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1.
Ophthalmic Res ; : 1-10, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31962334

RESUMO

Controversial results regarding the associations between aldose reductase (AR) genetic polymorphisms and diabetic retinopathy (DR) have been reported for many years. The present meta-analysis was performed to clarify the effects of the AR gene C(-106)T polymorphism on DR risk. The PubMed, Web of Sciences, Cochrane library, EMBASE, Chinese National Knowledge Infrastructure, and Wan Fang databases were extensively searched in Chinese to select relevant studies with an updated date of April 25, 2018. The Newcastle-Ottawa Scale (NOS) was applied to assess quality. The random-effects model was applied to calculate the pooled OR and 95% CI. This meta-analysis identified 23 studies with an average score of 7.52 for NOS analysis, including 4,313 DR cases and 5,128 diabetes mellitus (DM) control cases. In the overall analysis, a significant association between the AR gene C(-106)T polymorphism and DR susceptibility was found. In subgroups stratified by DM type and ethnicity, significantly increased risks for DR were found in DM type 1, East Asian populations, and Middle Eastern populations. Compared with DR control cases, the following associations were found: T vs. C: OR 0.91, 95% CI 0.85-0.97, I2 = 72.9%; CT + TT vs. CC: OR 0.75, 95% CI 0.68-0.81, I2 = 86.7%; and CT vs. CC: OR 0.86, 95% CI 0.78-0.94, I2 = 70.5%. The results of this meta-analysis showed a significant association between the AR gene C(-106)T polymorphism and susceptibility to DR in DM patients. DM patients with allele T and CT+TT genotype of the AR gene may have a lower risk of DR.

2.
Mol Cell ; 72(2): 380-394.e7, 2018 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-30293782

RESUMO

RNA splicing is a critical mechanism by which to modify transcriptome, and its dysregulation is the underlying cause of many human diseases. It remains challenging, however, to genetically modulate a splicing event in its native context. Here, we demonstrate that a CRISPR-guided cytidine deaminase (i.e., targeted-AID mediated mutagenesis [TAM]) can efficiently modulate various forms of mRNA splicing. By converting invariant guanines to adenines at either 5' or 3' splice sites (SS), TAM induces exon skipping, activation of alternative SS, switching between mutually exclusive exons, or targeted intron retention. Conversely, TAM promotes downstream exon inclusion by mutating cytidines into thymines at the polypyrimidine tract. Applying this approach, we genetically restored the open reading frame and dystrophin function of a mutant DMD gene in patient-derived induced pluripotent stem cells (iPSCs). Thus, the CRISPR-guided cytidine deaminase provides a versatile genetic platform to modulate RNA splicing and to correct mutations associated with aberrant splicing in human diseases.


Assuntos
Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Citidina Desaminase/genética , Processamento de RNA/genética , Sequência de Aminoácidos , Animais , Linhagem Celular , Distrofina/genética , Éxons/genética , Redes Reguladoras de Genes , Células HEK293 , Humanos , Íntrons/genética , Camundongos , Fases de Leitura Aberta/genética , Sítios de Splice de RNA/genética
3.
J Biol Chem ; 292(29): 12285-12295, 2017 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-28611064

RESUMO

Increasing evidence indicates that alternative processing of mRNA, including alternative splicing, 3' alternative polyadenylation, and regulation of mRNA stability/translation, represents a major mechanism contributing to protein diversification. For example, in alternative polyadenylation, the 3' end of the immunoglobulin heavy chain mRNA is processed during B cell differentiation, and this processing involves RNA-binding proteins. hnRNPLL (heterogeneous nuclear ribonucleoprotein L-like protein) is an RNA-binding protein expressed in terminally differentiated lymphocytes, such as memory T cells and plasma cells. hnRNPLL regulates various processes of RNA metabolism, including alternative pre-mRNA splicing and RNA stability. In plasma cells, hnRNPLL also regulates the transition from the membrane isoform of the immunoglobulin heavy-chain (mIgH) to the secreted isoform (sIgH), but the precise mechanism remains to be identified. In this study, we report that hnRNPLL specifically associates with cytoplasmic PABPC1 (poly(A)-binding protein 1) in both T cells and plasma cells. We found that although PABPC1 is not required for the alternative splicing of CD45, a primary target of hnRNPLL in lymphocytes, PABPC1 does promote the binding of hnRNPLL to the immunoglobulin mRNA and regulates switching from mIgH to sIgH in plasma cells. Given the recently identified role of PABPC1 in mRNA alternative polyadenylation, our findings suggest that PABPC1 recruits hnRNPLL to the 3'-end of RNA and regulates the transition from membrane Ig to secreted Ig through mRNA alternative polyadenylation. In conclusion, our study has revealed a mechanism that regulates immunoglobulin secretion in B cells via cooperation between a plasma cell-specific RBP (hnRNPLL) and a universally expressed RBP (PABPC1).


