Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.952
Filtrar
1.
Artigo em Inglês | MEDLINE | ID: mdl-33805292

RESUMO

Heme oxygenase (HO) is the rate-limiting enzyme in the heme catabolic pathway, which degrades heme into equimolar amounts of carbon monoxide, free iron, and biliverdin. Its inducible isoform, HO-1, has multiple protective functions, including immune modulation and pregnancy maintenance, showing dynamic alteration during perinatal periods. As its contribution to the development of perinatal complications is speculated, two functional polymorphisms of the HMOX1 gene, (GT)n repeat polymorphism (rs3074372) and A(-413)T single nucleotide polymorphism (SNP) (rs2071746), were studied for their association with perinatal diseases. We systematically reviewed published evidence on HMOX1 polymorphisms in perinatal diseases and clarified their possible significant contribution to neonatal jaundice development, presumably due to their direct effect of inducing HO enzymatic activity in the bilirubin-producing pathway. However, the role of these polymorphisms seems limited for other perinatal complications such as bronchopulmonary dysplasia. We speculate that this is because the antioxidant or anti-inflammatory effect is not directly mediated by HO but by its byproducts, resulting in a milder effect. For better understanding, subtyping each morbidity by the level of exposure to causative environmental factors, simultaneous analysis of both polymorphisms, and the unified definition of short and long alleles in (GT)n repeats based on transcriptional capacity should be further investigated.


Assuntos
Predisposição Genética para Doença , Heme Oxigenase-1 , Alelos , Heme Oxigenase-1/genética , Humanos , Recém-Nascido , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas
2.
J Biomed Nanotechnol ; 17(2): 196-204, 2021 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-33785091

RESUMO

Heterotopic ossification is a bona fide bone formation outside the normal skeleton. Traumatic injury and genetic mutations are the important risk factors of HO. Both injury-induced HO and hereditary HO severely affect human life quality. However, there were no effect therapies treating HO. Here, we performed the RNA-sequencing assay to examine dynamic process during HO initiation and development. Moreover, we found that oxidation-reduction process were significantly dysregulated following HO formation. Further, we characterized that Nuclear factor erythroid 2-related factor 2 (NRF2) expression conferred antioxidant property in macrophages and then helped chondrocytes formation. Instead, 3-Nitrotyrosine is expressed by T-lymphocytes, but not macrophages, causing deficient adaptive immunity. Inhibition of NRF2 markedly alleviated HO. Finally, we identified that PI3K/AKT signaling pathway is responsible for whole HO process, but ERK signaling is activated only in early stage. ERK pathway blockade effectively prevented HO. These findings revealed that oxidative stress induced by early immune response can be targeted in HO treatment.


Assuntos
Ossificação Heterotópica , Fosfatidilinositol 3-Quinases , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Humanos , Ossificação Heterotópica/genética , Ossificação Heterotópica/prevenção & controle , Estresse Oxidativo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Análise de Sequência de RNA
3.
Zhongguo Zhong Yao Za Zhi ; 46(6): 1460-1466, 2021 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-33787144

RESUMO

This project aimed to explore the protective effect of ginsenoside Rg_1 on hypoxia/reoxygenation(H/R)-induced H9 c2 cardiomyocyte injury and its underlying signaling pathway. The H/R model of H9 c2 cardiomyocytes was established and then the cells were divided into different treatment groups. CCK-8(cell counting kit-8) was used to detect the activity of cardiomyocytes; Brdu assay was used to detect the proliferation of H9 c2 cells; the caspase-3 activity was tested, and then the protein expression was assessed by Western blot. Flow cytometry was used to evaluate the apoptosis level of cardiomyocytes. Ginsenoside Rg_1 inhibited H/R-induced cardiomyocyte apoptosis and caspase-3 activity, promoted nuclear transcription of nuclear factor erythroid-2 related factor 2(Nrf2), and enhanced the expression of the downstream heme oxygenase-1(HO-1). Ginsenoside Rg_1 could increase Nrf2 nuclear transcription and HO-1 expression with the increase of concentration(10, 20, 40, 60 µmol·L~(-1)). However, the protective effect of ginsenoside Rg_1 on cardiomyocytes was significantly weakened after the transfection of Nrf2-siRNA. Ginsenoside Rg_1 could protect cardiomyocytes by activating the Nrf2/HO-1 pathway.


Assuntos
Ginsenosídeos , Apoptose , Ginsenosídeos/farmacologia , Heme Oxigenase-1/genética , Humanos , Hipóxia , Miócitos Cardíacos , Fator 2 Relacionado a NF-E2/genética
4.
Int J Mol Sci ; 22(3)2021 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-33540888

RESUMO

Macrophages are essential immune cells of the innate immune system. They participate in the development and regulation of inflammation. Macrophages play a fundamental role in fighting against bacterial infections by phagocytosis of bacteria, and they also have a specific role in immunomodulation by secreting pro-inflammatory cytokines. In bacterial infection, macrophages decrease the serum iron concentration by removing iron from the blood, acting as one of the most important regulatory cells of iron homeostasis. We examined whether the Gram-positive and Gram-negative cell wall components from various bacterial strains affect the cytokine production and iron transport, storage and utilization of THP-1 monocytes in different ways. We found that S. aureus lipoteichoic acid (LTA) was less effective in activating pro-inflammatory cytokine expression that may related to its effect on fractalkine production. LTA-treated cells increased iron uptake through divalent metal transporter-1, but did not elevate the expression of cytosolic and mitochondrial iron storage proteins, suggesting that the cells maintained iron efflux via the ferroportin iron exporter. E. coli and P. aeruginosa lipopolysaccharides (LPSs) acted similarly on THP-1 cells, but the rates of the alterations of the examined proteins were different. E. coli LPS was more effective in increasing the pro-inflammatory cytokine production, meanwhile it caused less dramatic alterations in iron metabolism. P. aeruginosa LPS-treated cells produced a smaller amount of pro-inflammatory cytokines, but caused remarkable elevation of both cytosolic and mitochondrial iron storage proteins and intracellular iron content compared to E. coli LPS. These results prove that LPS molecules from different bacterial sources alter diverse molecular mechanisms in macrophages that prepossess the outcome of the bacterial infection.


