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1.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 44(2): 244-252, 2022 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-35538759

RESUMO

Objective To explore the performance and mechanism of(+)-corynoline in treating triple negative breast cancer MDA-MB-436 cells and thus provide an option for the development of drugs against this cancer. Methods The viability,proliferation,apoptosis and migration/invasion of MDA-MB-436 cells treated with(+)-corynoline were detected by CCK-8 assay,colony formation assay,flow cytometry and Transwell assay,respectively.Furthermore,Western blotting was employed to determine the expression of related proteins,and RNA-Seq was performed for the MDA-MB-436 cells treated with(+)-corynoline. Results (+)-corynoline inhibited the proliferation and stemness and promoted the apoptosis of MDA-MB-436 cells.Further,(+)-corynoline may activate the oxidative phosphorylation pathway to play a role in inhibiting triple negative breast cancer. Conclusion (+)-corynoline can inhibit triple negative breast cancer cells,which helps to address the poor efficacy of existing chemotherapeutics and facilitate the development of drugs against this cancer.

2.
Sci Rep ; 11(1): 19749, 2021 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-34611194

RESUMO

Atherosclerosis and its consequences cause considerable morbidity and mortality world-wide. We have previously shown that expression of the DNA glycosylase NEIL3 is regulated in human atherosclerotic plaques, and that NEIL3-deficiency enhances atherogenesis in Apoe-/- mice. Herein, we identified a time point prior to quantifiable differences in atherosclerosis between Apoe-/-Neil3-/- mice and Apoe-/- mice. Mice at this age were selected to explore the metabolic and pathophysiological processes preceding extensive atherogenesis in NEIL3-deficient mice. Untargeted metabolomic analysis of young Apoe-/-Neil3-/- mice revealed significant metabolic disturbances as compared to mice expressing NEIL3, particularly in metabolites dependent on the gut microbiota. 16S rRNA gene sequencing of fecal bacterial DNA indeed confirmed that the NEIL3-deficient mice had altered gut microbiota, as well as increased circulating levels of the bacterially derived molecule LPS. The mice were challenged with a FITC-conjugated dextran to explore gut permeability, which was significantly increased in the NEIL3-deficient mice. Further, immunohistochemistry showed increased levels of the proliferation marker Ki67 in the colonic epithelium of NEIL3-deficient mice, suggesting increased proliferation of intestinal cells and gut leakage. We suggest that these metabolic alterations serve as drivers of atherosclerosis in NEIL3-deficient mice.


Assuntos
Aterosclerose/etiologia , Aterosclerose/metabolismo , Metabolismo Energético , Mucosa Intestinal/metabolismo , N-Glicosil Hidrolases/deficiência , Fatores Etários , Animais , Aterosclerose/patologia , Biomarcadores , Modelos Animais de Doenças , Suscetibilidade a Doenças , Disbiose , Microbioma Gastrointestinal , Predisposição Genética para Doença , Humanos , Imuno-Histoquímica , Camundongos , Camundongos Knockout , Permeabilidade
3.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 43(4): 634-641, 2021 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-34494537

RESUMO

Discoidin domain receptor 1(DDR1)is a critical member of the receptor tyrosine kinase family.It may be related to tumor invasion and metastasis,and the abnormal activation of DDR1 can lead to the occurrence and development of malignant tumors,inflammation,and fibrosis.DDR1 are involved in cell adhesion,migration,proliferation,secretion of cytokines,and remodeling of extracellular matrix,thus playing a critical role in various pathophysiological processes of the human body.In this review,we demonstrate the research progress of DDR1 in breast cancer and other malignant tumors,in order to provide a new theoretical basis for the prevention and treatment of breast cancer and other tumors.


Assuntos
Neoplasias da Mama , Receptor com Domínio Discoidina 1 , Neoplasias da Mama/genética , Adesão Celular , Feminino , Fibrose , Humanos , Receptores Proteína Tirosina Quinases/genética
4.
Eur Heart J ; 42(39): 4064-4072, 2021 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-34405870

