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1.
Drug Resist Updat ; 56: 100752, 2021 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-33765484

RESUMO

Immunotherapies such as CAR-T cell transfer and antibody-targeted therapy have produced promising clinical outcomes in patients with advanced and metastatic cancer that are resistant to conventional therapies. However, with increasing use of cancer immunotherapy in clinical treatment, multiple therapy-resistance mechanisms have gradually emerged. The tumor microenvironment (TME), an integral component of cancer, can significantly influence the therapeutic response. Thus, it is worth exploring the potential of TME in modulating therapy resistance, in the hope to devise novel strategies to reinforcing anti-cancer treatments such as immunotherapy. As a crucial recycling process in the complex TME, the role of autophagy in tumor immunity has been increasingly appreciated. Firstly, autophagy in tumor cells can affect their immune response through modulating MHC-I-antigen complexes, thus modulating immunogenic tumor cell death, changing functions of immune cells via secretory autophagy, reducing the NK- and CTL-mediated cell lysis and degradation of immune checkpoint proteins. Secondly, autophagy is critical for the differentiation, maturation and survival of immune cells in the TME and can significantly affect the immune function of these cells, thereby regulating the anti-tumor immune response. Thirdly, alteration of autophagic activity in stromal cells, especially in fibroblasts, can reconstruct the three-dimensional stromal environment and metabolic reprogramming in the TME. A number of studies have demonstrated that optimal induction or inhibition of autophagy may lead to effective therapeutic regimens when combined with immunotherapy. This review discusses the important roles of autophagy in tumor cells, immune cells and stromal cells in the context of tumor immunity, and the potential of combining the autophagy-based therapy with immunotherapy as novel therapeutic approaches against cancer.

2.
J Asian Nat Prod Res ; : 1-10, 2021 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-33550877

RESUMO

Eighteen novel 3/5(3,5)-(di)nitropaeonol hydrazone derivatives were prepared, and their structures well characterized by 1H NMR, HRMS, and mp. Due to the steric hindrance, the substituents on the C = N double bond of all hydrazine compounds (except E/Z = 4/1 for IV-1g, IV-1l, IV-2b, and E/Z = 3/2 for IV-1n, IV-3a) adopted E configuration. Among all compounds, four compounds 2, 4, IV-1j, and IV-1n exhibited potent nematicidal activity than their precursor paeonol, especially 5-nitropaeonol (2) and 3,5-dinitropaeonol (4) displayed the most potent nematicidal activity Heterodera glycines in vivo with LC50 values of 32.3307 and 36.7074 mg/L, respectively.

3.
Artigo em Inglês | MEDLINE | ID: mdl-33576560

RESUMO

Chiral gold(I)-cavitand complexes have been developed for the enantioselective alkoxycyclization of 1,6-enynes. This enantioselective cyclization has been applied for the first total synthesis of carbazole alkaloid (+)-mafaicheenamine C and its enantiomer, establishing its configuration as R. The cavity effect was also evaluated in the cycloisomerization of dienynes. A combination of experiments and theoretical studies demonstrates that the cavity of the gold(I) complexes forces the enynes to adopt constrained conformations, which results in the high observed regio- and stereoselectivities.

4.
Immunol Cell Biol ; 2020 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-33141986

RESUMO

Over the past decade, autophagy has emerged as a critical regulatory mechanism of the immune system through critically controlling various aspects of T cell biology and determining the fate of different T cell subsets. Autophagy maintains T cell development and survival by regulating the degradation of organelles and apoptotic proteins. The autophagic process also impacts the formation of memory T cells. Alteration of autophagy in T cells may lead to a variety of pathological conditions such as inflammation, autoimmune diseases and cancer. In this review, we discuss how autophagy impacts T cell differentiation, survival and memory, and its implication in immunotherapy for various diseases.

