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1.
Ren Fail ; 46(2): 2370439, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38938194

RESUMO

BACKGROUND: Chronic kidney disease (CKD) poses a significant public health challenge globally while impacting patients' physical function and quality of life. Addressing the issues of physical inactivity and pain management is essential during treatment to improve health-related quality of life. The present study investigated the effect of an aerobic training program with core stabilization exercises for hemodialysis (HD) patients on a transplant waiting list and renal transplant (RTx) patients. METHODS: A total of 45 patients with CKD were included in the 12-week study: 25 patients receiving HD (12 HD treatment group, 13 HD control group) and 20 patients with RTx (9 RTx treatment group, 11 RTx control group). Functional capacity was measured using the 6-min walk test, pain was measured using the visual analog scale, and health-related quality of life was measured using the Kidney Disease Quality of Life-Short Form 12 questionnaire. Nonparametric statistical tests were performed at a significance level of 0.05. RESULTS: Both the HD and RTx treatment groups showed significantly reduced times for the 6-min walking test (p = 0.002 and p = 0.008, respectively), significantly reduced pain severity (p = 0.002 and p = 0.008, respectively), and significantly improved quality of life scores (p = 0.006 and p = 0.041, respectively) by the end of the study compared with control groups. CONCLUSION: Based on the results, structured exercise programs could be effective therapies in CKD management. Therefore, health providers should promote their integration into routine care practices to enhance patient outcomes and well-being.


Assuntos
Terapia por Exercício , Transplante de Rim , Qualidade de Vida , Diálise Renal , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Terapia por Exercício/métodos , Adulto , Insuficiência Renal Crônica/terapia , Exercício Físico , Idoso , Manejo da Dor/métodos , Teste de Caminhada , Medição da Dor , Inquéritos e Questionários
2.
Ren Fail ; 45(1): 2203776, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37125610

RESUMO

In light chain amyloidosis (LA), the massive glomerular and vascular amyloid deposition leading to interstitial fibrosis/tubular atrophy (IFTA) is thought to be responsible for renal failure. The amyloid deposition in the interstitium and the tubular basement membrane (TBM) has received less attention in the study of LA. We, therefore, collected clinical and laboratory data on patients diagnosed with LA in our Nephrology Department and studied amyloid deposition in the TBM. Twelve LA patients were diagnosed by renal biopsy during a seven-year period. In 4 of the 12, amyloid deposition could also be detected in the TBM. In our first case of a patient with diabetes mellitus, non-amyloid fibrils resembling 'diabetic fibrillosis' were also seen by electron microscopy. Despite the double damage, IFTA was negligible, blood vessels were unaffected, and the glomerular deposition was segmental. In the other three cases, significant (>50%) IFTA and a severely reduced estimated glomerular filtration rate were already detected at the time of diagnosis and amyloid deposition was also observed in the blood vessels. These findings indicate the importance of TBM amyloid deposition in the progression of renal disease. This may represent a late-stage presentation of the disease with a heavy LC burden.


Assuntos
Amiloidose , Nefropatias , Humanos , Rim/patologia , Amiloidose/diagnóstico , Amiloidose/patologia , Nefropatias/diagnóstico , Nefropatias/patologia , Glomérulos Renais/patologia , Membrana Basal/patologia
3.
Int J Mol Sci ; 24(5)2023 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-36902231

RESUMO

Macrophages express the A subunit of coagulation factor XIII (FXIII-A), a transglutaminase which cross-links proteins through Nε-(γ-L-glutamyl)-L-lysyl iso-peptide bonds. Macrophages are major cellular constituents of the atherosclerotic plaque; they may stabilize the plaque by cross-linking structural proteins and they may become transformed into foam cells by accumulating oxidized LDL (oxLDL). The combination of oxLDL staining by Oil Red O and immunofluorescent staining for FXIII-A demonstrated that FXIII-A is retained during the transformation of cultured human macrophages into foam cells. ELISA and Western blotting techniques revealed that the transformation of macrophages into foam cells elevated the intracellular FXIII-A content. This phenomenon seems specific for macrophage-derived foam cells; the transformation of vascular smooth muscle cells into foam cells fails to induce a similar effect. FXIII-A containing macrophages are abundant in the atherosclerotic plaque and FXIII-A is also present in the extracellular compartment. The protein cross-linking activity of FXIII-A in the plaque was demonstrated using an antibody labeling the iso-peptide bonds. Cells showing combined staining for FXIII-A and oxLDL in tissue sections demonstrated that FXIII-A-containing macrophages within the atherosclerotic plaque are also transformed into foam cells. Such cells may contribute to the formation of lipid core and the plaque structurization.