RESUMO

AIMS: We recently reported five cases of vaccine-induced immune thrombotic thrombocytopenia (VITT) 7-10 days after receiving the first dose of the ChAdOx1 nCoV-19 adenoviral vector vaccine against corona virus disease 2019 (COVID-19). We aimed to investigate the pathogenic immunological responses operating in these patients. METHODS AND RESULTS: We assessed circulating inflammatory markers by immune assays and immune cell phenotyping by flow cytometry analyses and performed immunoprecipitation with anti-platelet factor (PF)4 antibody in plasma samples followed by mass spectrometry from all five patients. A thrombus was retrieved from the sinus sagittal superior of one patient and analysed by immunohistochemistry and flow cytometry. Precipitated immune complexes revealed multiple innate immune pathway triggers for platelet and leucocyte activation. Plasma contained increased levels of innate immune response cytokines and markers of systemic inflammation, extensive degranulation of neutrophils, and tissue and endothelial damage. Blood analyses showed activation of neutrophils and increased levels of circulating H3Cit, dsDNA, and myeloperoxidase-DNA complex. The thrombus had extensive infiltration of neutrophils, formation of neutrophil extracellular traps (NETs), and IgG deposits. CONCLUSIONS: The results show that anti-PF4/polyanion IgG-mediated thrombus formation in VITT patients is accompanied by a massive innate immune activation and particularly the fulminant activation of neutrophils including NETosis. These results provide novel data on the immune response in this rare adenoviral vector-induced VITT.


Assuntos
COVID-19 , Trombocitopenia , Vacinas , Complexo Antígeno-Anticorpo , Vacinas contra COVID-19 , Humanos , Imunidade Inata , SARS-CoV-2
5.
J Am Heart Assoc ; 10(14): e020656, 2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34259011

RESUMO

Background In cardiovascular diseases, atherosclerotic disorder are the most frequent and important with respect to morbidity and mortality. Inflammation mediated by immune cells is central in all parts of the atherosclerotic progress, and further understanding of the underlying mechanisms is needed. Growing evidence suggests that deamination of adenosine-to-inosine in RNA is crucial for a correct immune response; nevertheless, the role of adenosine-to-inosine RNA editing in atherogenesis has barely been studied. Several proteins have affinity for inosines in RNA, one being ENDOV (endonuclease V), which binds and cleaves RNA at inosines. Data on ENDOV in atherosclerosis are lacking. Methods and Results Quantitative polymerase chain reaction on ENDOV mRNA showed an increased level in human carotid atherosclerotic plaques compared with control veins. Inosine-ribonuclease activity as measured by an enzyme activity assay is detected in immune cells relevant for the atherosclerotic process. Abolishing EndoV in atherogenic apolipoprotein E-deficient (ApoE-/-) mice reduces the atherosclerotic plaque burden, both in size and lipid content. In addition, in a brain stroke model, mice without ENDOV suffer less damage than control mice. Finally, lack of EndoV reduces the recruitment of monocytes to atherosclerotic lesions in atherogenic ApoE-/- mice. Conclusions ENDOV is upregulated in human atherosclerotic lesions, and data from mice suggest that ENDOV promotes atherogenesis by enhancing the monocyte recruitment into the atherosclerotic lesion, potentially by increasing the effect of CCL2 activation on these cells.


Assuntos
Aorta Torácica/patologia , Aterosclerose/genética , Quimiocina CCL2/genética , Desoxirribonuclease (Dímero de Pirimidina)/genética , Regulação da Expressão Gênica , Monócitos/metabolismo , RNA/genética , Idoso , Animais , Aorta Torácica/metabolismo , Aterosclerose/metabolismo , Aterosclerose/patologia , Quimiocina CCL2/biossíntese , Citocinas , Desoxirribonuclease (Dímero de Pirimidina)/biossíntese , Modelos Animais de Doenças , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/patologia , Estudos Retrospectivos
6.
Atherosclerosis ; 324: 123-132, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33714552

RESUMO

BACKGROUND AND AIMS: Atherogenesis involves a complex interaction between immune cells and lipids, processes greatly influenced by the vascular smooth muscle cell (VSMC) phenotype. The DNA glycosylase NEIL3 has previously been shown to have a role in atherogenesis, though whether this is due to its ability to repair DNA damage or to other non-canonical functions is not yet clear. Hereby, we investigate the role of NEIL3 in atherogenesis, specifically in VSMC phenotypic modulation, which is critical in plaque formation and stability. METHODS: Chow diet-fed atherosclerosis-prone Apoe-/- mice deficient in Neil3, and NEIL3-abrogated human primary aortic VSMCs were characterized by qPCR, and immunohistochemical and enzymatic-based assays; moreover, single-cell RNA sequencing, mRNA sequencing, and proteomics were used to map the molecular effects of Neil3/NEIL3 deficiency in the aortic VSMC phenotype. Furthermore, BrdU-based proliferation assays and Western blot were performed to elucidate the involvement of the Akt signaling pathway in the transdifferentiation of aortic VSMCs lacking Neil3/NEIL3. RESULTS: We show that Neil3 deficiency increases atherosclerotic plaque development without affecting systemic lipids. This observation was associated with a shift in VSMC phenotype towards a proliferating, lipid-accumulating and secretory macrophage-like cell phenotype, without changes in DNA damage. VSMC transdifferentiation in Neil3-deficient mice encompassed increased activity of the Akt signaling pathway, supported by cell experiments showing Akt-dependent proliferation in NEIL3-abrogated human primary aortic VSMCs. CONCLUSIONS: Our findings show that Neil3 deficiency promotes atherosclerosis development through non-canonical mechanisms affecting VSMC phenotype involving activation of the Akt signaling pathway.