5.
Oncogene ; 39(43): 6704-6718, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32958832

RESUMO

Autophagy can protect stressed cancer cell by degradation of damaged proteins and organelles. However, the regulatory mechanisms behind this cellular process remain incompletely understood. Here, we demonstrate that RSK2 (p90 ribosomal S6 kinase 2) plays a critical role in ER stress-induced autophagy in breast cancer cells. We demonstrated that the promotive effect of RSK2 on autophagy resulted from directly binding of AMPKα2 in nucleus and phosphorylating it at Thr172 residue. IRE1α, an ER membrane-associated protein mediating unfolded protein response (UPR), is required for transducing the signal for activation of ERK1/2-RSK2 under ER stress. Suppression of autophagy by knockdown of RSK2 enhanced the sensitivity of breast cancer cells to ER stress both in vitro and in vivo. Furthermore, we demonstrated that inhibition of RSK2-mediated autophagy rendered breast cancer cells more sensitive to paclitaxel, a chemotherapeutic agent that induces ER stress-mediated cell death. This study identifies RSK2 as a novel controller of autophagy in tumor cells and suggests that targeting RSK2 can be exploited as an approach to reinforce the efficacy of ER stress-inducing agents against cancer.

6.
iScience ; 23(7): 101333, 2020 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-32679546

RESUMO

The viral antigen (Ag)-specific CD8+ cytotoxic T lymphocytes (CTLs) derived from pluripotent stem cells (PSCs), i.e., PSC-CTLs, have the ability to suppress hepatitis B virus (HBV) infection. After adoptive transfer, PSC-CTLs can infiltrate into the liver to suppress HBV replication. Nevertheless, the mechanisms by which the viral Ag-specific PSC-CTLs provoke the antiviral response remain to be fully elucidated. In this study, we generated the functional HBV surface Ag-specific CTLs from the induced PSC (iPSCs), i.e., iPSC-CTLs, and investigated the underlying mechanisms of the CTL-mediated antiviral replication in a murine model. We show that adoptive transfer of HBV surface Ag-specific iPSC-CTLs greatly suppressed HBV replication and prevented HBV surface Ag expression. We further demonstrate that the adoptive transfer significantly increased T cell accumulation and production of antiviral cytokines. These results indicate that stem cell-derived viral Ag-specific CTLs can robustly accumulate in the liver and suppress HBV replication through producing antiviral cytokines.

7.
Eur J Med Chem ; 199: 112421, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32428794

RESUMO

It has been realized that FDA approved drugs may have more molecular targets than is commonly thought. Thus, to find the exact drug-target interactions (DTIs) is of great significance for exploring the new molecular mechanism of drugs. Here, we developed a multi-scale system pharmacology (MSSP) method for the large-scale prediction of DTIs. We used MSSP to integrate drug-related and target-related data from multiple levels, the network structural data formed by known drug-target relationships for predicting likely unknown DTIs. Prediction results revealed that Ixabepilone, an epothilone B analog for treating breast cancer patients, may target Bcl-2, an oncogene that contributes to tumor progression and therapy resistance by inhibiting apoptosis. Furthermore, we demonstrated that Ixabepilone could bind with Bcl-2 and decrease its protein expression in breast cancer cells. The down-regulation of Bcl-2 by Ixabepilone is resulted from promoting its degradation by affecting p-Bcl-2. We further found that Ixabepilone could induce autophagy by releasing Beclin1 from Beclin1/Bcl-2 complex. Inhibition of autophagy by knockdown of Beclin1 or pharmacological inhibitor augmented apoptosis, thus enhancing the antitumor efficacy of Ixabepilone against breast cancer cells in vitro and in vivo. In addition, Ixabepilone also decreases Bcl-2 protein expression and induces cytoprotective autophagy in human hepatic carcinoma and glioma cells. In conclusion, this study not only provides a feasible and alternative way exploring new molecular mechanisms of drugs by combing computation DTI prediction, but also reveals an effective strategy to reinforce the antitumor efficacy of Ixabepilone.

