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1.
J Environ Pathol Toxicol Oncol ; 40(2): 45-53, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33822516

RESUMO

MiR-451 plays a tumor suppressive role in a variety of cancers. However, the function of miR-451 in acute myeloid leukemia (AML) has not been fully understood. Herein, we focused on the effect of miR-451 in pediatric AML and its regulatory mechanism. MiR-451 and high mobility group box 1 (HMGB1) levels were tested in bone marrow of pediatric AML patients and healthy controls, and in AML cells and HS-5 cells by qRT-PCR and Western blot analysis. HL-60 and THP-1 cells were treated with miR-451 mimics, pcDNA-HMGB1, and corresponding controls. The changes in apoptosis and autophagy were evaluated in miR-451 overexpressed AML cells with MTT and flow cytometry. The interaction between miR-451 and HMGB1 was determined by dual-luciferase reporter assay, qRT-PCR, and Western blot. After cells were co-transfected with pcDNA-HMGB1 and pc-DNA-ctrl, we investigated apoptosis and autophagy in miR-451 overexpressed cells perturbed by exogenous HMGB1 through MTT, flow cytometry, and Western blot. miR-451's role in drug sensitivity was further measured. Pediatric AML bone marrow and cell lines presented low expression of miR-451 coupled with high expression of HMGB1. HMGB1 was determined to be a functional target of miR-451. MiR-451 overexpression remarkably enhanced apoptosis and reduced autophagy in both AML cell lines, which was reversed by pcDNA-HMGB1 transfection. Additionally, exogenous miR-451 significantly enhanced the sensitivity of HL-60 cells to the chemotherapy drug As2O3. MiR-451 exerted a tumor suppressive effect in enhancing cell death and reducing autophagy of AML cells by targeting HMGB1. MiR-451 might be considered a candidate target for treating pediatric AML.


Assuntos
Proteína HMGB1/genética , Leucemia Mieloide Aguda/genética , MicroRNAs , Antineoplásicos/farmacologia , Apoptose , Trióxido de Arsênio/farmacologia , Autofagia , Criança , Células HL-60 , Proteína HMGB1/metabolismo , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Células THP-1
2.
Biomed Khim ; 67(1): 95-99, 2021 Jan.
Artigo em Russo | MEDLINE | ID: mdl-33645527

RESUMO

Intracellular signaling mediated by the HMGB1 protein, an agonist of TLRs, is considered as a possible target for the correction of pathologies of the neuroimmune system, however, the expression level of the Hmgb1 gene has not been previously studied in various brain structures of rats exposed to prolonged alcoholization followed by ethanol withdrawal. The study showed that long-term use of ethanol caused to an increase in the level of Hmgb1 mRNA in the striatum of rat brain. Alcohol withdrawal changed the level Hmgb1 mRNA in the striatum and amygdala on the 1st and 14th day. The data obtained may indicate that in different structures of the brain there are multidirectional changes in the molecular mechanisms of the neuroimmune response with prolonged use of ethanol and its withdrawal.


Assuntos
Alcoolismo , Proteína HMGB1 , Síndrome de Abstinência a Substâncias , Alcoolismo/genética , Animais , Encéfalo/metabolismo , Etanol/toxicidade , Proteína HMGB1/genética , Proteína HMGB1/metabolismo , Ratos , Síndrome de Abstinência a Substâncias/genética
3.
Life Sci ; 273: 119310, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33667517

RESUMO

AIMS: Alzheimer's disease (AD) is a leading health problem in which increased amyloid ß (Aß) accumulation may occur due to abnormal Aß precursor protein processing by ß-secretase 1 (BACE1) enzyme. Lately, neuro-inflammation was recognized as a significant contributor to its pathogenesis. Although the causes of AD are not yet well understood, much evidence has suggested that dyslipidemia has harmful effects on cognitive function and is inextricably involved in AD pathogenesis. Cholesterol is a vital molecule involved in neuronal development. Alteration in neuronal cholesterol levels affects Aß metabolism and results in neurodegeneration. Proprotein-convertase-subtilisin/kexin type-9 (PCSK9) was found to decrease neuronal cholesterol uptake by degradation of LDL-receptor related protein 1 (LRP-1) responsible for neuronal cholesterol uptake. Accordingly, this study was designed to evaluate the effect of PCSK9-inhibition by alirocumab (Aliro) in high-fat-cholesterol-diet (HFCD)-induced-AD-like condition. MAIN METHODS: Wistar Rats were divided into six groups; control; HFCD; HFCD and Memantine; HFCD and Aliro (4, 8 and 16 mg/kg/week) to test for ability of Aliro to modulate cognitive impairment, amyloidosis, brain cholesterol homeostasis and neuro-inflammation in HFCD-induced-AD-like condition. KEY FINDINGS: Our results demonstrated an association between PCSK9 inhibition by Aliro and amelioration of cognitive deficit, cholesterol hemostasis and reduction of neuro-inflammation. Aliro was able to alleviate hippocampal LRP-1expression levels and reduce brain cholesterol, hippocampal BACE1, Aß42, high-mobility-group-box-1 protein, receptor for advanced-glycation-end-products and toll like receptor-4 with subsequent decrease of different inflammatory mediators as nuclear-factor-kappa-B (NF-κB), tumor-necrosis-factor-alpha (TNF-α), interleukin-1beta (IL-1ß) and IL-6. SIGNIFICANCE: PCSK9-inhibition may represent a new therapeutic target in AD especially for HFCD-induced-AD-like condition.


