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1.
Cancer Cell ; 2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33577785

RESUMO

Glioblastoma (GBM) is the most aggressive nervous system cancer. Understanding its molecular pathogenesis is crucial to improving diagnosis and treatment. Integrated analysis of genomic, proteomic, post-translational modification and metabolomic data on 99 treatment-naive GBMs provides insights to GBM biology. We identify key phosphorylation events (e.g., phosphorylated PTPN11 and PLCG1) as potential switches mediating oncogenic pathway activation, as well as potential targets for EGFR-, TP53-, and RB1-altered tumors. Immune subtypes with distinct immune cell types are discovered using bulk omics methodologies, validated by snRNA-seq, and correlated with specific expression and histone acetylation patterns. Histone H2B acetylation in classical-like and immune-low GBM is driven largely by BRDs, CREBBP, and EP300. Integrated metabolomic and proteomic data identify specific lipid distributions across subtypes and distinct global metabolic changes in IDH-mutated tumors. This work highlights biological relationships that could contribute to stratification of GBM patients for more effective treatment.

2.
Cell Rep ; 33(9): 108418, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33264628

RESUMO

Neurodegenerative diseases are characterized by the formation and propagation of protein aggregates, especially amyloid fibrils. However, what normally suppresses protein misfolding and aggregation in metazoan cells remains incompletely understood. Here, we show that TRIM11, a member of the metazoan tripartite motif (TRIM) family, both prevents the formation of protein aggregates and dissolves pre-existing protein deposits, including amyloid fibrils. These molecular chaperone and disaggregase activities are ATP independent. They enhance folding and solubility of normal proteins and cooperate with TRIM11 SUMO ligase activity to degrade aberrant proteins. TRIM11 abrogates α-synuclein fibrillization and restores viability in cell models of Parkinson's disease (PD). Intracranial adeno-associated viral delivery of TRIM11 mitigates α-synuclein-mediated pathology, neurodegeneration, and motor impairments in a PD mouse model. Other TRIMs can also function as ATP-independent molecular chaperones and disaggregases. Thus, we define TRIMs as a potent and multifunctional protein quality-control system in metazoa, which might be applied to treat neurodegenerative diseases.

3.
Cell Metab ; 2020 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-33159852

RESUMO

The emergence of cancer from diverse normal tissues has long been rationalized to represent a common set of fundamental processes. However, these processes are not fully defined. Here, we show that forced expression of glucose-6-phosphate dehydrogenase (G6PD) affords immortalized mouse and human cells anchorage-independent growth in vitro and tumorigenicity in animals. Mechanistically, G6PD augments the NADPH pool by stimulating NAD+ kinase-mediated NADP+ biosynthesis in addition to converting NADP+ to NADPH, bolstering antioxidant defense. G6PD also increases nucleotide precursor levels through the production of ribose and NADPH, promoting cell proliferation. Supplementation of antioxidants or nucleosides suffices to convert immortalized mouse and human cells into a tumorigenic state, and supplementation of both is required when their overlapping metabolic consequences are minimized. These results suggest that normal cells have a limited capacity for redox balance and nucleotide synthesis, and overcoming this limit might represent a key aspect of oncogenic transformation.

4.
J Anal Methods Chem ; 2020: 8866250, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33062375

RESUMO

In this study, high-performance liquid chromatography (HPLC) and colorimeter were applied to evaluate the quality of different species and differently prepared slices of Zedoray Rhizome samples with the aid of chemometric tools. Fifty batches of Zedoray Rhizome samples from different species and forty-two batches of Zedoray Rhizome samples from differently prepared slices were collected. The quantitative method was developed using HPLC to simultaneously determine the contents of twelve chemical ingredients in Zedoray Rhizome. The colour parameters L, a, and b were measured by a colorimeter. Then, the collected data were analyzed by the principal component analysis and Pearson correlation analysis. The results showed that the proposed method was capable of accurately determining the contents of the twelve chemical ingredients and the colour parameters for the collected samples. There was a dramatic difference in the contents of the chemical ingredients and in the colour parameters among different species and differently prepared slices of Zedoray Rhizome samples. This study reveals that combining HPLC, colorimeter, and chemometric tools can provide a new approach to comprehensively evaluate the quality of Zedoray Rhizome samples.