Assuntos
Aterosclerose , Fator XIII , Placa Aterosclerótica , Humanos , Aterosclerose/metabolismo , Fator XIII/metabolismo , Células Espumosas/metabolismo , Lipoproteínas LDL/metabolismo , Macrófagos/metabolismo , Peptídeos/metabolismo , Placa Aterosclerótica/metabolismo
4.
Physiol Genomics ; 54(11): 457-469, 2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-36250559

RESUMO

The vast majority of studies focusing on the effects of endurance exercise on hematological parameters and leukocyte gene expression were performed in adult men, so our aim was to investigate these changes in young females. Four young (age 15.3 ± 1.3 yr) elite female athletes completed an exercise session, in which they accomplished the cycling and running disciplines of a junior triathlon race. Blood samples were taken immediately before the exercise, right after the exercise, and then 1, 2, and 7 days later. Analysis of cell counts and routine biochemical parameters were complemented by RNA sequencing (RNA-seq) to whole blood samples. The applied exercise load did not trigger remarkable changes in either cardiovascular or biochemical parameters; however, it caused a significant increase in the percentage of neutrophils and a significant reduction in the ratio of lymphocytes immediately after exercise. Furthermore, endurance exercise induced a characteristic gene expression pattern change in the blood transcriptome. Gene set enrichment analysis (GSEA) using the Reactome database revealed that the expression of genes involved in immune processes and neutrophil granulocyte activation was upregulated, whereas the expression of genes important in translation and rRNA metabolism was downregulated. Comparison of a set of immune cell gene signatures (ImSig) and our transcriptomic data identified 15 overlapping genes related to T-cell functions and involved in podosome formation and adhesion to the vessel wall. Our results suggest that RNA-seq to whole blood together with ImSig analysis are useful tools for the investigation of systemic responses to endurance exercise.


Assuntos
Corrida , Transcriptoma , Masculino , Humanos , Feminino , Adolescente , Transcriptoma/genética , Resistência Física/genética , Projetos Piloto , Atletas , Corrida/fisiologia
5.
Int J Mol Sci ; 23(15)2022 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-35955444

RESUMO

Given the abundance of heme proteins (cytochromes) in the mitochondrion, it is evident that a meticulously orchestrated iron metabolism is essential for cardiac health. Here, we examined the functional significance of myocardial ferritin heavy chain (FtH) in a model of acute myocardial infarction. We report that FtH deletion did not alter either the mitochondrial regulatory and surveillance pathways (fission and fusion) or mitochondrial bioenergetics in response to injury. Furthermore, deletion of myocardial FtH did not affect cardiac function, assessed by measurement of left ventricular ejection fraction, on days 1, 7, and 21 post injury. To identify the modulated pathways providing cardiomyocyte protection coincident with FtH deletion, we performed unbiased transcriptomic analysis. We found that following injury, FtH deletion was associated with upregulation of several genes with anti-ferroptotic properties, including heme oxygenase-1 (HO-1) and the cystine/glutamate anti-porter (Slc7a11). These results suggested that HO-1 overexpression mitigates ferroptosis via upregulation of Slc7a11. Indeed, using transgenic mice with HO-1 overexpression, we demonstrate that overexpressed HO-1 is coupled with increased Slc7a11 expression. In conclusion, we demonstrate that following injury, myocardial FtH deletion leads to a compensatory upregulation in a number of anti-ferroptotic genes, including HO-1. Such HO-1 induction leads to overexpression of Slc7a11 and protects the heart against ischemia-reperfusion-mediated ferroptosis, preserves mitochondrial function, and overall function of the myocardium.


Assuntos
Apoferritinas , Heme Oxigenase-1/metabolismo , Proteínas de Membrana/metabolismo , Animais , Apoferritinas/genética , Heme Oxigenase (Desciclizante)/metabolismo , Heme Oxigenase-1/genética , Camundongos , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Volume Sistólico , Função Ventricular Esquerda
6.
Ren Fail ; 43(1): 335-339, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33567947

RESUMO

The introduction of Bruton's tyrosine kinase inhibitor ibrutinib has made a significant progress in the treatment of chronic lymphocytic leukemia and other B-cell malignancies. Due to the reduction of cytokine release, it is effective in chronic graft-versus-host disease, and its use has also been suggested in autoimmune diseases and in prevention of COVID-19-associated lung damage. Despite this effect on the immune response, we report a severe hypersensitivity reaction in a 76-year-old male patient diagnosed with prolymphocytic leukemia. Four weeks after the ibrutinib start, non-oliguric acute kidney injury with proteinuria and microscopic hematuria developed and that was accompanied by lower limb purpuras and paresthesia. Renal biopsy revealed acute interstitial nephritis. Employing 1 mg/kg methylprednisolone administration, serum creatinine decreased from 365 µmol/L to 125 µmol/L at 11 days and the proteinuria-hematuria as well as the purpura, paresthesia resolved. Three months later at stabile eGFR of 56 ml/min/1.73 m2 methylprednisolone was withdrawn and a rituximab-venetoclax treatment was initiated without side effects. We conclude that despite the beneficial effect on cytokines response in Th1 direction, ibrutinib can cause acute interstitial nephritis. Early detection, discontinuation of ibrutinib, glucocorticoid administration may help to better preserve renal function, thereby lowering the risk of potential subsequent kidney injury.


