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1.
Braz. j. biol ; 84: e250575, 2024. tab, graf
Artigo em Inglês | MEDLINE, LILACS, VETINDEX | ID: biblio-1350309

RESUMO

Abstract Cancer is a fatal malignancy and its increasing worldwide prevalence demands the discovery of more sensitive and reliable molecular biomarkers. To investigate the GINS1 expression level and its prognostic value in distinct human cancers using a series of multi-layered in silico approach may help to establish it as a potential shared diagnostic and prognostic biomarker of different cancer subtypes. The GINS1 mRNA, protein expression, and promoter methylation were analyzed using UALCAN and Human Protein Atlas (HPA), while mRNA expression was further validated via GENT2. The potential prognostic values of GINS1 were evaluated through KM plotter. Then, cBioPortal was utilized to examine the GINS1-related genetic mutations and copy number variations (CNVs), while pathway enrichment analysis was performed using DAVID. Moreover, a correlational analysis between GINS1 expression and CD8+ T immune cells and a the construction of gene-drug interaction network was performed using TIMER, CDT, and Cytoscape. The GINS1 was found down-regulated in a single subtypes of human cancer while commonly up-regulated in 23 different other subtypes. The up-regulation of GINS1 was significantly correlated with the poor overall survival (OS) of Liver Hepatocellular Carcinoma (LIHC), Lung Adenocarcinoma (LUAD), and Kidney renal clear cell carcinoma (KIRC). The GINS1 was also found up-regulated in LIHC, LUAD, and KIRC patients of different clinicopathological features. Pathways enrichment analysis revealed the involvement of GINS1 in two diverse pathways, while few interesting correlations were also documented between GINS1 expression and its promoter methylation level, CD8+ T immune cells level, and CNVs. Moreover, we also predicted few drugs that could be used in the treatment of LIHC, LUAD, and KIRC by regulating the GINS1 expression. The expression profiling of GINS1 in the current study has suggested it a novel shared diagnostic and prognostic biomarker of LIHC, LUAD, and KIRC.


Resumo O câncer é uma doença maligna fatal e sua crescente prevalência mundial exige a descoberta de biomarcadores moleculares mais sensíveis e confiáveis. Investigar o nível de expressão de GINS1 e seu valor prognóstico em cânceres humanos distintos, usando uma série de abordagens in silico em várias camadas, pode ajudar a estabelecê-lo como um potencial biomarcador de diagnóstico e prognóstico compartilhado de diferentes subtipos de câncer. O mRNA de GINS1, a expressão da proteína e a metilação do promotor foram analisados ​​usando UALCAN e Human Protein Atlas (HPA), enquanto a expressão de mRNA foi posteriormente validada via GENT2. Os valores prognósticos potenciais de GINS1 foram avaliados por meio do plotter KM. Em seguida, o cBioPortal foi utilizado para examinar as mutações genéticas relacionadas ao GINS1 e as variações do número de cópias (CNVs), enquanto a análise de enriquecimento da via foi realizada usando DAVID. Além disso, uma análise correlacional entre a expressão de GINS1 e células imunes T CD8 + e a construção de uma rede de interação gene-droga foi realizada usando TIMER, CDT e Cytoscape. O GINS1 foi encontrado regulado negativamente em um único subtipo de câncer humano, enquanto comumente regulado positivamente em 23 outros subtipos diferentes. A regulação positiva de GINS1 foi significativamente correlacionada com a sobrevida global pobre (OS) de Carcinoma Hepatocelular de Fígado (LIHC), Adenocarcinoma de Pulmão (LUAD) e Carcinoma de Células Claras Renais de Rim (KIRC). O GINS1 também foi encontrado regulado positivamente em pacientes LIHC, LUAD e KIRC de diferentes características clínico-patológicas. A análise de enriquecimento de vias revelou o envolvimento de GINS1 em duas vias diversas, enquanto poucas correlações interessantes também foram documentadas entre a expressão de GINS1 e seu nível de metilação do promotor, nível de células imunes T CD8 + e CNVs. Além disso, também previmos poucos medicamentos que poderiam ser usados ​​no tratamento de LIHC, LUAD e KIRC, regulando a expressão de GINS1. O perfil de expressão de GINS1 no estudo atual sugeriu que é um novo biomarcador de diagnóstico e prognóstico compartilhado de LIHC, LUAD e KIRC.


