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1.
Int J Mol Sci ; 20(14)2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31340541

RESUMO

Apoptotic cell death is usually a response to the cell's microenvironment. In the kidney, apoptosis contributes to parenchymal cell loss in the course of acute and chronic renal injury, but does not trigger an inflammatory response. What distinguishes necrosis from apoptosis is the rupture of the plasma membrane, so necrotic cell death is accompanied by the release of unprocessed intracellular content, including cellular organelles, which are highly immunogenic proteins. The relative contribution of apoptosis and necrosis to injury varies, depending on the severity of the insult. Regulated cell death may result from immunologically silent apoptosis or from immunogenic necrosis. Recent advances have enhanced the most revolutionary concept of regulated necrosis. Several modalities of regulated necrosis have been described, such as necroptosis, ferroptosis, pyroptosis, and mitochondrial permeability transition-dependent regulated necrosis. We review the different modalities of apoptosis, necrosis, and regulated necrosis in kidney injury, focusing particularly on evidence implicating cell death in ectopic renal calcification. We also review the evidence for the role of cell death in kidney injury, which may pave the way for new therapeutic opportunities.


Assuntos
Lesão Renal Aguda/metabolismo , Proteínas Reguladoras de Apoptose/genética , Calcinose/metabolismo , Células Epiteliais/metabolismo , Rim/metabolismo , Necrose/metabolismo , Traumatismo por Reperfusão/metabolismo , Lesão Renal Aguda/tratamento farmacológico , Lesão Renal Aguda/genética , Lesão Renal Aguda/patologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Proteínas Reguladoras de Apoptose/classificação , Proteínas Reguladoras de Apoptose/metabolismo , Calcinose/genética , Calcinose/patologia , Calcinose/prevenção & controle , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , /genética , Regulação da Expressão Gênica , Humanos , /genética , Rim/efeitos dos fármacos , Rim/patologia , /genética , /genética , Necrose/genética , Necrose/patologia , Necrose/prevenção & controle , Substâncias Protetoras/farmacologia , Piroptose/efeitos dos fármacos , Piroptose/genética , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/patologia
2.
Biomed Res Int ; 2019: 5026860, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31355265

RESUMO

Aims: Calcifying fibrous tumor (CFT) is a very rare begin fibroblastic tumor featuring a widely anatomical distribution and may mimic various spindle cell tumors. Misdiagnosis and hence mistreatment are likely caused due to unfamiliarity to clinicians or junior pathologists. We collected a relatively large series of CFTs in our institution aiming at further summarizing their clinicopathologic features in Chinese patients and discussing the diagnosis and differential diagnosis in clinical practice. Methods: Clinicopathologic data of 22 CFTs were retrospectively reviewed. Histologic features were reevaluated and summarized. Immunostaining markers include CD34, SMA, Desmin, keratin, S100, ALK1, CD117, IgG, IgG4, and Ki-67. Follow-up of all cases was performed. Results: 22 CFTs include gastric (n=8), pulmonary (n=2), hepatic (n=2), cervical (n=1), appendiceal (n=1), esophageal (n=1), retroperitoneal (n=1), intra-abdominal (n=1), diaphragmatic (n=1), spermatic cord and scrotum (n=1), anconeal (n=1), mesenteric (n=1), and omental (n=1) lesions. Coexisting hepatocellular carcinoma, pancreatic carcinoma, pheochromocytoma, Castleman disease, and leiomyoma of the uterus and other metabolic or functional disorders were also appreciated. CFT histologically features spindle cells embedded dense hyalinized stroma with scattered psammomatous calcifications and lymphoplasmacytic infiltration and immunohistochemically for CD34. None of any individuals die of CFT per se. Conclusion: Our study discloses that CFT is a bona fide benign fibroblastic lesion, regardless of its developing location. Involvement of digestive tract seems much more common in the Chinese population. Awareness of the clinicopathologic characteristics of this rare entity and its mimickers contribute to avoiding misdiagnosis and mistreatment in clinical practice.


Assuntos
Calcinose , Proteínas de Neoplasias/metabolismo , Neoplasias de Tecido Fibroso , Adolescente , Adulto , Idoso , Calcinose/diagnóstico , Calcinose/metabolismo , Calcinose/patologia , Criança , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias de Tecido Fibroso/diagnóstico , Neoplasias de Tecido Fibroso/metabolismo , Neoplasias de Tecido Fibroso/patologia
3.
Mater Sci Eng C Mater Biol Appl ; 103: 109807, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31349397