5.
J Environ Sci (China) ; 95: 210-216, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32653182

RESUMO

The reaction of alkenes with ozone has great effect on atmospheric oxidation, its transient species can produce OH radicals and contribute to the formation of secondary organic aerosols (SOA). In the present study, the reaction of tetramethylethene (TME) with ozone was investigated using self-assembled low temperature matrix isolation system. The TME and ozone were co-deposited on a salt plate at 15 K, and then slowly warmed up the plate. The first transient species primary ozonide (POZ) was detected, indicating that the reaction followed Criegee mechanism. Then POZ began to decompose at 180 K. However, secondary ozonide (SOZ) was not observed according to Criegee mechanism. Probably, Criegee Intermediate (CI) did not react with inert carbonyl of acetone, but with remaining TME formed tetra-methyl epoxide (EPO).


Assuntos
Ozônio , Acetona , Aerossóis , Alcenos , Oxirredução
6.
Science ; 369(6502): 397-403, 2020 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-32703873

RESUMO

Embryonic stem cells can propagate indefinitely in a pluripotent state, able to differentiate into all types of specialized cells when restored to the embryo. What sustains their pluripotency during propagation remains unclear. Here, we show that core pluripotency factors OCT4 and SOX2 suppress chaperone-mediated autophagy (CMA), a selective form of autophagy, until the initiation of differentiation. Low CMA activity promotes embryonic stem cell self-renewal, whereas its up-regulation enhances differentiation. CMA degrades isocitrate dehydrogenases IDH1 and IDH2 and reduces levels of intracellular α-ketoglutarate, an obligatory cofactor for various histone and DNA demethylases involved in pluripotency. These findings suggest that CMA mediates the effect of core pluripotency factors on metabolism, shaping the epigenetic landscape of stem cells and governing the balance between self-renewal and differentiation.


Assuntos
Diferenciação Celular , Autofagia Mediada por Chaperonas , Células-Tronco Embrionárias/fisiologia , Animais , Linhagem Celular , Epigênese Genética , Histonas/fisiologia , Ácidos Cetoglutáricos/metabolismo , Camundongos , Fator 3 de Transcrição de Octâmero/fisiologia , Fatores de Transcrição SOXB1/fisiologia
7.
Mol Immunol ; 124: 153-160, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32580073

RESUMO

Patients with Huntington's diseases display reduced tumor incidence mediated by unclear mechanisms. Besides, the effects of characteristic overexpression of 97 polyglutamine protein (polyQ protein) on tumor surveillance by the host immune system have not been investigated. NK cells are cytotoxic innate lymphocytes that sense and kill stressed and transformed cells through recognition of abnormal molecular patterns. Here, we found that polyQ protein induced the accumulation of misfolded proteins in tumor cells and sensitized these tumor cells to NK cell cytolysis in vitro. Transcriptome analysis showed that polyQ protein overexpression caused an abnormal transcriptome changes in tumor cells, which might predispose these tumor cells to death upon NK cell cytolysis. However, on the other hand, polyQ protein in NK cells compromised NK cell cytolytic activity through forcing the accumulation of misfolded proteins. Furthermore, polyQ overexpression enriched oxidative phosphorylation related gene set in NK cells, which might lead to an exhaustion-like status of NK cells with reduced cytolytic activity. Therefore, our study shows that polyQ protein overexpression in tumors alone, but not in both tumor cells and NK cells, might result in increased tumor rejection by NK cells, revealing a dual role of polyQ protein on tumor surveillance by the immune system.