Assuntos
Parede Celular/química , Citocinas/metabolismo , Escherichia coli/química , Ferro/metabolismo , Lipopolissacarídeos/farmacologia , Pseudomonas aeruginosa/química , Staphylococcus aureus/química , Células THP-1/metabolismo , Ácidos Teicoicos/farmacologia , Transporte Biológico , Receptor 1 de Quimiocina CX3C/biossíntese , Receptor 1 de Quimiocina CX3C/genética , Quimiocina CX3CL1/metabolismo , Citocinas/biossíntese , Citosol/metabolismo , Ferritinas/biossíntese , Ferritinas/genética , Heme Oxigenase-1/biossíntese , Heme Oxigenase-1/genética , Hepcidinas/biossíntese , Hepcidinas/genética , Humanos , Mitocôndrias/metabolismo , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Oxirredutases/biossíntese , Oxirredutases/genética , RNA Mensageiro/biossíntese , RNA Neoplásico/genética , Células THP-1/efeitos dos fármacos
5.
Int J Mol Sci ; 22(3)2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33498175

RESUMO

Whilst the survival rates of childhood acute lymphoblastic leukemia (ALL) have increased remarkably over the last decades, the therapy resistance and toxicity are still the major causes of treatment failure. It was shown that overexpression of heme oxygenase-1 (HO-1) promotes proliferation and chemoresistance of cancer cells. In humans, the HO-1 gene (HMOX1) expression is modulated by two polymorphisms in the promoter region: (GT)n-length polymorphism and single-nucleotide polymorphism (SNP) A(-413)T, with short GT repeat sequences and 413-A variants linked to an increased HO-1 inducibility. We found that the short alleles are significantly more frequent in ALL patients in comparison to the control group, and that their presence may be associated with a higher risk of treatment failure, reflecting the role of HO-1 in chemoresistance. We also observed that the presence of short alleles may predispose to develop chemotherapy-induced neutropenia. In case of SNP, the 413-T variant co-segregated with short or long alleles, while 413-A almost selectively co-segregated with long alleles, hence it is not possible to determine if SNPs are actually of phenotypic significance. Our results suggest that HO-1 can be a potential target to overcome the treatment failure in ALL patients.


Assuntos
Neutropenia Febril Induzida por Quimioterapia/genética , Resistencia a Medicamentos Antineoplásicos/genética , Heme Oxigenase-1/genética , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Células Cultivadas , Neutropenia Febril Induzida por Quimioterapia/etiologia , Criança , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Regiões Promotoras Genéticas
6.
Int J Biol Macromol ; 171: 112-122, 2021 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-33418037

RESUMO

The aim of this study was to investigate the primary structure of an acetylated Cyclocarya paliurus polysaccharide (Ac-CPP0.1) and its protective effect on H2O2-treated dendritic cells. The backbone of Ac-CPP0.1 was →3)-ß-D-Galp-(1→, with some branches α-L-Araf-(1→ residues at O-6 and O-5, ß-D-Galp-(1→ and 3,5,6)-ß-D-Galf-(1 residues at O-4 and acetyl groups were substituted at the O-2 and O-6 positions of 3)-ß-D-Galp-(1 residues. The CPP0.1 and Ac-CPP0.1 significantly increased the levels of superoxide dismutase, glutathione peroxidase and catalase on H2O2-treated dendritic cells. Meanwhile, both CPP0.1 and Ac-CPP0.1 up-regulated the expression of Nrf2 (NF-E2-related factor 2) and down-regulated the Keap1 (Kelch-like ECH-associated protein-1), but Ac-CPP0.1 had a better effect on antioxidant capacity. These results indicated that potential application of Ac-CPP0.1 as an antioxidant agent.


Assuntos
Antioxidantes/farmacologia , Células Dendríticas/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Juglandaceae/química , Polissacarídeos/farmacologia , Acetilação , Animais , Antioxidantes/química , Antioxidantes/isolamento & purificação , Compostos de Bifenilo/antagonistas & inibidores , Células da Medula Óssea/citologia , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Catalase/genética , Catalase/metabolismo , Células Dendríticas/citologia , Células Dendríticas/metabolismo , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Peróxido de Hidrogênio/antagonistas & inibidores , Peróxido de Hidrogênio/farmacologia , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , NAD(P)H Desidrogenase (Quinona)/genética , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Picratos/antagonistas & inibidores , Extratos Vegetais/química , Folhas de Planta/química , Polissacarídeos/química , Polissacarídeos/isolamento & purificação , Cultura Primária de Células , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/metabolismo
7.
Int J Mol Sci ; 22(2)2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33430368

