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1.
Int Immunopharmacol ; 82: 106352, 2020 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-32143006

RESUMO

Growing evidence suggested that immune dysregulation is one of the crucial drivers to the development of endometriosis (EMS). Myeloid derived suppressor cells (MDSCs) represent a heterogeneous subset of immature myeloid cells, and have been reported to promote the onset and progression of EMS. Notch signaling pathway played a major role in immunological reactions. Studies have found Notch signaling pathway could regulate MDSCs. However, how the biological effects of Notch signaling pathway on MDSCs may work in EMS is still unknown. In our study, we first built an endometriosis induced mice model. Then we treated mice with DAPT, a Notch signaling pathway inhibitor, or saline. We found that the DAPT could prevent the progression of EMS. The ADAM17, Notch1, Jagged1 and Hes1 were overexpressed in EMS mice, however, when mice were treated with DAPT, the overexpression was reduced. Meanwhile, we found a lower level of MDSCs in the DAPT treated EMS mice as compared to EMS mice without DAPT, accompanied by an increase of T helper (TH) 17 cells and a decrease of regulatory T cells (Tregs). We also investigated the reactive oxygen species (ROS) in peritoneal and endometriotic cells. Our results showed that ROS level decreased in both peritoneal and endometriotic cells in the study group treated with DAPT. Overall, our study indicates for the first time that blockage of Notch signaling could lessen MDSCs and ROS, and therefore preventing the development of endometriosis.

2.
Nat Cell Biol ; 22(3): 282-288, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32066906

RESUMO

Clustered regularly interspaced short palindromic repeats (CRISPR), CRISPR interference and programmable base editing have transformed the manipulation of eukaryotic genomes for potential therapeutic applications1-4. Here, we exploited CRISPR interference and programmable base editing to determine their potential in editing a TERT gene promoter-activating mutation, which occurs in many diverse cancer types, particularly glioblastoma5-8. Correction of the -124C>T TERT promoter mutation to -124C was achieved using a single guide RNA (sgRNA)-guided and catalytically impaired Campylobacter jejuni CRISPR-associated protein 9-fused adenine base editor (CjABE). This modification blocked the binding of members of the E26 transcription factor family to the TERT promoter, reduced TERT transcription and TERT protein expression, and induced cancer-cell senescence and proliferative arrest. Local injection of adeno-associated viruses expressing sgRNA-guided CjABE inhibited the growth of gliomas harbouring TERT-promoter mutations. These preclinical proof-of-concept studies establish the feasibility of gene editing as a therapeutic approach for cancer and validate activated TERT-promoter mutations as a cancer-specific therapeutic target.

3.
Waste Manag ; 102: 492-498, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31751921

RESUMO

Heavy metal elements are the main pollutants in municipal solid waste incineration (MSWI) fly ash, the online detection of heavy metals in MSWI fly ash could benefit its subsequent solidification treatment and land-filling. In this paper, laser induced breakdown spectroscopy (LIBS) was introduced to the rapid measurement of heavy metal elements in MSWI fly ash. Considering the serious matrix effect in MSWI fly ash, the multiple linear regression model combined with internal standard method was used to establish the calibration curves of heavy metals. Validated samples were used to evaluate the performance of quantitative analysis models. The results show that linear regression coefficients (R2) of the calibration curves for Cd, Cr, Cu, Pb, Zn are 0.981, 0.988, 0.968, 0.978 and 0.993, respectively. The average relative error of the prediction results are from 6.8 to 20.3%. The detection limits of the heavy metal content are Cd (11.13 µg/g), Cr (44.87 µg/g), Cu (36.18 µg/g), Pb (10.83 µg/g), Zn (12.27 µg/g), respectively, which are far below those required in the Standard for Pollution Control on the Landfill Site of Municipal Solid Waste (GB16889-2008). All results indicate the great potential of LIBS sensor for online rapid detection of heavy metals in MSWI fly ash.


