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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.
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
3.
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
4.
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
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.
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
7.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 45(9): 1024-1034, 2020.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-33051415

RESUMO

OBJECTIVES: There is a significant increase of high-mobility group protein B1 (HMGB1) in plasma levels of patients with pulmonary hypertension, but the biological significance is still unclear. Anti-proliferative protein 1 (prohibitin 1, PHB1) is an important protein that maintains the homeostasis of vascular cells. This study aimed to investigate the effect of HMGB1 on pulmonary artery endothelial cells and the role of PHB1. METHODS: In vivo experiment: A rat model of pulmonary hypertension induced by monocrotaline (MCT) was constructed. The right ventricular systolic pressure (RVSP), and the weight ratio of right ventricle to left ventricle plus ventricular septum were used to evaluate the success of model. ELISA was used to detect the level of HMGB1 in rat's plasma. Western blotting was used to detect the level of PHB1 in rat's lung tissues. CD31 immunofluorescence was used to detect the integrity of pulmonary vascular endothelium. In vitro experiments: Pulmonary artery endothelial cell (PAEC) was incubated with HMGB1 to observe the effect of HMGB1 on PAEC injury. Overexpression and knockdown of PHB1 were conducted, and the role of PHB1 was investigated by detecting the levels of reative oxygen species and cytochrome c (cyto-c), and the activation of caspase-3. RESULTS: Compared with the control group, the level of HMGB1 in the plasma of rats with pulmonary hypertension was significantly increased (P<0.05), and the expression of PHB1 in the lung tissue was decreased accompanied with endothelial dysfunction (P<0.05); HMGB1 incubation damaged the pulmonary artery endothelium and down-regulated PHB1 expression (P<0.05), while overexpression of PHB1 reduced the PAEC damage and oxidative stress induced by HMGB1 (P<0.05). Meanwhile, PHB1 reduced HMGB1-induced cyto-c expression and caspase-3 cleavage by inhibiting oxidative stress (P<0.05). CONCLUSIONS: The down-regulation of PHB1 expression mediates HMGB1-induced PAEC injury, which is related to the induction of oxidative stress, the increase of cyto-c release, and the promotion of caspase-3 cleavage.


Assuntos
Proteína HMGB1 , Proteínas Repressoras , Animais , Células Endoteliais , Proteína HMGB1/genética , Humanos , Artéria Pulmonar , Ratos , Proteínas Repressoras/genética
8.
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
9.
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
10.
PLoS One ; 15(8): e0236727, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32750068

RESUMO

Low-power laser irradiation (LPLI) is clinically used to modulate inflammation, proliferation and apoptosis. However, its molecular mechanisms are still not fully understood. This study aimed to describe the effects of LPLI upon inflammatory, apoptotic and proliferation markers in submandibular salivary glands (SMGs) in an experimental model of chronic disorder, 24h after one time irradiation. Diabetes was induced in rats by the injection of streptozotocin. After 29 days, these animals were treated with LPLI in the SMG area, and euthanized 24h after this irradiation. Treatment with LPLI significantly decreased diabetes-induced high mobility group box 1 (HMGB1) and tumor necrosis factor alpha (TNF-α) expression, while enhancing the activation of the transcriptional factor cAMP response element binding (CREB) protein. LPLI also reduced the expression of bax, a mitochondrial apoptotic marker, favoring the cell survival. These findings suggest that LPLI can hamper the state of chronic inflammation and favor homeostasis in diabetic rats SMGs.


Assuntos
Diabetes Mellitus Experimental/radioterapia , Terapia com Luz de Baixa Intensidade , Transdução de Sinais/efeitos da radiação , Glândula Submandibular/efeitos da radiação , Animais , Apoptose , AMP Cíclico/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Feminino , Proteína HMGB1/genética , Proteína HMGB1/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Fosforilação , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/metabolismo
11.
J Pharmacol Sci ; 144(2): 69-75, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32713799