Assuntos
Injúria Renal Aguda/induzido quimicamente , Adenina/análogos & derivados , Nefrite Intersticial/induzido quimicamente , Piperidinas/efeitos adversos , Proteinúria/induzido quimicamente , Injúria Renal Aguda/tratamento farmacológico , Adenina/efeitos adversos , Idoso , Citocinas/efeitos dos fármacos , Glucocorticoides/uso terapêutico , Humanos , Rim/patologia , Leucemia Prolinfocítica/tratamento farmacológico , Masculino , Nefrite Intersticial/tratamento farmacológico , Inibidores de Proteínas Quinases , Proteinúria/tratamento farmacológico
7.
Int J Mol Sci ; 22(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34360940

RESUMO

With iron at its core, the tetrapyrrole heme ring is a cardinal prosthetic group made up of many proteins that participate in a wide array of cellular functions and metabolism. Once released, due to its pro-oxidant properties, free heme in sufficient amounts can result in injurious effects to the kidney and other organs. Heme oxygenase-1 (HO-1) has evolved to promptly attend to such injurious potential by facilitating degradation of heme into equimolar amounts of carbon monoxide, iron, and biliverdin. HO-1 induction is a beneficial response to tissue injury in diverse animal models of diseases, including those that affect the kidney. These protective attributes are mainly due to: (i) prompt degradation of heme leading to restraining potential hazardous effects of free heme, and (ii) generation of byproducts that along with induction of ferritin have proven beneficial in a number of pathological conditions. This review will focus on describing clinical aspects of some of the conditions with the unifying end-result of increased heme burden and will discuss the molecular mechanisms that ensue to protect the kidneys.


Assuntos
Heme/metabolismo , Hemoglobinúria/metabolismo , Nefropatias/metabolismo , Rabdomiólise/metabolismo , Animais , Ferritinas/metabolismo , Heme/urina , Heme Oxigenase-1/metabolismo , Hemoglobinúria/patologia , Humanos , Nefropatias/patologia , Rabdomiólise/patologia
8.
Int J Mol Sci ; 22(17)2021 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-34502172

RESUMO

Vascular calcification associated with high plasma phosphate (Pi) level is a frequent complication of hyperglycemia, diabetes mellitus, and chronic kidney disease. BGP-15 is an emerging anti-diabetic drug candidate. This study was aimed to explore whether BGP-15 inhibits high Pi-induced calcification of human vascular smooth muscle cells (VSMCs) under normal glucose (NG) and high glucose (HG) conditions. Exposure of VSMCs to Pi resulted in accumulation of extracellular calcium, elevated cellular Pi uptake and intracellular pyruvate dehydrogenase kinase-4 (PDK-4) level, loss of smooth muscle cell markers (ACTA, TAGLN), and enhanced osteochondrogenic gene expression (KLF-5, Msx-2, Sp7, BMP-2). Increased Annexin A2 and decreased matrix Gla protein (MGP) content were found in extracellular vesicles (EVs). The HG condition markedly aggravated Pi-induced VSMC calcification. BGP-15 inhibited Pi uptake and PDK-4 expression that was accompanied by the decreased nuclear translocation of KLF-5, Msx-2, Sp7, retained VSMC markers (ACTA, TAGLN), and decreased BMP-2 in both NG and HG conditions. EVs exhibited increased MGP content and decreased Annexin A2. Importantly, BGP-15 prevented the deposition of calcium in the extracellular matrix. In conclusion, BGP-15 inhibits Pi-induced osteochondrogenic phenotypic switch and mineralization of VSMCs in vitro that make BGP-15 an ideal candidate to attenuate both diabetic and non-diabetic vascular calcification.


Assuntos
Hiperglicemia/metabolismo , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Oximas/farmacologia , Fosfatos/metabolismo , Piperidinas/farmacologia , Calcificação Vascular/etiologia , Calcificação Vascular/metabolismo , Biomarcadores , Glicemia , Células Cultivadas , Matriz Extracelular/metabolismo , Regulação da Expressão Gênica , Hiperglicemia/sangue , Osteoblastos/metabolismo , Fosfatos/efeitos adversos , Calcificação Vascular/tratamento farmacológico
9.
Int J Mol Sci ; 22(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206377

RESUMO

Infiltration of red blood cells into atheromatous plaques and oxidation of hemoglobin (Hb) and lipoproteins are implicated in the pathogenesis of atherosclerosis. α1-microglobulin (A1M) is a radical-scavenging and heme-binding protein. In this work, we examined the origin and role of A1M in human atherosclerotic lesions. Using immunohistochemistry, we observed a significant A1M immunoreactivity in atheromas and hemorrhaged plaques of carotid arteries in smooth muscle cells (SMCs) and macrophages. The most prominent expression was detected in macrophages of organized hemorrhage. To reveal a possible inducer of A1M expression in ruptured lesions, we exposed aortic endothelial cells (ECs), SMCs and macrophages to heme, Oxy- and FerrylHb. Both heme and FerrylHb, but not OxyHb, upregulated A1M mRNA expression in all cell types. Importantly, only FerrylHb induced A1M protein secretion in aortic ECs, SMCs and macrophages. To assess the possible function of A1M in ruptured lesions, we analyzed Hb oxidation and heme-catalyzed lipid peroxidation in the presence of A1M. We showed that recombinant A1M markedly inhibited Hb oxidation and heme-driven oxidative modification of low-density lipoproteins as well plaque lipids derived from atheromas. These results demonstrate the presence of A1M in atherosclerotic plaques and suggest its induction by heme and FerrylHb in the resident cells.


