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1.
Front Immunol ; 13: 879501, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35572579

RESUMO

T cell hyporesponsiveness is crucial for the functional immune system and prevents the damage induced by alloreactive T cells in autoimmune pathology and transplantation. Here, we found low expression of PRDM1 in T cells from donor and recipients both related to the occurrence of acute graft-versus-host disease (aGVHD). Our systematic multiomics analysis found that the transcription factor PRDM1 acts as a master regulator during inducing human primary T cell hyporesponsiveness. PRDM1-overexpression in primary T cells expanded Treg cell subset and increased the expression level of FOXP3, while decreased expression had the opposite effects. Moreover, the binding motifs of key T cell function regulators, such as FOS, JUN and AP-1, were enriched in PRDM1 binding sites and that PRDM1 altered the chromatin accessibility of these regions. Multiomics analysis showed that PRDM1 directly upregulated T cell inhibitory genes such as KLF2 and KLRD1 and downregulated the T cell activation gene IL2, indicating that PRDM1 could promote a tolerant transcriptional profile. Further analysis showed that PRDM1 upregulated FOXP3 expression level directly by binding to FOXP3 upstream enhancer region and indirectly by upregulating KLF2. These results indicated that PRDM1 is sufficient for inducing human primary T cell hyporesponsiveness by transcriptomic and epigenetic manners.

2.
Curr Microbiol ; 78(4): 1448-1457, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33665724

RESUMO

This study explored the differences in the microbial diversity and physicochemical properties of mushroom residue and cow manure to provide a theoretical basis for the use of mushroom residue as cow bedding. High-throughput sequencing was used to analyze the bacterial community composition of mushroom residue and cow manure bedding and determine the physical and chemical properties of these different bedding materials. The results showed that the bacterial communities in the two types of bedding materials could be categorized into 6 classes, 13 orders, 32 families, and 48 genera. The dominant genus in the mushroom residue bedding samples after use by cows was Lactobacillus (36.37%) followed by Corynebacterium (22.15%). The dominant group in the cow manure bedding samples after use was "other" (28.8%), followed by Solibacillus (8.76%). The different bedding materials contained varying number of bacterial species. After use, 499 bacterial species were present in the cow manure bedding, while only 345 bacterial species were present in the mushroom residue bedding. The utilization rate of the mushroom residue bedding by dairy cows was 79%, whereas that of the cow manure bedding was 61%. The results of this study provide a theoretical basis for the application of mushroom residue bedding for dairy cows.


Assuntos
Agaricales , Abrigo para Animais , Animais , Bactérias/genética , Roupas de Cama, Mesa e Banho , Bovinos , Feminino , Esterco
3.
Cell Mol Immunol ; 18(5): 1172-1185, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33408344

RESUMO

Haploidentical stem cell transplantation (haplo-SCT) achieves superior or at least comparable clinical outcomes to HLA-matched sibling donor transplantation (MSDT) in treating hematological malignancies. To define the underlying regulatory dynamics, we analyzed time courses of leukemia burden and immune abundance of haplo-SCT or MSDT from multiple dimension. First, we employed two nonirradiated leukemia mouse models which carried human AML-ETO or MLL-AF9 fusion gene to establish haplo-identical and major histocompatibility (MHC)-matched transplantation models and investigated the immune cell dynamic response during leukemia development in vivo. We found that haplo-matching the MHCs of leukemia cells with recipient mouse T cells prolonged leukemic mice survival and reduced leukemia burden. The stronger graft-versus-leukemia activity in haplo-SCT group mainly induced by decreased apoptosis and increased cytotoxic cytokine secretion including tumor necrosis factor-α, interferon-γ, pore-forming proteins and CD107a secreted by T cells or natural killer cells. Furthermore, we conducted a prospective clinical trial which enrolled 135 patients with t(8;21) acute myeloid leukemia that displayed minimal residual disease before transplantation and underwent either haplo-SCT or MSDT. The results showed that the haplo-SCT slowed the kinetics of the leukemia burden in vivo and reduced the cumulative incidence of relapse compared with MSDT. Ex vivo experiments showed that, 1 year after transplantation, cytotoxic T lymphocytes from the haplo-SCT group had higher cytotoxicity than those from the MSDT group during the same period. Our results unraveled the role of immune cells in superior antileukemia effects of haplo-SCT compared with MSDT.