Assuntos
Citotoxicidade Imunológica/imunologia , Vigilância Imunológica/imunologia , Células Matadoras Naturais/imunologia , Neoplasias/imunologia , Peptídeos/metabolismo , Linhagem Celular Tumoral , Humanos , Dobramento de Proteína
8.
Retina ; 2020 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-32349103

RESUMO

PURPOSE: To evaluate spectral domain optical coherence tomography (SD-OCT) features of vitreoretinal lymphoma (VRL). METHODS: Review of records and SD-OCT images of vitreoretinal lymphoma evaluated at Ocular Oncology Service, Wills Eye Hospital between July 1, 2000, and April 1, 2019. RESULTS: There were 55 eyes of 32 patients included. At presentation, SD-OCT features included vitreous opacities (n = 36, 65%), preretinal deposits (n = 7, 13%), intraretinal deposits (n = 8, 15%), subretinal deposits (n = 20, 36%), retinal pigment epithelium abnormalities (n = 35, 64%), and subretinal pigment epithelium deposits (n = 35, 64%). Of 36 eyes with observed tumor progression, comparison (initial visit vs. time of progression) revealed more intraretinal deposits (17% vs. 50%, P = 0.005) at progression. Of 15 eyes with tumor recurrence, comparison (initial visit vs. time of recurrence) revealed more intraretinal deposits (7% vs. 47%, P = 0.04) at recurrence. At last visit, 39 eyes demonstrated tumor regression. By comparison (initial presentation vs. regression), there were less frequent vitreous opacities (67% vs. 0%, P < 0.001), intraretinal deposits (15% vs. 0%, P = 0.03), subretinal deposits (36% vs. 0%, P < 0.001), and subretinal pigment epithelium deposits (69% vs. 21%, P < 0.001) at regression. CONCLUSION: Using SD-OCT in patients with vitreoretinal lymphoma, local tumor regression correlated with a reduction in vitreous opacities, intraretinal deposits, subretinal deposits, and subretinal pigment epithelium deposits. SD-OCT is useful in judging vitreoretinal lymphoma response to therapy.

9.
Clin Exp Ophthalmol ; 48(5): 610-623, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32277560

RESUMO

IMPORTANCE: The impact of tumour thickness on radiation complications following plaque radiotherapy for uveal melanoma in the anti-vascular endothelial growth factor (VEGF) era remains unknown. BACKGROUND: To evaluate treatment outcomes following plaque radiotherapy and prophylactic intravitreal bevacizumab for uveal melanoma based on initial tumour thickness. DESIGN: This was a retrospective, interventional case series. PARTICIPANTS: Patients with uveal melanoma were included in this study. METHODS: A review of medical records was conducted of patients with uveal melanoma treated with plaque radiotherapy and prophylactic intravitreal bevacizumab from 7 July 2000 to 2 November 2018. MAIN OUTCOMES MEASURES: Radiation-related outcomes of cystoid macular oedema (CME), radiation maculopathy, papillopathy, retinopathy, iris neovascularization (NVI) and neovascular glaucoma (NVG) were compared based on tumour thickness (small [<3.0 mm] vs medium [3.1-8.0 mm] vs large [>8.0 mm]). RESULTS: Of 1131 eyes, 341 (30%) had small, 633 (56%) medium and 157 (14%) large melanoma. Comparison (small vs medium vs large) at 4 years following radiotherapy revealed large melanoma with greater Kaplan-Meier estimated risk of CME (37% vs 37% vs 63%, P < .001), earlier onset of CME (33 vs 26 vs 19 months, P < .001) and greater development of NVI (<1% vs 2% vs 13%, P < .001) and NVG (1% vs 2% vs 12%, P < .001). Radiation-induced maculopathy, papillopathy and retinopathy were not associated with tumour thickness. CONCLUSIONS AND RELEVANCE: Compared with small and medium uveal melanoma, large uveal melanoma demonstrated greater 48-month risk for CME, shorter time to CME onset and greater development of NVI and NVG following plaque radiotherapy and prophylactic intravitreal bevacizumab.