Assuntos
alfa-Globulinas/metabolismo , Aterosclerose/etiologia , Aterosclerose/metabolismo , Heme/metabolismo , Hemoglobinas/metabolismo , Peroxidação de Lipídeos , Oxirredução , Aterosclerose/patologia , Biomarcadores , Doenças das Artérias Carótidas/etiologia , Doenças das Artérias Carótidas/metabolismo , Doenças das Artérias Carótidas/patologia , Células Cultivadas , Progressão da Doença , Suscetibilidade a Doenças , Hemorragia/metabolismo , Hemorragia/patologia , Humanos , Imuno-Histoquímica , Miócitos de Músculo Liso/metabolismo , Placa Aterosclerótica/etiologia , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patologia
10.
Lab Invest ; 100(7): 986-1002, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32054994

RESUMO

The lysis of red blood cells was shown to occur in human ruptured atherosclerotic lesions and intraventricular hemorrhage (IVH) of the brain. Liberated cell-free hemoglobin was found to undergo oxidation in both pathologies. We hypothesize that hemoglobin-derived peptides are generated during hemoglobin oxidation both in complicated atherosclerotic lesions and IVH of the brain, triggering endothelial cell dysfunction. Oxidized hemoglobin and its products were followed with spectrophotometry, LC-MS/MS analysis and detection of the cross-linking of globin chains in complicated atherosclerotic lesions of the human carotid artery and the hemorrhaged cerebrospinal liquid of preterm infants. The vascular pathophysiologic role of oxidized hemoglobin and the resultant peptides was assessed by measuring endothelial integrity, the activation of endothelial cells and the induction of proinflammatory genes. Peptide fragments of hemoglobin (VNVDEVGGEALGRLLVVYPWTQR, LLVVYPWTQR, MFLSFPTTK, VGAHAGEYGAELERMFLSFPTTK, and FLASVSTVLTSKYR) were identified in ruptured atherosclerotic lesions and in IVH of the human brain. Fragments resulting from the oxidation of hemoglobin were accompanied by the accumulation of ferryl hemoglobin. Similar to complicated atherosclerotic lesions of the human carotid artery, a high level of oxidized and cross-linked hemoglobin was observed in the cerebrospinal fluid after IVH. Haptoglobin inhibited hemoglobin fragmentation provoked by peroxide. The resultant peptides failed to bind haptoglobin or albumin. Peptides derived from hemoglobin oxidation and ferryl hemoglobin induced intercellular gap formation, decreased junctional resistance in the endothelium, and enhanced monocyte adhesion to endothelial cells. Enhanced expression of TNF and the activation of NLRP3 and CASP1 followed by the increased generation of IL-1ß and nuclear translocation of the NF-κß transcription factor occurred in response to hemoglobin-derived peptides, and ferryl hemoglobin in endothelium was upregulated in both pathologies. We conclude that the oxidation of hemoglobin in complicated atherosclerotic lesions and intraventricular hemorrhage of the brain generates peptide fragments and ferryl hemoglobin with the potential to trigger endothelial cell dysfunction.


Assuntos
Doenças das Artérias Carótidas/metabolismo , Hemorragia Cerebral Intraventricular/metabolismo , Endotélio Vascular/fisiopatologia , Hemoglobinas , Encéfalo/metabolismo , Encéfalo/patologia , Doenças das Artérias Carótidas/patologia , Células Cultivadas , Hemorragia Cerebral Intraventricular/patologia , Cromatografia Líquida , Hemoglobinas/química , Hemoglobinas/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Oxirredução , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/metabolismo , Espectrometria de Massas em Tandem
11.
BMC Med Genet ; 21(1): 61, 2020 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-32216767

RESUMO

BACKGROUND: Wolcott-Rallison Syndrome (WRS) is a rare autosomal recessive disease that is the most common cause of neonatal diabetes in consanguineous families. WRS is caused by various genetic alterations of the Eukaryotic Translation Initiation Factor 2-Alpha Kinase 3 (EIF2AK3) gene. METHODS: Genetic analysis of a consanguineous family where two children were diagnosed with WRS was performed by Sanger sequencing. The altered protein was investigated by in vitro cloning, expression and immunohistochemistry. RESULTS: The first cases in Hungary, - two patients in one family, where the parents were fourth-degree cousins - showed the typical clinical features of WRS: early onset diabetes mellitus with hyperglycemia, growth retardation, infection-induced multiple organ failure. The genetic background of the disease was a novel alteration in the EIF2AK3 gene involving the splice site of exon 11- intron 11-12 boundary: g.53051_53062delinsTG. According to cDNA sequencing this created a new splice site and resulted in a frameshift and the development of an early termination codon at amino acid position 633 (p.Pro627AspfsTer7). Based on in vitro cloning and expression studies, the truncated protein was functionally inactive. Immunohistochemistry revealed that the intact protein was absent in the islets of pancreas, furthermore insulin expressing cells were also dramatically diminished. Elevated GRP78 and reduced CHOP protein expression were observed in the liver. CONCLUSIONS: The novel genetic alteration causing the absence of the EIF2AK3 protein resulted in insufficient handling of severe endoplasmic reticulum stress, leading to liver failure and demise of the patients.