Assuntos
Aloenxertos/imunologia , Doença Enxerto-Hospedeiro/imunologia , Teste de Histocompatibilidade , Leucemia Mieloide Aguda/imunologia , Transplante Haploidêntico , Adolescente , Adulto , Animais , Apoptose , Criança , Pré-Escolar , Citocinas/metabolismo , Progressão da Doença , Doença Enxerto-Hospedeiro/patologia , Transplante de Células-Tronco Hematopoéticas , Humanos , Células Matadoras Naturais/imunologia , Cinética , Leucemia Mieloide Aguda/patologia , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Análise Multivariada , Irmãos , Linfócitos T Citotóxicos/imunologia , Doadores de Tecidos , Adulto Jovem
4.
Sci China Life Sci ; 64(7): 1087-1096, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32880861

RESUMO

Acute graft-versus-host disease (aGVHD) is caused by allo-activated donor T cells infiltrating target organs. As a regulator of immune function, granulocyte colony-stimulating factor (G-CSF) has been demonstrated to relieve the aGVHD reaction. However, the role of G-CSF-primed donor T cells in specific target organs is still unknown. In this study, we employed a classical MHC-mismatched transplantation mouse model (C57BL/6 into BALB/c) and found that recipient mice transplanted with G-CSF-primed T cells exhibited prolonged survival compared with that of the PBS-treated group. This protective function against GVHD mediated by G-CSF-primed donor T cells was further confirmed by decreased clinical and pathological scores in this aGVHD mouse model, especially in the lung and gut. Moreover, we found that T cells polarized towards Th2 cells and regulatory T cells were increased in specific target organs. In addition, G-CSF treatment inhibited inducible co-stimulator (ICOS) expression and increased the expression of tolerance-related genes in recipient mice. Our study provides new insight into the immune regulatory effects of G-CSF on T cell-mediated aGVHD, especially for its precise regulation in GVHD target organs.


Assuntos
Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/prevenção & controle , Fator Estimulador de Colônias de Granulócitos/imunologia , Linfócitos T Reguladores/imunologia , Células Th2/imunologia , Animais , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Transplante Homólogo
5.
Oncogene ; 39(50): 7239-7252, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33037410

RESUMO

Epigenetic regulations play crucial roles in leukemogenesis and leukemia progression. SUV39H1 is the dominant H3K9 methyltransferase in the hematopoietic system, and its expression declines with aging. However, the role of SUV39H1 via its-mediated repressive modification H3K9me3 in leukemogenesis/leukemia progression remains to be explored. We found that SUV39H1 was down-regulated in a variety of leukemias, including MLL-r AML, as compared with normal individuals. Decreased levels of Suv39h1 expression and genomic H3K9me3 occupancy were observed in LSCs from MLL-r-induced AML mouse models in comparison with that of hematopoietic stem/progenitor cells. Suv39h1 overexpression increased leukemia latency and decreased the frequency of LSCs in MLL-r AML mouse models, while Suv39h1 knockdown accelerated disease progression with increased number of LSCs. Increased Suv39h1 expression led to the inactivation of Hoxb13 and Six1, as well as reversion of Hoxa9/Meis1 downstream target genes, which in turn decelerated leukemia progression. Interestingly, Hoxb13 expression is up-regulated in MLL-AF9-induced AML cells, while knockdown of Hoxb13 in MLL-AF9 leukemic cells significantly prolonged the survival of leukemic mice with reduced LSC frequencies. Our data revealed that SUV39H1 functions as a tumor suppressor in MLL-AF9-induced AML progression. These findings provide the direct link of SUV39H1 to AML development and progression.


Assuntos
Progressão da Doença , Leucemia Mieloide Aguda/patologia , Metiltransferases/metabolismo , Proteína de Leucina Linfoide-Mieloide/metabolismo , Proteínas de Fusão Oncogênica/metabolismo , Proteínas Repressoras/metabolismo , Animais , Apoptose , Linhagem Celular Tumoral , Transformação Celular Neoplásica , Feminino , Regulação Neoplásica da Expressão Gênica , Células-Tronco Hematopoéticas/citologia , Histonas/metabolismo , Humanos , Leucemia Mieloide Aguda/genética , Lisina/metabolismo , Metilação , Camundongos , Transcrição Genética
6.
Transplant Proc ; 52(1): 345-352, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31918969