RESUMO

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social communication, poor social interactions, and repetitive behaviors. We aimed to examine autism-like behaviors and related gene expressions in rats exposed to diesel exhaust (DE)-origin secondary organic aerosol (DE-SOA) perinatally. Sprague-Dawley pregnant rats were exposed to clean air (control), DE, and DE-SOA in the exposure chamber from gestational day 14 to postnatal day 21. Behavioral phenotypes of ASD were investigated in 10~13-week-old offspring using a three-chambered social behavior test, social dominance tube test, and marble burying test. Prefrontal cortex was collected to examine molecular analyses including neurological and immunological markers and glutamate concentration, using RT-PCR and ELISA methods. DE-SOA-exposed male and female rats showed poor sociability and social novelty preference, socially dominant behavior, and increased repetitive behavior. Serotonin receptor (5-HT(5B)) and brain-derived neurotrophic factor (BDNF) mRNAs were downregulated whereas interleukin 1 ß (IL-ß) and heme oxygenase 1 (HO-1) mRNAs were upregulated in the prefrontal cortex of male and female rats exposed to DE-SOA. Glutamate concentration was also increased significantly in DE-SOA-exposed male and female rats. Our results indicate that perinatal exposure to DE-SOA may induce autism-like behavior by modulating molecules such as neurological and immunological markers in rats.


Assuntos
Poluentes Atmosféricos/toxicidade , Transtorno do Espectro Autista/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Emissões de Veículos/toxicidade , Aerossóis/toxicidade , Animais , Transtorno do Espectro Autista/induzido quimicamente , Fator Neurotrófico Derivado do Encéfalo/genética , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Heme Oxigenase-1/genética , Humanos , Interleucina-1beta/genética , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Ratos , Ratos Sprague-Dawley , Receptores de Serotonina/genética
8.
Biochim Biophys Acta Mol Cell Res ; 1868(1): 118853, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32941941

RESUMO

Recently, oxidative stress is a common denominator in the pathogenesis of metal-induced neurotoxicity. Thus, antioxidant therapy is considered as a promising strategy for treating lead-related cognitive impairment. Here, we tested the hypothesis that astragaloside IV (AS-IV) ameliorates lead-associated cognitive deficits through Nrf2-dependent antioxidant mechanisms. Male Nrf2-KO and WT mice received drinking water with 2000 ppm lead and/or AS-IV by gavage for 8 weeks starting at 4 weeks of age. Morris water maze test and biochemical assays were employed to study cognition-enhancing and antioxidant effects of AS-IV. The signaling pathways involved were analyzed using RT-PCR and western blot technology. Significantly, AS-IV attenuated Morris water maze-based cognitive impairment in lead-intoxicated mice. Importantly, cognition-enhancing effect of AS-IV was lost in Nrf2-KO mice. In parallel, AS-IV suppressed lead acetate (PbAc)-induced oxidative stress, as measured by MDA. Mechanistically, AS-IV can up-regulate the expressions of the GCLc and HO-1 at the level of transcription and translation, but not SOD, TrxR activity, GCLm, Trx1, and NQO1 expression. Interestingly, AS-IV induced accumulation of Nrf2 in the nucleus, whereas Nrf2 mRNA levels were unchanged. Furthermore, AS-IV treatment resulted in elevated levels of phosphorylated Akt (active form) and phosphorylated GSK-3ß (inactive forms) but decreased level of phosphorylated Fyn. Collectively, our findings indicate that AS-IV may target Nrf2 to attenuate lead-triggered oxidative stress and subsequent cognitive impairments, suggesting that AS-IV is a potential candidate for the treatment of lead-associated cognitive diseases.


Assuntos
Disfunção Cognitiva/tratamento farmacológico , Heme Oxigenase-1/genética , Proteínas de Membrana/genética , Fator 2 Relacionado a NF-E2/genética , Compostos Organometálicos/toxicidade , Animais , Antioxidantes/farmacologia , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/genética , Glicogênio Sintase Quinase 3 beta/genética , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Células PC12 , Fosforilação/efeitos dos fármacos , Ratos , Espécies Reativas de Oxigênio/química , Saponinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Triterpenos/farmacologia
9.
Phytomedicine ; 80: 153370, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33113504