Assuntos
Amiloidose/tratamento farmacológico , Anticorpos Monoclonais Humanizados/farmacologia , Colesterol/toxicidade , Disfunção Cognitiva/tratamento farmacológico , Dieta Hiperlipídica/efeitos adversos , Memantina/farmacologia , Pró-Proteína Convertase 9/antagonistas & inibidores , Amiloidose/etiologia , Amiloidose/metabolismo , Amiloidose/patologia , Animais , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ácido Glutâmico/metabolismo , Proteína HMGB1/genética , Proteína HMGB1/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Ratos , Ratos Wistar , Receptor para Produtos Finais de Glicação Avançada/genética , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo
4.
Int Heart J ; 62(1): 162-170, 2021 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-33455985

RESUMO

High-mobility group box 1 (HMGB1) is increased in the myocardium under pressure overload (PO) and is involved in PO-induced cardiac remodeling. The mechanisms of the upregulation of cardiac HMGB1 expression have not been fully elucidated. In the present study, a mouse transverse aortic constriction (TAC) model was used, and an angiotensin II (Ang II) type 1 (AT1) receptor inhibitor (losartan) or Ang II type 2 (AT2) receptor inhibitor (PD123319) was administrated to mice for 14 days. Cardiac myocytes were cultured and treated with Ang II for 5 minutes to 48 hours conditionally with the blockage of the AT1 or AT2 receptor. TAC-induced cardiac hypertrophy was observed at 14 days after the operation, which was partially reversed by losartan, but not by PD123319. Similarly, the upregulated HMGB1 expression levels observed in both the serum and myocardium induced by TAC were reduced by losartan. Elevated cardiac HMGB1 protein levels, but not mRNA or serum levels, were significantly decreased by PD123319. Furthermore, HMGB1 expression levels in culture media and cardiac myocytes were increased following Ang II treatment in vitro, positively associated with the duration of treatment. Similarly, Ang II-induced upregulation of HMGB1 in vitro was inhibited by both losartan and PD123319. These results suggest that upregulation of HMGB1 in serum and myocardium under PO, which are partially derived from cardiac myocytes, may be induced by Ang II via the AT1 and AT2 receptors. Additionally, amelioration of PO-induced cardiac hypertrophy following losartan treatment may be associated with the reduction of HMGB1 expression through the AT1 receptor.


Assuntos
Angiotensina II/farmacologia , Proteína HMGB1/efeitos dos fármacos , Losartan/farmacologia , Miocárdio/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Aorta/patologia , Cardiomegalia/tratamento farmacológico , Cardiomegalia/metabolismo , Estudos de Casos e Controles , Constrição , Proteína HMGB1/sangue , Proteína HMGB1/metabolismo , Imidazóis/administração & dosagem , Imidazóis/farmacologia , Losartan/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/efeitos dos fármacos , Piridinas/administração & dosagem , Piridinas/farmacologia , Regulação para Cima , Vasoconstritores/farmacologia
5.
Life Sci ; 269: 118987, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33417958

RESUMO

AIMS: To explore the therapeutic effect of miR-129-5p carried by exosomes from Human Synovial Mesenchymal Stem Cell (HS-MSC) on osteoarthritis(OA). MATERIALS AND METHODS: The levels of miR-129-5p and high mobility group protein -1 (HMGB1) and interleukin-1ß (IL-1ß) in the joint fluid of OA patients were respectively detected via real-time quantitative reverse transcription-PCR (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). IL-1ß was taken to act on chondrocytes for the establishment of OA model in vitro. Ultracentrifugation was conducted to isolate HS-MSC exosomes (HS-MSC-Exo) from the supernatant. Western blot and ELISA were carried out to measure the expression of iNOS, COX2, MMP13, Collagen 2, TLR4, NF-κB, Caspase3, Bcl-2, HMGB1 in chondrocytes. Flow cytometry was conducted to detect the apoptosis of chondrocytes. Besides, bioinformatics was employed to predict the targeted relationship between miR-129-5p and HMGB1, which was further verified via dual luciferase activity experiments. KEY FINDINGS: The results illustrated that miR-129-5p was decreased in OA patients and IL-1ß-induced chondrocytes, while HMGB1 was notably upregulated. HS-MSC-Exo rich in miR-129-5p remarkably declined the inflammatory response and apoptosis of chondrocytes, while HS-MSC-Exo deficient in miR-129-5p increased the IL-1ß-mediated inflammatory response and apoptosis of chondrocytes. In terms of mechanism, miR-129-5p targets the 3'UTR end of HMGB1 and inhibits IL-1ß-mediated upregulation of HMGB1. SIGNIFICANCE: In a word, this paper proved that miR-129-5p, existing in HS-MSC-Exo, can suppress the IL-1ß-mediated OA by inhibiting HMGB1 release.