10.
Indian J Ophthalmol ; 68(3): 419, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32056992
11.
Asia Pac J Ophthalmol (Phila) ; 9(1): 29-38, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31990743

RESUMO

PURPOSE: The aim of this study was to determine the impact of age on radiation complications after plaque radiotherapy and prophylactic intravitreal bevacizumab for uveal melanoma. DESIGN: Retrospective cohort study. METHODS: Retrospective single-center study of plaque-irradiated uveal melanoma with prophylactic intravitreal bevacizumab at 4-month intervals from July 2000 to January 2018. RESULTS: Of 1131 eyes in 1131 patients, age was <50 years (n = 231), 50 to 70 years (n = 657), or >70 years (n = 243). Comparison by age category (<50 vs 50-70 vs >70 years) revealed the oldest group presenting with greatest tumor basal diameter (11.3 vs 11.3 vs 12.1 mm, P = 0.03) and worst visual acuity (20/40 vs 20/40 vs 20/50, P = 0.02). After plaque (mean follow-up 40 vs 42 vs 32 months, P < 0.001), radiation complications were most common in the youngest age group, including maculopathy (48% vs 39% vs 28%, P < 0.001), extramacular retinopathy (30% vs 25% vs 16%, P = 0.002), and papillopathy (21% vs 18% vs 12%, P = 0.03). The youngest age group had the highest Kaplan-Meier estimated 48-month cumulative probability for radiation maculopathy (62% vs 46% vs 47%, P = 0.001), extramacular retinopathy (36% vs 34% vs 29%, P = 0.03), and papillopathy (29% vs 26% vs 22%, P = 0.13). On subanalysis, the youngest age group had increased 48-month risk of developing radiation maculopathy when compared with the middle [hazard ratio (HR) = 1.5, P = 0.001] and older (HR = 1.6, P = 0.005) age groups and increased 48-month risk of developing extramacular radiation retinopathy compared with the older age group (HR = 1.5, P = 0.04). CONCLUSIONS: After plaque radiotherapy for uveal melanoma and prophylactic intravitreal bevacizumab at 4-month intervals, patients younger than 50 years old have an increased 48-month risk of radiation maculopathy.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Bevacizumab/uso terapêutico , Braquiterapia , Melanoma/radioterapia , Lesões por Radiação/prevenção & controle , Doenças Retinianas/prevenção & controle , Neoplasias Uveais/radioterapia , Acuidade Visual/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Injeções Intravítreas , Radioisótopos do Iodo/uso terapêutico , Edema Macular/fisiopatologia , Edema Macular/prevenção & controle , Masculino , Melanoma/tratamento farmacológico , Melanoma/fisiopatologia , Pessoa de Meia-Idade , Lesões por Radiação/fisiopatologia , Doenças Retinianas/fisiopatologia , Estudos Retrospectivos , Neoplasias Uveais/tratamento farmacológico , Neoplasias Uveais/fisiopatologia , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Adulto Jovem
12.
Nat Commun ; 11(1): 348, 2020 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-31953436

RESUMO

Tumor cells often exhibit augmented capacity to maintain endoplasmic reticulum (ER) homeostasis under adverse conditions, yet the underlying mechanisms are not well defined. Here, through the evaluation of all human TRIM proteins, we find that TRIM25 is significantly induced upon ER stress. Upregulation of TRIM25 ameliorates oxidative stress, promotes ER-associated degradation (ERAD), and reduces IRE1 signaling in the UPR pathway. In contrast, depletion of TRIM25 leads to ER stress and attenuates tumor cell growth in vitro and in vivo. Mechanistically, TRIM25 directly targets Keap1 by ubiquitination and degradation. This leads to Nrf2 activation, which bolsters anti-oxidant defense and cell survival. TRIM25 expression is positively associated with Nrf2 expression and negatively with Keap1 expression in hepatocellular carcinoma (HCC) xenografts and specimens. Moreover, high TRIM25 expression correlates with poor patient survival in HCC. These findings reveal TRIM25 as a regulator of ER homeostasis and a potential target for tumor therapy.


