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2.
PLoS One ; 15(7): e0235667, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32730271

RESUMO

Botswana's Okavango Delta is a World Heritage Site and biodiverse wilderness. In 2016-2018, following arrival of the annual flood of rainwater from Angola's highlands, and using continuous oxygen logging, we documented profound aquatic hypoxia that persisted for 3.5 to 5 months in the river channel. Within these periods, dissolved oxygen rarely exceeded 3 mg/L and dropped below 0.5 mg/L for up to two weeks at a time. Although these dissolved oxygen levels are low enough to qualify parts of the Delta as a dead zone, the region is a biodiversity hotspot, raising the question of how fish survive. In association with the hypoxia, histological samples, collected from native Oreochromis andersonii (threespot tilapia), Coptodon rendalli (redbreast tilapia), and Oreochromis macrochir (greenhead tilapia), exhibited widespread hepatic and splenic inflammation with marked granulocyte infiltration, melanomacrophage aggregates, and ceroid and hemosiderin accumulations. It is likely that direct tissue hypoxia and polycythemia-related iron deposition caused this pathology. We propose that Okavango cichlids respond to extended natural hypoxia by increasing erythrocyte production, but with significant health costs. Our findings highlight seasonal hypoxia as an important recurring stressor, which may limit fishery resilience in the Okavango as concurrent human impacts rise. Moreover, they illustrate how fish might respond to hypoxia elsewhere in the world, where dead zones are becoming more common.


Assuntos
Oxigênio/química , Tilápia/metabolismo , Animais , Ceroide/metabolismo , Eritrócitos/citologia , Eritrócitos/metabolismo , Feminino , Hemossiderina/metabolismo , Hipóxia , Ferro/metabolismo , Fígado/metabolismo , Fígado/patologia , Masculino , Oxigênio/metabolismo , Rios , Baço/metabolismo , Baço/patologia
3.
J Comp Pathol ; 176: 145-150, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32359628

RESUMO

An 8-year-old neutered female domestic shorthair cat was presented for further management of an apocrine gland cystadenocarcinoma. Extensive nodal metastasis was diagnosed and the cat was humanely destroyed 2 months after presentation. Post-mortem histopathology of the cystadenocarcinoma revealed areas of yellow-brown granular pigmentation on light microscopy, staining positively for reducing substances with Schmorl's stain and demonstrating autofluorescence on confocal microscopy. The cat's urine was black and also exhibited autofluorescence, and further analysis revealed increased free pentosidine. Based on these findings, it was presumed that the apocrine gland cystadenocarcinoma was producing lipofuscin-like pigments and that the characteristics of the urine were at least partially secondary to advanced glycation end-products.


Assuntos
Glândulas Apócrinas/patologia , Doenças do Gato/patologia , Cistadenocarcinoma/veterinária , Neoplasias das Glândulas Sudoríparas/veterinária , Animais , Gatos , Ceroide/urina , Feminino , Produtos Finais de Glicação Avançada/urina , Pigmentação
4.
Ultrastruct Pathol ; 42(6): 477-488, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30465462

RESUMO

Atherosclerotic plaque formation starts early in life, develops silently over decades, and often displays clear evidence of accelerated biological aging. Lipofuscin has been classically defined as "the most consistent and phylogenetically conserved cellular morphologic change of aging," however, despite this traditional view different lines of evidence have recently demonstrated that, besides aging, various noxious influences can engeder its accumulation in cells and also that specific experimental conditions can revert this effect. Lipofuscin has been also proven to interact with disease-related factors to enhance cell loss. Along with lipofuscin, ceroid, another autofluorescent lipopigment usually produced under various pathological conditions unrelated to aging, has been suggested to jeopardize cell performance and viability by inducing membrane fragility, mitochondrial dysfunction, DNA damage, and oxidative stress-induced apoptosis. With regard to atherosclerosis, very few investigations have been conducted to assess whether a link could exist between lipofuscin/ceroid accumulation and the progression of the disease and no information still exist regarding the anatomy and the ultrastructural diversification of lipofuscin and ceroid in the lesional vascular tissue. At the same time, data concerning their potential toxicity at the cellular level are fragmentary, dated, and scarce. The present study investigates the occurrence and distribution of lipofuscin and ceroid in human atherosclerotic plaque and adjacent healthy tissues and analyzes the ultrastructural changes associated with their accumulation within the cell.