Assuntos
Diabetes Mellitus Tipo 1/genética , Epífises/anormalidades , Mutação INDEL , Osteocondrodisplasias/genética , Sítios de Splice de RNA/genética , eIF-2 Quinase/genética , Pré-Escolar , Consanguinidade , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/patologia , Chaperona BiP do Retículo Endoplasmático , Estresse do Retículo Endoplasmático/genética , Epífises/patologia , Evolução Fatal , Feminino , Mutação da Fase de Leitura , Humanos , Hungria , Lactente , Falência Hepática/complicações , Falência Hepática/genética , Falência Hepática/patologia , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/patologia , Linhagem , Irmãos , Viroses/complicações , Viroses/patologia
12.
Arterioscler Thromb Vasc Biol ; 39(3): 413-431, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30700131

RESUMO

Objective- Calcific aortic valve disease is a prominent finding in elderly and in patients with chronic kidney disease. We investigated the potential role of iron metabolism in the pathogenesis of calcific aortic valve disease. Approach and Results- Cultured valvular interstitial cells of stenotic aortic valve with calcification from patients undergoing valve replacement exhibited significant susceptibility to mineralization/osteoblastic transdifferentiation in response to phosphate. This process was abrogated by iron via induction of H-ferritin as reflected by lowering ALP and osteocalcin secretion and preventing extracellular calcium deposition. Cellular phosphate uptake and accumulation of lysosomal phosphate were decreased. Accordingly, expression of phosphate transporters Pit1 and Pit2 were repressed. Translocation of ferritin into lysosomes occurred with high phosphate-binding capacity. Importantly, ferritin reduced nuclear accumulation of RUNX2 (Runt-related transcription factor 2), and as a reciprocal effect, it enhanced nuclear localization of transcription factor Sox9 (SRY [sex-determining region Y]-box 9). Pyrophosphate generation was also increased via upregulation of ENPP2 (ectonucleotide pyrophosphatase/phosphodiesterase-2). 3H-1, 2-dithiole-3-thione mimicked these beneficial effects in valvular interstitial cell via induction of H-ferritin. Ferroxidase activity of H-ferritin was essential for this function, as ceruloplasmin exhibited similar inhibitory functions. Histological analysis of stenotic aortic valve revealed high expression of H-ferritin without iron accumulation and its relative dominance over ALP in noncalcified regions. Increased expression of H-ferritin accompanied by elevation of TNF-α (tumor necrosis factor-α) and IL-1ß (interleukin-1ß) levels, inducers of H-ferritin, corroborates the essential role of ferritin/ferroxidase via attenuating inflammation in calcific aortic valve disease. Conclusions- Our results indicate that H-ferritin is a stratagem in mitigating valvular mineralization/osteoblastic differentiation. Utilization of 3H-1, 2-dithiole-3-thione to induce ferritin expression may prove a novel therapeutic potential in valvular mineralization.


Assuntos
Estenose da Valva Aórtica/metabolismo , Apoferritinas/fisiologia , Calcificação Vascular/metabolismo , Valva Aórtica/metabolismo , Valva Aórtica/patologia , Estenose da Valva Aórtica/patologia , Apoferritinas/antagonistas & inibidores , Apoferritinas/farmacologia , Transporte Biológico , Núcleo Celular/metabolismo , Células Cultivadas , Subunidade alfa 1 de Fator de Ligação ao Core/biossíntese , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Células Endoteliais/metabolismo , Regulação da Expressão Gênica , Interleucina-1beta/biossíntese , Interleucina-1beta/genética , Canais Iônicos/biossíntese , Ferro/farmacologia , Lisossomos/metabolismo , Fosfatos/metabolismo , Diester Fosfórico Hidrolases/biossíntese , Diester Fosfórico Hidrolases/genética , Fatores de Transcrição SOX9/metabolismo , Tionas/farmacologia , Tiofenos/farmacologia , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/genética , Calcificação Vascular/patologia
13.
Int J Mol Sci ; 22(1)2020 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-33374506