Assuntos
Humanos , Carcinoma de Células Renais/genética , Neoplasias Renais/genética , Neoplasias Hepáticas , Prognóstico , Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica , Regulação para Cima , Proteínas de Ligação a DNA , Variações do Número de Cópias de DNA
2.
Front Cell Dev Biol ; 10: 807289, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35372338

RESUMO

Schistosomiasis is a life-threatening parasitic disease caused by blood flukes, Schistosomes. In its intestinal type, the parasites reside in visceral/portal veins of the human hosts and lay eggs to excrete in feces via intestinal tracts, and some of the aberrant eggs plug into the liver via the portal blood flow. Ectopic growth of these eggs causes fatal granulomatosis and cirrhosis of the liver. The parasites ingest nutrients from the host blood plasma by using nonspecific and specific transport via their body surface and alimentary tracts. It is especially important for the female adults to obtain lipid molecules because they synthesize neither fatty acids nor sterols and yet produce egg yolk. Low-density lipoprotein receptors have been identified in the body of the Schistosomes but their functions in the parasite life cycle have not clearly been characterized. On the other hand, CD36-related protein was identified in the body and the eggs of Asian blood fluke, Schistosoma japonicum, and characterized as a molecule that mediates selective uptake of cholesteryl ester from the host plasma high-density lipoproteins (HDLs). This reaction was shown crucial for their eggs to grow to miracidia. Interestingly, abnormal large HDL generated in lack of cholesteryl ester transfer protein (CETP) is a poor substrate for this reaction, and, therefore, CETP deficiency resists pathogenic ectopic growth of the aberrant parasite eggs in the liver. This genetic mutation is exclusively found in East Asia, overlapping with the current and historic regions of Schistosoma japonicum epidemic, so that this infection could be related to high prevalence of CETP deficiency in East Asia.

3.
Clin. transl. oncol. (Print) ; 24(6): 1148-1156, junio 2022.
Artigo em Inglês | IBECS | ID: ibc-203813

RESUMO

PurposeAppropriate sub-classification of leukemia according to the immunophenotypic characteristics of the malignant cells may improve therapeutic strategies. The aim of this study was to investigate the prognostic value of CD10/CD34 surface markers in pediatric acute lymphoblastic leukemia (pALL).Patients and methodsA retrospective cohort study was performed in 79 children with ALL. Possible correlation between leukemia prognosis and CD10 CD34 immunophenotype was assessed using Kaplan–Meier and Cox regression analyses. A CD10- CD34- pre-B-ALL cell line was generated from a patient with resistant ALL. RN95 was characterized using light microscopy, immunophenotyping, karyotyping, and Western blotting. Drug sensitivity and resistant genes’ expression profile were assessed using MTT and RT-PCR assays.ResultsKaplan–Meier analysis showed negative correlation between CD10/CD34 double negativity and patients’ 2- and 5-year disease-free survival (DFS). Multivariate analysis indicated that the absence of CD10 and CD34 expression in the ALL patients was an independent negative prognostic marker for 2- and 5-year DFS. A novel cell line model, RN95, was developed with similar immunophenotype from a primary relapsed sample. Cells showed p53 positive functionality and demonstrated partial sensitivity to Vincristine, but complete resistance to Cytarabine. Overexpression of ABCB1, ABCA2, and ABCA3 was detected.ConclusionIn the current study, simultaneous absence of CD10 and CD34 cell surface markers was introduced as an unfavorable prognostic factor in pediatric B-ALL. Moreover, a special cell line was established to help delineation of novel therapeutics for B-ALL drug resistance.


