of VvBBX44 in anthocyanin biosynthesis.


Assuntos
Vitis , Antocianinas , Frutas/genética , Frutas/metabolismo , Regulação da Expressão Gênica de Plantas , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Vitis/genética , Vitis/metabolismo
20.
Vet Microbiol ; 256: 109038, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33845332

RESUMO

Cholesterol 25-hydroxylase (CH25 H), as a host restriction factor, has been reported to take a broad-spectrum antiviral effect. However, the role of CH25H in Senecavirus A (SVA) infection remains unknown. In this study, we first demonstrate that overexpression of CH25H inhibits SVA replication. Consistently, knockdown or knockout of the endogens CH25H promotes SVA infection. Further, the anti-SVA effect of 25-hydroxycholesterol (25HC), which is the product of CH25H, operates via inhibition of viral attachment and replication. On the other hand, the CH25H mutant (CH25H-M) lacking hydroxylase activity still restricts SVA infection, which can selectively interact and degrade SVA 3A protein via the ubiquitin-proteasome manner. Altogether, these results suggest that CH25H has an antiviral function in SVA infection and provides an alternative manner to control SVA.


Assuntos
Infecções por Picornaviridae/prevenção & controle , Picornaviridae/fisiologia , Esteroide Hidroxilases/metabolismo , Replicação Viral , Animais , Antivirais , Linhagem Celular , Cricetinae , Técnicas de Silenciamento de Genes , Técnicas de Inativação de Genes , Mutação , Infecções por Picornaviridae/virologia , Esteroide Hidroxilases/genética
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