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1.
Nutr Neurosci ; : 1-19, 2024 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-38319634

RESUMO

OBJECTIVES: Type 2 diabetes (T2D) is a metabolic disease of major public health concern. It impacts peripheral tissues and the central nervous system, leading to systemic dysmetabolism and neurocognitive impairments, including memory deficits, anxiety, and depression. The metabolic determinants of these neurocognitive impairments remain unidentified. Here, we sought to address this question by developing a proprietary (P-) high-fat diet (HFD), in which glucose intolerance precedes weight gain and insulin resistance. METHODS: The P-HFD model was nutritionally characterized, and tested in vivo in mice that underwent behavioral and metabolic testing. The diet was benchmarked against reference models. . RESULTS: P-HFD has 42% kcal from fat, high monounsaturated/polyunsaturated fatty acid ratio, and 10% (w/v) sucrose in drinking water. When administered, from the early stages of glucose intolerance alone, animals exhibit anxiety-like behavior, without depression nor recognition memory deficits. Long-term P-HFD feeding leads to weight gain, brain glucose hypometabolism as well as impaired recognition memory. Using an established genetic model of T2D (db/db) and of diet-induced obesity (60% kcal from fat) we show that additional insulin resistance and obesity are associated with depressive-like behaviors and recognition memory deficits. DISCUSSION: Our findings demonstrate that glucose intolerance alone can elicit anxiety-like behavior. Through this study, we also provide a novel nutritional model (P-HFD) to characterize the discrete effects of glucose intolerance on cognition, behavior, and the physiology of metabolic disease.

2.
Eur J Neurosci ; 56(11): 6003-6021, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36226387

RESUMO

Type 2 diabetes mellitus (T2DM) increases the risk of developing Alzheimer's disease (AD), which has been proposed to be driven by an abnormal neuroinflammatory response affecting cognitive function. However, the impact of T2DM on hippocampal function and synaptic integrity during aging has not been investigated. Here, we investigated the effects of aging in T2DM on AD-like pathology using the leptin receptor-deficient db/db mouse model of T2DM. Our results indicate that adult T2DM mice exhibited impaired spatial acquisition in the Morris water maze (MWM). Morphological analysis showed an age-dependent neuronal loss in the dentate gyrus. We found that astrocyte density was significantly decreased in all regions of the hippocampus in T2DM mice. Our analysis showed that microglial activation was increased in the CA3 and the dentate gyrus of the hippocampus in an age-dependent manner in T2DM mice. However, the expression of presynaptic marker protein (synaptophysin) and the postsynaptic marker protein [postsynaptic density protein 95 (PSD95)] was unchanged in the hippocampus of adult T2DM mice. Interestingly, synaptophysin and PSD95 expression significantly decreased in the hippocampus of aged T2DM mice, suggesting an impaired hippocampal synaptic integrity. Cytokine profiling analysis displayed a robust pro-inflammatory cytokine profile in the hippocampus of aged T2DM mice compared with the younger cohort, outlining the role of aging in exacerbating the neuroinflammatory profile in the diabetic state. Our results suggest that T2DM impairs cognitive function by promoting neuronal loss in the dentate gyrus and triggering an age-dependent deterioration in hippocampal synaptic integrity, associated with an aberrant neuroinflammatory response.


Assuntos
Doença de Alzheimer , Diabetes Mellitus Tipo 2 , Navegação Espacial , Camundongos , Animais , Sinaptofisina/metabolismo , Hipocampo/metabolismo , Doença de Alzheimer/metabolismo , Inflamação/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças
3.
Chem Biol Interact ; 361: 109958, 2022 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-35472412