Assuntos
Metais Pesados , Eliminação de Resíduos , Carbono , Cinza de Carvão , Incineração , Material Particulado , Resíduos Sólidos , Análise Espectral
4.
Cancer Immunol Res ; 8(1): 146-154, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31719056

RESUMO

T-cell receptor (TCR)-based biomarkers might predict patient response to immune checkpoint blockade (ICB) but need further exploration and validation for that use. We sequenced complementarity-determining region 3 of TCRß chains isolated from PD-1+ CD8+ T cells to investigate its value for predicting the response to anti-programmed cell death 1 (PD-1)/PD-ligand 1 (PD-L1) therapy in patients with non-small cell lung cancer (NSCLC). Two independent patient cohorts (cohort A, n = 25; cohort B, n = 15) were used as discovery and validation sets, respectively. Pre- and post-ICB peripheral blood samples were collected. In cohort A, patients with high PD-1+ CD8+ TCR diversity before ICB treatment showed better response to ICB and progression-free survival (PFS) compared with patients with low diversity [6.4 months vs. 2.5 months, HR, 0.39; 95% confidence interval (CI), 0.17-0.94; P = 0.021]. The results were validated in cohort B. Pre-ICB PD-1+ CD8+ TCR diversity achieved an optimal Youden's index of 0.81 (sensitivity = 0.87 and specificity = 0.94) for differentiating the ICB response in the merged dataset (cohort A plus cohort B). Patients with increased PD-1+ CD8+ TCR clonality after ICB treatment had longer PFS (7.3 months vs. 2.6 months, HR, 0.26; 95% CI, 0.08-0.86; P = 0.002) than those with decreased clonality. Thus, TCR diversity and clonality in peripheral blood PD-1+ CD8+ T cells may serve as noninvasive predictors of patient response to ICB and survival outcomes in NSCLC.

5.
Cancer Lett ; 469: 1-10, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31610265

RESUMO

Frequently occurring histone lysine succinylation is a newly identified histone modification that can be regulated by KAT2A histone succinyltransferase, which is also a histone acetyltransferase. KAT2A histone succinyltransferase activity is important for tumorigenesis; however, the mechanism underlying this tumor-promoting effect remains elusive. Here we demonstrate that KAT2A is highly expressed in human pancreatic ductal adenocarcinoma (PDAC) specimens and positively correlated with advanced stages of PDAC and short patients' survival. In addition, KAT2A expression in PDAC specimens is correlated with 14-3-3ζ expression, and KAT2A regulates H3K79 succinylation in the promoter region of YWHAZ (encoding for 14-3-3ζ) to promote YWHAZ mRNA and 14-3-3ζ expression, thereby preventing ß-catenin degradation. Expression of succinyltransferase activity-defective KAT2A Y645A reduces H3K79 succinylation and 14-3-3ζ expression, leading to decreased ß-catenin stability and subsequently decreased expression of cyclin D1, c-Myc, GLUT1, and LDHA. KAT2A-mediated 14-3-3ζ and ß-catenin expression promotes glycolysis, cell proliferation, and migration and invasion of PDAC cells with epithelial-to-mesenchymal transition. These findings reveal a novel and instrumental role of KAT2A-mediated histone succinylation in regulation of gene expression and ß-catenin stability to promote tumor cell proliferation and invasion.

6.
Chin Med J (Engl) ; 132(24): 2899-2904, 2019 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-31855969

RESUMO

BACKGROUND: Clinical outcomes of undifferentiated arthritis (UA) are diverse, and only 40% of patients with UA develop rheumatoid arthritis (RA) after 3 years. Discovering predictive markers at disease onset for further intervention is critical. Therefore, our objective was to analyze the clinical outcomes of UA and ascertain the predictors for RA development. METHODS: We performed a prospective, multi-center study from January 2013 to October 2016 among Chinese patients diagnosed with UA in 22 tertiary-care hospitals. Clinical and serological parameters were obtained at recruitment. Follow-up was undertaken in all patients every 12 weeks for 2 years. Predictive factors of disease progression were identified using multivariate Cox proportional hazards regression. RESULTS: A total of 234 patients were recruited in this study, and 17 (7.3%) patients failed to follow up during the study. Among the 217 patients who completed the study, 83 (38.2%) patients went into remission. UA patients who developed RA had a higher rheumatoid factor (RF)-positivity (42.9% vs. 16.8%, χ = 8.228, P = 0.008), anti-cyclic citrullinated peptide (CCP) antibody-positivity (66.7% vs. 10.7%, χ = 43.897, P < 0.001), and double-positivity rate of RF and anti-CCP antibody (38.1% vs. 4.1%, χ = 32.131, P < 0.001) than those who did not. Anti-CCP antibody but not RF was an independent predictor for RA development (hazard ratio 18.017, 95% confidence interval: 5.803-55.938; P < 0.001). CONCLUSION: As an independent predictor of RA, anti-CCP antibody should be tested at disease onset in all patients with UA.