Assuntos
Aterosclerose , DNA Glicosilases , Miócitos de Músculo Liso/enzimologia , Placa Aterosclerótica , Animais , Aterosclerose/genética , Proliferação de Células , Células Cultivadas , DNA Glicosilases/genética , Endodesoxirribonucleases , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Músculo Liso Vascular/citologia , N-Glicosil Hidrolases , Fenótipo
7.
Gland Surg ; 10(1): 371-377, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33633994

RESUMO

Phyllodes tumor of the breast (PTB) is a rare fibroepithelial breast neoplasm that accounts for less than 1% of breast tumors. Only a few cases related to pregnancy have been reported. It is not known how pregnancy affects the diagnosis, treatment and prognosis of breast tumors. Here we report a case of a 38-year-old female patient with a small, mobile palpable lump in the left breast for about 15 years. it was considered a benign lesion and no surgical treatment was performed at the beginning. The left breast mass became larger suddenly during pregnancy, However, she did not see the doctor and receive any treatment in time. The lump was resected one year after labor and confirmed to be malignant phyllodes of the breast by histopathology and immunohistochemistry. Unfortunately, local recurrence occurred within six months after the first operation, and lung metastasis occurred eight months later. And this patient finally died 13 months after the operation due to tumor progression. This is the first report of pregnancy-related malignant PTB, with local recurrence and distant metastasis in a short period. This case report highlights a situation: the patient should be diagnosed early and treated in time when she has a previous breast fibroadenoma, but suddenly increased during pregnancy.

8.
Int J Mol Sci ; 22(2)2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33467660

RESUMO

Multifactorial metabolic diseases, such as non-alcoholic fatty liver disease, are a major burden to modern societies, and frequently present with no clearly defined molecular biomarkers. Herein we used system medicine approaches to decipher signatures of liver fibrosis in mouse models with malfunction in genes from unrelated biological pathways: cholesterol synthesis-Cyp51, notch signaling-Rbpj, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling-Ikbkg, and unknown lysosomal pathway-Glmp. Enrichment analyses of Kyoto Encyclopedia of Genes and Genomes (KEGG), Reactome and TRANScription FACtor (TRANSFAC) databases complemented with genome-scale metabolic modeling revealed fibrotic signatures highly similar to liver pathologies in humans. The diverse genetic models of liver fibrosis exposed a common transcriptional program with activated estrogen receptor alpha (ERα) signaling, and a network of interactions between regulators of lipid metabolism and transcription factors from cancer pathways and the immune system. The novel hallmarks of fibrosis are downregulated lipid pathways, including fatty acid, bile acid, and steroid hormone metabolism. Moreover, distinct metabolic subtypes of liver fibrosis were proposed, supported by unique enrichment of transcription factors based on the type of insult, disease stage, or potentially, also sex. The discovered novel features of multifactorial liver fibrotic pathologies could aid also in improved stratification of other fibrosis related pathologies.


Assuntos
Ácidos Graxos/metabolismo , Cirrose Hepática/fisiopatologia , Fígado/fisiopatologia , Animais , Ácidos e Sais Biliares/química , Biomarcadores/metabolismo , Modelos Animais de Doenças , Feminino , Fibrose , Genoma , Humanos , Sistema Imunitário , Inflamação , Metabolismo dos Lipídeos , Lipídeos/química , Fígado/metabolismo , Cirrose Hepática/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Transdução de Sinais
9.
Biochem Biophys Res Commun ; 533(4): 631-637, 2020 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-33004177