RESUMO

The testis expresses peroxisome proliferator-activated receptor-γ (PPAR-γ), but its involvement in regulating diabetes-induced testicular dysfunction and DNA damage repair is not known. Pioglitazone-induced activation of PPAR-γ for 12 weeks in db/db obese diabetic mice increases bodyweights and reduces blood glucose levels, but PPAR-γ inhibition by 2-chloro-5-nitro-N-phenylbenzamide does not alter these parameters; instead, improves testis and epididymis weights and sperm count. Neither activation nor inhibition of PPAR-γ normalizes the diabetes-induced seminiferous epithelial degeneration. The PPAR-γ activation normalizes testicular lipid peroxidation, but its inhibition reduces lipid peroxidation and oxidative DNA damage (8-oxo-dG) in diabetic mice. As a response to diabetes-induced oxidative DNA damage, the base-excision repair (BER) mechanism proteins- 8-oxoguanine DNA glycosylases (OGG1/2) and X-ray repair cross-complementing protein-1 (XRCC1) increase, whereas the redox-factor-1 (REF1), DNA polymerase (pol) δ and poly (ADP-ribose) polymerase-1 (PARP1) show a tendency to increase suggesting an attempt to repair the oxidative DNA damage. The PPAR-γ stimulation inhibits OGG2, DNA pol δ, and XRCC1 in diabetic mice testes, but PPAR-γ inhibition reduces oxidative DNA damage and normalizes BER protein levels. In conclusion, type 2 diabetes negatively affects testicular structure and function and increases oxidative DNA damage and BER protein levels due to increased DNA damage. The PPAR-γ modulation does not significantly affect the structural changes in the testis. The PPAR-γ stimulation aggravates diabetes-induced effects on testis, including oxidative DNA damage and BER proteins, but PPAR-γ inhibition marginally recovers these diabetic effects indicating the involvement of the receptor in the reproductive effects of diabetes.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , PPAR gama/metabolismo , Animais , Dano ao DNA , Reparo do DNA , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 2/complicações , Masculino , Camundongos , Camundongos Obesos , Obesidade/complicações , Estresse Oxidativo , Poli(ADP-Ribose) Polimerases/metabolismo , Receptores para Leptina/genética , Receptores para Leptina/metabolismo
4.
Eur J Pharmacol ; 904: 174167, 2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-33974882

RESUMO

Microvascular changes and retinal degeneration precede diabetic retinopathy. Oxidative stress alters several intracellular signaling pathways, which form the basis of diabetic retinopathy. Many antioxidants have been investigated as possible preventive and therapeutic remedies for diabetic retinopathy. The current study investigated the modulatory effects of trans-resveratrol on streptozotocin-induced type 1 diabetes mediated changes in the transcription and levels of apoptosis-related proteins and mitogen-activated protein kinases (MAPKs) in the retinal pigment epithelium (RPE) of adult male dark Agouti rats. In control rats, 5 mg/kg/d trans-resveratrol administration for 30 days increased gene expressions of tumor suppressor protein 53, Bcl2-associated X protein, B-cell lymphoma-2 (Bcl2), Caspase-3 (CASP3), CASP8 and CASP9, p38αMAPK, c-Jun N-terminal kinase-1 (JNK1), and extracellular signal-regulated kinase-1 (ERK1). On the other hand, diabetes decreased gene expressions of CASP3, CASP8, p38αMAPK, JNK, and ERK1. Trans-resveratrol reversed the inhibited gene expressions of CASP8, p38αMAPK, JNK, and ERK1 to normal control levels in diabetic rats. Trans-resveratrol normalized diabetes-induced upregulation of CASP3 and -9, cytochrome-c, Bcl-2, and ERK1 proteins. In conclusion, Trans-resveratrol-induced alterations in gene expressions do not seem to affect RPE functions as they do not reflect as altered protein functions. Trans-resveratrol imparts its protective effects by normalizing apoptosis-related proteins and ERK1 but does not affect JNK proteins. Trans-resveratrol causes cytostasis in RPE of normal rats by upregulating Bcl2 protein and apoptotic proteins.