Assuntos
Humanos , Antígenos CD34 , Linhagem Celular , Neprilisina/análise , Neprilisina/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Resistência a Medicamentos , Estudos Retrospectivos
4.
Clin. transl. oncol. (Print) ; 24(6): 1157-1167, junio 2022. tab, graf
Artigo em Inglês | IBECS | ID: ibc-203814

RESUMO

PurposeA significant percentage of colorectal cancer patients proceeds to metastatic disease. We hypothesised that mitochondrial DNA (mtDNA) polymorphisms, generated by the high mtDNA mutation rate of energy-demanding clonal immune cell expansions and assessable in peripheral blood, reflect how efficiently systemic immunity impedes metastasis.Patients and methodsWe studied 44 rectal cancer patients from a population-based prospective biomarker study, given curative-intent neoadjuvant radiation and radical surgery for high-risk tumour stage and followed for metastatic failure. Blood specimens were sampled at the time of diagnosis and analysed for the full-length mtDNA sequence, composition of immune cell subpopulations and damaged serum mtDNA.ResultsWhole blood total mtDNA variant number above the median value for the study cohort, coexisting with an mtDNA non-H haplogroup, was representative for the mtDNA of circulating immune cells and associated with low risk of a metastatic event. Abundant mtDNA variants correlated with proliferating helper T cells and cytotoxic effector T cells in the circulation. Patients without metastatic progression had high relative levels of circulating tumour-targeting effector T cells and, of note, the naïve (LAG-3+) helper T-cell population, with the proportion of LAG-3+ cells inversely correlating with cell-free damaged mtDNA in serum known to cause antagonising inflammation.ConclusionNumerous mtDNA polymorphisms in peripheral blood reflected clonal expansion of circulating helper and cytotoxic T-cell populations in patients without metastatic failure. The statistical associations suggested that patient’s constitutional mtDNA manifests the helper T-cell capacity to mount immunity that controls metastatic susceptibility.


Assuntos
Humanos , DNA Mitocondrial/genética , Mitocôndrias/genética , Neoplasias Retais/genética , Estudos Prospectivos , Metástase Neoplásica
5.
Mult Scler Relat Disord ; 63: 103914, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35661565

RESUMO

BACKGROUND: It is urgent to increase studies aimed at exploring and understanding the role that psychological resilience plays in PwMS. To achieve this objective, an important requirement is to have properly validated instruments that allow exploring psychological resilience in MS patients. The aim of this study was to evaluate the validity and reliability of the 10-item CD-RISC in a sample of Spanish-speaking patients with MS (PwMS). METHODS: An online multicenter study was conducted on 214 MS patients from 11 Spanish-speaking countries (Argentina, Mexico, Dominican Republic, Chile, Spain, Cuba, Colombia, Uruguay, Paraguay, Peru, and El Salvador). Confirmatory factor analysis (CFA) was performed to assess the factor structure of the 10-item CD-RISC. Model fits were assessed through the χ2/df value, comparative fit index (CFI), and root mean square error of approximation (RMSEA). RESULTS: The 10-item CD-RISC showed good psychometric characteristics in our sample of PwMS. The single-factor model in the CFA yielded a good model fit (χ2=99.380(35), p<.001; χ2/df = 2.83; RMSEA=.090; CFI=.92). Cronbach's alpha of the CD-RISC-10 items version (Spanish version) was .88. The CD-RISC-10 was significantly correlated with quality of life scale (r = .420, p < .001), fear of relapse scale (r = -.327, p < .001), and fatigue scale (r = -.367, p < .001). CONCLUSIONS: The CD-RISC-10 has satisfactory psychometric properties and is a suitable tool for measuring resilience in Spanish-speaking patients with multiple sclerosis.

6.
J Immunol Methods ; 507: 113296, 2022 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-35675843

RESUMO

Microvascular endothelial cells (MVECs) have been an important tool in many research fields, while their purification remained challenging, particularly from thin and fragile tissues, such as murine intestinal mucosae. Therefore, we established an immunomagnetic method for isolating rat intestinal mucosal MVECs using an automatic magnetic separation system from the primary cell culture, which was preliminarily purified by the differential adhesion combined with mechanically scraping method. The CD31+ cells were separated and their purity was about 96.5%, which grew into a contact-inhibited cobblestone-like monolayer after about 6-day incubation. Transmission electron microscopy analysis showed the presence of Weibel-Palade bodies. The endothelial tubes formed on Matrigel for about 4-h cultivation. The MVECs could grow well until at least passage 10. Immunofluorescence staining indicated that factor VIII (FVIII), CD31 and CD34 were generally expressed in the MVECs. The fluorescence intensity of FVIII was higher after magnetic separation than before, while those of CD31 and CD34 didn't have significant difference. In conclusion, highly pure MVECs were isolated from rat intestinal mucosae using magnetic beads coated with anti-CD31 antibodies, and magnetic separation may influence the expression of FVIII.