RESUMO

Over the past decades, substantial work has established that hemoglobin oxidation and heme release play a pivotal role in hemolytic/hemorrhagic disorders. Recent reports have shown that oxidized hemoglobins, globin-derived peptides, and heme trigger diverse biological responses, such as toll-like receptor 4 activation with inflammatory response, reprogramming of cellular metabolism, differentiation, stress, and even death. Here, we discuss these cellular responses with particular focus on their mechanisms that are linked to the pathological consequences of hemorrhage and hemolysis. In recent years, endogenous gasotransmitters, such as carbon monoxide (CO) and hydrogen sulfide (H2S), have gained a lot of interest in connection with various human pathologies. Thus, many CO and H2S-releasing molecules have been developed and applied in various human disorders, including hemolytic and hemorrhagic diseases. Here, we discuss our current understanding of oxidized hemoglobin and heme-induced cell and tissue damage with particular focus on inflammation, cellular metabolism and differentiation, and endoplasmic reticulum stress in hemolytic/hemorrhagic human diseases, and the potential beneficial role of CO and H2S in these pathologies. More detailed mechanistic insights into the complex pathology of hemolytic/hemorrhagic diseases through heme oxygenase-1/CO as well as H2S pathways would reveal new therapeutic approaches that can be exploited for clinical benefit.


Assuntos
Monóxido de Carbono/uso terapêutico , Heme Oxigenase (Desciclizante)/metabolismo , Hemólise/efeitos dos fármacos , Sulfeto de Hidrogênio/uso terapêutico , Vasculite por IgA/tratamento farmacológico , Vasculite por IgA/metabolismo , Animais , Monóxido de Carbono/metabolismo , Monóxido de Carbono/farmacologia , Gerenciamento Clínico , Suscetibilidade a Doenças , Metabolismo Energético , Heme/metabolismo , Heme Oxigenase-1/metabolismo , Hemoglobinas/química , Hemoglobinas/metabolismo , Humanos , Sulfeto de Hidrogênio/metabolismo , Sulfeto de Hidrogênio/farmacologia , Vasculite por IgA/diagnóstico , Vasculite por IgA/etiologia , Metabolismo dos Lipídeos , Lipoproteínas LDL/metabolismo , Monócitos/imunologia , Monócitos/metabolismo , Oxirredução/efeitos dos fármacos , Peptídeos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo
14.
Int J Mol Sci ; 21(22)2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-33182600

RESUMO

Hemostasis disorder in patients with end-stage renal disease (ESRD) is frequently associated with bleeding diathesis but it may also manifest in thrombotic complications. Analysis of individual coagulation and fibrinolytic factors may shed light on the background of this paradox situation. Here we explored components essential for fibrin formation/stabilization in ESRD patients being on maintenance hemodiafiltration (HDF) or hemodialysis (HD). Pre-dialysis fibrinogen, factor XIII (FXIII) antigen concentrations and FXIII activity were elevated, while α2-plasmin inhibitor (α2PI) activity decreased. The inflammatory status, as characterized by C-reactive protein (CRP) was a key determinant of fibrinogen concentration, but not of FXIII and α2PI levels. During a 4-h course of HDF or HD, fibrinogen concentration and FXIII levels gradually elevated. When compensated for the change in plasma water, i.e., normalized for plasma albumin concentration, only FXIII elevation remained significant. There was no difference between HDF and HD treatments. Individual HDF treatment did not influence α2PI activity, however after normalization it decreased significantly. HD treatment had a different effect, α2PI activities became elevated but the elevation disappeared after normalization. Elevated fibrinogen and FXIII levels in ESRD patients might contribute to the increased thrombosis risk, while decreased α2PI activity might be associated with elevated fibrinolytic potential.


Assuntos
Complexo de Ataque à Membrana do Sistema Complemento/metabolismo , Falência Renal Crônica/sangue , Falência Renal Crônica/terapia , Adolescente , Adulto , Idoso , Coagulação Sanguínea , Proteína C-Reativa/metabolismo , Fator XIII/metabolismo , Feminino , Fibrinogênio/metabolismo , Fibrinólise , Hemodiafiltração , Hemorragia/sangue , Hemorragia/etiologia , Humanos , Falência Renal Crônica/congênito , Masculino , Pessoa de Meia-Idade , Diálise Renal , Fatores de Risco , Trombose/sangue , Trombose/etiologia , Adulto Jovem , alfa 2-Antiplasmina/metabolismo
15.
Int J Mol Sci ; 21(21)2020 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-33142923

RESUMO

Heme released from red blood cells targets a number of cell components including the cytoskeleton. The purpose of the present study was to determine the impact of free heme (20-300 µM) on human skeletal muscle fibres made available during orthopedic surgery. Isometric force production and oxidative protein modifications were monitored in permeabilized skeletal muscle fibre segments. A single heme exposure (20 µM) to muscle fibres decreased Ca2+-activated maximal (active) force (Fo) by about 50% and evoked an approximately 3-fold increase in Ca2+-independent (passive) force (Fpassive). Oxidation of sulfhydryl (SH) groups was detected in structural proteins (e.g., nebulin, α-actinin, meromyosin 2) and in contractile proteins (e.g., myosin heavy chain and myosin-binding protein C) as well as in titin in the presence of 300 µM heme. This SH oxidation was not reversed by dithiothreitol (50 mM). Sulfenic acid (SOH) formation was also detected in the structural proteins (nebulin, α-actinin, meromyosin). Heme effects on SH oxidation and SOH formation were prevented by hemopexin (Hpx) and α1-microglobulin (A1M). These data suggest that free heme has a significant impact on human skeletal muscle fibres, whereby oxidative alterations in structural and contractile proteins limit contractile function. This may explain and or contribute to the weakness and increase of skeletal muscle stiffness in chronic heart failure, rhabdomyolysis, and other hemolytic diseases. Therefore, therapeutic use of Hpx and A1M supplementation might be effective in preventing heme-induced skeletal muscle alterations.