Assuntos
Carcinoma Hepatocelular/metabolismo , Sobrevivência Celular/fisiologia , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Neoplasias Hepáticas/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Fatores de Transcrição/metabolismo , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Estresse do Retículo Endoplasmático/fisiologia , Endorribonucleases/metabolismo , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Fígado , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estresse Oxidativo , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Fatores de Transcrição/genética , Proteínas com Motivo Tripartido/genética , Ubiquitina-Proteína Ligases/genética , Ensaios Antitumorais Modelo de Xenoenxerto
13.
JAMA Ophthalmol ; 138(2): 136-146, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31830238

RESUMO

Importance: Radiation retinopathy following plaque radiotherapy for uveal melanoma can lead to vision loss that might be avoided with prophylactic anti-vascular endothelial growth factor treatment. Objective: To determine visual outcome following prophylactic intravitreal bevacizumab in patients with plaque-irradiated uveal melanoma. Design, Setting, and Participants: Retrospective, nonrandomized, interventional cohort study at Wills Eye Hospital, Philadelphia, Pennsylvania. Prophylactic bevacizumab was administered between 2008 and 2018 to 1131 eyes with irradiated uveal melanoma (bevacizumab group) and compared with 117 eyes with irradiated uveal melanoma between 2007 and 2009 (no bevacizumab [historical control] group). Interventions: Prophylactic intravitreal bevacizumab was provided at the time of plaque removal as well as 6 subsequent injections at 4-month intervals over 2 years. Main Outcomes and Measures: Visual acuity. Results: The median patient age was 61 years, 1195 of 1248 patients were white (96%), and 632 of 1248 were women (51%). The median tumor thickness was 4.0 mm, and median distance to foveola was 3.0 mm. A difference was not identified (bevacizumab vs control group) in demographic features, clinical features, or radiation parameters. The mean follow-up was 40 months vs 56 months (mean difference, -18; 95% CI, -24 to -13; P < .001). By survival analysis, the bevacizumab group demonstrated less optical coherence tomography evidence of cystoid macular edema at 24 months (28% vs 37%; hazard ratio [HR], 1.5; 95% CI, 1.1-2.2; P = .02) and 36 months (44% vs 54%; HR, 1.5; 95% CI, 1.1-2.1; P = .01), less clinical evidence of radiation maculopathy at 24 months (27% vs 36%; HR, 1.5; 95% CI, 1.0-2.2; P = .03), 36 months (44% vs 55%; HR, 1.50; 95% CI, 1.1-2.0; P = .01), and 48 months (61% vs 66%; HR, 1.4; 95% CI, 1.0-1.9; P = .03), and less clinical evidence of radiation papillopathy at 18 months (6% vs 12%; HR, 2.0; 95% CI, 1.1-3.9; P = .04). Nonparametric analysis documented better visual acuity outcomes in the bevacizumab group at all points, including 12 months (median logMAR visual acuity [Snellen equivalent]: 0.30 [20/40] vs 0.48 [20/60]; mean difference, -0.28; 95% CI, -0.48 to -0.07; P = .02), 24 months (0.40 [20/50] vs 0.70 [20/100]; mean difference, -0.52; 95% CI, -0.75 to -0.29; P < .001), 36 months (0.48 [20/60] vs 1.00 [20/200]; mean difference, -0.49; 95% CI, -0.76 to -0.21; P = .003), and 48 months (0.54 [20/70] vs 2.00 [counting fingers]; mean difference, -0.71; 95% CI, -1.03 to -0.38; P < .001). Conclusions and Relevance: These findings from a retrospective cohort of plaque radiotherapy and prophylactic intravitreal bevacizumab in patients with uveal melanoma suggest better visual outcomes when compared with nonrandomized historical control individuals through 4 years.


Assuntos
Bevacizumab/administração & dosagem , Melanoma/radioterapia , Neoplasias Uveais/radioterapia , Acuidade Visual , Terapia Combinada , Feminino , Humanos , Injeções Intravítreas , Masculino , Melanoma/mortalidade , Melanoma/patologia , Melanoma/fisiopatologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Neoplasias Uveais/mortalidade , Neoplasias Uveais/patologia , Neoplasias Uveais/fisiopatologia , Fator A de Crescimento do Endotélio Vascular/análise , Acuidade Visual/efeitos dos fármacos
14.
J Exp Med ; 217(2)2020 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-31662347