Assuntos
Aterosclerose/patologia , Ceroide/metabolismo , Lipofuscina/metabolismo , Placa Aterosclerótica/patologia , Adulto , Idoso , Envelhecimento/fisiologia , Aterosclerose/metabolismo , Feminino , Fibroblastos/metabolismo , Fibroblastos/ultraestrutura , Humanos , Lisossomos/metabolismo , Lisossomos/ultraestrutura , Masculino , Pessoa de Meia-Idade , Placa Aterosclerótica/metabolismo
5.
Chem Phys Lipids ; 213: 13-24, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29518380

RESUMO

Oxidised low density lipoprotein (LDL) was considered to be important in the pathogenesis of atherosclerosis, but the large clinical trials of antioxidants, including the first one using probucol (the PQRST Trial), failed to show benefit and have cast doubt on the importance of oxidised LDL. We have shown previously that LDL oxidation can be catalysed by iron in the lysosomes of macrophages. The aim of this study was therefore to investigate the effectiveness of antioxidants in preventing LDL oxidation at lysosomal pH and also establish the possible mechanism of oxidation. Probucol did not effectively inhibit the oxidation of LDL at lysosomal pH, as measured by conjugated dienes or oxidised cholesteryl esters or tryptophan residues in isolated LDL or by ceroid formation in the lysosomes of macrophage-like cells, in marked contrast to its highly effective inhibition of LDL oxidation at pH 7.4. LDL oxidation at lysosomal pH was inhibited very effectively for long periods by N,N'-diphenyl-1,4-phenylenediamine, which is more hydrophobic than probucol and has been shown by others to inhibit atherosclerosis in rabbits, and by cysteamine, which is a hydrophilic antioxidant that accumulates in lysosomes. Iron-induced LDL oxidation might be due to the formation of the superoxide radical, which protonates at lysosomal pH to form the much more reactive, hydrophobic hydroperoxyl radical, which can enter LDL and reach its core. Probucol resides mainly in the surface monolayer of LDL and would not effectively scavenge hydroperoxyl radicals in the core of LDL. This might explain why probucol failed to protect against atherosclerosis in various clinical trials. The oxidised LDL hypothesis of atherosclerosis now needs to be re-evaluated using different and more effective antioxidants that protect against the lysosomal oxidation of LDL.


Assuntos
Antioxidantes/química , Lipoproteínas LDL/química , Lisossomos/química , Animais , Antioxidantes/uso terapêutico , Aterosclerose/tratamento farmacológico , Linhagem Celular , Ceroide/química , Cromatografia Líquida de Alta Pressão , Cisteamina/química , Compostos Ferrosos/química , Humanos , Peróxido de Hidrogênio/química , Concentração de Íons de Hidrogênio , Lipoproteínas LDL/análise , Oxirredução , Probucol/química , Probucol/uso terapêutico , Coelhos
6.
Intern Med ; 53(23): 2705-9, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25447654

RESUMO

Hermansky-Pudlak syndrome (HPS) is a rare genetic disorder, the most common complication of which influencing the prognosis is pulmonary fibrosis. In the present report, we describe an autopsy case of a Japanese woman with HPS. The patient was diagnosed at 50 years of age based on the presence of oculocutaneous albinism, hemorrhagic diathesis, ceroid-lipofuscin accumulation and pulmonary fibrosis. Although systemic steroids, immunosuppressants and pirfenidone were administered for pulmonary involvement, she died from respiratory failure two years later. Obtaining an early diagnosis and taking into consideration the need for lung transplantation is necessary in order to improve the prognosis of HPS. We herein report this very rare Japanese case of HPS with a review of the treatment approaches for HPS complicated with pulmonary fibrosis.