RESUMO

BACKGROUND: More than 170 post-transcriptional RNA modifications regulate the localization, processing and function of cellular RNAs, and aberrant RNA modifications have been linked to a range of human diseases. The RNA modification landscape in atherosclerosis, the main underlying cause of cardiovascular diseases, is still largely unknown. METHODS: We used mass spectrometry to analyse a selection of RNA-modifying enzymes and the N6-methyladenosine (m6A) in carotid atherosclerotic lesion samples representing early and advanced stages of atherosclerosis as compared to non-atherosclerotic arteries from healthy controls. FINDINGS: (i) the detection of different levels of several enzymes involved in methylations occurring in rRNA and mRNA; (ii) these findings included changes in the levels of methyltransferases ('writers'), binding proteins ('readers') and demethylases ('erasers') during atherosclerosis as compared to non-atherosclerotic control arteries, with generally the most prominent differences in samples from early atherosclerotic lesions; and (iii) these changes were accompanied by a marked downregulation of m6A in rRNA, the most abundant and well-studied modification in mRNA with a wide range of effects on cell biology. INTERPRETATION: We show for the first time that RNA-modifying enzymes and the well-studied RNA modification m6A are differentially regulated in atherosclerotic lesions, which potentially could help creating new prognostic and treatment strategies.


Assuntos
Adenosina/análogos & derivados , Doenças das Artérias Carótidas/metabolismo , Metiltransferases/metabolismo , Placa Aterosclerótica/metabolismo , Processamento Pós-Transcricional do RNA , RNA Mensageiro/metabolismo , RNA Ribossômico/metabolismo , Adenosina/análise , Adenosina/metabolismo , Doenças das Artérias Carótidas/enzimologia , Doenças das Artérias Carótidas/genética , Cromatografia Líquida , Humanos , Metilação , Oxirredutases N-Desmetilantes/metabolismo , Placa Aterosclerótica/enzimologia , Placa Aterosclerótica/genética , Espectrometria de Massas em Tandem
10.
EBioMedicine ; 60: 102985, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32927275

RESUMO

BACKGROUND: During atherogenesis, cholesterol precipitates into cholesterol crystals (CC) in the vessel wall, which trigger plaque inflammation by activating the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome. We investigated the relationship between CC, complement and NLRP3 in patients with cardiovascular disease. METHODS: We analysed plasma, peripheral blood mononuclear cells (PBMC) and carotid plaques from patients with advanced atherosclerosis applying ELISAs, multiplex cytokine assay, qPCR, immunohistochemistry, and gene profiling. FINDINGS: Transcripts of interleukin (IL)-1beta(ß) and NLRP3 were increased and correlated in PBMC from patients with acute coronary syndrome (ACS). Priming of these cells with complement factor 5a (C5a) and tumour necrosis factor (TNF) before incubation with CC resulted in increased IL-1ß protein when compared to healthy controls. As opposed to healthy controls, systemic complement was significantly increased in patients with stable angina pectoris or ACS. In carotid plaques, complement C1q and C5b-9 complex accumulated around CC-clefts, and complement receptors C5aR1, C5aR2 and C3aR1 were higher in carotid plaques compared to control arteries. Priming human carotid plaques with C5a followed by CC incubation resulted in pronounced release of IL-1ß, IL-18 and IL-1α. Additionally, mRNA profiling demonstrated that C5a and TNF priming followed by CC incubation upregulated plaque expression of NLRP3 inflammasome components. INTERPRETATION: We demonstrate that CC are important local- and systemic complement activators, and we reveal that the interaction between CC and complement could exert its effect by activating the NLRP3 inflammasome, thus promoting the progression of atherosclerosis.


Assuntos
Doenças das Artérias Carótidas/etiologia , Doenças das Artérias Carótidas/metabolismo , Colesterol/metabolismo , Proteínas do Sistema Complemento/imunologia , Doença da Artéria Coronariana/etiologia , Doença da Artéria Coronariana/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Transdução de Sinais , Doenças das Artérias Carótidas/patologia , Complemento C5a/imunologia , Biologia Computacional/métodos , Doença da Artéria Coronariana/patologia , Citocinas/metabolismo , Suscetibilidade a Doenças , Perfilação da Expressão Gênica , Humanos , Inflamassomos/metabolismo , Mediadores da Inflamação/metabolismo , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Cristais Líquidos , Placa Aterosclerótica
11.
Europace ; 22(11): 1712-1717, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32830238