Assuntos
Exossomos/metabolismo , Proteína HMGB1/metabolismo , Células-Tronco Mesenquimais/metabolismo , MicroRNAs/metabolismo , Osteoartrite/metabolismo , Membrana Sinovial/metabolismo , Sequência de Bases , Condrócitos/metabolismo , Condrócitos/patologia , Feminino , Regulação da Expressão Gênica , Proteína HMGB1/genética , Humanos , Interleucina-1beta/metabolismo , Articulações/patologia , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Líquido Sinovial/metabolismo
6.
Nan Fang Yi Ke Da Xue Xue Bao ; 41(1): 87-92, 2021 Jan 30.
Artigo em Chinês | MEDLINE | ID: mdl-33509758

RESUMO

OBJECTIVE: To investigate the inhibitory effects of dihydromyricetin on the proliferation and migration of gastric cancer BGC-823 cells and explore the molecular mechanisms. METHODS: BGC-823 cells in routine culture were treated with different concentrations of dihydromyricetin (0, 40, 60, 80, 100, and 120 µg/mL) for 24 h, and the changes in cell viability were detected using CCK-8 assay; colony forming assay and Transwell assay were performed to assess the changes in colonyforming and migration abilities of the cells, respectively. The levels of MMP-2 and MMP-9 in the treated cells were determined using ELISA, and Western blotting was used to detect the expressions of E-cadherin, N-cadherin, cyclin D1, cyclin E1, HSP70 and HMGB1 and the phosphorylation levels of Akt and Stat3. RESULTS: CCK-8 assay showed that dihydromyricetin treatment dose-dependently inhibited the viability of BGC-823 cells (P < 0.05). Treatment with dihydromyricetin obviously suppressed the proliferation and migration of BGC-823 cells, significantly reduced the expression levels of cyclin D1, cyclin E1 and Ncadherin, enhanced E-cadherin expression, inhibited the phosphorylation of Akt and stat3, and downregulated HMGB1 expression in the cells. The results of ELISA demonstrated significantly lowered levels of MMP-2 and MMP-9 in dihydromyricetin-treated cells. CONCLUSIONS: Dihydromyricetin inhibits the proliferation and migration of BGC-823 cells through suppressing the activation of Akt/stat3 signaling pathways and HMGB1 expression.


Assuntos
Proteína HMGB1 , Neoplasias Gástricas , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Flavonóis , Proteína HMGB1/metabolismo , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator de Transcrição STAT3
7.
Life Sci ; 269: 119085, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33482190

RESUMO

Pulmonary fibrosis (PF), which is characterized by excessive matrix formation, may ultimately lead to irreversible lung damage and thus death. Fibroblast activation has been regarded as a central event during PF pathogenesis. In our previous study, we confirmed that the miR-627/high-mobility group box protein 1 (HMGB1)/Nuclear factor kappa beta (NF-κB) axis modulates transforming growth factor beta 1 (TGFß1)-induced pulmonary fibrosis. In the present study, we investigated the upstream factors leading to miR-627 dysregulation in the process of pulmonary fibroblast activation and PF. The lncRNA MIR155 host gene (MIR155HG) was found to be abnormally upregulated in pulmonary fibrosis tissues and TGFß1-stimulated normal human primary lung fibroblasts (NHLFs). By directly binding to miR-627, MIR155HG inhibited miR-627 expression. MIR155HG overexpression enhanced TGFß1-induced increases in HMGB1 protein expression and p65 phosphorylation, NHLF proliferation, and extracellular matrix (ECM) deposition. In contrast, miR-627 overexpression attenuated the TGFß1-induced changes in NHLFs and significantly reversed the effects of MIR155HG overexpression. Under TGFß1 stimulation, miR-627 inhibition promoted, whereas JSH-23 treatment inhibited NF-κB activation; in NHLFs, NF-κB overexpression upregulated, whereas JSH-23 treatment downregulated MIR155HG expression. In tissue samples, HMGB1 protein levels and p65 phosphorylation were increased; MIR155HG was negatively correlated with miR-627 and positively correlated with HMGB1. In conclusion, we validated that the MIR155HG/miR-627/HMGB1/NF-κB axis formed a regulatory loop that modulates TGFß1-induced NHLF activation. Considering the critical role of NHLF activation in PF pathogenesis, the NF-κB/MIR155HG/miR-627/HMGB1 regulatory loop could exert a vital effect on PF pathogenesis. Further in vivo and clinical investigations are required to confirm this model.