RESUMO

Hydroxyapatite (HAP) is not only a common component of most idiopathic CaOx stones, but also the core of Randall's plaque. HAP is a nest that can induce the formation of Randall's plaques and even kidney stones. We studied the toxic effects and mechanisms of four different types of nano-HAP crystals (H-Sphere, 72.5 nm × 72.5 nm; H-Needle, 37.2 nm × 162.7 nm; H-Rod, 42.3 nm × 115.3 nm; and H-Plate, 145.5 nm × 272.9 nm) on human renal proximal tubular epithelial cells (HK-2). HAP crystals could cause oxidative stress that triggered a series of cell dysfunction problems, resulting in decreased cell viability, loss of cell membrane integrity, cell swelling, and cell necrosis. The toxic effect of HAP was mainly attributed to its entry into cell by endocytosis and its accumulation in the lysosomes, causing the level of intracellular reactive oxygen species (ROS) to rise, the mitochondrial membrane potential (Δψm) to decrease, the lysosomal integrity to be destroyed, and the cell cycle blocked during the G0/G1 phase. The cytotoxicity of the four kinds of HAP crystals was ranked as follows: H-Sphere > H-Needle > H-Rod > H-Plate. The cytotoxicity of each crystal was positively correlated with low absolute zeta potential, conduciveness to internalized morphology, large specific surface area and aspect ratio, and small particle size. These results indicated that nano-HAP could damage HK-2 cells, and the physical properties of HAP crystals play a vital effect in their cytotoxicity.


Assuntos
Durapatita/química , Durapatita/toxicidade , Túbulos Renais Proximais/citologia , Apoptose/efeitos dos fármacos , Calcinose/metabolismo , Calcinose/patologia , Linhagem Celular , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Humanos , Medula Renal/metabolismo , Medula Renal/patologia , L-Lactato Desidrogenase/metabolismo , Lisossomos/efeitos dos fármacos , Lisossomos/patologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Nanopartículas Metálicas/química , Nanopartículas Metálicas/toxicidade , Microscopia Eletrônica de Varredura , Espécies Reativas de Oxigênio/metabolismo , Espectroscopia de Infravermelho com Transformada de Fourier , Testes de Toxicidade , Cálculos Urinários/etiologia , Difração de Raios X
4.
Mater Sci Eng C Mater Biol Appl ; 103: 109711, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31349489

RESUMO

Tendon calcification is a common but intractable problem leading to pain and activity limitation when injury or tendinopathy progresses into the late stage. This is because tendon stem/progenitor cells (TSPCs) can undergo aberrant osteogenic differentiation under inflammatory conditions. This study aims to investigate the effect of curcumin, a natural anti-inflammatory agent, on regulating the differentiation of TSPCs in tendon calcification. With inflammatory stimulation, TSPCs showed higher alkaline phosphatase activity and more frequent formation of mineralized nodules which were verified in the culture system; however, curcumin significantly alleviated these pathological changes. In in vivo function analysis, chitosan microsphere-encapsulated curcumin was delivered to injured sites of rat tendon ectopic calcification model. The inflammation in the tendon tissues of the curcumin group was significantly relieved. Controlled-release curcumin partially rescued tendon calcification and enhanced tendon regeneration in animal model. This study demonstrates that controlled-release curcumin can manipulate the fate decision of TSPCs, and that it promotes the tenogenesis and inhibits the osteogenesis of TSPCs in a pathological microenvironment, which provides a possible new therapeutic strategy for tendon disease.


Assuntos
Tendão do Calcâneo/metabolismo , Calcinose/tratamento farmacológico , Diferenciação Celular/efeitos dos fármacos , Curcumina/farmacologia , Células-Tronco/metabolismo , Tendão do Calcâneo/patologia , Animais , Calcinose/metabolismo , Calcinose/patologia , Curcumina/química , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacologia , Camundongos , Ratos , Células-Tronco/patologia
5.
Med Hypotheses ; 128: 25-27, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31203904

RESUMO

Nanobacteria or calcifying nanoparticles are 80-500 nm sized nano-organisms that are physically associated with carbonate apatite mineral formations. They have been indicated in various diseases, including kidney stone formation, Alzheimer's disease, and atherosclerosis. Nanoparticles contain calcium and apatite-binding protein fetuin-A, a calcification inhibitor. However, recent evidence indicates that fetuin-A can form nucleation seeds or nidi that grow in size through ion sedimentation to become larger amorphous nanoparticles in the presence of excess calcium and apatite ions. Fetuin-A also functions as an inhibitor of meprin, a metalloproteinase implicated in inflammation and neurodegenerative diseases. During inflammation, meprin functions to regulate chemokine activity of monocyte chemotactic protein 1, which is associated with chronic inflammatory diseases, including atherosclerosis, renal inflammatory diseases, and multiple sclerosis (MS). In addition, calcium phosphate nanocrystals that contain fetuin-A are pro-inflammatory to macrophages and promote vascular smooth muscle cell mineralization, potentiating a vicious cycle of inflammation and calcification. Thus, mineral stress and inflammation appear to be associated with each other. Furthermore, fetuin-A deficient mice exhibited reduced experimental autoimmune encephalomyelitis severity. Thus, fetuin-A plays a direct role in the neuroinflammatory response. Indeed, the level of fetuin-A in cerebrospinal fluid has been defined as a biomarker of disease activity in MS. MS is a chronic, inflammatory, demyelinating, and neurodegenerative disease of the central nervous system (CNS) with an unknown etiology. The "inside-out" model of MS, supported by recent data, states that the initial axonal degeneration in the CNS occurs before demyelination, which then stimulates an auto-immune attack. It was shown very recently that influx of calcium from the extracellular space through nanoscale ruptures of the axonal plasma membrane predict axon degeneration in neuroinflammation. Calcium is an activator of calpains, proteases that function to break down the cytoskeleton, leading to neurodegeneration. Nanoruptures of the plasma membrane were suggested to occur at the early stages of axon damage, especially at nodes of Ranvier, which are devoid of myelin. Here, I propose that calcifying nanoparticles may have a role in the etiology and/or pathophysiology of MS. The initial event causing neurodegeneration may be due to the nanoparticles that have been suggested to easily cross the blood-brain barrier. Following this, the nanoparticles may create nanoruptures in the axonal membrane and also increase the calcium concentration around and within the neurons by forming nidi for calcification, eventually causing neurodegeneration. Nanoparticles can self-replicate; hence, they may represent an infectious causative agent for the development of MS.