RESUMO

AIMS: Accessory pathways (APs) successfully ablated at the aortomitral continuity (AMC) were sporadically reported but relevant data are very limited. We aimed to describe the electrophysiological characteristics of AMC-AP and the related anatomy. METHODS AND RESULTS: This study involved eight (male/female = 3/5, mean age 42.6 ± 10.5 years) patients with left-sided AP successfully ablated in the AMC region. The retrograde atrial activation sequence was analysed and compared via recordings at the His-bundle (HB), coronary sinus (CS), and roving catheter during tachycardia, and the peak of QRS from the same cardiac circle used as time reference. Of the eight patients, two received prior ablations. During tachycardia, the activation time at the proximal CS (CSp), lateral CS (CSl), and HB region averaged 120 ± 26 ms, 124 ± 29 ms, and 117 ± 21 ms following the reference, respectively (P = 0.86). The latest atrial activation was recorded in the posterior CS which averaged 135 ± 25 ms following the reference. Placing the ablation catheter to AMC via retrograde approach was attempted in all cases but stable positioning achieved in none. Via transseptal approach, the ablation catheter could be easily placed at the AMC and recorded the earliest retrograde atrial activations with 60 ± 27 ms earlier than the relatively 'earliest' CS/HB recordings, and ablation at this site successfully eliminated AP conduction. No patients had recovered AP conduction after at least 12-month follow-up. CONCLUSION: AMC-AP is featured by recording comparable retrograde atrial activation times at CSp, CSl, and HB with the latest recordings at the posterior CS. Stable placement and successful ablation in the AMC via retrograde aortic approach was difficult but can be achieved via transseptal approach.


Assuntos
Feixe Acessório Atrioventricular , Ablação por Cateter , Feixe Acessório Atrioventricular/cirurgia , Adulto , Eletrocardiografia , Feminino , Átrios do Coração/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Taquicardia
12.
Nucleic Acids Res ; 48(8): 4463-4479, 2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32083667

RESUMO

Endonuclease V (EndoV) is a conserved inosine-specific ribonuclease with unknown biological function. Here, we present the first mouse model lacking EndoV, which is viable without visible abnormalities. We show that endogenous murine EndoV cleaves inosine-containing RNA in vitro, nevertheless a series of experiments fails to link an in vivo function to processing of such transcripts. As inosine levels and adenosine-to-inosine editing often are dysregulated in hepatocellular carcinoma (HCC), we chemically induced HCC in mice. All mice developed liver cancer, however, EndoV-/- tumors were significantly fewer and smaller than wild type tumors. Opposed to human HCC, adenosine deaminase mRNA expression and site-specific editing were unaltered in our model. Loss of EndoV did not affect editing levels in liver tumors, however mRNA expression of a selection of cancer related genes were reduced. Inosines are also found in certain tRNAs and tRNAs are cleaved during stress to produce signaling entities. tRNA fragmentation was dysregulated in EndoV-/- livers and apparently, inosine-independent. We speculate that the inosine-ribonuclease activity of EndoV is disabled in vivo, but RNA binding allowed to promote stabilization of transcripts or recruitment of proteins to fine-tune gene expression. The EndoV-/- tumor suppressive phenotype calls for related studies in human HCC.


Assuntos
Desoxirribonuclease (Dímero de Pirimidina)/genética , Neoplasias Hepáticas Experimentais/genética , Adenosina/metabolismo , Animais , Antineoplásicos/farmacologia , Carcinogênese , Linhagem Celular , Desoxirribonuclease (Dímero de Pirimidina)/metabolismo , Expressão Gênica , Humanos , Inosina/metabolismo , Fígado/metabolismo , Neoplasias Hepáticas Experimentais/induzido quimicamente , Neoplasias Hepáticas Experimentais/metabolismo , Neoplasias Hepáticas Experimentais/patologia , Camundongos Knockout , Edição de RNA , RNA de Transferência/metabolismo , Análise de Sequência de RNA , Sorafenibe/farmacologia
13.
Atherosclerosis ; 296: 74-82, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31870625

RESUMO

BACKGROUND AND AIMS: We have previously found increased levels of the cysteine protease legumain in plasma and plaques from patients with carotid atherosclerosis. This study further investigated legumain during acute cardiovascular events. METHODS: Circulating levels of legumain from patients and legumain released from platelets were assessed by enzyme-linked-immunosorbent assay. Quantitative PCR and immunoblotting were used to study expression, while localization was visualized by immunohistochemistry. RESULTS: In the SUMMIT Malmö cohort (n = 339 with or without type 2 diabetes and/or cardiovascular disease [CVD], and 64 healthy controls), the levels of circulating legumain were associated with the presence of CVD in non-diabetics, with no relation to outcome. In symptomatic carotid plaques and in samples from both coronary and intracerebral thrombi obtained during acute cardiovascular events, legumain was co-localized with macrophages in the same regions as platelets. In vitro, legumain was shown to be present in and released from platelets upon activation. In addition, THP-1 macrophages exposed to releasate from activated platelets showed increased legumain expression. Interestingly, primary peripheral blood mononuclear cells stimulated with recombinant legumain promoted anti-inflammatory responses. Finally, in a STEMI population (POSTEMI; n = 272), patients had significantly higher circulating legumain before and immediately after percutaneous coronary intervention compared with healthy controls (n = 67), and high levels were associated with improved outcome. CONCLUSIONS: Our data demonstrate for the first time that legumain is upregulated during acute cardiovascular events and is associated with improved outcome.