Assuntos
Matriz Extracelular/metabolismo , Fibroblastos/citologia , Proteína HMGB1/metabolismo , MicroRNAs/genética , NF-kappa B/metabolismo , Fibrose Pulmonar/patologia , RNA Longo não Codificante/genética , Estudos de Casos e Controles , Proliferação de Células , Fibroblastos/metabolismo , Regulação da Expressão Gênica , Proteína HMGB1/genética , Humanos , Pulmão/citologia , Pulmão/metabolismo , NF-kappa B/genética , Fibrose Pulmonar/genética , Fibrose Pulmonar/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo
8.
Cancer Sci ; 112(4): 1603-1613, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33453094

RESUMO

Breast cancer is the leading cause of cancer death in women. Hormone-receptor-positive breast cancer (HR + BC) is the most common pathological type of breast cancer, of which the main treatment method is endocrine therapy. Unfortunately, primary or acquired drug resistance greatly limits its efficacy. In recent years, the newly launched CDK4/6 inhibitors could effectively reverse endocrine resistance in breast cancer. However, considering their expensive price and side effects, it is particularly important to find out effective biomarkers and screen sensitive patients. Here, we found through bioinformatics analysis that high mobility group box 1 (HMGB1) expression increased in endocrine-resistant HR + BC. In clinical specimens, the higher expression of HMGB1 was associated with shorter progression-free survival (PFS) for HR + BC patients with endocrine therapy after surgery. For endocrine-resistant breast cancer, compared with HMGB1-negative patients, HMGB1-positive patients who received CDK4/6 inhibitors treatment benefited more in PFS. Moreover, we demonstrated that HMGB1 promoted tamoxifen resistance by combining with the Toll-like receptor 4 (TLR4) and activating nuclear factor kappa B (NF-κB) pathway. CDK4/6 inhibitors could downregulate the expression of HMGB1 and suppress the TLR4-NF-κB pathway, and in turn reverse tamoxifen resistance. These results illuminated the critical role of HMGB1 in the process of tamoxifen resistance, explained the mechanism of CDK4/6 inhibitors reversing tamoxifen resistance, and suggested the feasibility of HMGB1 as a potential biomarker for screening sensitive patients receiving CDK4/6 inhibitors.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos/fisiologia , Proteína HMGB1/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Tamoxifeno/farmacologia , Antineoplásicos Hormonais/farmacologia , Mama/efeitos dos fármacos , Mama/metabolismo , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Células MCF-7 , NF-kappa B/metabolismo , Intervalo Livre de Progressão , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Transdução de Sinais/efeitos dos fármacos
9.
Mol Immunol ; 130: 113-121, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33308900

RESUMO

Macrophages are the most abundant cells in tumor stroma and their polarization within tumor microenvironment exert the key roles in tumorigenesis. Astragaloside IV is a natural extract from traditional Chinese herbal Radix Astragali, and fulfills pleiotropic function in several cancers. Nevertheless, its function in ovarian cancer microenvironment remains elusive. In the present research, astragaloside IV exhibited little cytotoxicity within a certain dose range in THP-1 cells. Moreover, astragaloside IV suppressed the ratio of CD14+CD206+ cells in IL-4/IL-13-treated THP-1 macrophages and transcripts of M2 macrophage markers (including CD206, CCL24, PPARγ, Arg-1, IL-10), indicating the inhibitory effects of astragaloside IV on IL-4/IL-13-induced macrophage M2 polarization. Intriguingly, astragaloside IV antagonized M2 macrophages coculture-evoked cell proliferation, invasion and migration in ovarian cancer cells. During this process, administration with astragaloside IV restrained the high expression of high-mobility group box1 (HMGB1) and TLR4 in macrophages co-cultured with ovarian cancer cells, concomitant with decreases in release of M2 marker TGF-ß, MMP-9 and IL-10. Moreover, targeting the HMGB1 signaling reversed M2 macrophages-induced ovarian cancer cell proliferation, invasion and migration. Noticeably, exogenous HMGB1 overturned the inhibitory efficacy of astragaloside IV against macrophage M2 polarization-evoked malignant potential in ovarian cancer cells. Together, these findings suggest that astragaloside IV may protect against M2 macrophages-evoked malignancy in ovarian cancer cells by suppressing the HMGB1-TLR4 signaling. Therefore, astragaloside may alleviate the progression of ovarian cancer by regulating macrophage M2 polarization within tumor microenvironment, implying a promising therapeutic strategy against ovarian cancer.


Assuntos
Polaridade Celular/efeitos dos fármacos , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Neoplasias Ovarianas/patologia , Saponinas/farmacologia , Triterpenos/farmacologia , Movimento Celular/efeitos dos fármacos , Polaridade Celular/imunologia , Progressão da Doença , Feminino , Proteína HMGB1/metabolismo , Humanos , Macrófagos/fisiologia , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/metabolismo , Fenótipo , Transdução de Sinais/efeitos dos fármacos , Células THP-1 , Receptor 4 Toll-Like/metabolismo , Células Tumorais Cultivadas , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
11.
J Med Virol ; 93(4): 2396-2405, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33331649