Assuntos
Nanopartículas Calcificantes/efeitos adversos , Calcinose/metabolismo , Esclerose Múltipla/etiologia , Animais , Apatitas/química , Barreira Hematoencefálica/metabolismo , Nanopartículas Calcificantes/química , Cálcio/química , Sistema Nervoso Central/metabolismo , Quimiocinas/metabolismo , Encefalomielite Autoimune Experimental/metabolismo , Humanos , Inflamação , Íons , Camundongos , Esclerose Múltipla/metabolismo , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/metabolismo , alfa-2-Glicoproteína-HS/química
6.
Int J Mol Sci ; 20(9)2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31052252

RESUMO

Ectopic mineralization disorders comprise a broad spectrum of inherited or acquired diseases characterized by aberrant deposition of calcium crystals in multiple organs, such as the skin, eyes, kidneys, and blood vessels. Although the precise mechanisms leading to ectopic calcification are still incompletely known to date, various molecular targets leading to a disturbed balance between pro- and anti-mineralizing pathways have been identified in recent years. Vitamin K and its related compounds, mainly those post-translationally activated by vitamin K-dependent carboxylation, may play an important role in the pathogenesis of ectopic mineralization as has been demonstrated in studies on rare Mendelian diseases, but also on highly prevalent disorders, like vascular calcification. This narrative review compiles and summarizes the current knowledge regarding the role of vitamin K, its metabolism, and associated compounds in the pathophysiology of both monogenic ectopic mineralization disorders, like pseudoxanthoma elasticum or Keutel syndrome, as well as acquired multifactorial diseases, like chronic kidney disease. Clinical and molecular aspects of the various disorders are discussed according to the state-of-the-art, followed by a comprehensive literature review regarding the role of vitamin K in molecular pathophysiology and as a therapeutic target in both human and animal models of ectopic mineralization disorders.


Assuntos
Calcinose/metabolismo , Doenças Genéticas Inatas/metabolismo , Vitamina K/metabolismo , Anormalidades Múltiplas , Animais , Calcinose/genética , Doenças das Cartilagens , Doenças Genéticas Inatas/genética , Deformidades Congênitas da Mão , Humanos , Estenose da Valva Pulmonar , Vitamina K/genética
7.
Life Sci ; 228: 72-84, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31034839

RESUMO

AIMS: Calcific aortic valve disease (CAVD) emerges as a challenging clinical issue, which is associated with high cardiovascular mortality. It has been demonstrated that osteoblastic transformation of AVICs is a key mechanism of CAVD and C-C motif chemokine receptors (CCRs) may favor this process. Thus, we aimed to investigate whether CCRs were involved in osteoblastic transformation of AVICs during the development CAVD. MAIN METHODS: We first analyzed microarray data (GSE51472 and GSE12644) to identify differentially expressed genes between CAVD aortic valve tissue and normal samples, followed by verification of immunohistochemistry, qPCR and western blotting. Primary aortic valvular interstitial cells (AVICs) were incubated with specific inhibitors and/or siRNA of CCR2 and CCL2 under pro-calcifying medium. The levels of CCL2 in the medium were measured by ELISA. In addition, we used recombinant CCL2 to activate CCR2 in calcifying AVICs. Alizarin red S staining and calcium deposition were used to evaluate the degree of calcification. Western blotting was used to determine osteoblastic transformation of AVIC and total Akt and phosphorylated Akt expression. KEY FINDING: CCR2 levels were remarkably up-regulated in calcified aortic valve and calcifying AVICs. Silencing CCR2 inhibited the osteoblastic transformation and calcification of AVICs. In addition, recombinant CCL2 activated CCR2 and accelerated AVICs calcification through PI3K/Akt pathway. SIGNIFICANCE: We characterize abnormal activation of CCL2/CCR2 axis as a promoter of AVICs osteoblastic transformation and calcification. Our findings implicate the CCL2/CCR2-PI3K/Akt pathway as a potential target for treatment of CAVD.