Assuntos
Cisteína/metabolismo , Heme/farmacologia , Contração Muscular/efeitos dos fármacos , Fibras Musculares Esqueléticas/efeitos dos fármacos , Proteínas Musculares/metabolismo , Miofibrilas/efeitos dos fármacos , Sequência de Aminoácidos , Cálcio/metabolismo , Cisteína/química , Humanos , Espectrometria de Massas/métodos , Contração Muscular/fisiologia , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Miofibrilas/metabolismo , Miofibrilas/patologia , Oxirredução
16.
Int J Mol Sci ; 21(13)2020 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-32635347

RESUMO

Hemoglobin, heme and iron are implicated in the progression of atherosclerosis. Therefore, we investigated whether the hydrophobic fungal iron chelator siderophore, desferricoprogen (DFC) inhibits atherosclerosis. DFC reduced atherosclerotic plaque formation in ApoE-/- mice on an atherogenic diet. It lowered the plasma level of oxidized LDL (oxLDL) and inhibited lipid peroxidation in aortic roots. The elevated collagen/elastin content and enhanced expression of adhesion molecule VCAM-1 were decreased. DFC diminished oxidation of Low-density Lipoprotein (LDL) and plaque lipids catalyzed by heme or hemoglobin. Formation of foam cells, uptake of oxLDL by macrophages, upregulation of CD36 and increased expression of TNF-α were reduced by DFC in macrophages. TNF-triggered endothelial cell activation (vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecules (ICAMs), E-selectin) and increased adhesion of monocytes to endothelium were attenuated. The increased endothelial permeability and intracellular gap formation provoked by TNF-α was also prevented by DFC. DFC acted as a cytoprotectant in endothelial cells and macrophages challenged with a lethal dose of oxLDL and lowered the expression of stress-responsive heme oxygenase-1 as sublethal dose was employed. Saturation of desferrisiderophore with iron led to the loss of the beneficial effects. We demonstrated that DFC accumulated within the atheromas of the aorta in ApoE-/- mice. DFC represents a novel therapeutic approach to control the progression of atherosclerosis.


Assuntos
Dicetopiperazinas/farmacologia , Ácidos Hidroxâmicos/farmacologia , Placa Aterosclerótica/prevenção & controle , Sideróforos/farmacologia , Animais , Aorta/diagnóstico por imagem , Aorta/efeitos dos fármacos , Aorta/metabolismo , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Aterosclerose/patologia , Dieta Aterogênica , Dicetopiperazinas/farmacocinética , Modelos Animais de Doenças , Progressão da Doença , Células Espumosas/efeitos dos fármacos , Células Espumosas/patologia , Heme/metabolismo , Ácidos Hidroxâmicos/farmacocinética , Peroxidação de Lipídeos/efeitos dos fármacos , Lipoproteínas LDL/metabolismo , Ativação de Macrófagos/efeitos dos fármacos , Imageamento por Ressonância Magnética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Neurospora crassa/química , Estresse Oxidativo/efeitos dos fármacos , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patologia , Tomografia por Emissão de Pósitrons , Sideróforos/farmacocinética
17.
Int J Mol Sci ; 20(15)2019 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-31357546

RESUMO

The prevalence of vascular disorders continues to rise worldwide. Parallel with that, new pathophysiological pathways have been discovered, providing possible remedies for prevention and therapy in vascular diseases. Growing evidence suggests that endoplasmic reticulum (ER) stress is involved in a number of vasculopathies, including atherosclerosis, vascular brain events, and diabetes. Heme, which is released from hemoglobin or other heme proteins, triggers various pathophysiological consequence, including heme stress as well as ER stress. The potentially toxic free heme is converted by heme oxygenases (HOs) into carbon monoxide (CO), iron, and biliverdin (BV), the latter of which is reduced to bilirubin (BR). Redox-active iron is oxidized and stored by ferritin, an iron sequestering protein which exhibits ferroxidase activity. In recent years, CO, BV, and BR have been shown to control cellular processes such as inflammation, apoptosis, and antioxidant defense. This review covers our current knowledge about how heme induced endoplasmic reticulum stress (HIERS) participates in the pathogenesis of vascular disorders and highlights recent discoveries in the molecular mechanisms of HO-mediated cytoprotection in heme stress and ER stress, as well as crosstalk between ER stress and HO-1. Furthermore, we focus on the translational potential of HIERS and heme oxygenase-1 (HO-1) in atherosclerosis, diabetes mellitus, and brain hemorrhage.