8.
J Asian Nat Prod Res ; : 1-11, 2020 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-32406756

RESUMO

Two series of sulfonate derivatives of carvacrol and thymol were synthesized and screened in vitro for their anti-oomycete activity against Phytophthora capsici, respectively. Among all of 32 derivatives, five compounds 3a, 4a, 4k, 3n, and 4n exhibited more potent anti-oomycete activity against P. capsici with EC50 values of 66.66, 62.94, 68.65, 61.24, and 52.91 mg/L, respectively. This suggested that introduction of different substitutions at the hydroxyl position of 1/2 could have remarkable effect on anti-oomycete activity. Overall, when R1 = isopropyl and R2 = methyl, the anti-oomycete activities of the compounds were higher than that of the corresponding compounds of R1 = methyl and R2 = isopropyl.[Formula: see text].

9.
Aging (Albany NY) ; 12(10): 9275-9291, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32412910

RESUMO

BACKGROUND: Nucleus accumbens-associated protein 1 (NAC1) has multifaceted roles in cancer pathogenesis and progression, including the development of drug resistance, promotion of cytokinesis, and maintenance of "stem cell-like" phenotypes. NAC1 is a transcriptional co-regulator belonging to the bric-a-brac tramtrack broad (BTB) family of proteins, although it lacks the characteristic DNA binding motif of the BTB family. The formation of higher-order transcription complexes likely depends on its interaction with other DNA-binding co-factors. RESULTS: NAC1 interacts with BCL6 via its C-terminal BEN domain and forms a complex that binds the promoter region and activates transcription of the NAC1 target gene, FOXQ1. NAC1 and BCL6 were coordinately upregulated. Our analysis also identified a novel function of NAC1 in attenuating BCL6 auto-downregulation in ovarian cancer. Lastly, we found a significant overlap among NAC1- and BCL6-regulated genes in tumor cells, suggesting that NAC1 and BCL6 coordinately control transcription in cancer. CONCLUSIONS: The results of this study provide a novel mechanistic insight into the oncogenic roles of NAC1 and underline the importance of developing the NAC1/BCL6-targeted cancer therapy. METHODS: Using the Cistrome database and Chromatin Immunoprecipitation (ChIP) analyses, we identified BCL6 as a potential NAC1- interacting molecule. Co-immunoprecipitation (Co-IP), luciferase reporter assay, immunohistochemistry and microarray analysis were performed to analyze the interaction between NAC1 and BCL6 and the mechanisms by which they regulate the downstream genes including FOXQ1.

10.
J Asian Nat Prod Res ; : 1-13, 2020 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-32091234

RESUMO

Endeavor to discover biorational natural products-based insecticides, two series (27) of novel 9R/S-acyloxy derivatives of cinchonidine and cinchonine were prepared and assessed for their insecticidal activity against Mythimna separata in vivo by the leaf-dipping method at 1 mg/mL. Among all the compounds, especially derivatives 6l and 6o exhibited the best insecticidal activity with final mortality rates of 75.0% and 71.4%, respectively. Overall, a free 9-hydroxyl group is not a prerequisite for insecticidal activity and C9-substitution is well tolerated; the configuration of C8/9 position is important for insecticidal activity, and 9S-configuration is optimal; 6'-OCH3 moiety is not necessary, removal of it is also acceptable.

11.
Theranostics ; 10(4): 1833-1848, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32042339

RESUMO

Purpose: To determine the role of UCH-L1 in regulating ERα expression, and to evaluate whether therapeutic targeting of UCH-L1 can enhance the efficacy of anti-estrogen therapy against breast cancer with loss or reduction of ERα. Methods: Expressions of UCH-L1 and ERα were examined in breast cancer cells and patient specimens. The associations between UCH-L1 and ERα, therapeutic response and prognosis in breast cancer patients were analyzed using multiple databases. The molecular pathways by which UCH-L1 regulates ERα were analyzed using immunoblotting, qRT-PCR, immunoprecipitation, ubiquitination, luciferase and ChIP assays. The effects of UCH-L1 inhibition on the efficacy of tamoxifen in ERα (-) breast cancer cells were tested both in vivo and in vitro. Results: UCH-L1 expression was conversely correlated with ERα status in breast cancer, and the negative regulatory effect of UCH-L1 on ERα was mediated by the deubiquitinase-mediated stability of EGFR, which suppresses ERα transcription. High expression of UCH-L1 was associated with poor therapeutic response and prognosis in patients with breast cancer. Up-regulation of ERα caused by UCH-L1 inhibition could significantly enhance the efficacy of tamoxifen and fulvestrant in ERα (-) breast cancer both in vivo and in vitro. Conclusions: Our results reveal an important role of UCH-L1 in modulating ERα status and demonstrate the involvement of UCH-L1-EGFR signaling pathway, suggesting that UCH-L1 may serve as a novel adjuvant target for treatment of hormone therapy-insensitive breast cancers. Targeting UCH-L1 to sensitize ER negative breast cancer to anti-estrogen therapy might represent a new therapeutic strategy that warrants further exploration.