RESUMO

The mechanism of the papaverine (PV) for the treatment of cerebral ischemia remains unclear. A total of 42 mice induced with focal cerebral ischemia were randomly divided into three groups: PV,baicalin (BA)and vehicle group. Both PV and BA could significantly reduce the ischemic infarct volume (P < 0.05). Pathway enrichment analysis was performed on MetaCore™ to search the molecular pathways associated with the gene expression profile of PV, compared with vehicle and BA. Compared with vehicle, we found that 60% of the top 10 pathways in PV group were related to immune response. The top 10 biological processes of the targeted pathways were mainly related to the multiple immunomodulatory process of neuro-vascular inflammation, including immune_Th17-deried cytokins, regulation of angiogenesis, cell adhesion_Leucocyte chemotaxis, antigen presentation, cell adhesion_synaptic contact, and inflammation related to Amphoterin signaling. Moreover, compared with BA, 17 pathways of PV were identified, and 58.82% (10/17) were also related to immune response, especially, half of the top 10 pathways with the lower p-value. In these top 10 pathways, 4 were the cytokine-mediated signaling pathways, which play key role in inflammation, like IL-17 signaling pathways with the activation of G-CSF,IL-23,RANKL, p38MAPK and NF-κB.These findings indicate that PV may be an efficacious pluripotent anti-inflammatory agent against cerebral ischemic-reperfusion injury by targeting on multiple immunomodulatory process of neuro-vascular inflammation.


Assuntos
Anti-Inflamatórios , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/genética , Fatores Imunológicos , Papaverina/farmacologia , Papaverina/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/genética , Animais , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Proteína HMGB1/genética , Proteína HMGB1/metabolismo , Inflamação , Interleucina-17/genética , Interleucina-17/metabolismo , Masculino , Camundongos Endogâmicos , NF-kappa B/genética , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
12.
Cell Mol Immunol ; 17(9): 992-994, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32620787
13.
PLoS One ; 15(7): e0235614, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32678819

RESUMO

Both MicroRNAs and HMGB1 took part in pathological process of myocardial I/R injury though several signaling pathways. We hypothesized that mircoRNA451 (miR-451), a group of small non-coding RNAs, could improve this injury by inhibiting HMGB1. Male SD rats were randomly distributed into 5 groups and subjected to I/R process. After 24 hours of reperfusion injury, the serum content of CK and LDH, the content of MDA in tissue and activity of SOD were detected; The infarcted areas were defined by TTC staining and Evans Blue; TUNEL staining and cleaved-Caspase 3 were used to test apoptosis; HMGB1 was detected by real-time fluorescence quantitative PCR and Western Blotting. Compared with the I/R and I/R+Ad-GFP group, upregulation of miR-451 could reduce the infarcted areas, cardiomyocytes apoptosis index, expression of cleaved-caspase 3 and content of CK and LDH significantly(P<0.05); Meanwhile, upregulation of miR-451 could also obviously inhibit HMGB1, the increase of MDA and the decrease of SOD (P<0.05). So this study revealed that upregulation of miR-451 could prevent myocardial I/R injury by suppressing HMGB1.


Assuntos
Proteína HMGB1/genética , MicroRNAs/genética , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/metabolismo , Regulação para Cima , Animais , Apoptose/genética , Proteína HMGB1/metabolismo , Masculino , Malondialdeído/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/patologia , Ratos , Ratos Sprague-Dawley , Superóxido Dismutase/metabolismo
14.
Biomed Khim ; 66(3): 208-215, 2020 May.
Artigo em Russo | MEDLINE | ID: mdl-32588826

RESUMO

Alcohol use is a global socially significant problem that remains one of the leading risk factors for disability and premature death. One of the main pathological characteristics of alcoholism is the loss of cognitive control over the amount of consumed alcohol. Growing body of evidence suggests that alterations of neuroimmune communication occurring in the brain during prolonged alcoholization are one of the main mechanisms responsible for the development of this pathology. Ethanol consumption leads to activation of neuroimmune signaling in the central nervous system through many types of Toll-like receptors (TLRs), as well as the release of their endogenous agonists (HMGB1 protein, S100 protein, heat shock proteins, extracellular matrix breakdown proteins). Activation of TLRs triggers intracellular molecular cascades leading to increased expression of the innate immune system genes, particularly proinflammatory cytokines, subsequently causing the development of a persistent neuroinflammatory process in the central nervous system, which results in massive death of neurons and glial cells in the brain structures, which are primarily associated with the development of a pathological craving for alcohol. In addition, some subtypes of TLRs are capable of forming heterodimers with neuropeptide receptors (corticoliberin, orexin, ghrelin receptors), and may also have other functional relationships.