Assuntos
Antígenos de Bactérias , Toxinas Bacterianas , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Retinopatia Diabética , Sistema de Sinalização das MAP Quinases , Resveratrol , Epitélio Pigmentado da Retina , Animais , Masculino , Ratos , Aldeídos/metabolismo , Antígenos de Bactérias/farmacologia , Antígenos de Bactérias/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/genética , Toxinas Bacterianas/farmacologia , Toxinas Bacterianas/uso terapêutico , Glicemia/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Caspase 3/genética , Caspase 3/metabolismo , Caspase 8/genética , Caspase 8/metabolismo , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/metabolismo , Retinopatia Diabética/complicações , Retinopatia Diabética/prevenção & controle , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Resveratrol/farmacologia , Resveratrol/uso terapêutico , Epitélio Pigmentado da Retina/efeitos dos fármacos , Epitélio Pigmentado da Retina/lesões , Epitélio Pigmentado da Retina/metabolismo , Estreptozocina , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
5.
Eur J Pharmacol ; 846: 30-37, 2019 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-30659824

RESUMO

Under the sustained hyperglycemic state, oxidative stress induces irreparable DNA double-strand breaks resulting in germ cell death and testicular atrophy. Although molecular mechanisms underlying DNA damage repair in testicular cells are gradually getting unraveled, the effects on DNA double-strand breaks sensing are not precisely known. In this study, using streptozotocin-induced type 1 diabetic rats, we report that hyperglycemic state for one month or three months does not increase the levels of ataxia telangiectasia mutated (ATM) protein- an upstream kinase responsible for the phosphorylation of histone 2AX (Ɣ-H2AX)- after the formation of DNA double-strand breaks. The ATM expression is seminiferous epithelial stage-dependent in spermatogonia and primary spermatocytes, and the pattern of stage-dependent expression varies in diabetic rats, especially after three-month-long diabetes. However, the levels of metastasis-associated protein-1 (MTA1), an essential protein for ATM function, increase although not in a time-dependent manner. The amount of DNA double-strand breaks increases in a time- and stage-dependent manner as indicated by increased Ɣ-H2AX levels, especially in spermatogonia and primary spermatocytes, and in late spermatids in some tubular stages. Although ATM levels do not increase in diabetic rats, protein is expressed more or less in same testicular cells in which Ɣ-H2AX is expressed indicating that ATM might play a vital role in the phosphorylation of the histone. We conclude that diabetes upregulates MTA1-Ɣ-H2AX signaling in diabetic rat testis as a response to time-dependent increases in DNA double-strand breaks.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Histonas/metabolismo , Fosfoproteínas/metabolismo , Proteínas/metabolismo , Testículo/metabolismo , Animais , Quebras de DNA de Cadeia Dupla , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Tipo 1/genética , Masculino , Fosforilação , Ratos , Ratos Wistar , Transdução de Sinais , Espermátides/citologia , Espermátides/metabolismo , Espermatócitos/citologia , Espermatócitos/metabolismo , Espermatogônias/citologia , Espermatogônias/metabolismo , Estreptozocina , Regulação para Cima
6.
Eur J Pharmacol ; 834: 142-151, 2018 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-30030988

RESUMO

Genesis and progression of diabetic retinopathy are due to glucotoxicity-induced changes in intracellular milieu in the retina. This study investigated effects of trans-resveratrol on type 1 diabetes-induced changes in gene expressions and retinoic acid metabolism pathway in the RPE (retinal pigment epithelium) of Dark Agouti rats. Microarray analysis showed differential expressions of 833 genes in the RPE of 14 day-long diabetic rats, which increased to 1249 after they received 5 mg/kg trans-resveratrol. Diabetes inhibited the expression of retinoic acid metabolism pathway genes- Lpl, Lrat, RPE65, Rdh5, Rdh10, Rdh12, Rlbp1 and Rbp1 and increased Crabp1. Trans-resveratrol further downregulated the expression of these genes except Lpl, Rdh5, and Rdh12 but upregulated Cyp26b1. RT-PCR showed inhibition of Lrat, Rdh5, and Rdh10 in diabetic rats supplemented with or without trans-resveratrol on 14d. Trans-resveratrol normalized Rdh5 and increased Lrat and Rdh10 transcriptions compared to control and diabetic rats. Trans-resveratrol amplified diabetes-induced inhibition of RPE65, but it inhibited the induced increase in Crabp1 transcription on 30d. Trans-resveratrol reversed the diabetes-induced decrease in Cyp26b1 transcription on 14d and 30d and normalized Cyp3a9 transcription on 30d. Trans-resveratrol normalized the diabetes-induced increase in Rdh5, Rdh10, and Cyp3a9 protein levels, but it further increased Cyp26b1 protein level. In conclusion, diabetes differentially regulates numerous genes in the RPE, including that of retinoic acid metabolism pathway. Trans-resveratrol supplementation is beneficial to normalize long-term effects, but not short-term effects, of diabetes on retinoic acid metabolism pathway in the RPE.