Assuntos
Estenose da Valva Aórtica/patologia , Valva Aórtica/patologia , Calcinose/patologia , Osteoblastos/patologia , Receptores CCR2/metabolismo , Adulto , Idoso , Animais , Valva Aórtica/metabolismo , Estenose da Valva Aórtica/genética , Estenose da Valva Aórtica/metabolismo , Calcinose/genética , Calcinose/metabolismo , Células Cultivadas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteoblastos/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Interferência de RNA , Ratos Sprague-Dawley , Receptores CCR2/análise , Receptores CCR2/genética , Transdução de Sinais , Transcriptoma , Regulação para Cima
8.
J Bone Miner Metab ; 37(6): 944-956, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30963258

RESUMO

Warfarin, a vitamin K antagonist, is the most common anticoagulant used to prevent thromboembolisms associated with atrial fibrillation or following valvular surgery. Although several studies have revealed that long-term warfarin use accelerates aortic valve calcification and the development of aortic stenosis (AS), the detailed mechanism for this phenomenon remains unclear. Therefore, our aim was twofold: to establish the conditions for warfarin-induced calcification of human aortic valve interstitial cells (HAVICs) using high-inorganic phosphate (Pi) conditions and to investigate the underlying mechanism. We prepared and cultured HAVICs from aortic valves affected by calcific aortic valve stenosis (AS group) and aortic valves affected by aortic regurgitation but without any signs of calcification (non-AS group). Under Pi concentrations of 3.2 mM, warfarin significantly increased the calcification and alkaline phosphatase (ALP) activity of AS but not non-AS group HAVICs. Furthermore, gene expression of bone morphogenetic protein 2 (BMP2), a calcigenic marker, was significantly increased following 7 days of warfarin treatment. Warfarin-induced calcification of AS group HAVICs at 3.2 mM Pi was significantly inhibited by dorsomorphin, a Smad inhibitor, and the pregnane X receptor (PXR) inhibitors, ketoconazole and coumestrol, but was unaffected by SN-50, an NF-κB inhibitor. Warfarin was also able to increase BMP2 gene expression at a physiological Pi concentration (1.0 mM). Furthermore, excess BMP2 (30 ng/mL) facilitated warfarin-induced ALP upregulation and HAVIC calcification, an effect which was significantly reduced in the presence of coumestrol. Together, our results suggest that warfarin accelerates calcification of HAVICs from AS patients via the PXR-BMP2-ALP pathway.


Assuntos
Estenose da Valva Aórtica/induzido quimicamente , Estenose da Valva Aórtica/metabolismo , Valva Aórtica/patologia , Calcinose/induzido quimicamente , Calcinose/metabolismo , Fosfatos/efeitos adversos , Receptor de Pregnano X/metabolismo , Varfarina/efeitos adversos , Valva Aórtica/metabolismo , Estenose da Valva Aórtica/genética , Estenose da Valva Aórtica/patologia , Proteína Morfogenética Óssea 2/genética , Proteína Morfogenética Óssea 2/metabolismo , Calcinose/genética , Células Cultivadas , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Receptor de Pregnano X/antagonistas & inibidores
9.
Phytother Res ; 33(6): 1717-1725, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31016813

RESUMO

Inflammation is considered to be one of the initial critical factors in the occurrence of calcific heart valve disease. This study was to prove Nobiletin (NBT) inhibits inflammation-caused calcification of human valve interstitial cells (hVICs) and to elucidate the involved molecular mechanisms. Tumor necrosis factor-alpha (TNF-α)-induced hVICs were treated with or without NBT. Cell growth and calcification of hVICs were assessed. RNA sequencing was utilized to investigate the gene expression changes. Molecular target prediction and docking assay were further performed. NBT interfered with hVIC growth under TNF-α condition in a dose-dependent manner also presented a gradual decrease of positive Alizarin Red S staining, down-regulation of BMP2, and RUNX2 gene expression. Based on the global gene expression cluster, control and TNF-α plus NBT group showed a high similarity versus TNF-α only group. After Venn interaction of differential expression genes (DEGs), 2,236 common DEGs were identified to display different biological functions and signaling pathways. ABCG2 and AKR1B1 were further selected as prediction targets of NBT involved in RELA, TNF, BMP2, RUNX2, etc. interactions in mediating hVIC calcification. The results show that NBT is a natural product to prevent the occurrence of heart valve calcification.