Assuntos
Citoplasma/metabolismo , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , Cadeias Pesadas de Imunoglobulinas/metabolismo , Plasmócitos/metabolismo , Proteína I de Ligação a Poli(A)/metabolismo , Poliadenilação , RNA Mensageiro/metabolismo , Animais , Células Cultivadas , Ribonucleoproteínas Nucleares Heterogêneas/química , Ribonucleoproteínas Nucleares Heterogêneas/genética , Humanos , Switching de Imunoglobulina , Cadeias Pesadas de Imunoglobulinas/genética , Imunoprecipitação , Células Jurkat , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Plasmócitos/citologia , Plasmócitos/imunologia , Proteína I de Ligação a Poli(A)/antagonistas & inibidores , Proteína I de Ligação a Poli(A)/química , Proteína I de Ligação a Poli(A)/genética , Domínios e Motivos de Interação entre Proteínas , Interferência de RNA , Baço/citologia , Baço/imunologia , Linfócitos T/citologia , Linfócitos T/imunologia , Linfócitos T/metabolismo
4.
Transplantation ; 99(9): 1796-806, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25919768

RESUMO

BACKGROUND: T cell-mediated immune rejection is a key barrier to islet transplantation. Preliminary studies have shown that arsenic trioxide (As2O3) can inhibit T cell responses and prolong heart allograft survival. Here, we sought to investigate the possibility of using As2O3 to prolong islet allograft survival in an acute rejection model of Balb/c to C57B/6 mice. METHODS: Recipient mice were treated with As2O3 and/or rapamycin after islet allograft transplantation. At day 10 after transplantation, the graft, spleen, lymph nodes, and blood of the recipient mice were recovered for analysis. In vitro, to further examine the mechanism underlying As2O3 protection of islet allografts against T cell-mediated rejection, mixed lymphocyte reaction and apoptosis analyses of T cells were performed. The phosphorylation levels of IκBα and p38 were also evaluated to confirm the proliferation and apoptosis of As2O3-treated T cells. RESULTS: We found that As2O3 prolonged islet allograft survival by reducing inflammatory reactions, influencing cytokine synthesis and secretion and T-cell subset proportions, and inhibiting T-cell responses. Furthermore, As2O3 and rapamycin showed a synergistic effect in suppressing islet allotransplant rejection. CONCLUSIONS: Arsenic trioxide may prevent allograft rejection by inhibiting T-cell proliferation and inducing T-cell apoptosis.


Assuntos
Apoptose/efeitos dos fármacos , Arsenicais/farmacologia , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/efeitos dos fármacos , Imunossupressores/farmacologia , Transplante das Ilhotas Pancreáticas , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/cirurgia , Óxidos/farmacologia , Linfócitos T/efeitos dos fármacos , Animais , Trióxido de Arsênio , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/metabolismo , Rejeição de Enxerto/patologia , Proteínas I-kappa B/metabolismo , Imunidade Celular/efeitos dos fármacos , Ilhotas Pancreáticas/imunologia , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/patologia , Transplante das Ilhotas Pancreáticas/efeitos adversos , Ativação Linfocitária/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Inibidor de NF-kappaB alfa , Fosforilação , Transdução de Sinais/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/patologia , Fatores de Tempo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
5.
Diabetes ; 63(10): 3458-69, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24834979