Assuntos
Diabetes Mellitus Tipo 1/metabolismo , Resveratrol/farmacologia , Epitélio Pigmentado da Retina/efeitos dos fármacos , Epitélio Pigmentado da Retina/metabolismo , Tretinoína/metabolismo , Oxirredutases do Álcool/metabolismo , Animais , Diabetes Mellitus Tipo 1/enzimologia , Diabetes Mellitus Tipo 1/patologia , Indução Enzimática/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Ratos , Epitélio Pigmentado da Retina/patologia , Ácido Retinoico 4 Hidroxilase/biossíntese , Fatores de Tempo
7.
Toxicol Appl Pharmacol ; 339: 97-109, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-29229234

RESUMO

Hyperglycemia induces the formation of advanced glycation end products (AGEs) and their receptors (RAGEs), which alter several intracellular signaling mechanisms leading to the onset and progression of diabetic nephropathy. The present study focused on, i) modulatory effects of trans-resveratrol (3,5,4'-trihydroxy-trans-stilbene) on structural changes, AGE (NƐ-carboxymethyl-lysine), RAGE, oxidative stress and DNA damage, and apoptosis, and ii) localization of fibrotic changes, AGE, RAGE, 8-oxo-dG and 4-hydroxynonenal (4-HNE) in diabetic rat kidneys. Resveratrol (5mg/kg; po, administered during last 45days of 90-day-long hyperglycemic period) administration to streptozotocin-induced type 1 diabetic male Wistar rats reduced renal hypertrophy and structural changes (tubular atrophy, mesangial expansion or shrinkage, diffuse glomerulonephritis, and fibrosis), AGE accumulation, oxidative stress and DNA damage (8-oxo-dG), 4-HNE, caspase-3, and cleaved-caspase-3, but not the RAGE expression. The AGE accumulated in the mesangium, vascular endothelium, and proximal convoluted tubules and less intensely in distal convoluted tubules of diabetic rat kidneys. The RAGE expression increased in the convoluted tubules and collecting ducts of diabetic rat kidneys, but not in the mesangium. Diabetes increased the expression of 8-oxo-dG in nuclei and cytoplasm of renal cells, and 4-HNE in glomeruli, convoluted tubules, the loops of Henle and collecting ducts. Hyperglycemia-induced AGE-RAGE axis and oxidative stress in turn induced apoptosis in diabetic kidneys. Resveratrol mitigated all diabetic effects except the RAGE expression. In conclusion, Resveratrol significantly alleviates diabetes-induced glycation, oxidative damage, and apoptosis to inhibit the progression of diabetic nephropathy. Resveratrol supplementation may be useful to hinder the onset and progression of diabetic kidney diseases.