RESUMO

BACKGROUND: Cisplatin (DDP) is the first-in-class drug for advanced and non-targetable non-small-cell lung cancer (NSCLC). A recent study indicated that DDP could slightly induce non-apoptotic cell death ferroptosis, and the cytotoxicity was promoted by ferroptosis inducer. The agents enhancing the ferroptosis may therefore increase the anticancer effect of DDP. Several lines of evidence supporting the use of phytochemicals in NSCLC therapy. Ginkgetin, a bioflavonoid derived from Ginkgo biloba leaves, showed anticancer effects on NSCLC by triggering autophagy. Ferroptosis can be triggered by autophagy, which regulates redox homeostasis. Thus, we aimed to elucidate the possible role of ferroptosis involved in the synergistic effect of ginkgetin and DDP in cancer therapy. METHODS: The promotion of DDP-induced anticancer effects by ginkgetin was examined via a cytotoxicity assay and western blot. Ferroptosis triggered by ginkgetin in DDP-treated NSCLC was observed via a lipid peroxidation assay, a labile iron pool assay, western blot, and qPCR. With ferroptosis blocking, the contribution of ferroptosis to ginkgetin + DDP-induced cytotoxicity, the Nrf2/HO-1 axis, and apoptosis were determined via a luciferase assay, immunostaining, chromatin immunoprecipitation (CHIP), and flow cytometry. The role of ferroptosis in ginkgetin + DDP-treated NSCLC cells was illustrated by the application of ferroptosis inhibitors, which was further demonstrated in a xenograft nude mouse model. RESULTS: Ginkgetin synergized with DDP to increase cytotoxicity in NSCLC cells, which was concomitant with increased labile iron pool and lipid peroxidation. Both these processes were key characteristics of ferroptosis. The induction of ferroptosis mediated by ginkgetin was further confirmed by the decreased expression of SLC7A11 and GPX4, and a decreased GSH/GSSG ratio. Simultaneously, ginkgetin disrupted redox hemostasis in DDP-treated cells, as demonstrated by the enhanced ROS formation and inactivation of the Nrf2/HO-1 axis. Ginkgetin also enhanced DDP-induced mitochondrial membrane potential (MMP) loss and apoptosis in cultured NSCLC cells. Furthermore, blocking ferroptosis reversed the ginkgetin-induced inactivation of Nrf2/HO-1 as well as the elevation of ROS formation, MMP loss, and apoptosis in DDP-treated NSCLC cells. CONCLUSION: This study is the first to report that ginkgetin derived from Ginkgo biloba leaves promotes DDP-induced anticancer effects, which can be due to the induction of ferroptosis.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Biflavonoides/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Heme Oxigenase-1/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Fator 2 Relacionado a NF-E2/metabolismo , Células A549 , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Biflavonoides/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Cisplatino/administração & dosagem , Receptores ErbB/genética , Ferroptose/efeitos dos fármacos , Ginkgo biloba/química , Heme Oxigenase-1/genética , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos Nus , Folhas de Planta/química , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Mol Med ; 26(1): 90, 2020 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-32993497

RESUMO

Hydrogen sulfide (H2S) is a natural defence against the infections from enveloped RNA viruses and is likely involved also in Covid 19. It was already shown to inhibit growth and pathogenic mechanisms of a variety of enveloped RNA viruses and it was now found that circulating H2S is higher in Covid 19 survivors compared to fatal cases. H2S release is triggered by carbon monoxide (CO) from the catabolism of heme by inducible heme oxygenase (HO-1) and heme proteins possess catalytic activity necessary for the H2S signalling by protein persulfidation. Subjects with a long promoter for the HMOX1 gene, coding for HO-1, are predicted for lower efficiency of this mechanism. SARS-cov-2 exerts ability to attack the heme of hemoglobin and other heme-proteins thus hampering both release and signalling of H2S. Lack of H2S-induced persulfidation of the KATP channels of leucocytes causes adhesion and release of the inflammatory cytokines, lung infiltration and systemic endothelial damage with hyper-coagulability. These events largely explain the sex and age distribution, clinical manifestations and co-morbidities of Covid-19. The understanding of this mechanism may be of guidance in re-evaluating the ongoing therapeutic strategies, with special attention to the interaction with mechanical ventilation, paracetamol and chloroquine use, and in the individuation of genetic traits causing increased susceptibility to the disruption of these physiologic processes and to a critical Covid 19. Finally, an array of therapeutic interventions with the potential to clinically modulate the HO-1/CO/H2S axis is already available or under development. These include CO donors and H2S donors and a boost to the endogenous production of H2S is also possible.


Assuntos
Infecções por Coronavirus/imunologia , Sulfeto de Hidrogênio/metabolismo , Pneumonia Viral/imunologia , Monóxido de Carbono/metabolismo , Infecções por Coronavirus/complicações , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/terapia , Predisposição Genética para Doença , Heme Oxigenase (Desciclizante)/metabolismo , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Humanos , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/metabolismo , Pneumonia Viral/terapia , Fatores de Risco
11.
Int J Mol Sci ; 21(17)2020 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-32899231

RESUMO

The coronavirus disease of 2019 (COVID-19) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a global pandemic with increasing incidence and mortality rates. Recent evidence based on the cytokine profiles of severe COVID-19 cases suggests an overstimulation of macrophages and monocytes associated with reduced T-cell abundance (lymphopenia) in patients infected with SARS-CoV-2. The SARS-CoV-2 open reading frame 3 a (ORF3a) protein was found to bind to the human HMOX1 protein at a high confidence through high-throughput screening experiments. The HMOX1 pathway can inhibit platelet aggregation, and can have anti-thrombotic and anti-inflammatory properties, amongst others, all of which are critical medical conditions observed in COVID-19 patients. Here, we review the potential of modulating the HMOX1-ORF3a nexus to regulate the innate immune response for therapeutic benefits in COVID-19 patients. We also review other potential treatment strategies and suggest novel synthetic and natural compounds that may have the potential for future development in clinic.