Assuntos
Alcoolismo , Proteína HMGB1 , Receptores Toll-Like , Alcoolismo/genética , Alcoolismo/imunologia , Etanol , Proteína HMGB1/genética , Humanos , Neuroimunomodulação , Receptores Toll-Like/genética
15.
PLoS One ; 15(6): e0233643, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32479555

RESUMO

Chronic subdural hematoma (CSDH) is an angiogenic and inflammatory disease. Toll-like receptors (TLRs) transduce intracellular signals, resulting in the activation of nuclear factor κB (NF-κB), which leads to the production of inflammatory cytokines. High-mobility group box 1 (HMGB1) functions as a mediator of inflammatory responses through TLRs. In this study, we examined the expression of HMGB1 and components of the Toll-like receptor and NF-κB signaling pathways in the outer membrane of CSDH. Eight patients whose outer membrane was successfully obtained during trepanation surgery were included in this study. The expression of TLR4, myeloid differentiation factor 88 (MyD88), interleukin-1 receptor-associated kinase 4 (IRAK4), TNF receptor-associated factor 6 (TRAF6), TGFß-activated kinase 1 (Tak1), interferon regulatory factors 3 (IRF3), IκB kinase ß (IKKß), IKKγ, IκBε, IκBα, NF-κB/p65 and ß-actin was examined by Western blot analysis. The expression of TLR4, NF-κB/p65 and interleukin-6 (IL-6) was also examined by immunohistochemistry. The concentrations of HMGB1 and IL-6 in CSDH fluids were measured using ELISA kits. Above-mentioned molecules were detected in all cases. In addition, TLR4, NF-κB/p65 and IL-6 were localized in the endothelial cells of vessels within CSDH outer membranes. The concentrations of HMGB1 and IL-6 in CSDH fluids were significantly higher than that in the CSF and serum. There existed a correlation between the concentrations of HMGB1 and IL-6 in CSDH fluids. Our data suggest that HMGB1 in CSDH fluids produces the inflammatory cytokine IL-6 in endothelial cells through the Toll-like receptor and NF-κB signaling pathways. Anti-HMGB1 therapy might be a useful method to treat the growth of CSDH.


Assuntos
Proteína HMGB1/metabolismo , Hematoma Subdural Crônico/metabolismo , Interleucina-6/metabolismo , NF-kappa B/metabolismo , Receptor 4 Toll-Like/metabolismo , Idoso , Idoso de 80 Anos ou mais , Endotélio Vascular/metabolismo , Feminino , Proteína HMGB1/genética , Humanos , Fator Regulador 3 de Interferon/genética , Fator Regulador 3 de Interferon/metabolismo , Quinases Associadas a Receptores de Interleucina-1/genética , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Interleucina-6/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , MAP Quinase Quinase Quinases/genética , MAP Quinase Quinase Quinases/metabolismo , Masculino , Pessoa de Meia-Idade , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/genética , Transdução de Sinais , Receptor 4 Toll-Like/genética
16.
Zhonghua Zhong Liu Za Zhi ; 42(5): 391-395, 2020 May 23.
Artigo em Chinês | MEDLINE | ID: mdl-32482028

RESUMO

Objective: To investigate the expression of IGF1R-Ras and RAGE-HMGB1 signaling pathways in colorectal cancer patients with type 2 diabetes mellitus and their significance. Methods: The resected cancer tissues were obtained from 59 patients with colorectal cancer (CRC), including 29 patients with type 2 diabetes mellitus (CRC/DM group) and 30 with CRC alone (CRC group). The expressions of IGF1R, Ras, RAGE and HMGB1 in cancer tissues were detected by immunohistochemistry. The differences between the two groups were compared and the relationship between the expression and clinicopathological characteristics was analyzed. Results: In CRC/DM group, the positive rates of IGF1R and Ras were both 65.5% (19/29), and 51.7% (15/29) patients had IGF1R+ Ras+ immunophenotype, which were significantly higher than those in CRC group [33.3% (10/30), 36.7% (11/30) and 20.0% (6/30); P=0.013, 0.027 and 0.011, respectively]. The expression of IGF1R and Ras in CRC / DM group was positively correlated (r=0.479, P=0.017). The positive rate of RAGE expression in CRC group and CRC/DM group was 70.0% (21/30) and 72.4% (21/29) respectively, and the positive rate of HMGB1 expression was 46.7% (14/30) and 58.6% (17/29) respectively, neither was observed with significant difference (P=0.358 and 0.838). However, the proportion of patients with RAGE+ HMGB1+ immunophenotype in CRC/DM group [55.2% (16/29)] was higher than that in CRC Group [26.7% (8/30)] which was statistically significant (P=0.026), and the expression of both proteins was positively correlated in CRC/DM group (r=0.578, P=0.003). The clinicopathological analysis showed that in both groups the expression of IGF1R, Ras, RAGE and HMGB1 had no correlation with the sex, age, differentiation degree, tumor length, T stage and lymph node metastasis (P>0.05). Conclusion: Both IGF1R-Ras and RAGE-HMGB1 pathways may be involved in the oncogenesis of colorectal cancer in patients with type 2 diabetes.