Assuntos
Dano ao DNA/fisiologia , Diabetes Mellitus Tipo 1/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Glomérulos Renais/metabolismo , Estresse Oxidativo/fisiologia , Estilbenos/uso terapêutico , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Dano ao DNA/efeitos dos fármacos , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/patologia , Glomérulos Renais/efeitos dos fármacos , Glomérulos Renais/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Peroxidação de Lipídeos/fisiologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Resveratrol , Estilbenos/farmacologia
8.
Med Princ Pract ; 25(5): 408-16, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27165129

RESUMO

OBJECTIVE: The aim of this study was to investigate the possible migration of proliferating peripheral retinal pigment epithelial (RPE) cells and their association with differential gene expressions. MATERIALS AND METHODS: The RPE layer was obtained from the inner aspect of the eyeball of dark agouti rats (12-13 weeks old) and was mounted on glass slides. The peripheral RPE cell proliferation was evaluated using bromodeoxyuridine immunohistochemistry (n = 10). The cell migration was examined using the Dil tracer technique (n = 40) at the end of weeks 6, 10, 14 and 18. Affymetrix microarray analysis was used to investigate differential gene expressions in peripheral and central RPE cells, which was authenticated by RT-PCR using 4 RPE-specific genes (n = 10). RESULTS: In this study, peripheral RPE cells divided and appeared in clusters, but equatorial and central RPE cells rarely divided. The peripheral RPE cells migrated to the central RPE region in a time-dependent manner up to the end of week 14, but not later. The microarray analysis showed the expression of 9,645 out of a total of 35,220 genes studied. Among the 9,645 genes, 573 were differentially expressed (438 were upregulated and 135 were downregulated) in peripheral RPE cells as compared to central RPE cells. Of these 573 genes, 56 were associated with signaling pathways related to the regulation of cell proliferation, including Pax6, TGFß, BMP and Wnt, and 404 were associated with pathways of cell migration. CONCLUSIONS: In this study, peripheral RPE cells divided and migrated to the central region. This process was associated with differential gene expressions in these cells.


Assuntos
Proteínas Morfogenéticas Ósseas , Movimento Celular , Proliferação de Células , Epitélio Pigmentado da Retina , Animais , Masculino , Proteínas Morfogenéticas Ósseas/metabolismo , Movimento Celular/genética , Proliferação de Células/genética , Regulação para Baixo , Regulação da Expressão Gênica , Análise Serial de Proteínas , Epitélio Pigmentado da Retina/citologia , RNA Mensageiro , Transdução de Sinais , Fatores de Tempo , Regulação para Cima
9.
Toxicol Appl Pharmacol ; 289(3): 482-94, 2015 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-26499206

RESUMO

Diabetes adversely affects reproductive functions in humans and animals. The present study investigated the effects of Resveratrol on diabetes-induced alterations in oxidative stress, c-Jun N-terminal kinase (JNK) signaling and apoptosis in the testis. Adult male Wistar rats (13-15 weeks; n=6/group) were segregated into 1) normal control, 2) Resveratrol-treated (5mg/kg; ip; given during last 3 weeks), 3) Streptozotocin-induced diabetic and, 4) Resveratrol-treated diabetic groups, and euthanized on day 42 after the confirmation of diabetes. Resveratrol did not normalize blood glucose levels in diabetic rats. Resveratrol supplementation recovered diabetes-induced decreases in reproductive organ weights, sperm count and motility, intra-testicular levels of superoxide dismutase, catalase, and glutathione peroxidase and an increase in 4-hydroxynonenal activities (P<0.05). Resveratrol also recovered diabetes-induced increases in JNK signaling pathway proteins, namely, ASK1 (apoptosis signal-regulating kinase 1), JNKs (46 and 54 kDa isoforms) and p-JNK to normal control levels (P<0.05). Interestingly, the expression of a down-stream target of ASK1, MKK4 (mitogen-activated protein kinase kinase 4) and its phosphorylated form (p-MKK4) did not change in experimental groups. Resveratrol inhibited diabetes-induced increases in AP-1 (activator protein-1) components, c-Jun and ATF2 (activating transcription factor 2), but not their phosphorylated forms, to normal control levels (P<0.05). Further, Resveratrol inhibited diabetes-induced increase in cleaved-caspase-3 to normal control levels. In conclusion, Resveratrol alleviates diabetes-induced apoptosis in testis by modulating oxidative stress, JNK signaling pathway and caspase-3 activities, but not by inhibiting hyperglycemia, in rats. These results suggest that Resveratrol supplementation may be a useful strategy to treat diabetes-induced testicular dysfunction.