Assuntos
Síndrome de Hermanski-Pudlak/complicações , Síndrome de Hermanski-Pudlak/diagnóstico , Fibrose Pulmonar/complicações , Fibrose Pulmonar/diagnóstico , Insuficiência Respiratória/etiologia , Corticosteroides/administração & dosagem , Autopsia , Ceroide/metabolismo , Quimioterapia Combinada , Evolução Fatal , Feminino , Transtornos Hemorrágicos/complicações , Transtornos Hemorrágicos/diagnóstico , Síndrome de Hermanski-Pudlak/patologia , Humanos , Imunossupressores/administração & dosagem , Lipofuscina/metabolismo , Transplante de Pulmão , Pessoa de Meia-Idade , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/etiologia , Fibrose Pulmonar/patologia , Piridonas/administração & dosagem , Insuficiência Respiratória/patologia
7.
PLoS One ; 9(4): e95023, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24736558

RESUMO

Juvenile Neuronal Ceroid Lipofuscinosis (JNCL) is a lysosomal storage disease caused by an autosomal recessive mutation in CLN3 that leads to vision loss, progressive cognitive and motor decline, and premature death. Morphological evidence of astrocyte activation occurs early in the disease process and coincides with regions where neuronal loss eventually ensues. However, the consequences of CLN3 mutation on astrocyte function remain relatively ill-defined. Astrocytes play a critical role in CNS homeostasis, in part, by their ability to regulate the extracellular milieu via the formation of extensive syncytial networks coupled by gap junction (GJ) channels. In contrast, unopposed hemichannels (HCs) have been implicated in CNS pathology by allowing the non-discriminant passage of molecules between the intracellular and extracellular milieus. Here we examined acute brain slices from CLN3 mutant mice (CLN3Δex7/8) to determine whether CLN3 loss alters the balance of GJ and HC activity. CLN3Δex7/8 mice displayed transient increases in astrocyte HC opening at postnatal day 30 in numerous brain regions, compared to wild type (WT) animals; however, HC activity steadily decreased at postnatal days 60 and 90 in CLN3Δex7/8 astrocytes to reach levels lower than WT cells. This suggested a progressive decline in astrocyte function, which was supported by significant reductions in glutamine synthetase, GLAST, and connexin expression in CLN3Δex7/8 mice compared to WT animals. Based on the early increase in astrocyte HC activity, CLN3Δex7/8 mice were treated with the novel carbenoxolone derivative INI-0602 to inhibit HCs. Administration of INI-0602 for a one month period significantly reduced lysosomal ceroid inclusions in the brains of CLN3Δex7/8 mice compared to WT animals, which coincided with significant increases in astrocyte GJ communication and normalization of astrocyte resting membrane potential to WT levels. Collectively, these findings suggest that alterations in astrocyte communication may impact the progression of JNCL and could offer a potential therapeutic target.


Assuntos
Astrócitos/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Lipofuscinoses Ceroides Neuronais/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Biomarcadores , Encéfalo/metabolismo , Ceroide/metabolismo , Conexinas/genética , Conexinas/metabolismo , Feminino , Junções Comunicantes/metabolismo , Ácido Glutâmico/metabolismo , Homeostase , Lisossomos/metabolismo , Masculino , Glicoproteínas de Membrana/deficiência , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Knockout , Chaperonas Moleculares/genética , Mutação , Lipofuscinoses Ceroides Neuronais/genética
8.
Sarcoidosis Vasc Diffuse Lung Dis ; 30(3): 217-20, 2013 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-24284295