Assuntos
Infecções por Coronavirus/metabolismo , Heme Oxigenase-1/metabolismo , Pneumonia Viral/metabolismo , Proteínas Virais Reguladoras e Acessórias/metabolismo , Animais , Antivirais/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Heme Oxigenase-1/genética , Humanos , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Ligação Proteica
12.
Life Sci ; 257: 118088, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32663573

RESUMO

AIMS: Bone marrow stromal cells (BMSCs) have been reported to interact with multiple myeloma (MM) and exert a vital function of the survival of MM cells. Heme oxygenase-1 (HO-1), a cytoprotective enzyme, has the potential to become a hematological malignancies targeted gene. This study aimed to investigate the role of HO-1 in MM resistance of BMSCs and its possible mechanisms. MAIN METHODS: In this study, the expression of related proteins was detected by RT-qPCR and Western blot. HO-1 expression was regulated by lentivirus transfection. Cell viability and apoptosis were detected by Flow cytometry and CCK-8. Cytokine secretion was assayed by ELISA. The survival and carcinogenic abilities was detected by clone formation assay. KEY FINDINGS: HO-1 expression in the BMSCs of stage III MM patients was substantially increased, compared with that of healthy donors and stage I/II patients. The results of co-culture of BMSCs and MM cells indicated that, the upregulated HO-1 inhibited the apoptosis of co-cultured MM cells, while downregulated HO-1 promoted the chemosensitivity of co-cultured MM cells, moreover, the upregulated HO-1 in BMSCs increased the colony-formation ability of MM cells. This protective capability may be regulated by CXCL12/CXCR4 signaling. High HO-1 expression in BMSCs can promote the phosphorylation of the JAK2/STAT3 pathway, thereby increasing secretion of SDF-1 in BMSCs and activating CXCL12/CXCR4 signaling. In addition, direct contact between BMSCs and MM cells may cause drug resistance. SIGNIFICANCE: These results indicated that the regulation of HO-1 in BMSCs may be a new effective method of MM therapy.


Assuntos
Antineoplásicos/farmacologia , Heme Oxigenase-1/genética , Células-Tronco Mesenquimais/citologia , Mieloma Múltiplo/patologia , Idoso , Idoso de 80 Anos ou mais , Apoptose/genética , Estudos de Casos e Controles , Técnicas de Cocultura , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Janus Quinase 2/metabolismo , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Estadiamento de Neoplasias , Fator de Transcrição STAT3/metabolismo
13.
Zhonghua Gan Zang Bing Za Zhi ; 28(5): 410-415, 2020 May 20.
Artigo em Chinês | MEDLINE | ID: mdl-32536057

RESUMO

Objective: To investigate the effect of rosiglitazone (RGZ) on the expression of peroxisome proliferator-activated receptor gamma (PPARγ) and heme oxygenase-1 (HO-1) in hepatic stellate cells (HSCs). Methods: In vitro activated hepatic stellate cell-T6 (HSC-T6) as research subjects were divided into blank control group, RGZ intervention group, and RGZ + ZnPP-IX mutual intervention group. MTT colorimetry method was used to measure the condition of cell proliferation. ELISA was used to detect the content of hyaluronic acid (HA) and type III procollagen peptide (PIIIP) in the cell supernatant. Real-time quantative PCR, western blot and immunocytochemistry were used to detect the relative expression levels of PPARγ, HO-1 mRNA and protein. One-way analysis of variance was used to compare the sample mean between multiple groups, and LSD test was used for comparison between two groups. Results: The proliferation activity of HSC-T6 and the expressions of HA and PIIIP in the RGZ intervention group were significantly lower than those in the blank control group (P ​​< 0.01), but the relative expression levels of PPARγ and HO-1 mRNA and protein were significantly increased compared with the blank control group (PPARγ : 2.97 ± 0.22 vs. 1.07 ± 0.05, 0.96 ± 0.08 vs. 0.31 ± 0.03; HO-1: 4.28 ± 0.73 vs. 1.80 ± 0.36, 1.83 ± 0.26 vs. 0.61 ± 0.09), and the difference was statistically significant (P < 0.01). The proliferation activity of HSC-T6 and the expression of HA and PIIIP was higher in RGZ + ZnPP-IX mutual intervention group as compared with RGZ group (P < 0.05). HO-1 mRNA (3.16 ± 0.38 vs. 4.28 ± 0.73) and protein (1.31 ± 0.17 vs. 1.83 ± 0.26) relative expression levels was decreased, and the difference was statistically significant (P < 0.05). There was no statistically significant difference in the relative expression of PPARγ mRNA and protein (P > 0.05), however, there was a decreasing trend. HO-1 mRNA (1.80 ± 0.36) and protein (0.61 ± 0.09) relative expression was significantly increased in RGZ + ZnPP-IX group as compared to blank control group (P < 0.05). Immunocytochemical staining had consistency with the above results. Conclusion: The effect of rosiglitazone on inducing increased expression of PPARγ, and then inhibiting HSC proliferation activity and collagen production may be realized by regulating its downstream HO-1 expression.


Assuntos
Hipoglicemiantes , PPAR gama , Rosiglitazona , Proliferação de Células , Heme Oxigenase-1/genética , Células Estreladas do Fígado , Hipoglicemiantes/farmacologia , PPAR gama/genética , Rosiglitazona/farmacologia
14.
Life Sci ; 256: 117908, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32512011