RESUMO

BACKGROUND AND OBJECTIVE: The aim of this study was to investigate the effects of granulocyte colony-stimulating factor (G-CSF) on the proliferation and apoptosis of bone marrow (BM) B cells from healthy donors and its mechanism. MATERIALS AND METHODS: The proliferation ability and apoptosis of BM cells from healthy donors before and after in vivo G-CSF application were determined by multiparameter flow cytometry. The gene expression of B cells was detected by RNA-Seq. In vitro experiments were performed to investigate the effects of G-CSF on the proliferation and apoptosis of BM B cells through which gene. RESULTS: Treating healthy donors with G-CSF significantly decreased proliferation and increased apoptosis of BM B cells. The proliferation of CD19+CD27- B cell subgroup and CD19+CD24hiCD38hi B cell subset were also decreased. G-CSF also significantly altered proapoptotic genes, cell cycle arrest genes, and DNA replication and cell cycle genes, especially significantly increased SOCS1 expression of BM B cells. In vitro experiments showed that SOCS1 overexpression did not affect B cell proliferation ability and apoptosis. CONCLUSIONS: Our results suggest that extensive effects of G-CSF on BM B cells, such as inhibiting proliferation, inducing apoptosis, and altering a series of gene expression.


Assuntos
Apoptose/efeitos dos fármacos , Linfócitos B/efeitos dos fármacos , Células da Medula Óssea/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos/farmacologia , Adolescente , Adulto , Idoso , Transplante de Medula Óssea/métodos , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Proteína 1 Supressora da Sinalização de Citocina/biossíntese , Proteína 1 Supressora da Sinalização de Citocina/efeitos dos fármacos , Doadores de Tecidos , Adulto Jovem
7.
Biol Psychiatry ; 86(11): 820-835, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31060803

RESUMO

BACKGROUND: Methamphetamine (METH) is a highly addictive psychostimulant that strongly activates dopamine receptor signaling in the nucleus accumbens (NAc). However, how dopamine D1 and D2 receptors (D1Rs and D2Rs, respectively) as well as downstream signaling pathways, such as those involving Rac1 and Cdc42, modulate METH-induced behavioral and structural plasticity is largely unknown. METHODS: Using NAc conditional D1R and D2R deletion mice, Rac1 and Cdc42 mutant viruses, and a series of behavioral and morphological methods, we assessed the effects of D1Rs and D2Rs on Rac1 and Cdc42 in modulating METH-induced behavioral and structural plasticity in the NAc. RESULTS: D1Rs and D2Rs in the NAc consistently regulated METH-induced conditioned place preference, locomotor activation, and dendritic and spine remodeling of medium spiny neurons but differentially regulated METH withdrawal-induced spatial learning and memory impairment and anxiety. Interestingly, Rac1 and Cdc42 signaling were oppositely modulated by METH, and suppression of Rac1 signaling and activation of Cdc42 signaling were crucial to METH-induced conditioned place preference and structural plasticity but not to locomotor activation. D1Rs activated Rac1 and Cdc42 signaling, while D2Rs inhibited Rac1 signaling but activated Cdc42 signaling to mediate METH-induced conditioned place preference and structural plasticity but not locomotor activation. In addition, NAc D1R deletion aggravated METH withdrawal-induced spatial learning and memory impairment by suppressing Rac1 signaling but not Cdc42 signaling, while NAc D2R deletion aggravated METH withdrawal-induced anxiety without affecting Rac1 or Cdc42 signaling. CONCLUSIONS: D1Rs and D2Rs differentially regulate Rac1 and Cdc42 signaling to modulate METH-induced behavioral plasticity and the structural remodeling of medium spiny neurons in the NAc.


Assuntos
Metanfetamina/farmacologia , Neuropeptídeos/metabolismo , Núcleo Accumbens/efeitos dos fármacos , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Proteína cdc42 de Ligação ao GTP/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismo , Animais , Estimulantes do Sistema Nervoso Central/farmacologia , Dendritos/metabolismo , Dopaminérgicos/farmacologia , Feminino , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/metabolismo , Neuropeptídeos/genética , Núcleo Accumbens/metabolismo , Transdução de Sinais , Comportamento Espacial/efeitos dos fármacos , Comportamento Espacial/fisiologia , Proteína cdc42 de Ligação ao GTP/genética , Proteínas rac1 de Ligação ao GTP/genética
8.
Int J Cancer ; 141(2): 324-335, 2017 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-28411381