Assuntos
Estenose da Valva Aórtica/prevenção & controle , Valva Aórtica/efeitos dos fármacos , Valva Aórtica/patologia , Calcinose/prevenção & controle , Flavonas/farmacologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Adulto , Aldeído Redutase/genética , Aldeído Redutase/metabolismo , Valva Aórtica/metabolismo , Estenose da Valva Aórtica/genética , Estenose da Valva Aórtica/metabolismo , Estenose da Valva Aórtica/patologia , Calcinose/genética , Calcinose/metabolismo , Calcinose/patologia , Células Cultivadas , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Feminino , Flavonas/química , Regulação da Expressão Gênica/efeitos dos fármacos , Doenças das Valvas Cardíacas/genética , Doenças das Valvas Cardíacas/metabolismo , Doenças das Valvas Cardíacas/patologia , Doenças das Valvas Cardíacas/prevenção & controle , Humanos , Simulação de Acoplamento Molecular , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Fator de Necrose Tumoral alfa/efeitos adversos
10.
Hypertension ; 73(5): 983-989, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30879359

RESUMO

We examined the utility of coronary artery calcium (CAC) for cardiovascular risk stratification among hypertensive adults, including those fitting eligibility for SPRINT (Systolic Blood Pressure Intervention Trial). Additionally, we used CAC to identify hypertensive adults with cardiovascular disease (CVD) mortality rates equivalent to those observed in SPRINT who may, therefore, benefit from the most intensive blood pressure therapy. Our study population included 16 167 hypertensive patients from the CAC Consortium, among whom 6375 constituted a "SPRINT-like" population. We compared multivariable-adjusted hazard ratios of coronary heart disease and CVD deaths by CAC category (0, 1-99, 100-399, ≥400). Additionally, we generated a CAC-CVD mortality curve for patients aged >50 years to determine what CAC scores were associated with CVD death rates observed in SPRINT. Mean age was 58.1±10.6 years. During a mean follow-up of 11.6±3.6 years, there were 409 CVD deaths and 207 coronary heart disease deaths. Increasing CAC scores were associated with increased coronary heart disease and CVD mortality (coronary heart disease-CAC 100-399: hazard ratio [95% CI] 1.88 [1.04-3.40], CAC ≥400: 4.16 [2.34-7.39]; CVD-CAC 100-399: 1.93 [1.31-2.83], CAC ≥400: 3.51 [2.40-5.13]). A similar increased risk was observed across 10-year atherosclerotic CVD risk categories and in the SPRINT-like population. A CAC score of 220 (confidence range, 165-270) was associated with the CVD mortality rate observed in SPRINT. CAC risk stratifies adults with hypertension, including those who are SPRINT eligible. A CAC score of 220 can identify hypertensive adults with SPRINT-level CVD mortality risk and, therefore, may be reasonable for identifying candidates for aggressive blood pressure therapy.


Assuntos
Pressão Sanguínea/fisiologia , Calcinose/diagnóstico , Cálcio/metabolismo , Doença da Artéria Coronariana/diagnóstico , Vasos Coronários/diagnóstico por imagem , Hipertensão/complicações , Medição de Risco/métodos , Idoso , Calcinose/epidemiologia , Calcinose/metabolismo , Doenças Cardiovasculares/epidemiologia , Causas de Morte/tendências , Angiografia Coronária , Doença da Artéria Coronariana/epidemiologia , Doença da Artéria Coronariana/metabolismo , Vasos Coronários/metabolismo , Feminino , Seguimentos , Humanos , Hipertensão/epidemiologia , Hipertensão/fisiopatologia , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida/tendências , Tomografia Computadorizada por Raios X , Estados Unidos/epidemiologia
11.
Biomed Khim ; 65(1): 57-62, 2019 Jan.
Artigo em Russo | MEDLINE | ID: mdl-30816098

RESUMO

The mechanism of valve calcification that is the main cause of aortic stenosis formation and progression is not yet clear. In recent years, the role of the OPG/RANKL/RANK system is considered as one of possible variants of pathogenesis of valve calcification. In presented work the differences in OPG and sRANKL levels involved in the calcification processes in tissues of patients with severe aortic stenosis have been examined. The study was performed using three groups of patients: group 1 - patients with aortic stenosis, group 2 - patients with aortic aneurysm, and group 3 - patients with aortic stenosis and aortic dilatation. In patients with aortic stenosis, the level of RANKL was significantly higher, and the level of RANKL was higher in valve than in tissue. The negative correlation between aortic dilatation and RANKL level indicated the lack of RANKL influence on pathogenesis of aortic dilatation. The obtained data confirm the increased expression of RANKL in patients with aortic valve calcification. The results of this study confirm importance of the OPG/RANKL/RANK system in calcification in patients with aortic stenosis. Athough patients of all groups had comparable values of OPG (including patients with aortic dilatation), the RANKL level increased only in patients with aortic stenosis. This suggest involvement of some additional mechanisms influencing the increase of RANKL expression.