7.
Front Oncol ; 9: 1123, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31750240

RESUMO

Background: The identification of prognostic markers for non-small-cell lung carcinoma (NSCLC) is needed for clinical practice. The metabolism-reprogramming marker ketohexokinase (KHK)-A and acetyl-CoA synthetase 2 (ACSS2) phosphorylation at S659 (ACSS2 pS659) play important roles in tumorigenesis and tumor development. However, the clinical significance of KHK-A and ACSS2 pS659 in NSCLC is largely unknown. Methods: The expression levels of KHK-A and ACSS2 pS659 were assessed by immunohistochemistry analyses of surgical specimens from 303 NSCLC patients. The prognostic values of KHK-A and ACSS2 pS659 were evaluated by Kaplan-Meier methods and Cox regression models. Results: The expression levels of KHK-A and ACSS2 pS659 were significantly higher in NSCLC tissues than those in adjacent non-tumor tissues (P < 0.0001). KHK-A or ACSS2 pS659 alone and the combination of KHK-A and ACSS2 pS659 were inversely correlated with overall survival in NSCLC patients (P < 0.001). The multivariate analysis indicated that KHK-A or ACSS2 pS659 and KHK-A/ACSS2 pS659 were independent prognostic biomarkers for NSCLC (P = 0.008 for KHK-A, P < 0.001 for ACSS2 pS659, and P < 0.001 for KHK-A/ACSS2 pS659). Furthermore, the combination of KHK-A and ACSS2 pS659 can be used as a prognostic indicator for all stages of NSCLC. Conclusions: KHK-A or ACSS2 pS659 alone and the combination of KHK-A and ACSS2 pS659 can be used as prognostic markers for NSCLC. Our findings highlight the important role of metabolic reprogramming in NSCLC progression.

8.
Cancer Commun (Lond) ; 39(1): 54, 2019 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-31578148

RESUMO

BACKGROUND: Cancer cells reprogram metabolism for proliferation. Phosphoglycerate kinase 1 (PGK1), as a glycolytic enzyme and newly identified protein kinase, coordinates glycolysis and mitochondrial metabolism. However, the clinical significance of PGK1 expression and function in cancer progression is unclear. Here, we investigated the relationship between the progression and prognosis of multiple cancer types and PGK1 expression and its function in the mitochondrial metabolism regulation. METHODS: We performed pan-cancer analyses of PGK1 mRNA level and DNA methylation in 11,908 tumor tissues and 1582 paired normal tissues across 34 cancer types in The Cancer Genome Atlas datasets. Using specific antibodies against PGK1 S203 and PDHK1 T338 phosphorylation, we performed immunohistochemistry with tissue microarray assay in additional 818 cancer cases with 619 paired normal tissues from five cancer types. RESULTS: The PGK1 mRNA level was significantly elevated with hypomethylation in promotor regions and associated with advanced TNM stage in 15 and four cancer types, respectively. In breast carcinoma, elevated PGK1 mRNA level and promoter hypomethylation were associated with poor prognosis. Positively correlated PGK1 S203 and PDHK1 T338 phosphorylation levels were significantly associated with short overall survival (OS) in cancers of the breast, liver, lung, stomach, and esophagus and with advanced TNM stage in breast and esophageal cancers. PGK1 pS203 and PDHK1 pT338 were also independent predictors of short OS in liver, lung, and stomach cancer. CONCLUSIONS: The elevated expression, promoter hypomethylation, and phosphorylation of PGK1 and PDHK1 were related with disease progression and short OS in diverse types of cancer. PGK1 and PDHK1 phosphorylation may be potential prognostic biomarkers.