RESUMO

Islet transplantation is a therapeutic option for type 1 diabetes, but its long-term success is limited by islet allograft survival. Many factors imperil islet survival, especially the adverse effects and toxicity due to clinical immunosuppressants. Compound (Cpd) K is a synthesized analog of highly unsaturated fatty acids from Isatis tinctoria L. (Cruciferae). Here we investigated the therapeutic effect of Cpd K in diabetic mice and found that it significantly prolonged islet allograft survival with minimal adverse effects after 10 days. Furthermore, it reduced the proportion of CD4(+) and CD8(+) T cells in spleen and lymph nodes, inhibited inflammatory cell infiltration in allografts, suppressed serum interleukin-2 and interferon-γ secretion, and increased transforming growth factor-ß and Foxp3 mRNA expression. Surprisingly, Cpd K and rapamycin had a synergistic effect. Cpd K suppressed proliferation of naïve T cells by inducing T-cell anergy and promoting the generation of regulatory T cells. In addition, nuclear factor-κB signaling was also blocked. Taken together, these findings indicate that Cpd K may have a potential immunosuppressant effect on islet transplantation.


Assuntos
Diabetes Mellitus Experimental/cirurgia , Ginsenosídeos/uso terapêutico , Sobrevivência de Enxerto/efeitos dos fármacos , Imunossupressores/uso terapêutico , Transplante das Ilhotas Pancreáticas , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/patologia , Proliferação de Células/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/patologia , Ginsenosídeos/farmacologia , Tolerância Imunológica/efeitos dos fármacos , Imunossupressores/farmacologia , Interferon gama/sangue , Interleucina-2/sangue , Camundongos , Baço/efeitos dos fármacos , Baço/patologia
6.
Xenotransplantation ; 18(4): 252-61, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21848543

RESUMO

BACKGROUND: Memory T cells are a significant barrier to the induction of transplant tolerance. Our previous study demonstrated that multiple applications of anti-CD44 monoclonal antibody (mAb) could significantly inhibit CD4(+) memory T cells from mediating rejection of cardiac allografts. Now, we sought to explore the effect and mechanism of anti-CD44 mAb on the rejection of islet allografts and xenografts mediated by CD4(+) memory T cells. METHODS: In this study, we first engrafted skin grafts of C57BL/6 (B6) mice or Dark Agouti (DA) rats onto BALB/c mice to induce donor-reactive memory T cells. We adoptively transferred purified CD4(+) memory T cells to BALB/c origin nude mice and then transplanted islet allografts and xenografts to produce the Allo-Tx and Xeno-Tx models, respectively. We subsequently administered multiple anti-CD44 mAb and observed changes in the survival times of the islet grafts. RESULTS: In the Allo-Tx model, the mean survival time (MST) of the grafts was 7.7 days in the isotype group, and 20.3 days in the anti-CD44 group. In the Xeno-Tx model, the MST of the grafts was 7.2 days in the isotype group and 8.2 days in the anti-CD44 group. Compared with the isotype group, CD4(+) T cells on the grafts in the anti-CD44 group were significantly decreased in both the Allo-Tx and Xeno-Tx models, but the proportion of CD4(+) memory T cells in the spleens and draining lymph nodes of the recipient nude mice in the anti-CD44 group was significantly decreased in the Allo-Tx model, while it was increased in the Xeno-Tx model. The production of donor-specific IgG antibody in the anti-CD44 group did not vary in the Allo-Tx model, while it was markedly elevated in the Xeno-Tx model. Furthermore, the expression of interferon gamma in the anti-CD44 group was markedly decreased in both the Allo-Tx and Xeno-Tx models, while the expression of IL-4 in the anti-CD44 group was significantly increased only in the Xeno-Tx model. CONCLUSION: Multiple applications of the anti-CD44 mAb could significantly inhibit donor-reactive CD4(+) memory T cells from rejecting grafts via a Th1-dependent pathway, but xenoreactive CD4(+) memory T cells can avoid the effects of anti-CD44 mAb to reject islet xenografts via a Th2-dependent pathway.