Assuntos
Estenose da Valva Aórtica , Calcinose/metabolismo , Osteoprotegerina/metabolismo , Ligante RANK/metabolismo , Valva Aórtica/patologia , Humanos , Receptor Ativador de Fator Nuclear kappa-B/metabolismo
12.
BMJ Case Rep ; 12(3)2019 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-30904891

RESUMO

Pulmonary alveolar microlithiasis (PAM) is a rare disease characterised by calcific deposits in lung parenchyma. PAM being a progressive disease with dissociation between severity of clinical symptoms and radiological picture, it is often detected incidentally. Mutations in the SLC34A2 gene encoding the type IIb sodium phosphate cotransporter in alveolar type II cells are considered to be involved in the pathogenesis of PAM. The majority of the patients are diagnosed usually between the ages of 20 and 40 years, although paediatric PAM has also been reported. Diagnosis is confirmed by combination of radiological features, bronchial lavage and histopathological testing. At present, lung transplant is the only definitive treatment available. Though rare, the prevalence of PAM is worldwide. Till June 2018, 86 cases have been reported from India and 1042 cases have been reported worldwide. We report three cases from India, including a student, cement factory worker and a tailor, which will highlight the varied clinical and radiological presentations of this rare disease along with the response to treatment.


Assuntos
Alendronato/administração & dosagem , Broncodilatadores/administração & dosagem , Calcinose/diagnóstico por imagem , Doenças Genéticas Inatas/diagnóstico por imagem , Pneumopatias/diagnóstico por imagem , Adulto , Alendronato/uso terapêutico , Líquido da Lavagem Broncoalveolar/química , Broncodilatadores/uso terapêutico , Calcinose/metabolismo , Tosse/etiologia , Dispneia/etiologia , Doenças Genéticas Inatas/metabolismo , Hemoptise/etiologia , Humanos , Índia , Pneumopatias/metabolismo , Masculino , Inaladores Dosimetrados , Radiografia , Tomografia Computadorizada por Raios X , Adulto Jovem
13.
J Am Coll Cardiol ; 73(9): 1043-1054, 2019 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-30846099

RESUMO

BACKGROUND: Intraleaflet hematomas are associated with advanced stages of aortic valve calcification and suspected to be involved in disease progression. However, the mechanism by which the entry of blood cells into the valves affects the biology of aortic valvular interstitial cells (VICs) remains to be elucidated. OBJECTIVES: This study sought to evaluate the putative link between intraleaflet hematoma and aortic valve calcification and to assess its pathophysiological implications. METHODS: The spatial relationship between calcium deposits and intraleaflet hematomas was analyzed by whole-mount staining of calcified and noncalcified human aortic valves, obtained in the context of heart transplantation and from patients who underwent surgical valve replacement. Endothelial microfissuring was evaluated by en face immunofluorescence and scanning electron microscopic analyses of the fibrosa surface. Red blood cell (RBC) preparations were used in vitro to assess, by immunofluorescence microscopy and Alizarin red staining, the potential impact of intraleaflet hematomas on phenotypic changes in VICs. RESULTS: Intraleaflet hematomas, revealed by iron deposits and RBCs into the fibrosa, secondary to endothelial microfissuring, were consistently found in noncalcified valves. The contact of primary VICs derived from these valves with RBCs resulted in a global inflammatory and osteoblastic phenotype, reflected by the up-regulation of interleukin-6, interleukin-1ß, bone sialoprotein, osteoprotegerin, receptor activator of nuclear factor kappa B, bone morphogenic protein 2, and muscle segment homeobox 2, the production of osteocalcin, and the formation of calcium deposits. CONCLUSIONS: The acquisition of an osteoblastic phenotype in VICs that come into contact with the senescent RBCs of intraleaflet hematomas may play a critical role in the initiation of calcium deposition into the fibrosa of human aortic valves.


Assuntos
Estenose da Valva Aórtica/diagnóstico , Valva Aórtica/diagnóstico por imagem , Valva Aórtica/patologia , Calcinose/diagnóstico , Cálcio/metabolismo , Ferro/metabolismo , Idoso , Valva Aórtica/metabolismo , Estenose da Valva Aórtica/metabolismo , Calcinose/metabolismo , Células Cultivadas , Progressão da Doença , Endotélio Vascular/metabolismo , Endotélio Vascular/ultraestrutura , Feminino , Humanos , Masculino , Microscopia Eletrônica de Varredura , Microscopia de Fluorescência , Pessoa de Meia-Idade , Fenótipo
14.
Stem Cell Res ; 35: 101395, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30776674

RESUMO

Several SLC20A2 mutations have been implicated as potential causes of Fahr's disease, a subtype of primary familial brain calcification (PFBC), but very few patient-derived induced pluripotent stem cell (iPSC) models have been established. We have identified a novel SLC20A2 mutation in a family with Fahr's disease. We subsequently obtained dermal fibroblasts from a patient in this family. These fibroblasts were successfully transformed into iPSCs by employing episomal plasmids expressing OCT3/4, SOX2, KLF4, LIN28, and L-MYC. Our approach offers a resource and a platform for further research into the mechanism of Fahr's disease and could facilitate development and screening of pharmaceutical and gene therapies.