Assuntos
Doenças Cardiovasculares/metabolismo , Cisteína Endopeptidases/biossíntese , Macrófagos/enzimologia , Infarto do Miocárdio com Supradesnível do Segmento ST/sangue , Doença Aguda , Sequência de Aminoácidos , Plaquetas/metabolismo , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/patologia , Doenças das Artérias Carótidas/metabolismo , Doenças das Artérias Carótidas/patologia , Estudos Transversais , Cisteína Endopeptidases/sangue , Cisteína Endopeptidases/genética , Cisteína Endopeptidases/farmacologia , Citocinas/farmacologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Seguimentos , Humanos , Lipopolissacarídeos/farmacologia , Monócitos/efeitos dos fármacos , Intervenção Coronária Percutânea , Placa Aterosclerótica/química , Ativação Plaquetária , Proteínas Recombinantes/farmacologia , Infarto do Miocárdio com Supradesnível do Segmento ST/mortalidade , Infarto do Miocárdio com Supradesnível do Segmento ST/cirurgia , Suécia/epidemiologia , Células THP-1
14.
Pain ; 161(2): 338-350, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31651577

RESUMO

Two recent studies suggest that experimental pain sensitivity is associated with low-grade systemic inflammation. However, only 2 biomarkers have been identified, and the studies were conducted in adult individuals where confounding effects of comorbid diseases cannot be excluded. We therefore tested associations between pain sensitivity and 119 inflammation-related serum biomarkers in 827 healthy adolescents (15-19 years) in the population-based Tromsø Study: Fit Futures. The main outcome measure was cold-pressor pain tolerance (CPT), tested by placing the dominant hand in circulating cold (3°C) water for a maximum of 105 seconds. Secondary outcomes were heat and pressure pain threshold and tolerance. Twelve proteins and 6 fatty acids were significantly associated with CPT after adjustment for possible confounding factors and correction for multiple comparisons. Of these, all fatty acids and 10 proteins were protective, ie, higher biomarkers levels were associated with increased CPT, whereas 2 biomarkers were associated with lower tolerance. Taken together, these biomarkers predicted completion of the tolerance test with a C-statistic of 0.65. Results for heat and pressure pain tolerance were remarkably similar, strengthening the generalizability of our findings. In this cohort of young healthy individuals, we found a relationship between inflammation-related biomarkers and pain tolerance and thresholds. Biomarkers with anti-inflammatory and analgesic effects predominated, suggesting that the development of prophylactic dietary or pharmaceutical treatments may be possible.


Assuntos
Citocinas/metabolismo , Ácidos Graxos/metabolismo , Inflamação/metabolismo , Limiar da Dor/fisiologia , Dor/metabolismo , Adolescente , Biomarcadores/metabolismo , Temperatura Baixa , Feminino , Temperatura Alta , Humanos , Masculino , Pressão , Modelos de Riscos Proporcionais , Adulto Jovem
15.
Am J Transplant ; 19(4): 1050-1060, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30312541

RESUMO

Cardiac allograft vasculopathy (CAV) causes heart failure after heart transplantation (HTx), but its pathogenesis is incompletely understood. Notch signaling, possibly modulated by everolimus (EVR), is essential for processes involved in CAV. We hypothesized that circulating Notch ligands would be dysregulated after HTx. We studied circulating delta-like Notch ligand 1 (DLL1) and periostin (POSTN) and CAV in de novo HTx recipients (n = 70) randomized to standard or EVR-based, calcineurin inhibitor-free immunosuppression and in maintenance HTx recipients (n = 41). Compared to healthy controls, plasma DLL1 and POSTN were elevated in de novo (P < .01; P < .001) and maintenance HTx recipients (P < .001; P < .01). Use of EVR was associated with a treatment effect for DLL1. For de novo HTx recipients, a change in DLL1 correlated with a change in CAV at 1 (P = .021) and 3 years (P = .005). In vitro, activation of T cells increased DLL1 secretion, attenuated by EVR. In vitro data suggest that also endothelial cells and vascular smooth muscle cells (VSMCs) could contribute to circulating DLL1. Immunostaining of myocardial specimens showed colocalization of DLL1 with T cells, endothelial cells, and VSMCs. Our findings suggest a role of DLL1 in CAV progression, and that the beneficial effect of EVR on CAV could reflect a suppressive effect on DLL1. Trial registration numbers-SCHEDULE trial: ClinicalTrials.gov NCT01266148; NOCTET trial: ClinicalTrials.gov NCT00377962.