RESUMO

BACKGROUND: Excessive alcohol intake contributes to severe liver damage involving oxidative stress and inflammatory responses, which make them promising therapeutic targets. Previous studies have demonstrated that empagliflozin (EMPA) showed cardiovascular, renal, and cerebral benefits potentially mediated through its antioxidant and anti-inflammatory actions. AIMS: This experiment aimed to evaluate the hepatoprotective effect of EMPA on alcoholic liver disease (ALD) and the possible underlying mechanisms. MATERIALS AND METHODS: Serum biochemical parameters and the liver contents of malondialdehyde (MDA), nitric oxide (NO), reduced glutathione (GSH), and superoxide dismutase (SOD) were measured. Real-time qPCR was conducted to determine the gene expression of peroxisome proliferator-activated receptor gamma (PPAR-γ), nuclear factor erythroid 2-related factor 2 (Nrf-2), and heme oxygenase-1 (Hmox-1). In addition, ELISA was performed to measure tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß, IL-6, Nrf-2, and PPAR-γ. Nuclear factor-kappa B (NF-κB) was detected by immunohistochemical staining using an anti-NF-κB p65 antibody. KEY FINDINGS: Our results revealed that the serum levels of alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase were significantly reduced by EMPA. EMPA also decreased the content of MDA and NO and increased the activities of SOD and GSH in liver homogenates. Moreover, EMPA inhibited the release of proinflammatory cytokines, including TNF-α, IL-1ß, and IL-6, via the downregulation of NF-κB. These changes were associated with an improvement in histopathological deterioration. The protective effect of EMPA against oxidative stress and inflammation was associated with the upregulation of PPAR-γ, Nrf-2, and their target gene Hmox-1. SIGNIFICANCE: EMPA showed protective activities against ethanol-induced liver injury by suppressing inflammation and oxidative stress via modulation of the NF-κB/Nrf-2/PPAR-γ axis.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Compostos Benzidrílicos/farmacologia , Doença Hepática Crônica Induzida por Substâncias e Drogas/prevenção & controle , Fator de Transcrição de Proteínas de Ligação GA/metabolismo , Glucosídeos/farmacologia , NF-kappa B/metabolismo , PPAR gama/metabolismo , Alanina Transaminase/metabolismo , Fosfatase Alcalina/metabolismo , Animais , Anti-Inflamatórios/metabolismo , Antioxidantes/metabolismo , Aspartato Aminotransferases/metabolismo , Compostos Benzidrílicos/metabolismo , Doença Hepática Crônica Induzida por Substâncias e Drogas/metabolismo , Descoberta de Drogas , Etanol/efeitos adversos , Regulação da Expressão Gênica/efeitos dos fármacos , Glucosídeos/metabolismo , Glutationa/metabolismo , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Interleucinas/metabolismo , Fígado/metabolismo , Masculino , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , PPAR gama/genética , Superóxido Dismutase/metabolismo
15.
Medicine (Baltimore) ; 99(26): e20433, 2020 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-32590729

RESUMO

Bronchopulmonary dysplasia (BPD) is a chronic lung disease common in premature infants and is one of the leading causes of disability and death in newborns. The Keap-1/Nrf2 signaling pathway plays an important role in antioxidant and anti-inflammatory.Ten clean-grade, healthy pregnant Sprague-Dawley rats (purchased from Experimental Animal Center of Peking university, China) naturally gave birth to 55 neonatal rats from which 40 were selected and randomly divided into a hyperoxia group and a control group (N = 20, each). Thirty-two BPD patient samples are from Neonatal Department of the second Hospital of Jilin University from November 30, 2016 to May 1 2019.In present study, we observed that lung tissues of the control group did not undergo obvious pathological changes, whereas in the hyperoxia group, lung tissues had disordered structures. With increased time of hyperoxia exposure, the alveolar wall became attenuated. Under hypoxia conditions, the activity of oxidative stress-related enzymes (CAT, GSH-Px, SOD) in lung samples was significantly lower than that before treatment. The expression level of Keap1 mRNA and protein in the hyperoxia group was slightly lower than that of control group. The expression of Nrf2 and HO-1 mRNA and protein in the hyperoxia group was significantly higher than that of control group. For the infants with BPD, we found that the activity of SOD, GSH-Px, and CAT was significantly different from those of control group.We constructed a premature BPD animal model and found the abnormal of oxidative stress in different groups and the expression levels of Keap1/Nrf2 signaling pathway-related molecules, and we validated the results in premature infants with BPD.


Assuntos
Displasia Broncopulmonar/genética , Displasia Broncopulmonar/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Pulmão/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Animais , Animais Recém-Nascidos , Estudos de Casos e Controles , Catalase/metabolismo , Modelos Animais de Doenças , Feminino , Glutationa Peroxidase/metabolismo , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Humanos , Hiperóxia , Hipóxia , Recém-Nascido Prematuro , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Pulmão/patologia , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Fator 2 Relacionado a NF-E2/genética , Gravidez , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais , Superóxido Dismutase/metabolismo
16.
Am J Physiol Renal Physiol ; 318(6): F1531-F1538, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32390514

RESUMO

Renal ischemia-reperfusion injury (I/R) usually occurs in renal transplantation and partial nephrectomy, which could lead to acute kidney injury. However, the effective treatment for renal I/R still remains limited. In the present study, we investigated whether inhibition of chromobox 7 (CBX7) could attenuate renal I/R injury in vivo and in vitro as well as the potential mechanisms. Adult male mice were subjected to right renal ischemia and reperfusion for different periods, both with and without the CBX7 inhibitor UNC3866. In addition, human kidney cells (HK-2) were subjected to a hypoxia/reoxygenation (H/R) process for different periods, both with or without the CBX7 inhibitor or siRNA for CBX7. The results showed that expression of CBX7, glucose regulator protein-78 (GRP78), phosphorylated eukaryotic translation initiation factor-2α (p-eIF2α), and C/EBP homologous protein (CHOP) were increased after extension of I/R and H/R periods. Moreover, overexpression of CBX7 could elevate the expression of CBX7, GRP78, p-eIF2α, and CHOP. However, CBX7 inhibition with either UNC3866 or genetic knockdown led to reduced expression of GRP78, p-eIF2α, and CHOP through nuclear factor-erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 activation in I/R and H/R injury. Furthermore, ML385, the Nrf2 inhibitor, could elevate endoplasmic reticulum stress levels, abrogating the protective effects of UNC3866 against renal I/R injury. In conclusion, our results demonstrated that CBX7 inhibition alleviated acute kidney injury by preventing endoplasmic reticulum stress via the Nrf2/HO-1 pathway, indicating that CBX7 inhibitor could be a potential therapeutic target for renal I/R injury.