9.
Mol Cell ; 76(6): 885-895.e7, 2019 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-31629659

RESUMO

Hypoxia, which occurs during tumor growth, triggers complex adaptive responses in which peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) plays a critical role in mitochondrial biogenesis and oxidative metabolism. However, how PGC-1α is regulated in response to oxygen availability remains unclear. We demonstrated that lysine demethylase 3A (KDM3A) binds to PGC-1α and demethylates monomethylated lysine (K) 224 of PGC-1α under normoxic conditions. Hypoxic stimulation inhibits KDM3A, which has a high KM of oxygen for its activity, and enhances PGC-1α K224 monomethylation. This modification decreases PGC-1α's activity required for NRF1- and NRF2-dependent transcriptional regulation of TFAM, TFB1M, and TFB2M, resulting in reduced mitochondrial biogenesis. Expression of PGC-1α K224R mutant significantly increases mitochondrial biogenesis, reactive oxygen species (ROS) production, and tumor cell apoptosis under hypoxia and inhibits brain tumor growth in mice. This study revealed that PGC-1α monomethylation, which is dependent on oxygen availability-regulated KDM3A, plays a critical role in the regulation of mitochondrial biogenesis.


Assuntos
Neoplasias Encefálicas/enzimologia , Histona Desmetilases com o Domínio Jumonji/metabolismo , Mitocôndrias/enzimologia , Biogênese de Organelas , Oxigênio/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Processamento de Proteína Pós-Traducional , Animais , Apoptose , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Células HeLa , Células Hep G2 , Humanos , Histona Desmetilases com o Domínio Jumonji/genética , Metilação , Camundongos Endogâmicos BALB C , Camundongos Nus , Mitocôndrias/patologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Carga Tumoral , Hipóxia Tumoral , Microambiente Tumoral
10.
Reprod Biol Endocrinol ; 17(1): 78, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31615517

RESUMO

BACKGROUND: Immune dysregulation is one of the mechanisms to promote endometriosis (EMS). Various T cell subpopulations have been reported to play different roles in the development of EMS. The mucosa-associated invariant T cell (MAIT) is an important T cell subset in the pathogenesis of various autoimmune diseases. Evidence has indicated that there are three functionally distinct MAIT subsets: CD4+, CD8+ and CD4/CD8-/- (double negative, DN) MAIT cells. Till now, the associations between endometriosis and MAIT have not been studied. Our research investigates different MAIT subpopulations in peripheral blood (PB) and peritoneal fluid (PF) from EMS patients. METHODS: Thirty-two EMS patients and eighteen controls were included. PB and PF were collected. Tests of cytokines in plasma and PF were performed by ELISA kit. Characterisations of MAIT were done by flow cytometry. MAIT cells have been defined as CD3 + CD161 + Vα7.2+ cells. Based on CD4 and CD8 expression, they were divided into CD8+MAIT, CD4+MAIT and DN MAIT. RESULTS: Enrichments of MAIT cells, especially CD4 and CD8 MAIT subsets were found. Moreover, CD8 MAIT cells had a high activation in the EMS group. EMS patients produced higher level of IL-8/12/17 as compared to these from controls. On the contrary, control patients exhibited an impressive upregulation of DN MAIT cells, however, these DN MAIT cells from controls showed a higher expression of PD-1. Lastly, we performed the relevance analysis, and discovered that the accumulation of PB MAIT cells positively correlated with an elevated level of serum CA125 production in EMS group. CONCLUSION: These results suggest that different MAIT subsets play distinct roles in the progression of endometriosis.

11.
Nat Commun ; 10(1): 4266, 2019 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-31537781

RESUMO

Decreased expression of 4-hydroxyphenylpyruvic acid dioxygenase (HPD), a key enzyme for tyrosine metabolism, is a cause of human tyrosinemia. However, the regulation of HPD expression remains largely unknown. Here, we demonstrate that molecular chaperone TTC36, which is highly expressed in liver, is associated with HPD and reduces the binding of protein kinase STK33 to HPD, thereby inhibiting STK33-mediated HPD T382 phosphorylation. The reduction of HPD T382 phosphorylation results in impaired recruitment of FHA domain-containing PELI1 and PELI1-mediated HPD polyubiquitylation and degradation. Conversely, deficiency or depletion of TTC36 results in enhanced STK33-mediated HPD T382 phosphorylation and binding of PELI1 to HPD and subsequent PELI1-mediated HPD downregulation. Ttc36-/- mice have reduced HPD expression in the liver and exhibit tyrosinemia, damage to hippocampal neurons, and deficits of learning and memory. These findings reveal a previously unknown regulation of HPD expression and highlight the physiological significance of TTC36-STK33-PELI1-regulated HPD expression in tyrosinemia and tyrosinemia-associated neurological disorders.