Assuntos
Diabetes Mellitus Experimental/complicações , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Estilbenos/farmacologia , Doenças Testiculares/etiologia , Doenças Testiculares/metabolismo , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Diabetes Mellitus Experimental/metabolismo , Glutationa Peroxidase/metabolismo , Hiperglicemia/metabolismo , MAP Quinase Quinase 4/metabolismo , Masculino , Ratos , Ratos Wistar , Resveratrol , Estreptozocina/farmacologia , Superóxido Dismutase/metabolismo , Fator de Transcrição AP-1/metabolismo
10.
Exp Toxicol Pathol ; 67(2): 117-24, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25467746

RESUMO

Although diabetes induces retinopathy its effects on retinal pigment epithelium (RPE) are not clearly known. The present study investigated the effects of streptozotocin-induced diabetes on RPE cell proliferation and the expression of extracellular signal-regulated kinases 1 and 2 (ERK1/2), and c-Jun N-terminal kinases (JNKs) in rats. The bromodeoxyuridine immunohistochemistry revealed diabetes induced RPE cell proliferation at the end of first and second weeks in dark Agouti rats and at the end of first week in Wistar rats, but it inhibited the proliferation in both strains at the end of fifth week (P<0.05). A further analysis at the end of second week in the dark Agouti rats showed the cell proliferation, but not apoptosis, in association with an increase in ERK1/2 expression (P<0.05). However, the increased ERK level did not affect the expression of one of its substrates, the transcription factor c-Fos, suggesting that this protein has no role in the induction of the RPE cell proliferation. On the other hand, although total JNKs showed a decrease in the diabetic group (P<0.05), the JNKp46 isoform was increased and the JNKp54 isoform was decreased, but without any effects on one of their substrates, the transcription factor, c-Myc. Our results indicate that the RPE cell proliferation in diabetic rats may be mediated through mitogen-activated protein kinases. Thus, modulation of mitogen-activated protein kinases signaling may be a putative therapeutic option to alleviate the genesis of diabetes-induced retinal disruptions including retinopathy.


Assuntos
Proliferação de Células , Diabetes Mellitus Experimental , Sistema de Sinalização das MAP Quinases , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Epitélio Pigmentado da Retina/ultraestrutura , Animais , Western Blotting , Diabetes Mellitus Experimental/enzimologia , Diabetes Mellitus Experimental/patologia , Masculino , Microscopia Eletrônica de Transmissão , Ratos Endogâmicos
11.
Eur J Pharmacol ; 737: 29-40, 2014 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-24846010

RESUMO

Molecular mechanisms responsible for diabetes-induced testicular dysfunction are not well understood. This study investigated oxidative stress, stage-dependent DNA base modification and expression of poly (ADP ribose) polymerase 1 (PARP1) in the testes of streptozotocin-induced diabetic rats. Hyperglycemia led to testicular dysfunction characterized by impaired sperm parameters and testicular structure at the end of first (DM1) and third (DM3) month after the induction of diabetes. In the testis, total oxidant levels increased and total antioxidant levels decreased, which led to the induction of oxidative stress status. The oxidative stress up-regulated the levels of 8-oxo-7, 8-dihydro-2'-deoxyguanosine - an oxidized form of the DNA base, deoxyguanosine - in a stage-dependent manner. In DM1, stage VII-IX tubules showed more cytoplasmic expression of 8-oxo-7, 8-dihydro-2'-deoxyguanosine in all germ cell types and the Sertoli cells than did the other stage tubules, which suggested mitochondrial DNA damage. In DM3, mainly a stage-dependent nuclear expression of 8-oxo-7, 8-dihydro-2'-deoxyguanosine was observed in germ cells, but not in the Sertoli cells. Diabetes increased the cytoplasmic expression of 4-hydroxynonenal and concurrently inhibited the expression of both full length and 89kDa large cleaved-fragment of PARP1 in DM1 and DM3. The germ and Sertoli cells showed the nuclear expression of the protein in a stage-dependent manner, which decreased from DM1 to DM3. The increase in oxidative DNA damage and a decrease in PARP1 led to a stage-dependent induction of apoptosis of testicular cells. In conclusion, diabetes-induced oxidative stress, oxidative DNA damage and apoptosis occur in parallel with PARP1 inhibition in the testis.