RESUMO

Hermansky-Pudlak Syndrome (HPS) is a rare autosomal recessive disorder presenting with oculocutaneous albinism, bleeding diathesis and lysosomal accumulation of ceroid lipofuscin which leads to interstitial fibrosis in lung. Pulmonary fibrosis which is usually associated with HPS-1 and HPS-4 subtypes usually manifests in the third/fourth decades of life representing with giant lamellar bodies of alveolar type-II-cells and their apparent degeneration causes restrictive lung disease. Pulmonary manifestation of this syndrome may lead to premature death. Pulmonary Alveolar Proteinosis(PAP) is another rare disease characterized by alveolar deposition of surfactant phospholipids and proteins secondary to defective clearance by alveolar macrophages. PAP may occur as autoimmune diseases and/or secondary to toxic inhalation, systemic infections or hematological disorders. None of the cases were reported secondary to HPS according to the best our knowledge. As well, pulmonary involvement of HPS was never reported as PAP. We report the first case of PAP in a patient with HPS.


Assuntos
Síndrome de Hermanski-Pudlak , Proteinose Alveolar Pulmonar , Ceroide , Humanos , Pulmão/metabolismo , Fibrose Pulmonar
9.
Biosci Rep ; 33(2): e00023, 2013 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-23249249

RESUMO

NCLs (neuronal ceroid lipofuscinoses) form a group of eight inherited autosomal recessive diseases characterized by the intralysosomal accumulation of autofluorescent pigments, called ceroids. Recent data suggest that the pathogenesis of NCL is associated with the appearance of fragmented mitochondria with altered functions. However, even if an impairement in the autophagic pathway has often been evoked, the molecular mechanisms leading to mitochondrial fragmentation in response to a lysosomal dysfunction are still poorly understood. In this study, we show that fibroblasts that are deficient for the TPP-1 (tripeptidyl peptidase-1), a lysosomal hydrolase encoded by the gene mutated in the LINCL (late infantile NCL, CLN2 form) also exhibit a fragmented mitochondrial network. This morphological alteration is accompanied by an increase in the expression of the protein BNIP3 (Bcl2/adenovirus E1B 19 kDa interacting protein 3) as well as a decrease in the abundance of mitofusins 1 and 2, two proteins involved in mitochondrial fusion. Using RNAi (RNA interference) and quantitative analysis of the mitochondrial morphology, we show that the inhibition of BNIP3 expression does not result in an increase in the reticulation of the mitochondrial population in LINCL cells. However, this protein seems to play a key role in cell response to mitochondrial oxidative stress as it sensitizes mitochondria to antimycin A-induced fragmentation. To our knowledge, our results bring the first evidence of a mechanism that links TPP-1 deficiency and oxidative stress-induced changes in mitochondrial morphology.


Assuntos
Aminopeptidases/genética , Dipeptidil Peptidases e Tripeptidil Peptidases/genética , Mitocôndrias/metabolismo , Lipofuscinoses Ceroides Neuronais/metabolismo , Estresse Oxidativo/genética , Serina Proteases/genética , Aminopeptidases/deficiência , Autofagia/genética , Células Cultivadas , Ceroide/metabolismo , Dipeptidil Peptidases e Tripeptidil Peptidases/deficiência , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Lisossomos/metabolismo , Lisossomos/patologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Lipofuscinoses Ceroides Neuronais/patologia , Serina Proteases/deficiência
10.
J Neurosci Res ; 90(11): 2163-72, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22847174