RESUMO

Interaction of HOXA9/MEIS1/PBX3 is responsible for hematopoietic system transformation in MLL-rearranged (MLL-r) leukemia. Of these genes, HOXA9 has been shown to be critical for leukemia cell survival, while MEIS1 has been identified as an essential regulator for leukemia stem cell (LSC) maintenance. Although significantly high expression of PBX3 was observed in clinical acute myeloid leukemia (AML) samples, the individual role of PBX3 in leukemia development is still largely unknown. In this study, we explored the specific role of PBX3 and its associated regulatory network in leukemia progression. By analyzing the clinical database, we found that the high expression of PBX3 is significantly correlated with a poor prognosis in AML patients. ChIP-Seq/qPCR analysis in MLL-r mouse models revealed aberrant epigenetic modifications with increased H3K79me2, and decreased H3K9me3 and H3K27me3 levels in LSCs, which may account for the high expression levels of Pbx3. To further examine the role of Pbx3 in AML maintenance and progression, we used the CRISPR/Cas9 system to delete Pbx3 in leukemic cells in the MLL-AF9 induced AML mouse model. We found that Pbx3 deletion significantly prolonged the survival of leukemic mice and decreased the leukemia burden by decreasing the capacity of LSCs and promoting LSC apoptosis. In conclusion, we found that PBX3 is epigenetically aberrant in the LSCs of MLL-r AML and is essential for leukemia development. Significantly, the differential expression of PBX3 in normal and malignant hematopoietic cells suggests PBX3 as a potential prognostic marker and therapeutic target for MLL-r leukemia.


Assuntos
Histona-Lisina N-Metiltransferase/genética , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Leucemia Mieloide Aguda/patologia , Proteína de Leucina Linfoide-Mieloide/genética , Células-Tronco Neoplásicas/citologia , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Regulação para Cima , Animais , Apoptose , Linhagem Celular Tumoral , Epigênese Genética , Feminino , Regulação Leucêmica da Expressão Gênica , Histonas/metabolismo , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Prognóstico
9.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 24(3): 637-42, 2016 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-27342483

RESUMO

OBJECTIVE: To explore the role of PDK1 in T-ALL development through establishing the Notch1-induced T-ALL mouse model by using Mx1-cre; LoxP system to knock-out PDK1. METHODS: Cell cycle and apoptosis of leukemic cells were detected by flow cytometry, and relative expression of tumor-related genes and transcription factors of leukemic cells were determined by quantitative real-time PCR. RESULTS: Notch1-induced T-ALL mouse model with inducible knock-out of PDK1 was established successfully. Compared to T-ALL control mouse model, PDK1 knock-out mice showed a significant longer survival time (P<0.01). There was no difference of cell cycle between control and PDK1 knock-out mice, and the apoptosis rate of leukemic cells in PDK1 knock-out mice was higher than that of control mice (P<0.001). PDK1 knock-out resulted in decreased expression of tumor-related genes and transcription factors, such as c-Myc and NF-κB (P<0.01), and increased expression level of P53 (P<0.01). CONCLUSION: PDK1 knock-out can inhibit the development of T-ALL, and its mechanism may be the leukemia progression inhibited by regulating the apoptosis and expression of multiple related genes and transcription factors.


Assuntos
Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Receptor Notch1/genética , Animais , Apoptose , Ciclo Celular , Modelos Animais de Doenças , Regulação Leucêmica da Expressão Gênica , Camundongos , Camundongos Knockout , NF-kappa B/genética , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Piruvato Desidrogenase Quinase de Transferência de Acetil , Reação em Cadeia da Polimerase em Tempo Real , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
10.
Exp Hematol ; 42(12): 1031-40.e1-4, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25201756

RESUMO

Mammalian target of rapamycin (mTOR) is composed of two distinct biochemical complexes, mTORC1 and mTORC2. In response to nutrients and growth factors, mTORC1 is known to control cellular growth by regulating the translational regulators S6 kinase 1 and 4E binding protein 1, whereas mTORC2 mediates cell proliferation and survival by activating Akt through phosphorylation at Ser473. Studies have shown that the deregulation of mTORC2 leads to the development of myeloproliferative disorder and leukemia in the phosphatase and tensin homolog deleted on chromosome ten (PTEN)-deleted mouse model. However, the mechanism by which mTORC2 specifically affects leukemogenesis is still not fully understood. Here, we investigated the role of mTORC2 in NOTCH1-driven T-cell acute lymphoblastic leukemia (T-ALL) in a Rictor-deficient mouse model. We found that, by deleting Rictor, an essential component of mTORC2, leukemia progression was significantly suppressed by arresting a greater proportion of Rictor(△/△) leukemic cells at the G0 phase of the cell cycle. Furthermore, the absence of Rictor led to the overexpression of chemotaxis-related genes, such as CCR2, CCR4 and CXCR4, which contributed to the homing and migration of Rictor-deficient T-ALL cells to the spleen but not the bone marrow. In addition, we demonstrated that inactivation of mTORC2 caused the overexpression of forkhead box O3 and its downstream effectors and eased the progression of leukemia in T-ALL mice. Our study thus indicates that forkhead box O3 could be a potential drug target for the treatment of T-ALL leukemia.