7.
Immunology ; 2022 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-35689599

RESUMO

In the gut, secretory immunoglobulin A is the predominant humoral response against commensals, although healthy hosts also produce microbiota-specific IgG antibodies. During intestinal inflammation, the content of IgG in the lumen increases along with the proportion of commensal bacteria coated with this antibody, suggesting signalling through the IgG-CD64 axis in the pathogenesis of inflammatory bowel diseases. In this work, we evaluated day by day the frequency of faecal bacteria coated with IgA and IgG during the development of DSS colitis. We studied the phenotype and phagocytic activity of F4/80+ CD64+ colonic macrophages, as well as the production of cytokines and nitric oxide by lamina propria or bone marrow-derived macrophages after stimulation with IgA+ , IgG+ and IgA+ IgG+ bacteria. We found that the percentage of faecal IgA+ IgG+ double-coated bacteria increased rapidly during DSS colitis. Also, analysis of the luminal content of mice with colitis showed a markedly superior ability to coat fresh bacteria. IgA+ IgG+ bacteria were the most potent stimulus for phagocytic activity involving CD64 and Dectin-1 receptors. IgA+ IgG+ bacteria observed during the development of DSS colitis could represent a new marker to monitor permeability and inflammatory progression. The interaction of IgA+ IgG+ bacteria with CD64+ F4/80+ macrophages could be part of the complex cascade of events in colitis. Interestingly, after stimulation, CD64+ colonic macrophages showed features similar to those of restorative macrophages that are relevant for tissue repair and healing.

8.
Mol Immunol ; 149: 13-26, 2022 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-35696849

RESUMO

Multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) are demyelinating neuroinflammatory diseases identified by the accumulation and aggregation of misfolded proteins in the brain. The Sel1L-Hrd1 complex comprising endoplasmic reticulum associated degradation (ERAD) is an ER-protein quality control system (ERQC) in the cell. Unfortunately, the contribution of ERAD to the development of these diseases has not been well explored. In this study, we used mice with a conditional deletion (KO) of Sel1L in T cells to dissect the role of ERAD on T cells and its contribution to the development of EAE. The results showed that Sel1L KO mice developed more severe EAE than the control wild type (WT) mice. Although, no obvious effects on peripheral T cells in steady state, more CD44-CD25+ double-negative stage 3 (DN3) cells were detected in the thymus. Moreover, Sel1L deficiency promoted the differentiation of Th1 and Th17 cells and upregulated the proliferation and apoptosis of CD4 T cells in vitro. Regarding the mechanism analyzed by RNA sequencing, 437 downregulated genes and 271 upregulated genes were detected in Sel1L deletion CD4 T cells, which covered the activation, proliferation, differentiation and apoptosis of these T cells. Thus, this study declared that the dysfunction of Sel1L in ERAD in T cells exacerbated the severity of EAE and indicated the important role of ERQC in maintaining immune homeostasis in the central nervous system.

9.
Immunity ; 2022 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-35750048

RESUMO

As the establishment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cell memory in children remains largely unexplored, we recruited convalescent COVID-19 children and adults to define their circulating memory SARS-CoV-2-specific CD4+ and CD8+ T cells prior to vaccination. We analyzed epitope-specific T cells directly ex vivo using seven HLA class I and class II tetramers presenting SARS-CoV-2 epitopes, together with Spike-specific B cells. Unvaccinated children who seroconverted had comparable Spike-specific but lower ORF1a- and N-specific memory T cell responses compared with adults. This agreed with our TCR sequencing data showing reduced clonal expansion in children. A strong stem cell memory phenotype and common T cell receptor motifs were detected within tetramer-specific T cells in seroconverted children. Conversely, children who did not seroconvert had tetramer-specific T cells of predominantly naive phenotypes and diverse TCRαß repertoires. Our study demonstrates the generation of SARS-CoV-2-specific T cell memory with common TCRαß motifs in unvaccinated seroconverted children after their first virus encounter.