RESUMO

SARS-CoV-2 triggers a dysregulated innate immune system activation. As the mevalonate pathway (MVP) prevents the activation of inflammasomes and cytokine release and regulates endosomal transport, compromised signaling could be associated with the pathobiology of COVID-19. Prior transcriptomic studies of host cells in response to SARS-CoV-2 infection have not reported to date the effects of SARS-CoV-2 on the MVP. In this study, we accessed public data sets to report in silico investigations into gene expression. In addition, we proposed candidate genes that are thought to have a direct association with the pathogenesis of COVID-19, and which may be dependent on signals derived from the MVP. Our results revealed dysregulation of genes involved in the MVP. These results were not found when investigating the gene expression data from host cells infected with H3N2 influenza virus, H1N1 influenza virus, or respiratory syncytial virus. Our manually curated gene set showed significant gene expression variability in A549 cells infected with SARS-CoV-2, as per Blanco-Melo et al. data set (GSE147507). In light of the present findings, SARS-CoV-2 could hijack the MVP, leading to hyperinflammatory responses. Prompt reconstitution of this pathway with available agents should be considered in future studies.


Assuntos
/metabolismo , Ácido Mevalônico/metabolismo , /metabolismo , Células A549 , Autofagia , /imunologia , Simulação por Computador , Citocinas/imunologia , Citocinas/metabolismo , Proteína HMGB1/genética , Proteína HMGB1/metabolismo , Interações Hospedeiro-Patógeno , Humanos , Vírus da Influenza A Subtipo H1N1/genética , Vírus da Influenza A Subtipo H1N1/metabolismo , Vírus da Influenza A Subtipo H3N2/genética , Vírus da Influenza A Subtipo H3N2/metabolismo , Influenza Humana/imunologia , Influenza Humana/metabolismo , Proteína 1 com Domínio SAM e Domínio HD/genética , Proteína 1 com Domínio SAM e Domínio HD/metabolismo , Transdução de Sinais , Transcriptoma , Replicação Viral
12.
Nat Commun ; 11(1): 6352, 2020 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-33311518

RESUMO

Immunosuppressive molecules are extremely valuable prognostic biomarkers across different cancer types. However, the diversity of different immunosuppressive molecules makes it very difficult to accurately predict clinical outcomes based only on a single immunosuppressive molecule. Here, we establish a comprehensive immune scoring system (ISSGC) based on 6 immunosuppressive ligands (NECTIN2, CEACAM1, HMGB1, SIGLEC6, CD44, and CD155) using the LASSO method to improve prognostic accuracy and provide an additional selection strategy for adjuvant chemotherapy of gastric cancer (GC). The results show that ISSGC is an independent prognostic factor and a supplement of TNM stage for GC patients, and it can improve their prognosis prediction accuracy; in addition, it can distinguish GC patients with better prognosis from those with high prognostic nutritional index score; furthermore, ISSGC can also be used as a tool to select GC patients who would benefit from adjuvant chemotherapy independent of their TNM stages, MSI status and EBV status.


Assuntos
Biomarcadores Tumorais/metabolismo , Quimioterapia Adjuvante/métodos , Proteína HMGB1/metabolismo , Neoplasias Gástricas/imunologia , Idoso , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Moléculas de Adesão Celular/metabolismo , Feminino , Humanos , Receptores de Hialuronatos/metabolismo , Lectinas/metabolismo , Masculino , Pessoa de Meia-Idade , Nectinas/metabolismo , Estadiamento de Neoplasias , Prognóstico , Receptores Virais/metabolismo , Neoplasias Gástricas/patologia , Fatores de Tempo
13.
Cells ; 9(12)2020 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-33321691

RESUMO

Increasing evidence suggests that inflammatory responses are involved in the progression of brain injuries induced by a diverse range of insults, including ischemia, hemorrhage, trauma, epilepsy, and degenerative diseases. During the processes of inflammation, disruption of the blood-brain barrier (BBB) may play a critical role in the enhancement of inflammatory responses and may initiate brain damage because the BBB constitutes an interface between the brain parenchyma and the bloodstream containing blood cells and plasma. The BBB has a distinct structure compared with those in peripheral tissues: it is composed of vascular endothelial cells with tight junctions, numerous pericytes surrounding endothelial cells, astrocytic endfeet, and a basement membrane structure. Under physiological conditions, the BBB should function as an important element in the neurovascular unit (NVU). High mobility group box-1 (HMGB1), a nonhistone nuclear protein, is ubiquitously expressed in almost all kinds of cells. HMGB1 plays important roles in the maintenance of chromatin structure, the regulation of transcription activity, and DNA repair in nuclei. On the other hand, HMGB1 is considered to be a representative damage-associated molecular pattern (DAMP) because it is translocated and released extracellularly from different types of brain cells, including neurons and glia, contributing to the pathophysiology of many diseases in the central nervous system (CNS). The regulation of HMGB1 release or the neutralization of extracellular HMGB1 produces beneficial effects on brain injuries induced by ischemia, hemorrhage, trauma, epilepsy, and Alzheimer's amyloidpathy in animal models and is associated with improvement of the neurological symptoms. In the present review, we focus on the dynamics of HMGB1 translocation in different disease conditions in the CNS and discuss the functional roles of extracellular HMGB1 in BBB disruption and brain inflammation. There might be common as well as distinct inflammatory processes for each CNS disease. This review will provide novel insights toward an improved understanding of a common pathophysiological process of CNS diseases, namely, BBB disruption mediated by HMGB1. It is proposed that HMGB1 might be an excellent target for the treatment of CNS diseases with BBB disruption.