RESUMO

Myeloid-derived suppressor cells (MDSCs) are "polarized" myeloid cells that effectively promote tumorigenesis by inhibiting antitumor immunity. How myeloid cells acquire the protumoral properties during tumorigenesis is poorly understood. We report here that the polarity protein TIPE2 (tumor necrosis factor-α-induced protein 8-like 2) mediates the functional polarization of murine and human MDSCs by specifying their pro- and antitumoral properties. Tumor cells induced the expression of TIPE2 in Gr1+CD11b+ cells through reactive oxygen species (ROS). TIPE2 in turn increased the expression of protumoral mediators such as CCAAT/enhancer-binding protein-ß while inhibiting the expression of antitumoral mediators. Consequently, tumor growth in TIPE2-deficient mice was significantly diminished, and TIPE2-deficient MDSCs markedly inhibited tumor growth upon adoptive transfer. Pharmaceutical blockade of ROS inhibited TIPE2 expression in MDSCs and reduced tumor growth in mice. These findings indicate that TIPE2 plays a key role in the functional polarization of MDSCs and represents a new therapeutic target for cancer immunotherapy.


Assuntos
Carcinogênese/metabolismo , Polaridade Celular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias Pulmonares/sangue , Acetilcisteína/análogos & derivados , Acetilcisteína/farmacologia , Transferência Adotiva , Animais , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/metabolismo , Feminino , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias Pulmonares/patologia , Lisina/análogos & derivados , Lisina/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Células Mieloides/metabolismo , Células Supressoras Mieloides , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transfecção
15.
J Neuroinflammation ; 16(1): 278, 2019 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-31883532

RESUMO

BACKGROUND: Uveitis is a potentially sight-threatening form of ocular inflammation that affects the uvea in the wall of the eye. Currently available treatments for uveitis have exhibited profound adverse side effects. However, KS23 is a novel 23-amino-acid anti-inflammatory peptide derived from adiponectin that may have the capability to function as a safe alternative to these existing treatment options. We, therefore, evaluated the preventive effect of KS23 in experimental autoimmune uveitis (EAU). METHODS: EAU was induced in mice via immunization with the peptide interphotoreceptor retinoid binding protein 161-180 (IRBP161-180). KS23 was then administered every 2 days via intraperitoneal injection to induce protection against EAU. Clinical and histopathological scores were employed to evaluate the disease progression. Inflammatory cytokines were also quantified using ELISA, and the expression levels of specific chemokines and chemokine receptors were assessed via qRT-PCR. In addition, the proportions of Th1 and Th17 cells were detected via flow cytometry, and the expression levels of specific proteins were quantified from the retina of mice using western blot analysis, to elucidate the specific mechanism of action employed by KS23 to suppress the inflammation associated with EAU. RESULTS: KS23 was found to significantly improve EAU-associated histopathological scores, while decreasing the expression of pro-inflammatory cytokines (IFN-γ, TNF-α, IL-6, and IL-17A), chemokines (LARC, RANTES, MIG, IP-10), and chemokine receptors (CCR6 and CXCR3). The proportions of Th1 and Th17 cells were also suppressed following intraperitoneal injection with KS23. The anti-inflammatory mechanism employed by KS23 was determined to be associated with the activation of AMPK and subsequent inhibition of NF-κB. CONCLUSIONS: KS23 decreased the proportions of Th1 and Th17 cells to effectively ameliorate the progression of EAU. It may, therefore, serve as a promising potential therapeutic agent for uveitis.