Assuntos
Neoplasias Colorretais/patologia , Diabetes Mellitus Tipo 2/complicações , Genes ras/genética , Proteína HMGB1/metabolismo , Receptor IGF Tipo 1/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/complicações , Neoplasias Colorretais/metabolismo , Proteína HMGB1/genética , Humanos , Prognóstico , Receptor IGF Tipo 1/genética
17.
Neoplasma ; 67(4): 871-879, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32386483

RESUMO

Non-small cell lung cancer (NSCLC) is a major source of cancer mortality. Long non-coding RNA DSCAM-AS1 has been certified to be involved in the pathogenesis of NSCLC. This study aimed to further investigate the potential mechanism of DSCAM-AS1 in NSCLC progression. The expressions of DSCAM-AS1, miR-577, and high mobility group box 1 (HMGB1) were detected by quantitative real-time polymerase chain reaction (qRT-PCR) or western blot assay. Cell viability was assessed by Cell Counting Kit-8 (CCK-8) assay. Flow cytometry assay was conducted to monitor cell apoptosis. Cell migration and invasion were measured by transwell assay. Wnt/ß-catenin pathway-related factors were detected by western blot assay. The relationship between DSCAM-AS1, miR-577, and HMGB1 was validated by bioinformatics analysis and dual-luciferase reporter assay. The xenograft mouse model was established to analyze tumor growth in vivo. DSCAM-AS1 and HMGB1 were upregulated, while miR-577 was downregulated in NSCLC tissues and cells. DSCAM-AS1 promoted cell proliferation, migration and invasion, and restrained cell apoptosis in NSCLC cells. Overexpression of HMGB1 reversed the effects of DSCAM-AS1 depletion on the progression of NSCLC. DSCAM-AS1 modulated HMGB1 expression by sponging miR-577. DSCAM-AS1 regulated the Wnt/ß-catenin pathway by regulating miR-577 and HMGB1. DSCAM-AS1 knockdown blocked the tumor growth in vivo. In conclusion, DSCAM-AS1 facilitated NSCLC progression by regulating the HMGB1-mediated Wnt/ß-catenin pathway, providing a promising therapeutic target for NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Proteína HMGB1 , Neoplasias Pulmonares , MicroRNAs , RNA Longo não Codificante , Animais , Carcinoma Pulmonar de Células não Pequenas/genética , Moléculas de Adesão Celular , Regulação Neoplásica da Expressão Gênica , Proteína HMGB1/genética , Proteína HMGB1/metabolismo , Humanos , Neoplasias Pulmonares/genética , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/fisiologia
18.
Toxicol Lett ; 331: 92-101, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32446815

RESUMO

Aflatoxin G1 (AFG1) is a member of the carcinogenic aflatoxin family. Our previous studies indicated that oral administration of AFG1 caused tumor necrosis factor (TNF)-α-dependent inflammation that enhanced oxidative DNA damage in alveolar epithelial cells, which may be related to AFG1-induced lung carcinogenesis. High mobility group box-1 (HMGB1) is a nuclear DNA-binding protein; the intracellular and extracellular roles of HMGB1 have been shown to contribute to DNA repair and sterile inflammation. The role of HMGB1 in DNA damage in an aflatoxin-induced lung inflammatory environment was investigated in this study. Upregulation of HMGB1, TLR2, and RAGE was observed in AFG1-induced lung inflamed tissues and adenocarcinoma. Blocking AFG1-induced inflammation by neutralization of TNF-α inhibited the upregulation of HMGB1 in mouse lung tissues, suggesting that AFG1-induced TNF-α-dependent inflammation regulated HMGB1 expression. In the in vitro human pulmonary epithelial cell line model, Beas-2b, AFG1 directly enhanced the cytosolic translocation of HMGB1 and its extracellular secretion. The addition of extracellular soluble HMGB1 protected AFG1-induced DNA damage through the TLR2/NF-κB pathway in Beas-2b cells. In addition, blockade of endogenous HMGB1 by siRNA significantly enhanced AFG1-induced damage. Thus, our findings showed that both extracellularly-released and nuclear and cytosolic HMGB1 could protect the cell from AFG1-induced cell damage in a TNF-α-dependent lung inflammatory environment.