10.
Chemosphere ; : 135427, 2022 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-35750231

RESUMO

The toxic chemical element cadmium (Cd) in paddy fields triggered increasing problems of growth inhibition and food security in rice consistently. In this study, we found Metarhizium robertsii, which is widely used as a bioinsecticide and biofertilizer in agriculture and recently found to be resistant to Cd, developed intraradical and extraradical symbiotic hyphae in rice seedlings, and successfully colonized in the rice rhizosphere soil to more than 103 CFUs g-1 soil at harvesting. M. robertsii colonization significantly reduced Cd accumulations in both hydroponically cultured seedlings and the matured rice cultured in Cd contaminated potting soil (2 ppm). Notably, Cd accumulation reduction of the roots, stems, leaves, husks and grains of the matured rice induced by the fungus were 44.3%, 32.1%, 35.3%, 31.9% and 24.7%, respectively. It was caused by the M. robertsii-induced suppression of Cd intake transporter gene osNramp5 in the rice roots, and the chemical stabilizing of Cd to the residual fraction in the rhizosphere soil. In addition, the colonization of M. robertsii significantly promoted the growth characters and the photosynthesis of the rice plants. This is achieved by the increase of endogenous hormone levels of indole-3-acetic, gibberellin A3 and brassinolide induced by M. robertsii. Furthermore, the fungus enhanced the antioxidative capacities via increasing enzyme activities of catalase, peroxidase and the production of glutathione, ascorbic acid, proline in the rice plants. Our work provides theoretical basis for expanding the use of M. robertsii as in situ Cd accumulation reduction and detoxification agents for rice in contaminated paddy fields.

11.
Immunology ; 2022 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-35751879

RESUMO

Though the PD-L1 checkpoint inhibitor avelumab has shown efficacy in the treatment of some types of cancer, improved treatment strategies are desperately needed. We evaluated whether combined treatment with avelumab and adoptively transferred T-NK cells can provide enhanced anti-cancer effects for treating PD-L1-expressing tumors. Our results demonstrate that avelumab specifically targets tumor cells with high PD-L1 expression, and that cytolytic effects are mediated by T-NK effector cells cultured from patient peripheral blood monocytic cell populations. The effects were dependent on CD16 and the perforin/granzyme pathway, supporting a role for the T-NK subpopulation. In vivo assays verified the efficacy of T-NK cells in combination with avelumab in reducing tumor growth. Furthermore, T-NK + avelumab prolonged survival in a mouse orthotopic xenograft model. Collectively, our findings provide a basis for the combined use of adoptively transferred T-NK cells with avelumab as a novel strategy for cancer treatment.

12.
EBioMedicine ; 81: 104090, 2022 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-35665682

RESUMO

BACKGROUND: Dysfunction of CD8+ T cells in people living with HIV-1 (PLWH) receiving anti-retroviral therapy (ART) has restricted the efficacy of dendritic cell (DC)-based immunotherapies against HIV-1. Heterogeneous immune exhaustion and metabolic states of CD8+ T cells might differentially associate with dysfunction. However, specific parameters associated to functional restoration of CD8+ T cells after DC treatment have not been investigated. METHODS: We studied association of restoration of functional HIV-1-specific CD8+ T cell responses after stimulation with Gag-adjuvant-primed DC with ART duration, exhaustion, metabolic and memory cell subsets profiles. FINDINGS: HIV-1-specific CD8+ T cell responses from a larger proportion of PLWH on long-term ART (more than 10 years; LT-ARTp) improved polyfunctionality and capacity to eliminate autologous p24+ infected CD4+ T cells in vitro. In contrast, functional improvement of CD8+ T cells from PLWH on short-term ART (less than a decade; ST-ARTp) after DC treatment was limited. This was associated with lower frequencies of central memory CD8+ T cells, increased co-expression of PD1 and TIGIT and reduced mitochondrial respiration and glycolysis induction upon TCR activation. In contrast, CD8+ T cells from LT-ARTp showed increased frequencies of TIM3+ PD1- cells and preserved induction of glycolysis. Treatment of dysfunctional CD8+ T cells from ST-ARTp with combined anti-PD1 and anti-TIGIT antibodies plus a glycolysis promoting drug restored their ability to eliminate infected CD4+ T cells. INTERPRETATION: Together, our study identifies specific immunometabolic parameters for different PLWH subgroups potentially useful for future personalized DC-based HIV-1 vaccines. FUNDING: NIH (R21AI140930), MINECO/FEDER RETOS (RTI2018-097485-A-I00) and CIBERINF grants.