RESUMO

Autofluorescent storage material (ASM) is an aging pigment that accumulates during the normal course of senescence. Although the role of ASM has yet to be fully elucidated, ASM has been implicated in age-related neurodegeneration. In this study, we determined the level of ASM in chloride channel 3 (ClC-3) gene-deficient (KO) mice both in response to aging and following mild global ischemia. To understand the mechanism of action of the ASM, mice subjected to ischemia were treated with the cyclooxygenase (COX) inhibitor indomethacin or with the noncompetitive glutamate receptor antagonist MK-801. ClC-3 KO mice displayed age-related neurodegeneration of the neocortex as well as the hippocampus. The cortical layers in particular granular layers became thinner with aging. ASM accumulated in the brains of ClC-3 KO mice was increased seven- to 50-fold over that observed in the corresponding regions of their wild-type littermates. Young wild-type mice survived longer than age-matched ClC-3 KO mice after permanent global ischemia. However, in the case of older animals, the survival curves were similar. The ASM also increased four- to fivefold 10 days after mild global ischemia, an effect that was suppressed by treatment with indomethacin and MK-801. These results suggest that temporary ischemia might trigger a process similar to aging in the brain, mimicking the effect of age-related neurodegenerative diseases.


Assuntos
Envelhecimento/genética , Isquemia Encefálica/genética , Encéfalo/patologia , Ceroide/análise , Canais de Cloreto/deficiência , Lipofuscina/análise , Envelhecimento/metabolismo , Envelhecimento/patologia , Animais , Encéfalo/metabolismo , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Canais de Cloreto/biossíntese , Canais de Cloreto/genética , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos ICR , Camundongos Knockout , Degeneração Neural/genética , Degeneração Neural/metabolismo , Degeneração Neural/patologia , Imagem Óptica
11.
J Histochem Cytochem ; 60(3): 229-42, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22108647

RESUMO

Sensitive non-heme iron histochemistry--namely, the perfusion-Perls method and perfusion-Turnbull method--was applied to study the distribution and age-related accumulation of non-heme ferric iron and ferrous iron in mouse ovary. Light and electron microscopic studies revealed that non-heme ferric iron is distributed predominantly in stromal tissue, especially in macrophages. By contrast, the distribution of non-heme ferrous iron was restricted to a few ovoid macrophages. Aged ovaries exhibited remarkable non-heme iron accumulation in all stromal cells. In particular, non-heme ferrous iron level was increased in stromal tissue, suggestive of increased levels of redox-active iron, which can promote oxidative stress. Moreover, intense localization of both non-heme ferric and ferrous iron was observed in aggregated large stromal cells that were then characterized as ceroid-laden enlarged macrophages with frothy cytoplasm. Intraperitoneal iron overload in adult mice resulted in non-heme iron deposition in the entire stroma and generation of enlarged macrophages, suggesting that excessive iron accumulation induced macrophage morphological changes. The data indicated that non-heme iron accumulation in ovarian stromal tissue may be related to aging of the ovary due to increasing oxidative stress.


Assuntos
Envelhecimento/metabolismo , Compostos Férricos/análise , Compostos Ferrosos/análise , Sobrecarga de Ferro/metabolismo , Macrófagos/metabolismo , Ovário/metabolismo , Estresse Oxidativo , Envelhecimento/patologia , Animais , Ceroide/biossíntese , Feminino , Compostos Férricos/metabolismo , Compostos Ferrosos/metabolismo , Humanos , Sobrecarga de Ferro/induzido quimicamente , Sobrecarga de Ferro/patologia , Complexo Ferro-Dextran , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica , Ovário/efeitos dos fármacos , Ovário/patologia , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Perfusão
12.
J Histochem Cytochem ; 59(8): 769-79, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21804079

RESUMO

Ceroid and lipofuscin are autofluorescent granules thought to be generated as a consequence of chronic oxidative stress. Because ceroid and lipofuscin are persistent in tissue, their measurement can provide a lifetime history of exposure to chronic oxidative stress. Although ceroid and lipofuscin can be measured by quantification of autofluorescent granules, current methods rely on subjective assessment. Furthermore, there has not been any evaluation of variables affecting quantitative measurements. The article describes a simple statistical approach that can be readily applied to quantitate ceroid and lipofuscin. Furthermore, it is shown that several factors, including magnification tissue thickness and tissue level, can affect precision and sensitivity. After optimizing for these factors, the authors show that ceroid and lipofuscin can be measured reproducibly in the skeletal muscle of dystrophic mice (ceroid) and aged mice (lipofuscin).