12.
J Asian Nat Prod Res ; : 1-12, 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-32009450

RESUMO

Three series of sulfonate derivatives of paeonol were synthesized and screened in vitro for their anti-oomycete activity against P. capsici, respectively. Among all the compounds, 4m displayed the best promising and pronounced anti-oomycete activity against P. capsici than zoxamide, with the EC50 values of 24.51 and 26.87 mg/L, respectively. The results show that acetyl and 4-OCH3 are two necessary groups. The existence of these two sites is closely related to the anti-oomycete activity. Relatively speaking, hydroxyl group is well tolerated, and the results showed that after modification of hydroxyl group with sulfonyl, the anti-oomycete activity was significantly increased.[Formula: see text].

13.
Comb Chem High Throughput Screen ; 23(3): 232-238, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31985371

RESUMO

BACKGROUND: Plant secondary metabolites play an essential role in the discovery of novel insecticide due to their unique sources and potential target sites. Paeonol, the main phenolic components in Moutan Cortex, is recognized as a safe and potent botanical insecticide to many insects. The structural modification of paeonol in this study into phenylsulfonylhydrazone derivatives is proved an effective approach for the development of novel insecticides, those derivatives being more toxic than paeonol. However, there have been no reports on the insecticidal activity of paeonol-based phenylsulfonylhydrazone derivatives in controlling Mythimna separata. METHODS: We have been working to discover biorational natural products-based insecticides. Twelve novel paeonol-based phenylsulfonylhydrazone derivatives have been successfully prepared by structural modification of paeonol, and the insecticidal activity against M. separata by the leafdipping method at the concentration of 1 mg/mL has been evaluated. RESULTS: Insecticidal activity revealed that out of 12 title compounds, derivatives 5c and 5f displayed the best against M. separate with the FMR both of 53.6% than toosendanin (FMR = 50.0%). CONCLUSION: The results suggested that for the paeonol-based phenylsulfonylhydrazone series derivatives, the proper substituent of arylsulfonyl R at the hydroxyl position of paeonol was very important for their insecticidal activity. These preliminary results will pave the way for further modification of paeonol in the development of potential new insecticides.

14.
J Asian Nat Prod Res ; 22(12): 1197-1206, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31773971

RESUMO

Gramine can be intelligently and efficiently supplied with N, N-dimethylamino group and then reacted with the corresponding sulfonyl chlorides to synthesize N, N-dimethylarylsulfonamides. We herein designed and controlled synthesis of N, N-dimethylarylsulfonamide derivatives, and first reported the results of the nematicidal activity of 15 title compounds 3a-o against Meloidogyne incongnita in vitro, respectively. Among all of the title derivatives, compounds 3a, 3c, 3k, and 3o exhibited potent nematicidal activity with median lethal concentration (LC50) values ranging from 0.22 to 0.26 mg/L. Most noteworthy, N, N-dimethyl-4-methoxyphenylsulfonamide (3c) and N, N-dimethyl-8-quinolinesulfonamide (3o) showed the best promising and pronounced nematicidal activity, with LC50 values of 0.2381 and 0.2259 mg/L, respectively.