Assuntos
Doenças dos Gânglios da Base , Calcinose , Técnicas de Reprogramação Celular , Células-Tronco Pluripotentes Induzidas , Mutação , Doenças Neurodegenerativas , Proteínas Cotransportadoras de Sódio-Fosfato Tipo III , Adolescente , Doenças dos Gânglios da Base/genética , Doenças dos Gânglios da Base/metabolismo , Doenças dos Gânglios da Base/patologia , Calcinose/genética , Calcinose/metabolismo , Calcinose/patologia , Linhagem Celular , Derme/metabolismo , Derme/patologia , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/patologia , Masculino , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Proteínas Cotransportadoras de Sódio-Fosfato Tipo III/genética , Proteínas Cotransportadoras de Sódio-Fosfato Tipo III/metabolismo
16.
Biochem Biophys Res Commun ; 510(2): 303-308, 2019 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-30704756

RESUMO

Idiopathic Basal Ganglia Calcification (IBGC) is a rare neuropsychiatric illness also known as Fahr's disease or Primary Familial Brain Calcification (PFBC). IBGC is caused by SLC20A2 variants, which encodes the inorganic phosphate (Pi) transporter PiT-2, a transmembrane protein associated with Pi homeostasis. We have reported novel SLC20A2 variants in the Japanese population and established an induced pluripotent stem cells (iPSCs) from an IBGC patient carrying a SLC20A2 variant. To investigate the effect of these SLC20A2 variants identified in our previous study, we used Chinese hamster ovary (CHO) cells expressing these variant proteins using the Flp-In system (Flp-In CHO cells), and showed that variant SLC20A2 proteins significantly disrupted the Pi transport activity in Flp-In CHO cells. Endothelial cells (ECs) represent important target cells for elucidating the pathology of IBGC. Using patient-derived iPSCs in this study, we differentiated these cells into ECs and found no significant difference in their differentiation capacity into ECs compared with control iPSCs. However, the Pi transport activity of IBGC patient-derived iPS-ECs was significantly decreased compared with that of control iPS-ECs without changing the gene expression of the other SLC 20 family members. We confirmed that SLC20A2 variants caused the loss of function of the Pi transport activity in both Flp-In CHO cells and disease-specific iPSCs. This is the first report to show an in vitro model of iPSCs in IBGC with patient-identified SLC20A2 variants. These useful tools will help in elucidating IBGC pathogenesis and can be used for screening drug candidates.


Assuntos
Doenças dos Gânglios da Base/metabolismo , Calcinose/metabolismo , Células Endoteliais/citologia , Células-Tronco Pluripotentes Induzidas/citologia , Doenças Neurodegenerativas/metabolismo , Fosfatos/metabolismo , Proteínas Cotransportadoras de Sódio-Fosfato Tipo III/metabolismo , Animais , Transporte Biológico , Células CHO , Diferenciação Celular , Cricetinae , Cricetulus , Fosfatos/química
17.
Arterioscler Thromb Vasc Biol ; 39(4): 826-833, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30700133

RESUMO

Objective- We examined the association of cardiovascular health (CVH) metrics with the development and progression of coronary artery calcium (CAC) among apparently healthy adults. Approach and Results- This cohort study included 65 494 men and women 30 years of age and older free of cardiovascular disease at baseline who underwent a comprehensive exam including CAC scoring. CVH metrics were defined according to the American Heart Association Life's Simple 7 metrics based on smoking, diet, physical activity, body mass index, blood pressure, total cholesterol, and fasting glucose. CVH scores range from 0 (all metrics considered unhealthy) to 7 (all metrics considered healthy). Participants were followed-up for a maximum of 6.6 years. Compared with participants with ideal CVH scores 0-1, the multivariable-adjusted difference in the change in geometric means of CAC scores over 5 years of follow-up were -0.40 (-0.62 to -0.19), -0.83 (-1.03 to -0.63), -1.06 (-1.25 to -0.86), -1.22 (-1.42 to -1.03), and -1.05 (-1.42 to -0.69) in participants with ideal CVH scores 2, 3, 4, 5, and 6-7, respectively. The inverse association between CVH scores and progression of CAC was observed both in participants with no CAC and in those with CAC detectable at baseline. Conclusions- A higher ideal CVH metrics score was strongly associated with a lower prevalence of CAC and with lower progression of CAC in males and females in a large cohort of healthy adults. Our findings suggest that maintaining a healthy life habits could help reduce the development and progression of subclinical atherosclerosis and ultimately prevent clinically cardiovascular event.