Assuntos
Ceroide/análise , Lipofuscina/análise , Músculo Quadríceps/química , Envelhecimento/metabolismo , Animais , Interpretação Estatística de Dados , Feminino , Fluorescência , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos mdx , Distrofia Muscular de Duchenne/metabolismo , Distrofia Muscular de Duchenne/patologia , Músculo Quadríceps/patologia , Sensibilidade e Especificidade
13.
J Biomed Opt ; 16(1): 011011, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21280898

RESUMO

Accumulation of the lipid-protein complex ceroid is a characteristic of atherosclerotic plaque. The mechanism of ceroid formation has been extensively studied, because the complex is postulated to contribute to plaque irreversibility. Despite intensive research, ceroid deposits are defined through their fluorescence and histochemical staining properties, while their composition remains unknown. Using Raman and fluorescence spectral microscopy, we examine the composition of ceroid in situ in aorta and coronary artery plaque. The synergy of these two types of spectroscopy allows for identification of ceroid via its fluorescence signature and elucidation of its chemical composition through the acquisition of a Raman spectrum. In accordance with in vitro predictions, low density lipoprotein (LDL) appears within the deposits primarily in its peroxidized form. The main forms of modified LDL detected in both coronary artery and aortic plaques are peroxidation products from the Fenton reaction and myeloperoxidase-hypochlorite pathway. These two peroxidation products occur in similar concentrations within the deposits and represent ∼40 and 30% of the total LDL (native and peroxidized) in the aorta and coronary artery deposits, respectively. To our knowledge, this study is the first to successfully employ Raman spectroscopy to unravel a metabolic pathway involved in disease pathogenesis: the formation of ceroid in atherosclerotic plaque.


Assuntos
Biomarcadores/análise , Ceroide/análise , Placa Aterosclerótica/química , Placa Aterosclerótica/diagnóstico , Espectrometria de Fluorescência/instrumentação , Análise Espectral Raman/instrumentação , Desenho de Equipamento , Análise de Falha de Equipamento , Humanos
14.
Biochem J ; 435(1): 207-16, 2011 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-21210766

RESUMO

Cellular deposits of oxidized and aggregated proteins are hallmarks of a variety of age-related disorders, but whether such proteins contribute to pathology is not well understood. We previously reported that oxidized proteins form lipofuscin/ceroid-like bodies with a lysosomal-type distribution and up-regulate the transcription and translation of proteolytic lysosomal enzymes in cultured J774 mouse macrophages. Given the recently identified role of lysosomes in the induction of apoptosis, we have extended our studies to explore a role for oxidized proteins in apoptosis. Oxidized proteins were biosynthetically generated in situ by substituting oxidized analogues for parent amino acids. Apoptosis was measured with Annexin-V/PI (propidium iodide), TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP nick-end labelling), MMP (mitochondrial membrane permeabilization), caspase activation and cytochrome c release, and related to lysosomal membrane permeabilization. Synthesized proteins containing the tyrosine oxidation product L-DOPA (L-3,4-dihydroxyphenylalanine) were more potent inducers of apoptosis than proteins containing the phenylalanine oxidation product o-tyrosine. Apoptosis was dependent upon incorporation of oxidized residues, as indicated by complete abrogation in cultures incubated with the non-incorporation control D-DOPA (D-3,4-dihydroxyphenylalanine) or when incorporation was competed out by parent amino acids. The findings of the present study suggest that certain oxidized proteins could play an active role in the progression of age-related disorders by contributing to LMP (lysosomal membrane permeabilization)-initiated apoptosis and may have important implications for the long-term use of L-DOPA as a therapeutic agent in Parkinson's disease.