Assuntos
Barreira Hematoencefálica/metabolismo , Doenças do Sistema Nervoso Central/metabolismo , Proteína HMGB1/metabolismo , Animais , Sistema Nervoso Central/metabolismo , Regulação da Expressão Gênica , Humanos , Transporte Proteico
14.
Cell Death Dis ; 11(12): 1072, 2020 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-33318474

RESUMO

Hypoxia-reperfusion injury is one of the major risk factors for neurodegeneration. However, it is unclear whether ischaemic damage in brain microvascular endothelial cells plays roles in neurodegeneration, particularly in the amyloidogenic changes contributing to the development of Alzheimer's disease (AD) pathologies. Therefore, we investigated the roles of hypoxia-reoxygenation (H/R)-induced release of high mobility group box protein 1 (HMGB1), a risk molecule for AD pathogenesis in the ischaemic damaged brain, from human brain microvascular endothelial cells (HBMVECs) in neuronal amyloid-beta (Aß) production. H/R increased nuclear-cytosolic translocation and secretion of HMGB1 in HBMVECs, along with increased permeability and HMGB1-dependent p-c-Jun activation. In addition, H/R increased the expression of Sirtuin 1 (Sirt1), coincident with an increase of intracellular Sirt1-HMGB1 binding in HBMVECs. H/R increased the acetylation of HMGB1 and extracellular secretion, which was significantly inhibited by Sirt1 overexpression. Furthermore, Sirt1 contributed to autophagy-mediated endogenous HMGB1 degradation. More importantly, treatment of neuronal cells with conditioned medium from H/R-stimulated HBMVECs (H/R-CM) activated their amyloidogenic pathways. The neuronal amyloidogenic changes (i.e. increased levels of extracellular Aß40 and Aß42) by H/R-CM from HBMVECs were further increased by Sirt1 inhibition, which was significantly suppressed by neutralization of the HMGB1 in H/R-CM. Collectively, our results suggest that HMGB1 derived from H/R-stimulated HBMVECs contributes to amyloidogenic pathways in neurons playing roles in the pathogenesis of AD, which are regulated by endothelial Sirt1.


Assuntos
Amiloide/metabolismo , Encéfalo/irrigação sanguínea , Células Endoteliais/patologia , Proteína HMGB1/metabolismo , Microvasos/patologia , Neurônios/patologia , Oxigênio/farmacologia , Sirtuína 1/metabolismo , Acetilação/efeitos dos fármacos , Peptídeos beta-Amiloides/metabolismo , Autofagossomos/efeitos dos fármacos , Autofagossomos/metabolismo , Hipóxia Celular/efeitos dos fármacos , Linhagem Celular , Permeabilidade da Membrana Celular/efeitos dos fármacos , Meios de Cultivo Condicionados/farmacologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Humanos , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Neurônios/metabolismo , Estabilidade Proteica/efeitos dos fármacos
15.
J Toxicol Sci ; 45(11): 673-680, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33132241

RESUMO

The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) have been approved for non-small cell lung cancer. Although EGFR TKIs are less toxic than traditional cytotoxic therapies, they cause many severe idiosyncratic drug reactions. Reactive metabolites can cause cellular damage with the release of danger-associated molecular patterns (DAMPs), which is thought to be involved in immune activation. Inflammasomes can be activated by DAMPs, and this may be a common mechanism by which DAMPs initiate an immune response. We tested the ability of afatinib, dacomitinib, erlotinib, gefitinib, and osimertinib to induce the release of DAMPs that activate inflammasomes. Human hepatocarcinoma functional liver cell-4 (FLC-4) cells were used for bioactivation of drugs, and the detection of inflammasome activation was performed with the human macrophage cell line, THP-1 cells. Gefitinib is known to be oxidized to a reactive iminoquinone metabolite. We found that the supernatant from the incubation of gefitinib with FLC-4 cells for 7 days led to increased caspase-1 activity and production of IL-1ß by THP-1 cells. In the supernatant of FLC-4 cells with gefitinib, the heat shock protein (HSP) 40, 70 and 90 were significantly increased. In addition, activated THP-1 cells secreted high mobility group box 1 (HMGB1) protein. These results support the hypothesis that the reactive iminoquinone metabolite can cause the release of DAMPs from hepatocytes, which in turn, can activate inflammasomes. Inflammasome activation may be an important step in the activation of the immune system by gefitinib, which in some patients, can cause immune-related adverse events.