Assuntos
Anticorpos Monoclonais/imunologia , Linfócitos T CD4-Positivos/imunologia , Receptores de Hialuronatos/imunologia , Transplante das Ilhotas Pancreáticas/imunologia , Células Th2/imunologia , Transplante Heterólogo/imunologia , Transplante Homólogo/imunologia , Animais , Antígenos CD4/imunologia , Proliferação de Células , Diabetes Mellitus Experimental , Feminino , Sobrevivência de Enxerto/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , Ratos , Transplante Heterólogo/patologia , Transplante Homólogo/patologia
7.
Immunol Lett ; 138(2): 122-8, 2011 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-21477620

RESUMO

Donor-reactive memory T cells mediated accelerated rejection is known as a barrier to the survival of transplanted organs. We investigated the combination of different monoclonal antibodies (mAbs) and donor-specific transfusion (DST) in memory T cells-based adoptive mice model. In the presence of donor-reactive memory T cells, the mean survival time (MST) of grafts in the anti-CD40L/LFA-1/DST group was 49.8d. Adding anti-CD44/CD70 mAbs to anti-CD40L/LFA-1/DST treatment. The MST was more than 100 d (MST>100 d). Compared with anti-CD40L/LFA-1/DST group, anti-CD40L/LFA-1/CD44/CD70/DST group notably reduced the expansion of memory T cells, enhanced the proportion of CD4+Foxp3+ regulatory T cells (Tregs) and suppressed donor-specific responses. Our data suggest that anti-CD40L/LFA-1/CD44/CD70mAbs and DST can synergistically inhibit accelerated rejection mediated by memory T cells to induce long-lived heart allograft acceptance in mice.


Assuntos
Anticorpos Monoclonais , Rejeição de Enxerto , Sobrevivência de Enxerto/imunologia , Transplante de Coração , Imunomodulação , Isoantígenos/imunologia , Monócitos , Linfócitos T Reguladores/imunologia , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacologia , Ligante CD27/antagonistas & inibidores , Ligante CD27/imunologia , Ligante de CD40/antagonistas & inibidores , Ligante de CD40/imunologia , Proliferação de Células/efeitos dos fármacos , Feminino , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Transplante de Coração/imunologia , Receptores de Hialuronatos/imunologia , Memória Imunológica , Antígeno-1 Associado à Função Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Monócitos/imunologia , Monócitos/transplante , Transplante de Pele/imunologia , Baço/citologia , Baço/imunologia , Transplante Homólogo
8.
Transpl Immunol ; 24(4): 195-202, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21396447

RESUMO

BACKGROUND: Alloreactive memory T cells are a major obstacle to transplantation acceptance due to their capacity for accelerated rejection. METHODS: C57BL/6 mice that had rejected BALB/c skin grafts 4 weeks earlier were used as recipients. The recipient mice were treated with anti-CD154/LFA-1 with or without anti-CD70 during the primary skin transplantation and anti-CD154/LFA-1 or not during the secondary transplantation of BALB/c heart. We evaluated the impact of combinations of antibody-mediated blockade on the generation of memory T cells and graft survival after fully MHC-mismatched transplantations. RESULTS: One month after the primary skin transplantation, the proportions of CD4(+) memory T cells/CD4(+) T cells and CD8(+)memory T cells/CD8(+) T cells in the anti-CD154/LFA-1 combination group were 47.32±4.28% and 23.18±2.77%, respectively. In the group that included anti-CD70 treatment, the proportions were reduced to 34.10±2.71% and 12.19±3.52% (P<0.05 when comparing the proportion of memory T cells between the two groups). The addition of anti-CD70 to the treatment regimen prolonged the mean survival time following secondary heart transplantation from 10days to more than 90days (P<0.001). Furthermore, allogenic proliferation of recipient splenic T cells and graft-infiltrating lymphocytes were significantly decreased. Meanwhile, the proportion of regulatory T cells was increased to 9.46±1.48% on day 100 post-transplantation (P<0.05). CONCLUSIONS: The addition of anti-CD70 to the anti-CD154/LFA-1 combination given during the primary transplantation reduced the generation of memory T cells. This therapy regimen provided a potential means to alleviate the accelerated rejection mediated by memory T cells during secondary heart transplantation and markedly prolong the survival of heart allografts.


Assuntos
Rejeição de Enxerto/tratamento farmacológico , Transplante de Coração , Imunoterapia , Subpopulações de Linfócitos T/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos , Animais , Anticorpos Monoclonais/administração & dosagem , Ligante CD27/imunologia , Ligante de CD40/imunologia , Células Cultivadas , Rejeição de Enxerto/imunologia , Humanos , Imunização , Memória Imunológica , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/patologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/patologia , Tolerância ao Transplante
9.
Xenotransplantation ; 17(6): 460-8, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-21158947