Assuntos
Apoptose , Levodopa/efeitos adversos , Levodopa/metabolismo , Monócitos/metabolismo , Biossíntese de Proteínas , Tirosina/efeitos adversos , Tirosina/metabolismo , Envelhecimento , Anexina A5/metabolismo , Caspase 3/metabolismo , Linhagem Celular , Ceroide/efeitos adversos , Fragmentação do DNA , Ativação Enzimática , Humanos , Membranas Intracelulares , Lipofuscina/efeitos adversos , Lisossomos , Potencial da Membrana Mitocondrial , Membranas Mitocondriais , Oxirredução , Permeabilidade
15.
Am J Pathol ; 177(1): 271-9, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20489146

RESUMO

Deficiency in Cathepsin D (CtsD), the major cellular lysosomal aspartic proteinase, causes the congenital form of neuronal ceroid lipofuscinoses (NCLs). CtsD-deficient mice show severe visceral lesions like lymphopenia in addition to their central nervous system (CNS) phenotype of ceroid accumulation, microglia activation, and seizures. Here we demonstrate that re-expression of CtsD within the CNS but not re-expression of CtsD in visceral organs prevented both central and visceral pathologies of CtsD(-/-) mice. Our results suggest that CtsD was substantially secreted from CNS neurons and drained from CNS to periphery via lymphatic routes. Through this drainage, CNS-expressed CtsD acts as an important modulator of immune system maintenance and peripheral tissue homeostasis. These effects depended on enzymatic activity and not on proposed functions of CtsD as an extracellular ligand. Our results furthermore demonstrate that the prominent accumulation of ceroid/lipofuscin and activation of microglia in brains of CtsD(-/-) are not lethal factors but can be tolerated by the rodent CNS.


Assuntos
Catepsina D/metabolismo , Sistema Nervoso Central/metabolismo , Modelos Animais de Doenças , Linfopenia/metabolismo , Lipofuscinoses Ceroides Neuronais/metabolismo , Animais , Catepsina D/genética , Sistema Nervoso Central/patologia , Ceroide/metabolismo , Dependovirus/genética , Dependovirus/metabolismo , Vetores Genéticos , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/metabolismo , Lipofuscinoses Ceroides Neuronais/patologia , Neurônios/metabolismo , Taxa de Sobrevida , Timo/citologia , Distribuição Tecidual , Vísceras/metabolismo , Vísceras/patologia
16.
Mol Genet Metab ; 99(4): 389-95, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20061169

RESUMO

Chediak-Higashi syndrome is characterized by oculocutaneous albinism, a bleeding tendency and severe recurrent infections. Age-dependent formations of autofluorescent ceroid-like substances have been noted in a variety of tissues. In this study, we isolated an autofluorescent ceroid-like aggregate from purified Beige mouse liver lysosomes and analyzed the composition of the aggregate by ion trap mass-spectrometry. In addition to lysosomal proteins, this aggregate contains proteins normally localized in the ER, mitochondria, peroxisomes, and the cytosol. Bip, a luminal ER protein was abundant in lysosomal ceroid. The ER, mitochondria, and cytosol proteins could arise in lysosomes through stimulation of autophagy, but we found no differences between normal and CHS fibroblasts in the degree of lysosomal acidity and in the level of conversion of soluble microtubular-associated protein 1 light chain 3 type I to membrane-associated type II, an accepted probe for hyper-autophagy suggesting that ceroid formation is unlikely to arise via this mechanism.


Assuntos
Ceroide/metabolismo , Síndrome de Chediak-Higashi/metabolismo , Fígado/metabolismo , Lisossomos/metabolismo , Animais , Autofagia , Células Cultivadas , Modelos Animais de Doenças , Fluorescência , Espectrometria de Massas , Camundongos , Proteínas/metabolismo , Proteômica
17.
J Wildl Dis ; 46(1): 320-5, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20090053

RESUMO

Two striped dolphins (Stenella coeruleoalba) were found stranded on the Catalonian Spanish coast. The main pathologic finding in both animals was the existence of multiple granulomatous lesions in the blubber, microscopically composed of macrophages and multinucleated cells containing vacuolar material. This material was identified as ceroid pigment due to its ultrastructural morphology, autofluorescence, and positive staining with periodic acid-Schiff and Ziehl-Neelsen techniques. The special stains and electron microscopy did not reveal any microorganisms associated with the lesions. These findings are very suggestive of "nutritional panniculitis," a well-defined entity associated with vitamin E deficiency that has been rarely described in free-living species.