Assuntos
Proteínas de Transporte/fisiologia , Fatores de Transcrição Forkhead/fisiologia , Complexos Multiproteicos/fisiologia , Proteínas de Neoplasias/fisiologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Receptor Notch1/fisiologia , Serina-Treonina Quinases TOR/fisiologia , Animais , Medula Óssea/patologia , Proteínas de Transporte/genética , Movimento Celular , Transformação Celular Neoplásica , Quimiotaxia/genética , Progressão da Doença , Proteína Forkhead Box O3 , Regulação Leucêmica da Expressão Gênica , Alvo Mecanístico do Complexo 2 de Rapamicina , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Complexos Multiproteicos/antagonistas & inibidores , Especificidade de Órgãos , Quimera por Radiação , Proteína Companheira de mTOR Insensível à Rapamicina , Fase de Repouso do Ciclo Celular , Baço/patologia , Serina-Treonina Quinases TOR/antagonistas & inibidores
11.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 21(4): 1063-8, 2013 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-23998613

RESUMO

Mammalian target of rapamycin complex (mTORC) is an important center for regulating cellular growth, survival and metabolism. mTORC plays a vital role in maintenance of normal physiological activities and homeostasis in organism. According to protein components, mTORC can be divided into two distinct protein complexes: mTORC1 and mTORC2. The main protein components of mTORC2 include mTOR, Rictor, mLST8, Deptor, mSin1, Protor and Hsp70. By means of activating AKT, PKCα, SGK1 and so on, the mTORC regulates many vital activities:embryonic development, cytoskeletal reconstitution,cell migration and protein post-translational modification. The abnormality of mTORC2 signaling pathway has been confirmed to be associated with tumorigenesis, therefore, further understanding the components, functions and signalling pathway of mTORC2 will provide a new insights in developing targeted cancer therapy. In this review, the structure and signalling pathway of mTORC2 and its roles in hematological malignancies are discussed and summarised.


Assuntos
Neoplasias Hematológicas , Complexos Multiproteicos , Transdução de Sinais , Serina-Treonina Quinases TOR , Animais , Humanos , Alvo Mecanístico do Complexo 2 de Rapamicina
12.
J Environ Sci (China) ; 16(5): 802-7, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15559816

RESUMO

The landfill of municipal solid waste (MSW) could be regarded as denitrification reactor and involved in ammonia nitrogen biological removal process. In this research, the process was applied to municipal solid waste collected in Shanghai, China, which was characterized by high food waste content. The NH4(+) removal efficiency in the system of SBR nitrifying reactor followed by fresh and matured landfilled waste layer in series was studied. In the nitrifying reactor, above 90% of NH4(+) in leachate was oxidized to NO2(-) and NO3(-). Then high concentrated NO2 and N3(-) were removed in the way of denitrification process in fresh landfilled waste layer. At the same time, degradation of fresh landfilled waste was accelerated. Up to the day 120, 136.5 gC/(kg dry waste) and 17.9 gN/(kg dry waste) were converted from waste layer. It accounted for 50.15% and 86.89% of the total carbon and nitrogen content of preliminary fresh waste, which was 4.42 times and 5.17 times higher than that of reference column respectively. After filtering through matured landfilled waste, BOD5 concentration in leachate dropped to below 100 mg/L, which would not affect following nitrification adversely. Because the matured landfilled waste acted as a well methanogenic reactor, 23% of carbon produced accumulatively from fresh landfilled waste degradation was converted into CH4.


Assuntos
Amônia/metabolismo , Anaerobiose , Reatores Biológicos , Eliminação de Resíduos/métodos , Amônia/química , Biodegradação Ambiental , Carbono/metabolismo , Concentração de Íons de Hidrogênio , Fatores de Tempo
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