13.
Biochim Biophys Acta Mol Cell Res ; 1869(9): 119303, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35659617

RESUMO

OBJECTIVE: Glioma stem cells (GSCs) are a minority population of glioma cells that regarded as the cause of tumor formation and recurrence. Identifying new molecular strategies targeting GSCs must be urgently developed to treat glioblastoma. In this study, one of CD98 light chain-L type amino acid transporter 1 (LAT1) was found as a potential GSC marker. LAT1 served as EAA transporter has been shown to be closely related with tumor invasion, metastasis, angiogenesis, and radiosensitivity. METHODS: LAT1+ and LAT1- glioma cells were sorted by flow cytometry. Cellular immunofluorescence, sphere-formation arrays, and in vitro limiting dilution experiments were used to identify cell stemness. Differentiated glioma stem cells were cultured, and the expressions of ß-tubulinIII, GFAP, and LAT1 were detected by Western blot. Nude mouse models were constructed to observe tumor formation and metastasis in nude mice. RESULTS: LAT1+ glioma cells were testified a small percentage of all cells and selected as the subsequent sorting marker. LAT1+ cells were separated from U87 and U251 cells could express high level of stem cell markers, and possessed GSC properties including self-renewal ability and multi-directional differentiation potential. But LAT1- cells did not have these characteristics. In addition, LAT1+ cells were able to generate tumors in vivo, tumor size of LAT1+ cells formed were much bigger than that of LAT1- cells. CONCLUSION: Our study, including molecular, cell, vitro and vivo experiments, has shown that LAT1+ cells possess GSC properties, and present for the first time that LAT1 can be used as a new marker for GSCs screening.


Assuntos
Glioblastoma , Glioma , Animais , Linhagem Celular Tumoral , Glioblastoma/metabolismo , Glioma/patologia , Camundongos , Camundongos Nus , Células-Tronco Neoplásicas/metabolismo
14.
Eur J Immunol ; 2022 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-35689391

RESUMO

Higher frequencies of polyfunctional PD1+ CD8+ T cells exhibited a stronger capacity to kill tumor cells in vitro and in vivo experiments. These results suggested that peripheral polyfunctional PD1+ CD8+ T cells demonstrated strong immune protection. This study also provided a potential combined treatment strategy with anti-PD1 and CAR-T therapy.

15.
Exp Cell Res ; 417(2): 113219, 2022 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-35643179

RESUMO

Induction of differentiation sensitizes chronic myeloid leukemia (CML) cells to the BCR-ABL inhibitor imatinib by mechanisms that remain unknown. We previously identified the BCR-ABL downstream effector CD69 which inhibits imatinib-induced CML cell differentiation. Herein, we found that the erythroid differentiation inducers activin A and aclacinomycin A induced expression of erythroid markers (α-globin, ζ-globin, GATA-1, and glycophorin A) and simultaneously reduced CD69 levels in K562 CML cells. Blockade of p38MAPK by SB203580 and shRNA eliminated the inhibitory effect of activin A on the promoter, mRNA, and protein levels and positive cell population of CD69. CD69 overexpression inhibited activin A-induced erythroid marker expression. Pretreatment of K562 cells with activin A to induce differentiation followed by a subtoxic concentration of imatinib caused growth inhibition and apoptosis that was reduced by CD69 overexpression. Activin A also reduced the expression of CD69's potential downstream molecule metallothionein 2A (MT2A) via p38MAPK. MT2A-knockdown reduced CD69 inhibition of activin A-induced erythroid marker expression. Furthermore, MT2A-knockdown reduced CD69 inhibition of activin A-imatinib sequential treatment-mediated growth inhibition and apoptosis in K562 and BCR-ABL-expressing CD34+ cells. These results suggest that CD69 inhibits activin A induction of erythroid differentiation-mediated CML cell sensitivity to imatinib via MT2A. Therefore, activin A induction of erythroid differentiation sensitizes BCR-ABL-positive cells to imatinib by downregulating the erythroid differentiation suppressors CD69 and MT2A.


Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Proteínas Quinases p38 Ativadas por Mitógeno , Ativinas , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Apoptose , Diferenciação Celular , Resistencia a Medicamentos Antineoplásicos , Proteínas de Fusão bcr-abl/metabolismo , Humanos , Mesilato de Imatinib/farmacologia , Células K562 , Lectinas Tipo C/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Metalotioneína , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
16.
Sci Total Environ ; 839: 156290, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-35644402

RESUMO

The excessive accumulation of wheat grain metals and metalloids caused by ambient air contamination has drawn an increasing concern. However, at present, the differences in the pathways of cadmium and lead accumulation in wheat grains in an air-soil-wheat system are not clear. In this study, wheat was grown around a lead­zinc smelting area and exposed to different soil Pb and Cd levels and different ambient air Pb and Cd levels. Lead and Cd accumulation in wheat grains was examined in this study. Two models of wheat grain Pb and Cd concentrations were established based on the 3 variables including soil Pb and Cd concentration, ambient air Pb and Cd concentration, and soil pH. The results showed that total suspended particulate (TSP), soil, and wheat grains exhibited different degrees of Pb and Cd contamination in the study area, and the contamination of Cd is more serious than Pb contamination. The Pb in wheat grains was more likely to derive from ambient air than from soil, whereas the impact of ambient air on the accumulation of Cd in wheat grains might be very limited. This speculation was confirmed by the results of the predictor variable relative weight method based on the multiple regression analysis. Introduction of ambient air factor (TSP Pb and Cd) greatly improved the modeling effect of wheat grains Pb, while the modeling of grain Cd was more dependent on soil pH and total soil Cd. This research suggests that the reduction in wheat grain Pb is likely to be achieved by the control over ambient air Pb, whereas the reduction in the wheat grain Cd by the remediation of soil pollutants.


Assuntos
Poluentes do Solo , Solo , Cádmio/análise , Poeira/análise , Grão Comestível/química , Chumbo/análise , Poluentes do Solo/análise , Triticum/metabolismo , Zinco/análise
17.
Environ Pollut ; 307: 119559, 2022 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-35654253

RESUMO

Arbuscular mycorrhizal fungi (AMF) and plant rhizosphere microbes reportedly enhance plant tolerance to abiotic stresses and promote plant growth in contaminated soils. The co-contamination of soil by heavy metals (e.g., Cd) and rare earth elements (e.g., La) represents a severe environmental problem. Although the influence of AMF in the phytoremediation of contaminated soils is well documented, the underlying interactive mechanisms between AMF and rhizosphere microbes are still unclear. We conducted a greenhouse pot experiment to evaluate the effects of AMF (Claroideoglomus etunicatum) on maize growth, nutrient and metal uptake, rhizosphere microbial community, and functional genes in soils with separate and combined applications of Cd and La. The purpose of this experiment was to explore the mechanism of AMF affecting plant growth and metal uptake via interactions with rhizosphere microbes. We found that C. etunicatum (i) significantly enhanced plant nutritional level and biomass and decreased metal concentration in the co-contaminated soil; (ii) significantly altered the structure of maize rhizosphere bacterial and fungal communities; (iii) strongly enriched the abundance of carbohydrate metabolism genes, ammonia and nitrate production genes, IAA (indole-3-acetic acid) and ACC deaminase (1-aminocyclopropane-1-carboxylate) genes, and slightly altered the abundance of P-related functional genes; (iv) regulated the abundance of microbial quorum sensing system and metal membrane transporter genes, thereby improving the stability and adaptability of the rhizosphere microbial community. This study provides evidence of AMF improving plant growth and resistance to Cd and La stresses by regulating plant rhizosphere microbial communities and aids our understanding of the underlying mechanisms.


Assuntos
Metais Pesados , Microbiota , Micorrizas , Poluentes do Solo , Biodegradação Ambiental , Cádmio/análise , Fungos , Metais Pesados/análise , Micorrizas/metabolismo , Raízes de Plantas/metabolismo , Plantas/metabolismo , Rizosfera , Solo/química , Microbiologia do Solo , Poluentes do Solo/análise , Zea mays/metabolismo
18.
Cell Rep ; 39(11): 110952, 2022 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-35675811