Assuntos
Lesão Renal Aguda/prevenção & controle , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Rim/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Oligopeptídeos/farmacologia , Complexo Repressor Polycomb 1/antagonistas & inibidores , Traumatismo por Reperfusão/prevenção & controle , Lesão Renal Aguda/enzimologia , Lesão Renal Aguda/genética , Lesão Renal Aguda/patologia , Animais , Hipóxia Celular , Linhagem Celular , Heme Oxigenase-1/genética , Humanos , Rim/enzimologia , Rim/patologia , Masculino , Proteínas de Membrana/genética , Camundongos , Fator 2 Relacionado a NF-E2/genética , Complexo Repressor Polycomb 1/genética , Complexo Repressor Polycomb 1/metabolismo , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/patologia , Transdução de Sinais
17.
Life Sci ; 253: 117678, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32376267

RESUMO

AIMS: The endoplasmic reticulum (ER) stress response plays a crucial role in the development of nonalcoholic steatohepatitis (NASH). Heme oxygenase-1 (HO-1) exerts beneficial effects against oxidative injury in NASH. This study is aimed to clarify whether HO-1 is an effective therapeutic strategy for NASH via regulation of ER stress. METHODS: The C57BL/6J mice were fed with methionine-choline deficient (MCD) for 4 weeks and high fat-high carbohydrate-high cholesterol (HFD) diet for 16 weeks, with hemin or zinc protoporphyrin IX (ZnPP-IX), respectively. The LO-2 cells were cultured in palmitic medium, with transfected pEX-HO-1 or sh-HO-1 plasmid for 24 h. Meanwhile, thirty NASH patients and 15 health controls were enrolled. The ER ultrastructure was observed by transmission electron microscopy (TEM) and confocal microscopy. The expressions of mRNAs and proteins of HO-1, ER stress related genes were detected by real time PCR, western blot and immunohistochemical staining, respectively. RESULTS: The swelled and broken rough endoplasmic reticulums were observed in MCD and HFD fed mice. The reactive hepatic expression of HO-1 was related with the increased ROS production and ER stress, companied with upregulation of GRP78, p-IRE1, PERK, ATF6. Through hemin administration, hepatocyte apoptosis was suppressed companied down-regulation of CHOP, caspase12 and up-regulation of BCL2. Conserved results were exhibited in ZnPP-IX administrated mice and HO-1 silent cells. Consistent results were observed in the NASH Patients. CONCLUSIONS: HO-1 could serve as a protective factor in the progression of nutritional steatohepatitis by suppresses hepatocyte excessive ER stress and might be a potential target for therapy of nonalcoholic steatohepatitis.


Assuntos
Estresse do Retículo Endoplasmático/fisiologia , Heme Oxigenase-1/genética , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Espécies Reativas de Oxigênio/metabolismo , Animais , Apoptose/fisiologia , Células Cultivadas , Progressão da Doença , Hemina/administração & dosagem , Hepatócitos/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Confocal , Microscopia Eletrônica de Transmissão , Hepatopatia Gordurosa não Alcoólica/genética , Protoporfirinas/administração & dosagem
18.
Am J Kidney Dis ; 76(1): 100-108, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32354559

RESUMO

RATIONALE & OBJECTIVE: Recent studies in the human immunodeficiency virus (HIV)-infected population have suggested that there are genetic predispositions to the development of chronic kidney disease (CKD) in this context. We investigated the association of genetic polymorphisms of the genes encoding apolipoprotein L1 (APOL1), transforming growth factor ß1 (TGF-ß1; a profibrotic cytokine), and heme oxygenase 1 (HMOX1) with prevalent CKD among adults with and without HIV infection. STUDY DESIGN: Case-control study. SETTING & PARTICIPANTS: West African adults including 217 HIV-infected patients with CKD (HIV+/CKD+ group), 595 HIV-infected patients without CKD (HIV+/CKD- group), 269 with CKD and no HIV infection (HIV-/CKD+ group), and 114 with neither CKD nor HIV (HIV-/CKD- group). EXPOSURE: The genetic polymorphisms with reference single-nucleotide polymorphism (rs) identification numbers rs1800469 (TGF-ß1), rs1800470 (TGF-ß1), rs121918282 (TGF-ß1); rs60910145 (APOL1 G1 risk allele), rs73885319 (APOL1 G1 risk allele), rs71785313 (APOL1 G2 risk allele), and rs743811 (HMOX1); HIV. OUTCOME: CKD. ANALYTICAL APPROACH: Single-nucleotide polymorphism (SNP) genotyping of rs1800469 (TGF-ß1), rs1800470 (TGF-ß1), rs121918282 (TGF-ß1); rs60910145 (APOL1), rs73885319 (APOL1), rs71785313 (APOL1), and rs743811 (HMOX1) was performed. Hardy-Weinberg equilibrium was evaluated for all SNPs, and minor allele frequencies were reported. A case-control analysis was performed, and multivariable logistic regression was used to control for potential confounders. RESULTS: Minor allele frequencies for TGF-ß1 (rs1800469, rs1800470, and rs1800471), APOL1 (rs60910145, rs73885319, and rs71785313), and HMOX1 (rs743811) were 0.25, 0.46, 0.46, 0.44, 0.45, 0.17, and 0.14, respectively. Among HIV-positive individuals, only TGF-ß1 rs1800470 (GG vs AA), APOL1 (in the recessive model), and hypertension were associated with prevalent CKD (adjusted ORs of 0.44 [95% CI, 0.20-0.97], 2.54 [95% CI, 1.44-4.51], and 2.17 [95% CI, 1.35-3.48], respectively). No SNP polymorphisms were associated with prevalent CKD among HIV-negative individuals. LIMITATIONS: The lack of histopathology data for proper categorization of the type of HIV-related nephropathy. CONCLUSIONS: APOL1 polymorphisms were highly prevalent in this population and among adult patients infected with HIV and were associated with increased CKD risk. The TGF-ß1 (rs1800470) polymorphism was associated with reduced risk, and HMOX1 polymorphisms were unassociated with CKD.