Assuntos
Everolimo/uso terapêutico , Transplante de Coração/efeitos adversos , Imunossupressores/uso terapêutico , Peptídeos e Proteínas de Sinalização Intracelular/sangue , Proteínas de Membrana/sangue , Doenças Vasculares/etiologia , Adulto , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
16.
J Am Heart Assoc ; 7(2)2018 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-29330254

RESUMO

BACKGROUND: Soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1) has been shown to be increased in patients with acute ischemic stroke. Here, we evaluated plasma sLOX-1 levels and vascular carotid plaque LOX-1 (ie, OLR1) gene expression in patients with ischemic stroke and transient ischemic attack (TIA) with particular focus on their relation to time since symptom onset. METHODS AND RESULTS: Plasma sLOX-1 (n=232) and carotid plaque OLR1 gene expression (n=146) were evaluated in patients who were referred to evaluation for carotid endarterectomy, as well as in healthy control plasma (n=81). Patients were categorized according to presence of acute ischemic stroke or transient ischemic attack (n=35) ≤7 days, >7 days ≤3 months (n=90), >3 months (n=40), or no reported symptoms before study inclusion (n=67). Our major findings were the following: (1) Patients with carotid atherosclerosis had increased plasma sLOX-1 levels as compared with controls. (2) Plaque OLR1 mRNA levels were increased in carotid plaques (n=146) compared with nonatherosclerotic vessels (ie, common iliac arteries of organ donors, n=10). (3) There were no differences in sLOX plasma levels or OLR1 gene expression when analyzed according to the time since relevant cerebral ischemic symptoms. (4) Also patients with severe carotid atherosclerosis without any previous ischemic events had raised sLOX-1 levels. (5) Immunostaining showed colocalization between LOX-1 and macrophages within the carotid plaques. (6) Also patients with acute stroke (within 7 days) caused by atrial fibrillation (n=22) had comparable raised sLOX-1 levels. CONCLUSIONS: sLOX-1 levels are elevated in patients with ischemic stroke and transient ischemic attack independent of cause and time since the ischemic event.


Assuntos
Isquemia Encefálica/sangue , Doenças das Artérias Carótidas/sangue , Ataque Isquêmico Transitório/sangue , Receptores Depuradores Classe E/sangue , Acidente Vascular Cerebral/sangue , Idoso , Biomarcadores/sangue , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/genética , Doenças das Artérias Carótidas/diagnóstico , Doenças das Artérias Carótidas/genética , Estudos de Casos e Controles , Feminino , Humanos , Ataque Isquêmico Transitório/diagnóstico , Ataque Isquêmico Transitório/genética , Masculino , Pessoa de Meia-Idade , Placa Aterosclerótica , Medição de Risco , Fatores de Risco , Receptores Depuradores Classe E/genética , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/genética , Regulação para Cima
17.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 38(2): 222-7, 2016 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-27181902

RESUMO

The pathogenesis of acute brain ischemia is very complex, involving multiple mechanisms including excessive free radical generation. Oxidative stress means the imbalance between the generation and removal of free radicals. Once acute brain ischemia occurs, the reactive oxygen species interact with large numbers of biomacromolecules, irreversibly change or destroy the functions of cellular lipids, proteins, and nucleic acids, and thus initiate cell signaling pathways. However, the molecular biological characteristics of oxidative stress and the way to prevent and treat acute brain ischemia still need further investigations.


Assuntos
Isquemia Encefálica/fisiopatologia , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Isquemia Encefálica/metabolismo , Humanos , Transdução de Sinais
18.
Artigo em Inglês | MEDLINE | ID: mdl-27141234

RESUMO

BACKGROUND: Mice lacking glycosylated lysosomal membrane protein (Glmp (gt/gt) mice) have liver fibrosis as the predominant phenotype due to chronic liver injury. The Glmp (gt/gt) mice grow and reproduce at the same rate as their wild-type siblings. Life expectancy is around 18 months. METHODS: Wild-type and Glmp (gt/gt) mice were studied between 1 week and 18 months of age. Livers were analyzed using histological, immunohistochemical, biochemical, and qPCR analyses. RESULTS: It was shown that Glmp (gt/gt) mice were not born with liver injury; however, it appeared shortly after birth as indicated by excess collagen expression, deposition of fibrous collagen in the periportal areas, and increased levels of hydroxyproline in Glmp (gt/gt) liver. Liver functional tests indicated a chronic, mild liver injury. Markers of inflammation, fibrosis, apoptosis, and modulation of extracellular matrix increased from an early age, peaking around 4 months of age and followed by attenuation of these signals. To compensate for loss of hepatocytes, the oval cell compartment was activated, with the highest activity of the oval cells detected at 3 months of age, suggesting insufficient hepatocyte proliferation in Glmp (gt/gt) mice around this age. Although constant proliferation of hepatocytes and oval cells maintained adequate hepatic function in Glmp (gt/gt) mice, it also resulted in a higher frequency of liver tumors in older animals. CONCLUSIONS: The Glmp (gt/gt) mouse is proposed as a model for slowly progressing liver fibrosis and possibly as a model for a yet undescribed human lysosomal disorder.