Assuntos
Meios de Cultura/efeitos adversos , Gefitinibe/efeitos adversos , Hepatócitos , Inflamassomos/imunologia , Ativação de Macrófagos/efeitos dos fármacos , Inibidores de Proteínas Quinases/efeitos adversos , Células THP-1/imunologia , Alarminas/metabolismo , Caspase 1/metabolismo , Linhagem Celular , Gefitinibe/metabolismo , Proteína HMGB1/metabolismo , Humanos , Interleucina-1beta/metabolismo , Inibidores de Proteínas Quinases/metabolismo , Quinonas/efeitos adversos , Quinonas/metabolismo , Células THP-1/metabolismo
16.
Nat Commun ; 11(1): 4951, 2020 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-33009382

RESUMO

Immunogenic cell death (ICD) and tumour-infiltrating T lymphocytes are severely weakened by elevated reactive oxygen species (ROS) in the tumour microenvironment. It is therefore of critical importance to modulate the level of extracellular ROS for the reversal of immunosuppressive environment. Here, we present a tumour extracellular matrix (ECM) targeting ROS nanoscavenger masked by pH sensitive covalently crosslinked polyethylene glycol. The nanoscavenger anchors on the ECM to sweep away the ROS from tumour microenvironment to relieve the immunosuppressive ICD elicited by specific chemotherapy and prolong the survival of T cells for personalized cancer immunotherapy. In a breast cancer model, elimination of the ROS in tumour microenvironment elicited antitumour immunity and increased infiltration of T lymphocytes, resulting in highly potent antitumour effect. The study highlights a strategy to enhance the efficacy of cancer immunotherapy by scavenging extracellular ROS using advanced nanomaterials.


Assuntos
Antineoplásicos/farmacologia , Espaço Extracelular/metabolismo , Depuradores de Radicais Livres/metabolismo , Morte Celular Imunogênica , Espécies Reativas de Oxigênio/metabolismo , Animais , Linhagem Celular Tumoral , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Proteína HMGB1/metabolismo , Morte Celular Imunogênica/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Tamanho da Partícula , Polietilenoglicóis/química , Microambiente Tumoral/efeitos dos fármacos
17.
Proc Natl Acad Sci U S A ; 117(41): 25543-25552, 2020 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-32999071

RESUMO

Asbestos causes malignant transformation of primary human mesothelial cells (HM), leading to mesothelioma. The mechanisms of asbestos carcinogenesis remain enigmatic, as exposure to asbestos induces HM death. However, some asbestos-exposed HM escape cell death, accumulate DNA damage, and may become transformed. We previously demonstrated that, upon asbestos exposure, HM and reactive macrophages releases the high mobility group box 1 (HMGB1) protein that becomes detectable in the tissues near asbestos deposits where HMGB1 triggers chronic inflammation. HMGB1 is also detectable in the sera of asbestos-exposed individuals and mice. Searching for additional biomarkers, we found higher levels of the autophagy marker ATG5 in sera from asbestos-exposed individuals compared to unexposed controls. As we investigated the mechanisms underlying this finding, we discovered that the release of HMGB1 upon asbestos exposure promoted autophagy, allowing a higher fraction of HM to survive asbestos exposure. HMGB1 silencing inhibited autophagy and increased asbestos-induced HM death, thereby decreasing asbestos-induced HM transformation. We demonstrate that autophagy was induced by the cytoplasmic and extracellular fractions of HMGB1 via the engagement of the RAGE receptor and Beclin 1 pathway, while nuclear HMGB1 did not participate in this process. We validated our findings in a novel unique mesothelial conditional HMGB1-knockout (HMGB1-cKO) mouse model. Compared to HMGB1 wild-type mice, mesothelial cells from HMGB1-cKO mice showed significantly reduced autophagy and increased cell death. Autophagy inhibitors chloroquine and desmethylclomipramine increased cell death and reduced asbestos-driven foci formation. In summary, HMGB1 released upon asbestos exposure induces autophagy, promoting HM survival and malignant transformation.


Assuntos
Asbestos/efeitos adversos , Autofagia/efeitos dos fármacos , Transformação Celular Neoplásica/induzido quimicamente , Proteína HMGB1/metabolismo , Mesotelioma/metabolismo , Adulto , Idoso , Animais , Células Cultivadas , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Humanos , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Exposição Ocupacional
18.
Mol Med ; 26(1): 98, 2020 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-33126860