Assuntos
Proteínas de Membrana/metabolismo , Proteínas Mitocondriais/metabolismo , Proteínas Nucleares/metabolismo , Oxirredutases/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Tirosinemias/patologia , Ubiquitina-Proteína Ligases/metabolismo , Animais , Linhagem Celular , Células HEK293 , Hipocampo/patologia , Humanos , Masculino , Aprendizagem em Labirinto/fisiologia , Proteínas de Membrana/genética , Memória/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Mitocondriais/genética , Fosforilação , Transdução de Sinais/fisiologia , Ubiquitinação
12.
Mol Cell ; 76(3): 516-527.e7, 2019 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-31492635

RESUMO

The PTEN tumor suppressor is frequently mutated or deleted in cancer and regulates glucose metabolism through the PI3K-AKT pathway. However, whether PTEN directly regulates glycolysis in tumor cells is unclear. We demonstrate here that PTEN directly interacts with phosphoglycerate kinase 1 (PGK1). PGK1 functions not only as a glycolytic enzyme but also as a protein kinase intermolecularly autophosphorylating itself at Y324 for activation. The protein phosphatase activity of PTEN dephosphorylates and inhibits autophosphorylated PGK1, thereby inhibiting glycolysis, ATP production, and brain tumor cell proliferation. In addition, knockin expression of a PGK1 Y324F mutant inhibits brain tumor formation. Analyses of human glioblastoma specimens reveals that PGK1 Y324 phosphorylation levels inversely correlate with PTEN expression status and are positively associated with poor prognosis in glioblastoma patients. This work highlights the instrumental role of PGK1 autophosphorylation in its activation and PTEN protein phosphatase activity in governing glycolysis and tumorigenesis.


Assuntos
Neoplasias Encefálicas/enzimologia , Glioblastoma/enzimologia , Glucose/metabolismo , Glicólise , PTEN Fosfo-Hidrolase/metabolismo , Fosfoglicerato Quinase/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Glioblastoma/genética , Glioblastoma/patologia , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , PTEN Fosfo-Hidrolase/genética , Fosfoglicerato Quinase/genética , Fosforilação , Prognóstico , Transdução de Sinais , Fatores de Tempo , Carga Tumoral , Tirosina
13.
Reprod Biomed Online ; 39(4): 704-711, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31427176

RESUMO

RESEARCH QUESTION: Immunological disorders have been reported to promote the progression of endometriosis. Several recent studies have shown that myeloid-derived suppressor cells (MDSC) drive the progression of endometriosis. The aim of this case-control study was to test whether CCR5 and its ligands drive MDSC accumulation and play a role in the progression of endometriosis. DESIGN: Thirty-six endometriosis patients and 20 controls were recruited. All subjects underwent laparoscopy. An ELISA kit was used to define CCR5 ligands in plasma and peritoneal fluid from endometriosis patients; flow cytometry was then used to characterize CCR5+MDSC in peripheral blood and peritoneal fluid. RESULTS: Data showed that endometriosis patients displayed a significantly higher production of plasma CCL3 (P = 0.046) and peritoneal fluid CCL3/5 (P = 0.042/0.036) compared with those from the uterine leiomyoma group. Furthermore, the concentrations of peritoneal fluid CCL5 were elevated in late stage patients compared with those from the uterine leiomyoma group. Accumulation of blood CCR5+Mo-MDSC was detected in endometriosis patients compared with those from both the ovarian dermoid cysts and uterine leiomyoma groups. Endometriosis patients also showed an elevation of CCR5+MDSC and CCR5+Mo-MDSC in peritoneal fluid samples compared with uterine leiomyoma samples. It was also found that enrichment of CCR5+MDSC (r = 0.6807; P < 0.0001) and CCR5+Mo-MDSC (r = 0.6893; P < 0.0001) were correlated with enhanced production of CCL5 in peritoneal fluid from endometriosis patients. CONCLUSIONS: This study showed that CCR5 and its ligands could drive the progression of endometriosis by enhancing the accumulation of MDSC. These findings might produce a promising treatment that targets CCR5+MDSC for endometriosis patients.