Assuntos
Adiponectina/análogos & derivados , Adiponectina/farmacologia , Anti-Inflamatórios/farmacologia , Células Th1/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Uveíte/imunologia , Animais , Modelos Animais de Doenças , Regulação para Baixo , Inflamação/imunologia , Inflamação/patologia , Camundongos , Peptídeos/farmacologia , Retina/imunologia , Retina/patologia , Células Th1/imunologia , Células Th17/imunologia , Uveíte/patologia
16.
Eur J Ophthalmol ; : 1120672119888985, 2019 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-31760781

RESUMO

PURPOSE: To describe the outcome of ultra-low-dose (boom-boom) radiotherapy for choroidal lymphoma. METHODS: Retrospective series of three consecutive patients with biopsy-proven choroidal lymphoma treated with ultra-low-dose radiotherapy. RESULTS: The three patients (two male, one female) of mean age 70 years (range, 64-74 years) demonstrated presenting visual acuity in the affected eye between 20/40 and 20/50. The choroidal lymphoma was unilateral in all cases and presented with multifocal yellow patchy choroidal infiltration, located in all four quadrants and measuring mean 2.9 mm (range, 1.9-4.0 mm) in thickness by ultrasonography. Anterior epibulbar extension of 5 mm diameter was noted in one case. By enhanced depth imaging optical coherence tomography, the choroidal infiltration demonstrated classic undulating appearance (n = 3), with subretinal fluid (n = 2) and intraretinal edema (n = 1). There was no systemic lymphoma in any case. Biopsy was performed in all three cases and was diagnostic (n = 1) or suggestive (n = 2) of B-cell lymphoma. Management involved ultra-low-dose radiotherapy (4 Gy delivered in two fractions, "boom-boom"). On follow-up (mean = 14 months, range = 6-24 months), complete tumor regression on ophthalmoscopy was documented in all three cases, with enhanced depth imaging optical coherence tomography and ultrasonography demonstrating evidence of lymphoma resolution and visual acuity improvement to 20/25-20/40. There were no radiation complications. CONCLUSION: In this small case series, ultra-low-dose (boom-boom) radiotherapy was effective for choroidal lymphoma with favorable response and minimal side effects.

17.
Immunity ; 51(5): 840-855.e5, 2019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31606264

RESUMO

TCF-1 is a key transcription factor in progenitor exhausted CD8 T cells (Tex). Moreover, this Tex cell subset mediates responses to PD-1 checkpoint pathway blockade. However, the role of the transcription factor TCF-1 in early fate decisions and initial generation of Tex cells is unclear. Single-cell RNA sequencing (scRNA-seq) and lineage tracing identified a TCF-1+Ly108+PD-1+ CD8 T cell population that seeds development of mature Tex cells early during chronic infection. TCF-1 mediated the bifurcation between divergent fates, repressing development of terminal KLRG1Hi effectors while fostering KLRG1Lo Tex precursor cells, and PD-1 stabilized this TCF-1+ Tex precursor cell pool. TCF-1 mediated a T-bet-to-Eomes transcription factor transition in Tex precursors by promoting Eomes expression and drove c-Myb expression that controlled Bcl-2 and survival. These data define a role for TCF-1 in early-fate-bifurcation-driving Tex precursor cells and also identify PD-1 as a protector of this early TCF-1 subset.


Assuntos
Linfócitos T CD8-Positivos/metabolismo , Redes Reguladoras de Genes , Fator 1 de Transcrição de Linfócitos T/metabolismo , Transcrição Genética , Animais , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Doença Crônica , Perfilação da Expressão Gênica , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Camundongos , Receptor de Morte Celular Programada 1/metabolismo , Fator 1 de Transcrição de Linfócitos T/genética , Viroses/genética , Viroses/imunologia , Viroses/virologia
18.
J Immunol Methods ; 474: 112629, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31279523