RESUMO

BACKGROUND: Mechanical ventilation, in combination with supraphysiological concentrations of oxygen (i.e., hyperoxia), is routinely used to treat patients with respiratory distress, such as COVID-19. However, prolonged exposure to hyperoxia compromises the clearance of invading pathogens by impairing macrophage phagocytosis. Previously, we have shown that the exposure of mice to hyperoxia induces the release of the nuclear protein high mobility group box-1 (HMGB1) into the pulmonary airways. Furthermore, extracellular HMGB1 impairs macrophage phagocytosis and increases the mortality of mice infected with Pseudomonas aeruginosa (PA). The aim of this study was to determine whether GTS-21 (3-(2,4-dimethoxybenzylidene) anabaseine), an α7 nicotinic acetylcholine receptor (α7nAChR) agonist, could (1) inhibit hyperoxia-induced HMGB1 release into the airways; (2) enhance macrophage phagocytosis and (3) increase bacterial clearance from the lungs in a mouse model of ventilator-associated pneumonia. METHOD: GTS-21 (0.04, 0.4, and 4 mg/kg) or saline were administered by intraperitoneal injection to mice that were exposed to hyperoxia (≥ 99% O2) and subsequently challenged with PA. RESULTS: The systemic administration of 4 mg/kg i.p. of GTS-21 significantly increased bacterial clearance, decreased acute lung injury and decreased accumulation of airway HMGB1 compared to the saline control. To determine the mechanism of action of GTS-21, RAW 264.7 cells, a macrophage-like cell line, were incubated with different concentrations of GTS-21 in the presence of 95% O2. The phagocytic activity of macrophages was significantly increased by GTS-21 in a dose-dependent manner. In addition, GTS-21 significantly inhibited the cytoplasmic translocation and release of HMGB1 from RAW 264.7 cells and attenuated hyperoxia-induced NF-κB activation in macrophages and mouse lungs exposed to hyperoxia and infected with PA. CONCLUSIONS: Our results indicate that GTS-21 is efficacious in improving bacterial clearance and reducing acute lung injury via enhancing macrophage function by inhibiting the release of nuclear HMGB1. Therefore, the α7nAChR represents a possible pharmacological target to improve the clinical outcome of patients on ventilators by augmenting host defense against bacterial infections.


Assuntos
Compostos de Benzilideno/farmacologia , Hiperóxia/imunologia , Macrófagos Alveolares/efeitos dos fármacos , Infecções por Pseudomonas/tratamento farmacológico , Piridinas/farmacologia , Lesão Pulmonar Induzida por Ventilação Mecânica/tratamento farmacológico , Receptor Nicotínico de Acetilcolina alfa7/antagonistas & inibidores , Animais , Modelos Animais de Doenças , Proteína HMGB1/metabolismo , Hiperóxia/dietoterapia , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fagocitose/efeitos dos fármacos , Pseudomonas aeruginosa , Células RAW 264.7
19.
Nat Commun ; 11(1): 4561, 2020 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-32917873

RESUMO

The protein high-mobility group box 1 (HMGB1) is released into the extracellular space in response to many inflammatory stimuli, where it is a potent signaling molecule. Although research has focused on downstream HMGB1 signaling, the means by which HMGB1 exits the cell is controversial. Here we demonstrate that HMGB1 is not released from bone marrow-derived macrophages (BMDM) after lipopolysaccharide (LPS) treatment. We also explore whether HMGB1 is released via the pore-forming protein gasdermin D after inflammasome activation, as is the case for IL-1ß. HMGB1 is only released under conditions that cause cell lysis (pyroptosis). When pyroptosis is prevented, HMGB1 is not released, despite inflammasome activation and IL-1ß secretion. During endotoxemia, gasdermin D knockout mice secrete HMGB1 normally, yet secretion of IL-1ß is completely blocked. Together, these data demonstrate that in vitro HMGB1 release after inflammasome activation occurs after cellular rupture, which is probably inflammasome-independent in vivo.


Assuntos
Proteína HMGB1/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Macrófagos/metabolismo , Proteínas de Ligação a Fosfato/metabolismo , Animais , Modelos Animais de Doenças , Endotoxemia/metabolismo , Feminino , Proteína HMGB1/genética , Inflamassomos/metabolismo , Interleucina-1beta/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Lipopolissacarídeos/efeitos adversos , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas de Ligação a Fosfato/genética , Piroptose , Transdução de Sinais
20.
DNA Cell Biol ; 39(9): 1711-1722, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32833553

RESUMO

High mobility group box 1 (HMGB1) is essential for the pathogenesis of liver injury and liver fibrosis. We previously revealed that miR-146b promotes hepatic stellate cells (HSCs) activation and proliferation. Nevertheless, the potential mechanisms are still unknown. Herein, HMGB1 increased HSCs proliferation and COL1A1 and α-SMA protein levels. However, the knockdown of miR-146b inhibited HSCs proliferation and COL1A1 and α-SMA protein levels induced via HMGB1 treatment. miR-146b was upregulated by HMGB1 and miR-146b targeted hepatocyte nuclear factor 1A (HNF1A) 3'-untranslated region (3'UTR) to modulate its expression negatively. Further, we confirmed that HMGB1 might elicit miR-146b expression via p65 within HSCs. Knockdown or block of HMGB1 relieved the CCl4-induced liver fibrosis. In fibrotic liver tissues, miR-146b expression was positively correlated with p65 mRNA, but HNF1A mRNA was inversely correlated with p65, and miR-146b expression. In summary, our findings suggest that HMGB1/p65/miR-146b/HNF1A signaling exerts a crucial effect on liver fibrogenesis via the regulation of HSC function.


Assuntos
Proteína HMGB1/metabolismo , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Cirrose Hepática/metabolismo , Transdução de Sinais , Regiões 3' não Traduzidas , Animais , Linhagem Celular , Proteína HMGB1/genética , Células Estreladas do Fígado/metabolismo , Fator 1-alfa Nuclear de Hepatócito/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Ratos , Ratos Sprague-Dawley , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo
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