14.
Biomed Res Int ; 2019: 6071308, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31428639

RESUMO

The senescence of mesenchymal stem cells (MSCs) plays a crucial role in the development and progression of systemic lupus erythematosus (SLE). Exosomes, small spherical bilayer proteolipid vesicles, contribute to the communication between various cells and their microenvironment by transferring information via their cargo, including the proteins, lipids, and RNAs. While exosomal miRNAs participate in various biological activities, correlations of circulating exosomes with senescent signs of BM-MSCs remain unclear. In our study, we aimed at exploring the roles of circulating exosomal miRNAs in the senescence of MSCs. We found that exosomes derived from SLE serum could increase the proportions of SA-ß-gal positive cells, disorganize cytoskeletons, and reduce growth rates. Moreover, the expression of miR-146a declined significantly in serum exosomes of SLE patients compared with healthy controls. miR-146a could be internalized into MSCs via exosomes and participate in MSCs senescence through targeting TRAF6/NF-κB signaling. These results clarified the novel mechanism of MSCs senescence in SLE patients.


Assuntos
Senescência Celular , Exossomos/metabolismo , Lúpus Eritematoso Sistêmico/metabolismo , Células-Tronco Mesenquimais/metabolismo , MicroRNAs/metabolismo , Transdução de Sinais , Adulto , Exossomos/patologia , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lúpus Eritematoso Sistêmico/patologia , Células-Tronco Mesenquimais/patologia , NF-kappa B/metabolismo
15.
Aging (Albany NY) ; 11(13): 4338-4353, 2019 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-31303606

RESUMO

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease involving multiple organs and systems. Mesenchymal stem cells (MSCs) from SLE patients have demonstrated defects such as impaired growth, senescence phenotype and immunomodulatory functions. Some studies have suggested the close connection between inflammation microenvironment and cellular senescence. In the current study, we detected cytokines levels in bone marrow supernatant by the quantitative proteomics analysis, and found the expression of HMGB1 was remarkably increased in bone marrow from SLE patients. Senescence associated-ß-galactosidase (SA-ß-gal) staining, F-actin staining and flow cytometry were used to detect the senescence of cells. After stimulation of HMGB1 in normal MSCs, the ratio of SA-ß-gal positive in BM-MSCs was increased, the organization of cytoskeleton was disordered, and TLR4-NF-κB signaling was activated. Finally, Ethyl pyruvate (EP) (40 mg/kg and 100 mg/kg, three times a week), a high security HMGB1 inhibitor, was injected intraperitoneally to treat MRL/lpr mice for 8 weeks. We demonstrated that EP alleviated the clinical aspects of lupus nephritis and prolonged survival of MRL/lpr mice. In the meantime, EP reversed the senescent phenotype of BM-MSCs from MRL/lpr mice. HMGB1 could be a promising target in SLE patients, and might be one of the reasons of recurrence after MSCs transplantation.

16.
Nat Commun ; 10(1): 2863, 2019 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-31253779

RESUMO

Cancer stem cells (CSCs) represent a major source of treatment resistance and tumor progression. However, regulation of CSCs stemness is not entirely understood. Here, we report that TSPAN8 expression is upregulated in breast CSCs, promotes the expression of the stemness gene NANOG, OCT4, and ALDHA1, and correlates with therapeutic resistance. Mechanistically, TSPAN8 interacts with PTCH1 and inhibits the degradation of the SHH/PTCH1 complex through recruitment of deubiquitinating enzyme ATXN3. This results in the translocation of SMO to cilia, downstream gene expression, resistance of CSCs to chemotherapeutic agents, and enhances tumor formation in mice. Accordingly, expression levels of TSPAN8, PTCH1, SHH, and ATXN3 are positively correlated in human breast cancer specimens, and high TSPAN8 and ATXN3 expression levels correlate with poor prognosis. These findings reveal a molecular basis of TSPAN8-enhanced Sonic Hedgehog signaling and highlight a role for TSPAN8 in promoting cancer stemness.