RESUMO

Frataxin is the protein that is down-regulated in Friedreich ataxia (FRDA), an autosomal recessive genetic disease caused by an intronic GAA repeat expansion in intron-1 of the FXN gene. The GAA repeats result in epigenetic silencing of the FXN gene and reduced expression of the cytosolic full-length frataxin (1-210) protein. Full length frataxin translocates to the mitochondria, leading to formation of mature frataxin (81-210) formed by cleavage of the mitochondrial targeting sequence at K-80 of the full-length protein. There are currently no approved treatments for FRDA, although experimental approaches involving up-regulation or replacement of mature frataxin protein through numerous approaches are being tested. Many of the pre-clinical studies of these experimental approaches are conducted in mouse and monkey models as well as in human cell lines. Consequently, well-validated antibodies are required for use in western blot analysis to determine whether levels of various forms of frataxin have been increased. Here we examined the specificity of five commercially available anti-frataxin antibodies and determined whether they detect mature frataxin in mouse heart tissue. Four protein standards of monkey, human, and mouse frataxin as well as mouse heart tissue were examined using polyacrylamide gel electrophoresis (PAGE) in combination with western blot analysis. One antibody failed to detect any of the frataxin standards or endogenous frataxin in mouse heart tissue. Three of the antibodies detected a protein in mouse heart tissue that ran slightly faster on PAGE (at 23.4 kDa) to that predicted for full-length frataxin (23.9 kDa). One antibody detected all four frataxin standards as well as endogenous mouse mature frataxin in mouse tissue. Significantly, this antibody, which will be useful for monitoring mature frataxin levels in monkey, human, and mouse tissues, did not detect a protein in mouse heart tissue at 23.4 kDa. Therefore, antibodies detecting the immunoreactive protein at 23.4 kDa could be misleading when testing for the up-regulation of frataxin in animal models.


Assuntos
Anticorpos/imunologia , Western Blotting , Proteínas de Ligação ao Ferro/análise , Miocárdio/química , Animais , Especificidade de Anticorpos , Eletroforese em Gel de Poliacrilamida , Humanos , Proteínas de Ligação ao Ferro/imunologia , Macaca fascicularis , Camundongos Endogâmicos C57BL , Peso Molecular , Miocárdio/imunologia , Isoformas de Proteínas , Reprodutibilidade dos Testes , Especificidade da Espécie
19.
Zhongguo Zhong Yao Za Zhi ; 44(2): 314-318, 2019 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-30989951

RESUMO

Nine compounds were isolated from chloroform fraction of Houttuynia cordata,and the isolates were identified as follows:( S)-5,6,6 a,7-tetrahydro-2,10-dimethoxy-4 H-dibenzo [DE,G] quinoline-1,9-diol( 1),( +)-isoboldine ß-N-oxide( 2),liriotulipiferine( 3),telitoxinone( 4),isoboldine( 5),(-)-clovane-2ß,9α-diol( 6),benzoic acid( 7),acantrifoside E( 8),and dibutyl phthalate( 9). Among them,compound 1 was new,and compounds 2-9 were reported from this species for the first time.


Assuntos
Medicamentos de Ervas Chinesas/química , Houttuynia/química , Compostos Fitoquímicos/análise , Extratos Vegetais/química , Clorofórmio
20.
Nat Commun ; 10(1): 1495, 2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30940803

RESUMO

The inflammasome has an essential function in innate immune, responding to a wide variety of stimuli. Here we show that the lncRNA Neat1 promotes the activation of several inflammasomes. Neat1 associates with the NLRP3, NLRC4, and AIM2 inflammasomes in mouse macrophages to enhance their assembly and subsequent pro-caspase-1 processing. Neat1 also stabilizes the mature caspase-1 to promote interleukin-1ß production and pyroptosis. Upon stimulation with inflammasome-activating signals, Neat1, which normally resides in the paraspeckles, disassociates from these nuclear bodies and translocates to the cytoplasm to modulate inflammasome activation using above mechanism. Neat1 is also up-regulated under hypoxic conditions in a HIF-2α-dependent manner, mediating the effect of hypoxia on inflammasomes. Moreover, in the mouse models of peritonitis and pneumonia, Neat1 deficiency significantly reduces inflammatory responses. These results reveal a previously unrecognized role of lncRNAs in innate immunity, and suggest that Neat1 is a common mediator for inflammasome stimuli.


Assuntos
Inflamassomos/imunologia , Inflamação/imunologia , Macrófagos/imunologia , RNA Longo não Codificante/imunologia , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/imunologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/imunologia , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/imunologia , Caspase 1/genética , Caspase 1/imunologia , Células Cultivadas , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/imunologia , Feminino , Humanos , Inflamassomos/genética , Inflamação/genética , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , RNA Longo não Codificante/genética
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