Assuntos
Antinematódeos , Tylenchoidea , Animais , Antinematódeos/farmacologia , Estrutura Molecular
15.
J Asian Nat Prod Res ; 22(6): 578-587, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31046458

RESUMO

Sixteen sulfonate derivatives of maltol were synthesized and screened in vitro for their anti-oomycete and nematicidal activity against Phytophthora capsici and Bursaphelenchus xylophilus, respectively. Among all the compounds, 3e, 3m, and 3p exhibited the most promising and pronounced anti-oomycete activity against P. capsici than zoxamide, and the EC50 values of 25.42, 18.44, 23.69, and 27.99 mg/L, respectively; compounds 3e, 3m, 3n, and 3p exhibited potent nematicidal activity with LC50 values ranging from 1 to 2 mg/L, especially 3m and 3n showed the best promising and pronounced nematicidal activity, with LC50 values of 1.1762 and 1.2384 mg/L, respectively. [Formula: see text].


Assuntos
Phytophthora , Antinematódeos , Estrutura Molecular , Pironas
16.
J Asian Nat Prod Res ; 22(7): 678-688, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31120307

RESUMO

A series of sulfonate derivatives of sesamol were synthesized and evaluated for their insecticidal activity against a crop-threatening agricultural pest, the pre-third-instar larvae of Mythimna separata in vivo. Among all the target compounds, compounds 3b, 3g, 3h, and 3p exhibited more promising insecticidal activity than sesamol and toosendanin, and the final mortality rates (FMRs) of 3b, 3g, 3h, 3p, 1, and toosendanin were 60.7%/60.7%/67.9%/53.6%/32.1%/50.0%, respectively. Especially compound 3h exhibited the most potent insecticidal activity with FMRs of 67.9%. This suggested that a 4-fluorophenylsulfonyl group introduced at the hydroxyl position of sesamol was necessary for obtaining the most potent compound.[Formula: see text].


Assuntos
Inseticidas , Mariposas , Animais , Benzodioxóis , Larva , Estrutura Molecular , Fenóis
17.
J Oncol ; 2019: 3267207, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31885572

RESUMO

Heat shock proteins (HSPs) are highly conserved molecular chaperones with divergent roles in various cellular processes. The HSPs are classified according to their molecular size as HSP27, HSP40, HSP60, HSP70, and HSP90. The HSPs prevent nonspecific cellular aggregation of proteins by maintaining their native folding energetics. The disruption of this vital cellular process, driven by the aberrant expression of HSPs, is implicated in the progression of several different carcinomas. Many HSPs are also actively involved in promoting the proliferation and differentiation of tumor cells, contributing to their metastatic phenotype. Upregulation of these HSPs is associated with the poor outcome of anticancer therapy in clinical settings. On the other hand, these highly expressed HSPs may be exploited as viable immunotherapeutic targets for different types of cancers. This review discusses recent advances and perspectives on the research of HSP-based cancer immunotherapy.

18.
Front Pharmacol ; 10: 391, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31057406

RESUMO

Bcl-2 family protein is an important factor in regulating apoptosis and is associated with cancer. The anti-apoptotic proteins of Bcl-2 family, such as Bcl-2, are overexpression in numerous tumors, and contribute to cancer formation, development, and therapy resistance. Therefore, Bcl-2 is a promising target for drug development, and several Bcl-2 inhibitors are currently undergoing clinical trials. In this study, we carried out a QSAR-based virtual screening approach to develop potential Bcl-2 inhibitors from the SPECS database. Surface plasmon resonance (SPR) binding assay was performed to examine the interaction between Bcl-2 protein and the screened inhibitors. After that, we measured the anti-tumor activities of the 8 candidate compounds, and found that compound M1 has significant cytotoxic effect on breast cancer cells. We further proved that compound M1 downregulated Bcl-2 expression and activated apoptosis by inducing mitochondrial dysfunction. In conclusion, we identified a novel Bcl-2 inhibitor by QSAR screening, which exerted significant cytotoxic activity in breast cancer cells through inducing mitochondria-mediated apoptosis.