Assuntos
Proteínas Hedgehog/metabolismo , Células-Tronco Neoplásicas/fisiologia , Tetraspaninas/metabolismo , Animais , Neoplasias da Mama , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal , Feminino , Regulação Neoplásica da Expressão Gênica , Proteínas Hedgehog/genética , Humanos , Camundongos , Camundongos Nus , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/terapia , Interferência de RNA , RNA Interferente Pequeno , Transdução de Sinais , Regulação para Cima
17.
Hepatology ; 70(6): 2018-2034, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31077594

RESUMO

Methionine adenosyltransferase α1 (MATα1, encoded by MAT1A) is responsible for hepatic biosynthesis of S-adenosyl methionine, the principal methyl donor. MATα1 also act as a transcriptional cofactor by interacting and influencing the activity of several transcription factors. Mat1a knockout (KO) mice have increased levels of cytochrome P450 2E1 (CYP2E1), but the underlying mechanisms are unknown. The aims of the current study were to identify binding partners of MATα1 and elucidate how MATα1 regulates CYP2E1 expression. We identified binding partners of MATα1 by coimmunoprecipitation (co-IP) and mass spectrometry. Interacting proteins were confirmed using co-IP using recombinant proteins, liver lysates, and mitochondria. Alcoholic liver disease (ALD) samples were used to confirm relevance of our findings. We found that MATα1 negatively regulates CYP2E1 at mRNA and protein levels, with the latter being the dominant mechanism. MATα1 interacts with many proteins but with a predominance of mitochondrial proteins including CYP2E1. We found that MATα1 is present in the mitochondrial matrix of hepatocytes using immunogold electron microscopy. Mat1a KO hepatocytes had reduced mitochondrial membrane potential and higher mitochondrial reactive oxygen species, both of which were normalized when MAT1A was overexpressed. In addition, KO hepatocytes were sensitized to ethanol and tumor necrosis factor α-induced mitochondrial dysfunction. Interaction of MATα1 with CYP2E1 was direct, and this facilitated CYP2E1 methylation at R379, leading to its degradation through the proteasomal pathway. Mat1a KO livers have a reduced methylated/total CYP2E1 ratio. MATα1's influence on mitochondrial function is largely mediated by its effect on CYP2E1 expression. Patients with ALD have reduced MATα1 levels and a decrease in methylated/total CYP2E1 ratio. Conclusion: Our findings highlight a critical role of MATα1 in regulating mitochondrial function by suppressing CYP2E1 expression at multiple levels.

18.
Sci Rep ; 9(1): 6428, 2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015523

RESUMO

Mistletoe (Viscum album) is a type of parasitic plant reported to have anticancer activity including in hepatocellular carcinoma (HCC). However, the mechanism of mistletoe's anticancer activity, and its effectiveness in treating HCC are not fully understood. We report here that mistletoe extracts, including Fraxini (grown on ash trees) and Iscador Q and M (grown on oak and maple trees), exert strong antiproliferative activity in Hep3B cells, with median inhibitory concentrations (IC50) of 0.5 µg/mL, 7.49 µg/mL, and 7.51 µg/mL, respectively. Results of Reversed Phase Proteomic Array analysis (RPPA) suggests that Fraxini substantially down-regulates c-Myc expression in Hep3B cells. Fraxini-induced growth inhibition (at a concentration of 1.25 µg/ml) was less pronounced in c-Myc knockdown Hep3B cells than in control cells. Furthermore, in the Hep3B xenograft model, Fraxini-treated (8 mg/kg body weight) mice had significantly smaller tumors (34.6 ± 11.9 mm3) than control mice (161.6 ± 79.4 mm3, p < 0.036). Similarly, c-Myc protein expression was reduced in Fraxini treated Hep3B cell xenografts compared to that of control mice. The reduction of c-Myc protein levels in vitro Hep3B cells appears to be mediated by the ubiquitin-proteasome system. Our results suggest the importance of c-Myc in Fraxini's antiproliferative activity, which warrants further investigation.