Assuntos
Estresse do Retículo Endoplasmático , Heme Oxigenase (Desciclizante)/metabolismo , Heme/metabolismo , Doenças Vasculares/etiologia , Doenças Vasculares/metabolismo , Animais , Biomarcadores , Suscetibilidade a Doenças , Regulação da Expressão Gênica , Humanos , Especificidade de Órgãos , Estresse Oxidativo , Transdução de Sinais
18.
Clin Chem Lab Med ; 56(7): 1117-1125, 2018 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-29425104

RESUMO

BACKGROUND: Serum angiotensin-converting enzyme (ACE) activity determination can aid the early diagnosis of sarcoidosis. We aimed to optimize a fluorescent kinetic assay for ACE activity by screening the confounding effects of endogenous ACE inhibitors and interfering factors. Genotype-dependent and genotype-independent reference values of ACE activity were established, and their diagnostic accuracies were validated in a clinical study. METHODS: Internally quenched fluorescent substrate, Abz-FRK(Dnp)P-OH was used for ACE-activity measurements. A total of 201 healthy individuals and 59 presumably sarcoidotic patients were enrolled into this study. ACE activity and insertion/deletion (I/D) genotype of the ACE gene were determined. RESULTS: Here we report that serum samples should be diluted at least 35-fold to eliminate the endogenous inhibitor effect of albumin. No significant interferences were detected: up to a triglyceride concentration of 16 mM, a hemoglobin concentration of 0.71 g/L and a bilirubin concentration of 150 µM. Genotype-dependent reference intervals were considered as 3.76-11.25 U/L, 5.22-11.59 U/L, 7.19-14.84 U/L for II, ID and DD genotypes, respectively. I/D genotype-independent reference interval was established as 4.85-13.79 U/L. An ACE activity value was considered positive for sarcoidosis when it exceeded the upper limit of the reference interval. The optimized assay with genotype-dependent reference ranges resulted in 42.5% sensitivity, 100% specificity, 100% positive predictive value and 32.4% negative predictive value in the clinical study, whereas the genotype-independent reference range proved to have inferior diagnostic efficiency. CONCLUSIONS: An optimized fluorescent kinetic assay of serum ACE activity combined with ACE I/D genotype determination is an alternative to invasive biopsy for confirming the diagnosis of sarcoidosis in a significant percentage of patients.


Assuntos
Ensaios Enzimáticos/métodos , Peptidil Dipeptidase A/sangue , Peptidil Dipeptidase A/normas , Sarcoidose/diagnóstico , Adulto , Idoso , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Peptidil Dipeptidase A/genética , Polimorfismo Genético , Valores de Referência
19.
Appl Microbiol Biotechnol ; 102(6): 2817-2825, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29423632

RESUMO

Aspergillus fumigatus is an opportunistic pathogen, the leading cause of invasive and disseminated aspergillosis in systemic immunocompromised patients, and an important cause of mortality. The aim of the present study was to adapt a pulmonary aspergillosis murine model, to determine pathodynamical parameters quantitatively, and to follow the progression of fungal infection in vivo. The nasal inoculation of Aspergillus conidia in mice previously subjected to immunosuppression with cyclophosphamide (CP) turned out to be a more suitable model than that of immunosuppressed with hydrocortisone (HC). The following parameters were found to correlate quantitatively with the progress of the infection: (i) survival rate, (ii) weight loss of mice, (iii) infected focal plaque size, (iv) hyphal density, (v) hyphal length distribution of A. fumigatus, and the (vi) the histopathological status and scores. These parameters will be essential elements for the development of antifungal drugs and therapies, and important for the investigation of the pathogenicity in different strains of A. fumigatus.


Assuntos
Aspergillus fumigatus/crescimento & desenvolvimento , Modelos Animais de Doenças , Hifas/crescimento & desenvolvimento , Aspergilose Pulmonar Invasiva/microbiologia , Aspergilose Pulmonar Invasiva/patologia , Animais , Peso Corporal , Contagem de Colônia Microbiana , Histocitoquímica , Hospedeiro Imunocomprometido , Camundongos , Índice de Gravidade de Doença , Análise de Sobrevida
20.
Artif Organs ; 42(9): 925-932, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29682748

RESUMO

Hemodiafiltration (HDF) during chronic renal replacement therapy (RRT) is a relatively new practice phenomenon, emerging over the last two decades. While the technological platforms utilized during chronic RRT are in many cases similar or effectively identical to conventional hemodialysis (HD), significant differences may emerge in daily practice. Several authors of this review moved practice site between the United States and the European Union and transitioned from an HD-based practice to predominantly HDF-practicing networks. In doing so, we became keenly aware of the potential pitfalls nephrologists may be facing during such transitions. This brief review is intended to provide a succinct overview of several practical concerns and complications nephrologists may encounter in daily practice of end-stage renal disease care, including but not limited to management of electrolytes, renal anemia and treatment goals and settings during HDF.


Assuntos
Hemodiafiltração/métodos , Falência Renal Crônica/terapia , Diálise Renal/métodos , Humanos , Pacientes Ambulatoriais
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