Assuntos
Apoptose , Dano ao DNA , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Inibidores de Poli(ADP-Ribose) Polimerases , Testículo/metabolismo , Testículo/patologia , 8-Hidroxi-2'-Desoxiguanosina , Animais , Desoxiguanosina/análogos & derivados , Desoxiguanosina/metabolismo , Diabetes Mellitus Experimental/enzimologia , Diabetes Mellitus Experimental/fisiopatologia , Regulação Enzimológica da Expressão Gênica , Masculino , Tamanho do Órgão , Estresse Oxidativo , Poli(ADP-Ribose) Polimerases/metabolismo , Ratos , Ratos Sprague-Dawley , Reprodução , Epitélio Seminífero/patologia , Células de Sertoli/patologia , Contagem de Espermatozoides , Motilidade dos Espermatozoides , Espermatozoides/patologia , Espermatozoides/fisiologia , Testículo/fisiopatologia
12.
Exp Eye Res ; 88(3): 610-2, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18992244

RESUMO

Drusen are extra-cellular deposits that form between the retinal pigment epithelium (RPE) and Bruch's membrane (BM). Numerous and/or confluent drusen are a significant risk factor for age-related macular degeneration (AMD). Here, using whole mounted human RPE preparation we show that RPE cell morphology changes in association with drusen. These changes included an increase in cell size and distortion in the regularity of their distribution. Further, although binucleation is relatively rare in human RPE, there was a marked increase in the number of binucleated RPE cell associated with individual druse. Surprisingly many of these changes were found at distances up to 400 microm from drusen.


Assuntos
Drusas Retinianas/patologia , Epitélio Pigmentado da Retina/patologia , Idoso , Núcleo Celular/patologia , Tamanho Celular , Humanos , Pessoa de Meia-Idade
13.
Mol Vis ; 14: 1784-91, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18843376

RESUMO

PURPOSE: To investigate the capacity of mature retinal pigment epithelium (RPE) cells to enter the cell cycle in vivo using a range of RPE-specific and proliferative specific markers in both pigmented and albino rats. METHODS: Whole-mounted retinas of both Dark Agouti and albino rats were immunolabeled with cell cycle markers Ki67 or PCNA and double labeled with RPE cell marker RPE65 or CRALBP. The number and distribution of these cells was mapped. An additional group of Dark Agouti rats were given repeated intraperitoneal injections of Bromodeoxyuridine (BrdU )for 20 days and then sacrificed 30 days later. The retinas were then processed for BrdU detection and Otx, a RPE cell-specific marker. For comparison, human RPE tissue from a postmortem donor was also labeled for Ki67. RESULTS: In both pigmentation phenotypes, a subpopulation of mature RPE cells in the periphery were positive for both cell cycle markers. These cells were negative for Caspase 3, hence were not apoptotic. Ki67-positive cells were also seen in human RPE. Further, many cells positive for BrdU were identified in similar retinal regions, confirming that RPE cells not only enter the cell cycle but also divide, albeit at a slow cell cycle rate. There was a ten fold increase in the number of RPE cells positive for cell cycle markers in albino (approximately 200 cells) compared to pigmented rats (approximately 20 cells). CONCLUSIONS: Peripheral RPE cells in rats have the capacity to enter the cell cycle and complete cellular division.


Assuntos
Ciclo Celular , Diferenciação Celular , Epitélio Pigmentado da Retina/citologia , Animais , Bromodesoxiuridina/metabolismo , Divisão Celular , Proliferação de Células , Antígeno Ki-67/metabolismo , Pigmentação , Ratos , Ratos Wistar , Fatores de Tempo
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