RESUMO

BACKGROUND: Donor-reactive memory T cells are known to accelerate allograft rejection; in our previous study, we reported that combined monoclonal antibodies (mAbs) could prolong islet allograft survival in alloantigen-primed mice. In this study, we examine the effects of donor-reactive memory T cells on the xenograft survival and methods to prolong the islet graft survival. METHODS: To collect donor-reactive T cells, we performed full-thickness rat skin xenografting on BALB/c mice and isolated the T cells from the mice after 6-8 weeks. These cells were then adoptively transferred to syngenic mice 1 day before rat-to-mouse islet transplantation. Three experimental groups were established in the adoptive transfer model: recipient mice treated with isotype mAbs (isotype group); mice treated with anti-CD40L mAb (anti-CD40L group); and mice treated with anti-CD40L, anti-OX40L, and anti-CD122 mAbs (3-combined group). RESULTS: Lewis rat islet xenografts transplanted in naïve mice showed a mean survival time (MST) of 12.8 days, while the graft rejection was accelerated if the recipient mice were treated with adoptively transferred donor-reactive T cells (MST, 8.67 days). Treatment with anti-CD40L mb could not reverse the accelerated rejection (MST, 9.3 days). However, when anti-CD40L mb was combined with anti-OX40L and anti-CD122 mAbs, there was a considerable increase in the MST, which was 72.2 days. Compared to the isotype group, the 3-combined group had significantly lesser proportion of memory T cells and greater proportion of regulatory T cells (Tregs) in the spleen. Meanwhile, in the 3-combined group, the production of anti-rat antibodies was markedly inhibited. CONCLUSION: Treatment with a combination of antibodies could significantly reverse the accelerated rejection mediated by donor-reactive memory T cells by inhibiting cellular and humoral immune responses.


Assuntos
Anticorpos/imunologia , Antígenos Heterófilos/imunologia , Rejeição de Enxerto/imunologia , Memória Imunológica/imunologia , Linfócitos T/imunologia , Transferência Adotiva , Animais , Transplante das Ilhotas Pancreáticas/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Ratos , Ratos Endogâmicos Lew
10.
Biochem Biophys Res Commun ; 341(3): 804-9, 2006 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-16442077

RESUMO

CD38 has multiple roles in biology, including T lymphocyte signaling, neutrophil migration, neurotransmission, cell proliferation, apoptosis, and bone remodeling. To study the transcriptional control of the CD38 gene, we cloned a putative 1.8 kb promoter fragment from a rabbit genomic DNA library. Primer extension analysis indicated two transcription start sites consistent with the absence of a TATA box. Sequence analysis revealed several AP-1, AP-4, myo-D, GATA, and SP-1 sequences. MC3T3.E1 (osteoblast) or RAW-C3 (osteoclast precursor macrophage) cells were then transfected with the CD38 promoter or its deletion fragments ligated to the luciferase reporter gene. Except for the shortest 41 bp fragment, all fragments showed significant luciferase activity. There was a marked stimulation of basal activity in the 93 bp fragment that contained a GC box and SP-1 site. Furthermore, there were significant differences in the activity of the fragments in MC3T3.E1 and RAW-C3 cells. Intracellular Ca(2+) elevations by ionomycin (10muM) in MC3T3.E1 cells inhibited promoter activity, except in the short 41 bp. In contrast, cAMP elevation by exposure to forskolin (100 microM) inhibited activation of all fragments, except the 0.6 and 1.2kb fragments. Finally, TNF-alpha stimulated promoter activity in RAW-C3 cells transfected with the 93 bp and 1.0 kb fragments, consistent with the stimulation of CD38 mRNA by TNF-alpha. Physiologically, therefore, modulation of the expression of the NAD(+)-sensing enzyme, CD38, by Ca(2+), cAMP, and cytokines, such as TNF-alpha may contribute to coupling the intense metabolic activity of osteoclasts and osteoblasts to their respective bone-resorbing and bone-forming functions.


Assuntos
ADP-Ribosil Ciclase 1/genética , Regulação da Expressão Gênica/genética , Regiões Promotoras Genéticas/genética , Animais , Sequência de Bases , Linhagem Celular , Clonagem Molecular , DNA Complementar/genética , Camundongos , Dados de Sequência Molecular , Osteoclastos/metabolismo , Coelhos , Transcrição Genética/genética , Fator de Necrose Tumoral alfa/genética , Regulação para Cima
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