19.
Arch Physiol Biochem ; 122(1): 36-45, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26707125

RESUMO

Glycosylated lysosomal membrane protein (GLMP) has been reported to enhance the expression from a peroxisome proliferator-activated receptor alpha (PPARα) responsive promoter, but also to be an integral lysosomal membrane protein. Using myotubes established from wild-type and Glmp(gt/gt) mice, the importance of GLMP in skeletal muscle was examined. Glmp(gt/gt) myotubes expressed a more glycolytic phenotype than wild-type myotubes. Myotubes from Glmp(gt/gt) mice metabolized glucose faster and had a larger pool of intracellular glycogen, while oleic acid uptake, storage and oxidation were significantly reduced. Gene expression analyses indicated lower expression of three PPAR-isoforms, a co-regulator of PPAR (PGC1α) and several genes important for lipid metabolism in Glmp(gt/gt) myotubes. However, ablation of GLMP did not seem to substantially impair the response to PPAR agonists. In conclusion, myotubes established from Glmp(gt/gt) mice were more glycolytic than myotubes from wild-type animals, in spite of no differences in muscle fiber types in vivo.


Assuntos
Ácidos Graxos/metabolismo , Deleção de Genes , Glucose/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Masculino , Proteínas de Membrana/deficiência , Camundongos , Fibras Musculares Esqueléticas/citologia , Fibras Musculares Esqueléticas/efeitos dos fármacos , Músculo Esquelético/citologia , Músculo Esquelético/metabolismo , Ácido Oleico/metabolismo , Oxirredução/efeitos dos fármacos , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Receptores Ativados por Proliferador de Peroxissomo/metabolismo
20.
PLoS One ; 10(6): e0129402, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26047317

RESUMO

Ablation of glycosylated lysosomal membrane protein (GLMP, formerly known as NCU-G1) has been shown to cause chronic liver injury which progresses into liver fibrosis in mice. Both lysosomal dysfunction and chronic liver injury can cause metabolic dysregulation. Glmp gt/gt mice (formerly known as Ncu-g1gt/gt mice) were studied between 3 weeks and 9 months of age. Body weight gain and feed efficiency of Glmp gt/gt mice were comparable to wild type siblings, only at the age of 9 months the Glmp gt/gt siblings had significantly reduced body weight. Reduced size of epididymal fat pads was accompanied by hepatosplenomegaly in Glmp gt/gt mice. Blood analysis revealed reduced levels of blood glucose, circulating triacylglycerol and non-esterified fatty acids in Glmp gt/gt mice. Increased flux of glucose, increased de novo lipogenesis and lipid accumulation were detected in Glmp gt/gt primary hepatocytes, as well as elevated triacylglycerol levels in Glmp gt/gt liver homogenates, compared to hepatocytes and liver from wild type mice. Gene expression analysis showed an increased expression of genes involved in fatty acid uptake and lipogenesis in Glmp gt/gt liver compared to wild type. Our findings are in agreement with the metabolic alterations observed in other mouse models lacking lysosomal proteins, and with alterations characteristic for advanced chronic liver injury.


Assuntos
Lipogênese/genética , Fígado/metabolismo , Lisossomos/metabolismo , Proteínas de Membrana/genética , Tecido Adiposo/metabolismo , Animais , Glicemia/metabolismo , Western Blotting , Células Cultivadas , Epididimo/metabolismo , Ácidos Graxos/sangue , Expressão Gênica , Transportador de Glucose Tipo 2/genética , Transportador de Glucose Tipo 2/metabolismo , Hepatócitos/metabolismo , Hepatomegalia/sangue , Hepatomegalia/genética , Metabolismo dos Lipídeos/genética , Fígado/patologia , Masculino , Proteínas de Membrana/metabolismo , Camundongos Knockout , /metabolismo , Piruvato Desidrogenase Quinase de Transferência de Acetil , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Esplenomegalia/sangue , Esplenomegalia/genética , Triglicerídeos/sangue , Ganho de Peso/genética
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