RESUMO

Sequence homology between SARS-CoV-2 and common-cold human coronaviruses (HCoVs) raises the possibility that memory responses to prior HCoV infection can affect T cell response in COVID-19. We studied T cell responses to SARS-CoV-2 and HCoVs in convalescent COVID-19 donors and identified a highly conserved SARS-CoV-2 sequence, S811-831, with overlapping epitopes presented by common MHC class II proteins HLA-DQ5 and HLA-DP4. These epitopes are recognized by low-abundance CD4 T cells from convalescent COVID-19 donors, mRNA vaccine recipients, and uninfected donors. TCR sequencing revealed a diverse repertoire with public TCRs. T cell cross-reactivity is driven by the high conservation across human and animal coronaviruses of T cell contact residues in both HLA-DQ5 and HLA-DP4 binding frames, with distinct patterns of HCoV cross-reactivity explained by MHC class II binding preferences and substitutions at secondary TCR contact sites. These data highlight S811-831 as a highly conserved CD4 T cell epitope broadly recognized across human populations.


Assuntos
COVID-19 , SARS-CoV-2 , Alelos , Linfócitos T CD4-Positivos , Vacinas contra COVID-19 , Epitopos de Linfócito T , Antígenos HLA , Humanos , Receptores de Antígenos de Linfócitos T
19.
J Hazard Mater ; 436: 129216, 2022 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-35739738

RESUMO

Iron (Fe) oxides and fulvic acid (FA) are the key components affecting the fate of cadmium (Cd) in soil. The presence of FA influences Fe mineral transformation, and FA may complicate phase transformation and dynamic behavior of Cd. How varying Fe minerals and FA affect Cd immobilization during the ferrihydrite transformation induced by various Fe(II) concentrations, however, is still lack of quantitative understanding. In this study, we built a model for Cd species quantification during phase transformation based on mechanistic insights obtained from batch experiments. Spectroscopic analysis showed that Fe(II) concentrations affected secondary Fe minerals formation under the condition of co-existence of Cd and FA, and ultimately changed the distribution of Cd and FA. Microscopic analysis revealed that besides surface adsorption, part of Cd was sequestrated by magnetite, whereas FA was able to diffuse into lepidocrocite defects. The model revealed that adsorbed Cd was mainly controlled by FA and ferrihydrite, and direct complexation of Cd by FA had a strong impact on the continuous change in Cd at lower Fe(II) concentration. The results contribute to an in-depth understanding of the mobility of Cd in the environment and provide a method for quantifying the dynamic behavior of heavy metals in multi-reactant systems.

20.
Antioxidants (Basel) ; 11(6)2022 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-35740005

RESUMO

Platelets play a role in transfusion reaction via reactive oxygen species (ROS) generation and CD40 ligand (CD40L) expression. In this study, we aimed to test the hypothesis that the mixing of packed red blood cells (pRBCs) and washed platelets has a causal effect on platelet ROS generation and CD40L expression. Thus, a better understanding of this causality relationship may help interrupt the chain of events and avoid an uncontrollable transfusion reaction. We simulated transfusion in vitro by mixing pRBCs and washed platelets. Donor cross-matched stored pRBCs) from our blood bank and recipient whole blood from patients undergoing coronary artery bypass graft surgery prepared into washed platelets were used. Briefly, donor pRBCs were added to washed recipient platelets to form 1%, 5%, or 10% (v/v) mixtures. The mixed blood sample was used to determine platelet ROS generation (dichlorofluorescein fluorescence levels) and CD40L expression. The effect of antioxidants (20 mM glutamine and 20 mM dipeptiven) on ROS generation and CD40L expression was also evaluated. Platelet ROS generation was not significantly associated with the mixing of pRBCs and washed platelets (p = 0.755), glutamine treatment (p = 0.800), or dipeptiven treatment (p = 0.711). The expression of CD40L by platelets increased significantly (p < 0.001), and no significant difference was noted after treatment with glutamine (p = 0.560) or dipeptiven (p = 0.618). We observed that the mixing pRBCs and washed platelets had no effect via ROS, whereas CD40L could directly induce transfusion reactions. Furthermore, platelets did not causally express ROS or CD40L after being mixed with pRBCs. Although antioxidants are more accessible than anti-CD40L antibodies, platelet ROS may not serve as a therapeutic target for antioxidants. Nevertheless, CD40L expression may be a valuable therapeutic target for managing transfusion reactions.

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