Assuntos
Calcinose/patologia , Cálcio/análise , Doença da Artéria Coronariana/patologia , Vasos Coronários/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Glicemia/análise , Pressão Sanguínea , Índice de Massa Corporal , Calcinose/metabolismo , Colesterol/sangue , Doença da Artéria Coronariana/metabolismo , Vasos Coronários/metabolismo , Dieta , Progressão da Doença , Exercício , Jejum/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , República da Coreia/epidemiologia , Risco , Fumar/epidemiologia
18.
Nucl Med Commun ; 40(6): 604-610, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30688757

RESUMO

BACKGROUND: Fluorine-18-labeled sodium fluoride (F-NaF) uptake measured with PET in the vessel walls can indicate active microcalcification, a potential biomarker of higher-risk plaques, which are not indicated by macrocalcification measured with computed tomography (CT). The aim of this study was to determine the extent to which F-NaF uptake is correlated with calcification at arterial plaques in cancer patients undergoing whole-body PET/CT imaging. PATIENTS AND METHODS: Image data from 179 patients who underwent F-NaF PET/CT were evaluated retrospectively. Plaques were categorized into four groups by calcium score (CS) on CT: CS1 (≥1000); CS2 (400-999); CS3 (100-399), and CS4 (<100) and into three groups by F-NaF target-to-background ratio (TBR) on PET: TBRlow (≤1.0), TBRmedium (1.0-1.5), and TBRhigh (>1.5). Correlations between F-NaF uptake and CS were evaluated. RESULTS: Plaques with F-NaF uptake or arterial calcification were observed in 122 (76%) of the 179 patients. We found a weak but statistically significant positive correlation between CS and F-NaF uptake. The TBR in CS1 plaques was higher than those in CS3 and CS4 plaques, and the TBR in CS2 plaques was higher than that in CS3 plaques (P<0.05). Compared with patients whose plaques were with F-NaF uptake (TBR>1.5) or arterial calcification (CS>0), patients without plaques of F-NaF uptake or calcification were significantly younger (P=0.00) or with significantly more women (P=0.02). CONCLUSION: Our finding of a weak but significant positive correlation between F-NaF uptake and arterial calcification suggests that F-NaF PET/CT could provide complementary information of active microcalcification for atherosclerosis evaluation in cancer patients.


Assuntos
Artérias/diagnóstico por imagem , Calcinose/diagnóstico por imagem , Radioisótopos de Flúor , Neoplasias/complicações , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Fluoreto de Sódio/metabolismo , Imagem Corporal Total , Idoso , Artérias/metabolismo , Transporte Biológico , Calcinose/complicações , Calcinose/metabolismo , Cálcio/metabolismo , Feminino , Humanos , Masculino , Neoplasias/diagnóstico por imagem , Neoplasias/patologia , Estudos Retrospectivos
19.
Ann Biomed Eng ; 47(4): 1106-1115, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30671754

RESUMO

miR-214 has been recently found to be significantly downregulated in calcified human aortic valves (AVs). ER stress, especially the ATF4-mediated pathway, has also been shown to be significantly upregulated in calcific AV disease. Since elevated cyclic stretch is one of the major mechanical stimuli for AV calcification and ATF4 is a validated target of miR-214, we investigated the effect of cyclic stretch on miR-214 expression as well as those of ATF4 and two downstream genes (CHOP and BCL2L1). Porcine aortic valve (PAV) leaflets were cyclically stretched at 15% for 48 h in regular medium and for 1 week in osteogenic medium to simulate the early remodeling and late calcification stages of stretch-induced AV disease, respectively. For both stages, 10% cyclic stretch served as the physiological counterpart. RT-qPCR revealed that miR-214 expression was significantly downregulated during the late calcification stage, whereas the mRNA expression of ATF4 and BCL2L1 was upregulated and downregulated, respectively, during both early remodeling and late calcification stages. When PAV leaflets were statically transfected with miR-214 mimic in osteogenic medium for 2 weeks, calcification was significantly reduced compared to the control mimic case. This implies that miR-214 may have a protective role in stretch-induced calcific AV disease.


Assuntos
Estenose da Valva Aórtica/metabolismo , Valva Aórtica/metabolismo , Valva Aórtica/patologia , Calcinose/metabolismo , Regulação da Expressão Gênica , MicroRNAs/metabolismo , Regulação para Cima , Fator 4 Ativador da Transcrição/biossíntese , Animais , Estenose da Valva Aórtica/patologia , Calcinose/patologia , Suínos , Fator de Transcrição CHOP/biossíntese , Proteína bcl-X/biossíntese
20.
Clin Calcium ; 29(2): 165-170, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-30679396

RESUMO

Analysis of a mutant mouse exhibiting accelerated aging identified phosphorus as a pro-aging factor in mammals. In the blood, phosphorus exists in the form of phosphate ions and colloidal particles composed of solid-phase calcium-phosphate and serum protein fetuin-A, which are termed calciprotein particles(CPP). Blood CPP levels increase with age and decline of renal function. Because CPP have the ability to induce inflammation and vascular smooth muscle cell calcification in vitro, we hypothesize that CPP may serve as a pathogen that accelerates aging. Therapeutic interventions in phosphate and/or CPP may open a new avenue for practical anti-aging medicine.


Assuntos
Calcinose , Minerais/metabolismo , Miócitos de Músculo Liso/citologia , alfa-2-Glicoproteína-HS , Animais , Calcinose/metabolismo , Inflamação , Camundongos , Minerais/química , Miócitos de Músculo Liso/fisiologia
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