Assuntos
Ceroide , Paniculite/veterinária , Stenella , Deficiência de Vitamina E/veterinária , Animais , Evolução Fatal , Feminino , Masculino , Paniculite/etiologia , Paniculite/patologia , Deficiência de Vitamina E/complicações
19.
Microsc Res Tech ; 71(11): 822-30, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18767051

RESUMO

It is well known that factors such as aging and water quality may influence pigmented macrophages (PMacs) in fishes, but it is not established yet if PMacs undergo seasonal and breeding dependent variations. This study explored this caveat and reports qualitative histological and stereological data on liver PMacs from wild female Ohrid trout, Salmo letnica, during the annual breeding cycle. Data showed that a minority of PMacs contained melanin and that the vast majority of them contained only hemosiderin or hemosiderin and lipofuscin/ceroid pigment. It was suggested that this is the normal scenario for the species. One remarkable result was the demonstration of a striking increase, after spawning, of the relative and total volumes of the hepatic macrophages, both parenchyma and stroma located. Because the melano PMacs did not vary, those changes were due to fluctuations in the hemosiderin-laden PMacs. We concluded that Ohrid trout presented a pigment composition in liver macrophages that differed from other fish, including salmonids, where most liver phagocytes essentially display melanin. Our quantitative data support interspecies differences in the amount of liver macrophages and also that after spawning expansion of the macrophage pool is crucial and most likely connected with the needs of liver remodeling (leading to a decrease in hepatic mass). So, we suggested that the hormonal (sex steroidal) constellation influenced the liver macrophage pool. Additionally, we proved that the use of fish liver macrophages for biomonitoring should take into account the considerable natural breeding/seasonal dependent variations that are expected to occur.


Assuntos
Fígado/citologia , Macrófagos/citologia , Reprodução , Salmonidae/fisiologia , Animais , Contagem de Células , Ceroide/análise , Hemossiderina/análise , Lipofuscina/análise , Macrófagos/química , Melaninas/análise
20.
Exp Aging Res ; 34(3): 282-95, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18568984

RESUMO

The artificial ceroid/lipofuscin pigments originated from different organ tissues, including liver, brain, heart, and kidney of rats, and biomaterials were studied with improved fluorometric techniques. With all tissue materials exposed under ultraviolet (UV) light, a series of similar fluorescent colors were observed under microfluorometer. Analogous fluorescence spectra were also demonstrated with a three-dimensional (3-D) front-surface fluorometric technique despite of the tissue differences. Measured with 3-D fluorometry, relatively simple lipofuscin-like fluorophores were observed from the reactions of malondialdehyde (MDA) with critical biological macromolecules, such as bovine serum albumin (BSA) and DNA. Our results demonstrated that the biomaterials from different tissues have a similar fate under accelerated oxidative/carbonyl stresses but may be differentiated by a fluorescence intensity ratio.


Assuntos
Envelhecimento/metabolismo , Ceroide/análise , Lipofuscina/análise , Animais , Ceroide/biossíntese , Peroxidação de Lipídeos/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos da radiação , Lipofuscina/biossíntese , Masculino , Malondialdeído/farmacologia , Pigmentos Biológicos/análise , Pigmentos Biológicos/biossíntese , Ratos , Ratos Sprague-Dawley , Projetos de Pesquisa , Espectrometria de Fluorescência/métodos , Raios Ultravioleta
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