19.
Cancer Biol Ther ; 20(8): 1105-1112, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30929569

RESUMO

Background: Among all breast cancer subtypes, triple-negative breast cancer (TNBC) has aggressive clinical manifestations including more frequent relapses and metastases. The roles of PD-L1 expression and tumor-infiltrating lymphocytes (TILs) in TNBC clinicopathological behaviors and patients' survival outcomes remain unclear. Methods: TNBC (108 cases) patients with at least 5-year follow-up were analyzed for PD-L1 expression and TILs by immunohistochemistry. We also analyzed the relationships between PD-L1 expression, TILs and clinicopathological characteristics. Furthermore, we explored the effect of PD-L1 expression and TILs on prognosis as illustrated by disease-free survival (DFS). Results: The expression of PD-L1 was related to more aggressive clinicopathological behaviors in TNBC patients including a larger tumor size, higher incidence of PL-1-ALN, more frequent distant metastasis, and a reduced disease-free survival. In contrast, patients with high-level TILs showed less aggressive disease progression hence a better prognosis compared to patients with low-level TILs. Among patients with high-level TILs, PD-L1 expression was correlated with adverse prognosis. Conclusions: Expression of PD-L1 and low-level TILs in TNBC patients were associated with adverse clinical outcomes. However, the positive impact of high-level TILs was attenuated by PD-L1 expression. Our results suggest potential biomarkers for a selection of indicated cases in the TNBC patients for anti-PD-L1/anti-PD1 immunotherapy.


Assuntos
Antígeno B7-H1/genética , Biomarcadores Tumorais , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/imunologia , Adulto , Idoso , Antígeno B7-H1/metabolismo , Terapia Combinada , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologia , Microambiente Tumoral
20.
JCI Insight ; 4(7)2019 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-30777937

RESUMO

The autoantigen-specific Tregs from pluripotent stem cells (PSCs), i.e., PSC-Tregs, have the ability to suppress autoimmunity. PSC-Tregs can be programmed to be tissue associated and to infiltrate into local inflamed tissues to suppress autoimmune responses after adoptive transfer. Nevertheless, the mechanisms by which the autoantigen-specific PSC-Tregs suppress the autoimmune response remain to be fully elucidated. In this study, we generated functional autoantigen-specific Tregs from the induced PSC (iPSCs), i.e., iPSC-Tregs, and investigated the underlying mechanisms of autoimmunity suppression by these Tregs in a type 1 diabetes (T1D) murine model. A double-Tg mouse model of T1D was established in F1 mice, in which the first generation of RIP-mOVA Tg mice that were crossed with OT-I T cell receptor (TCR) Tg mice was challenged with vaccinia viruses expressing OVA (VACV-OVA). We show that adoptive transfer of OVA-specific iPSC-Tregs greatly suppressed autoimmunity in the animal model and prevented the insulin-secreting pancreatic ß cells from destruction. Further, we demonstrate that the adoptive transfer significantly reduced the expression of ICAM-1 in the diabetic pancreas and inhibited the migration of pathogenic CD8+ T cells and the production of the proinflammatory IFN-γ in the pancreas. These results indicate that the stem cell-derived tissue-associated Tregs can robustly accumulate in the diabetic pancreas, and, through downregulating the expression of ICAM-1 in the local inflamed tissues and inhibiting the production of proinflammatory cytokine IFN-γ, suppress the migration and activity of the pathogenic immune cells that cause T1D.


Assuntos
Transferência Adotiva/métodos , Autoimunidade , Diabetes Mellitus Tipo 1/terapia , Linfócitos T Reguladores/transplante , Animais , Diferenciação Celular , Linhagem Celular , Movimento Celular/imunologia , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/patologia , Modelos Animais de Doenças , Regulação para Baixo , Humanos , Células-Tronco Pluripotentes Induzidas , Molécula 1 de Adesão Intercelular/imunologia , Molécula 1 de Adesão Intercelular/metabolismo , Interferon gama/imunologia , Interferon gama/metabolismo , Camundongos , Camundongos Transgênicos , Pâncreas/imunologia , Pâncreas/patologia , Linfócitos T Reguladores/imunologia
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