19.
Braz J Med Biol Res ; 52(4): e8131, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30994732

RESUMO

The leading cause of death in systemic lupus erythematosus (SLE) patients is infection. The objective of this study was to evaluate the distribution of lymphocyte subsets in untreated SLE patients with infections. This was a cross-sectional study. Data from January 2017 to May 2018 were collected. Flow cytometry was used to measure the peripheral lymphocyte subsets including CD3+T cells, CD4+T cells, CD8+T cells, CD19+B cells, CD3-CD16+CD56NK cells, and CD3+CD16+CD56NKT cells in 25 healthy controls and 52 treatment-naive SLE patients, among whom 13 were complicated with infections. Association between the lymphocyte subsets and infections was further analyzed. SLE patients with infections (n=13) showed a significantly higher incidence rate of fever (84.6 vs 28.2%) and serositis (84.6 vs 23.1%), increased level of erythrocyte sedimentation rate (60.5±30.1 vs 37.4±27.1 mm/h), serum C-reactive protein (CRP) (102.7±94.9 vs 9.4±14.9 mg/L), procalcitonin (PCT) (1.07±0.08 vs 0.16±0.13 µg/L), and lower blood hemoglobin (Hb) (93.0±20.5 vs 110.4±16.0 g/L) level compared with non-infection patients (n=39) (all P<0.05). In comparison with non-infectious SLE patients (387.9±261.6/µL), CD4+T cells count decreased significantly in infectious SLE patients (217.8±150.4/µL) (P<0.05), and it was negatively correlated with infection-related indicators including PCT (r=-0.573, P=0.041) and CRP (r=-0.596, P=0.032) levels. Our findings suggested that abnormalities of peripheral lymphocyte subsets were related to the immune disorder of lupus itself, regardless of immunosuppressive treatment. Monitoring lymphocyte subsets, especially CD4+T cells, may be helpful for identifying the presence of infection in SLE patients.


Assuntos
/sangue , Lúpus Eritematoso Sistêmico/sangue , Subpopulações de Linfócitos , Adulto , Proteína C-Reativa/análise , Estudos de Casos e Controles , Estudos Transversais , Feminino , Citometria de Fluxo , Humanos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Pró-Calcitonina/sangue , Valores de Referência , Fatores de Risco , Estatísticas não Paramétricas , Adulto Jovem
20.
Int J Rheum Dis ; 22(6): 1077-1083, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30968568

RESUMO

OBJECTIVE: The impact of pulmonary infection (PI) on mortality of patients with systemic lupus erythematosus (SLE) has been established. Nevertheless, the effect of risk factors in mortality remains controversial. The objective of this study is to determine the risk factors of short-term mortality among SLE patients with PI. METHOD: The clinical data of 54 SLE patients with 59 episodes of PI who were hospitalized from January 2013 to May 2018 was retrospectively analyzed. Demographic data, clinical features, and outcomes were collected. Logistic regression analysis was carried out to determine the independent predictors of 60-day mortality during hospitalization. We used receiver operating characteristics (ROC) curves to verify the indices as mortality predictors in the study patients. RESULTS: There were a total of 54 patients with 59 episodes of PI. There were 12 deaths during hospitalization. In multivariate analysis, 24-hour urinary protein (24h-PRO) (odds ratio [OR]: 2.713, 95% CI: 1.234-5.965, P = 0.013), peripheral lymphocyte count (OR: 0.066, 95% CI: 0.005-0.887, P = 0.040), and serum complement 3 level (C3) (OR: 0.097, 95% CI: 0.010-0.954, P = 0.045) were associated with mortality among our cohort of SLE patients with PI. ROC curve values were 0.818 for lymphocyte count (95% CI: 0.696-0.907, P = 0.001), 0.894 for 24h-PRO (95% CI: 0.786-0.959, P < 0.001) and 0.825 for C3 (95% CI: 0.704-0.912, P = 0.001). The cut-off value of lymphocytes, 24h-PRO and C3 were 0.53 × 109 /L, 0.92 g and 0.52 g/L, respectively. CONCLUSION: The presence of albuminuria, lymphopenia and low complement C3 levels were independent prognostic predictors of short-term mortality in SLE patients with PI.


Assuntos
Lúpus Eritematoso Sistêmico/mortalidade , Infecções Respiratórias/mortalidade , Adolescente , Adulto , Idoso de 80 Anos ou mais , Albuminúria/mortalidade , Biomarcadores/sangue , Complemento C3/análise , Feminino , Mortalidade Hospitalar , Hospitalização , Humanos , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/terapia , Linfopenia/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Infecções Respiratórias/diagnóstico , Infecções Respiratórias/terapia , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Adulto Jovem
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