Assuntos
Apolipoproteína L1/genética , Infecções por HIV/genética , Heme Oxigenase-1/genética , Polimorfismo de Nucleotídeo Único/genética , Insuficiência Renal Crônica/genética , Fator de Crescimento Transformador beta1/genética , Adulto , Idoso , Feminino , Estudos de Associação Genética , Infecções por HIV/diagnóstico , Infecções por HIV/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Nigéria/epidemiologia , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/epidemiologia
19.
Am J Chin Med ; 48(4): 967-985, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32431178

RESUMO

Inflammation and endoplasmic reticulum (ER) stress have been documented to contribute to the development of atherosclerosis. Ginsenoside Rb2 has been reported to exhibit antidiabetic effects. However, the effects of Rb2 on atherosclerotic responses such as inflammation and ER stress in endothelial cells and monocytes remain unclear. In this study, the expression of inflammation and ER stress markers was determined using a Western blotting method. Concentrations of tumor necrosis factor alpha (TNF[Formula: see text]) and monocyte chemoattractant protein-1 (MCP-1) in culture media were assessed by enzyme-linked immunosorbent assay (ELISA) and apoptosis was evaluated by a cell viability assay and a caspase-3 activity measurement kit. We found that exposure of HUVECs and THP-1 monocytes to Rb2 attenuated inflammation and ER stress, resulting in amelioration of apoptosis and THP-1 cell adhesion to HUVECs under lipopolysaccharide (LPS) condition. Increased AMPK phosphorylation and heme oxygenase (HO)-1 expression, including GPR120 expression were observed in Rb2-treated HUVECs and THP-1 monocytes. Downregulation of both, AMPK phosphorylation and HO-1expression rescued these observed changes. Furthermore, GPR120 siRNA mitigated Rb2-induced AMPK phosphorylation. These results suggest that Rb2 inhibits LPS-mediated apoptosis and THP-1 cell adhesion to HUVECs by GPR120/AMPK/HO-1-associated attenuating inflammation and ER stress. Therefore, Rb2 can be used as a potential therapeutic molecule for treatment of atherosclerosis.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Aterosclerose/tratamento farmacológico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/genética , Ginsenosídeos/farmacologia , Ginsenosídeos/uso terapêutico , Lipopolissacarídeos/efeitos adversos , Fitoterapia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Apoptose/efeitos dos fármacos , Apoptose/genética , Aterosclerose/induzido quimicamente , Aterosclerose/genética , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Expressão Gênica/efeitos dos fármacos , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Inflamação , Fosforilação/efeitos dos fármacos , Receptores Acoplados a Proteínas-G/genética , Receptores Acoplados a Proteínas-G/metabolismo , Células THP-1 , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
20.
Chemosphere ; 253: 126654, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32464761

RESUMO

Heme oxygenase-1(HO-1) is a stress-inducible enzyme that mediates antioxidative and cytoprotective effects to maintain cellular redox homeostasis. In the present study, the full sequence of HO-1 was cloned from golden pompano(Trachinotus ovatus) by RT-PCR and RACE-PCR. The full cDNA sequence of HO-1 was 1349 bp in length which comprised of a 726 bp open reading frame (ORF) preceded by 262 bp 5'-untranslated region (UTR), and followed by a 360 bp 3'UTR, encoding 241 amino acid residues. Phylogenetic analysis revealed that HO-1 showed highest similarity to that of Takifugu rubripes. Tissue distribution analysis showed that the expression level of HO-1 was relatively high in heart, liver and spleen. A trial was conducted to investigate the response of Nrf2/HO-1 signaling pathway to oxidative stress induced by copper. The results showed that mRNA expression of NF-E2-related nuclear factor2 (Nrf2), Kelch-like-ECH-associated protein1 (keap1), superoxide dismutase (SOD), catalase (CAT), HO-1, NAD(P)H quinone oxidoreductase 1 (NQO1) and Glutathione peroxidase (GSH-PX) all significantly increased in copper treated group than that in the control group. This work provides new insight into the molecular mechanism underlying the Nrf2/HO-1 pathway in oxidative response in T. ovatus.


Assuntos
Cobre/farmacologia , Heme Oxigenase-1/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Perciformes/metabolismo , Transdução de Sinais , Animais , Antioxidantes/metabolismo , Heme Oxigenase-1/metabolismo , Oxirredutases/metabolismo , Análise de Sequência de DNA , Distribuição Tecidual
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...