Assuntos
Adenocarcinoma/patologia , Aflatoxinas/toxicidade , Células Epiteliais/efeitos dos fármacos , Proteína HMGB1/metabolismo , Neoplasias Pulmonares/patologia , Pulmão/efeitos dos fármacos , Pneumonia/patologia , Adenocarcinoma/induzido quimicamente , Adenocarcinoma/metabolismo , Animais , Linhagem Celular , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Proteína HMGB1/genética , Humanos , Pulmão/metabolismo , Pulmão/patologia , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/metabolismo , Camundongos Endogâmicos BALB C , Pneumonia/induzido quimicamente , Pneumonia/metabolismo , RNA Interferente Pequeno/genética
19.
PLoS One ; 15(4): e0230392, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32275672

RESUMO

OBJECTIVES: High-mobility group box 1 protein (HMGB1) fragment enhances bone marrow-derived mesenchymal stem cell (BM-MSC) recruitment to damaged tissue to promote tissue regeneration. This study aimed to evaluate whether systemic injection of HMGB1 fragment could promote tissue repair in a rat model of myocardial infarction (MI). METHODS: HMGB1 (n = 14) or phosphate buffered saline (n = 12, control) was administered to MI rats for 4 days. Cardiac performance and left ventricular remodeling were evaluated using ultrasonography and immunostaining. BM-MSC recruitment to damaged tissue in green fluorescent protein-bone marrow transplantation (GFP-BMT) models was evaluated using immunostaining. RESULTS: At four weeks post-treatment, the left ventricular ejection fraction was significantly improved in the HMGB1 group compared to that in the control. Interstitial fibrosis and cardiomyocyte hypertrophy were also significantly attenuated in the HMGB1 group compared to the control. In the peri-infarction area, VEGF-A mRNA expression was significantly higher and TGFß expression was significantly attenuated in the HMGB1 group than in the control. In GFP-BMT rats, GFP+/PDGFRα+ cells were significantly mobilized to the peri-infarction area in the HMGB1 group compared to that in the control, leading to the formation of new vasculature. In addition, intravital imaging revealed that more GFP+/PDGFRα+ cells were recruited to the peri-infarction area in the HMGB1 group than in the control 12 h after treatment. CONCLUSIONS: Systemic administration of HMGB1 induced angiogenesis and reduced fibrosis by recruiting PDGFRα+ mesenchymal cells from the bone marrow, suggesting that HMGB1 administration might be a new therapeutic approach for heart failure after MI.


Assuntos
Proteína HMGB1/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Infarto do Miocárdio/tratamento farmacológico , Indutores da Angiogênese/farmacologia , Animais , Modelos Animais de Doenças , Fibrose/tratamento farmacológico , Proteína HMGB1/genética , Proteína HMGB1/metabolismo , Coração/fisiopatologia , Insuficiência Cardíaca/tratamento farmacológico , Masculino , Células-Tronco Mesenquimais/metabolismo , Infarto do Miocárdio/fisiopatologia , Ratos , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Regeneração/efeitos dos fármacos
20.
Sci Rep ; 10(1): 6340, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32286320

RESUMO

Fowl cholera is a serious, highly contagious disease caused by the bacterium Pasteurella multocida (P. multocida) in a range of avian species and is characterized by an acute form of septicaemia. The pathogenic mechanism of chicken lung injury caused by the bacterium is unclear. Therefore, P. multocida Q (a reference standard strain isolated from chicken) and 1G1 (a clinic isolated strain from duck) were selected to infect chickens, establishing fowl cholera-induced laying hen models. Several important proteins involved in the process of lung injury were identified and quantified using immunohistochemistry and WB. The results showed that chicken lungs infected with bacteria for 24 h showed congestion and edema. The inflammatory factors HMGB1 and IL-6, intercellular matrix MMP, the cell apoptosis-associated caspase-3 and necrotic apoptosis signal molecules RIPK1 and RIPK3 were widely expressed in the lungs of group Q and were significantly different compared with those of 1G1 group and uninfected group (P < 0.05). The results indicated that RIPK1 and RIPK3 are involved in the injury process of chicken lungs after infection with P. multocida, and the mechanisms of lung injury induced by different strains are different.


Assuntos
Proteínas Aviárias/metabolismo , Pulmão/metabolismo , Infecções por Pasteurella/veterinária , Doenças das Aves Domésticas/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Animais , Apoptose , Proteínas Aviárias/genética , Galinhas , Proteína HMGB1/genética , Proteína HMGB1/metabolismo , Inflamação , Interleucina-6/genética , Interleucina-6/metabolismo , Pulmão/microbiologia , Pulmão/patologia , Metaloproteinases da Matriz/genética , Metaloproteinases da Matriz/metabolismo , Infecções por Pasteurella/metabolismo , Infecções por Pasteurella/microbiologia , Pasteurella multocida/patogenicidade , Doenças das Aves Domésticas/microbiologia , Proteína Serina-Treonina Quinases de Interação com Receptores/genética
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