Histology and histopathology Vol.21, nº 7 (2006)
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- PublicationOpen AccessHistological recovery of the hepatocytes is based on the redox system upregulation in the animal models of mutant superoxide dismutase (SOD)1-linked amyotrophic lateral sclerosis(Murcia : F. Hernández, 2006) Kato, Massuo J.; Kato, S.; Abe, Y.; Nishino, T.; Ohama, E.; Aoki, M.; Itoyama, Y.Histological rescue of superoxide dismutase1 (SOD1)-mutated hepatocytes from mutant SOD1 stress is investigated from the viewpoint of upregulation of the redox system [peroxiredoxin (Prx) and glutathione peroxidase (GPx)]. Histopathological and immunohistochemical studies using antibodies against PrxI/PrxII/GPxI were carried out on specimens from four different strains of animal models of mutant SOD1- linked familial amyotrophic lateral sclerosis (ALS). In the livers of the ALS animal models in the presymptomatic stage without motor neuron loss, both swollen and eosinophilic hepatocytes with vacuolation pathology were observed. After developing motor deficits, this swelling and vacuolation ceased to be apparent. In the terminal stage when severe motor neuron loss was observed, these hepatocytes recovered and appeared normal. In redox system-related immunohistochemical preparations, almost all of the normal hepatocytes expressed the redox system-related enzymes PrxI/PrxII/GPxI. In the presymptomatic stage, some hepatocytes did not express redox system-related enzymes. After clinical onset, over 75% of hepatocytes showed overexpression of PrxI/PrxII/GPxI, i. e., upregulation of the redox system. At the end stage, near normal PrxI/PrxII/GPxI expression was observed again in the hepatocytes. Redox system upregulation in SOD1- mutated hepatocytes rescues hepatocytes from the mutant SOD1 stress that leads to motor neuron death.
- PublicationOpen AccessAltered patterns of RB expression define groups of soft tissue sarcoma patients with distinct biological and clinical behavior(Murcia : F. Hernández, 2006) Polsky, D.; Mastorides, S.; Kim, D.; Dudas, M.; Leon, L.; Leung, D.; Woodruff, J.M.; Brennan, M.F.; Osman, I.; Cordon-Cardo, C.Background: Function of the retinoblastoma tumor suppressor protein (pRB) may be compromised at a genetic level by gene loss or mutation or at a posttranslational level by hyperphosphorylation. In this study, we examined adult soft tissue sarcomas (ASTS) to determine if alterations of pRB were associated with distinct patterns of pRB expression and clinical outcome. Design: We investigated 86 ASTS patients using monoclonal antibodies that distinguish between hyperphosphorylated and underphosphorylated pRB products. We also used microsatellite analysis to investigate the genetic status of the RB locus. We correlated pRB alterations with proliferative activity, and with clinicopathological outcomes. Results: Altered patterns of pRB expression are common in ASTS occurring in 84% of cases, and it is significantly associated with proliferative activity (p<0.001). Patients whose tumors either lack expression of pRB, or express hyperphosphorylated forms of pRB, have poor survivals compared to patients whose tumors exhibit a normal, underphosphorylated pattern of pRB expression (p=0.03). In addition, 63% of cases lacking expression of pRB showed loss-of-heterozygosity at the locus Conclusions: Inactivation of pRB is common in adult STS, which may be due to either gene loss or posttranslational modification, namely hyperphosphorylation. Both mechanisms are associated with tumor cell proliferation and poor survival.
- PublicationOpen AccessHistone modifications in status epilepticus induced by Kainate(Murcia : F. Hernández, 2006) Taniura, H.; Sng, J.C.G.; Yoneda, Y.Animal models of epilepsy have allowed the determination of the basic molecular and cellular mechanisms of epileptogenesis. Generalized limbic seizures and subsequent status epilepticus can be induced by either pilocarpine, the muscarinic acetylcholine receptor agonist or kainate, the glutamate receptor agonist. There has been increasing interest that chromatin remodeling might play a critical role in gene regulation even in non-dividing cells such as neurons. One form of chromatin remodeling is histone aminoterminal modification that can generate synergistic or antagonistic affinities for the interactions of transcriptional factors, in turn causing changes in gene activity. Two widely studied histone modification processes are histone acetylation and phosphorylation. While histone hyperacetylation indicates an increase in gene activity, its hypoacetylation marks gene repression. Both states are controlled by a dynamic interplay of histone acetyltransferase (HAT) and histone deacetylase (HDAC). We have found the upregulation of acetylation and phosphorylation of histones, coupled with status epilepticus after kainate administration. c-fos and c-jun mRNA have been sequentially induced in response to kainate, in different hippocampal subpopulations starting from the dentate gyrus and spreading to the cornus ammonis regions well correlated with the spatiotemporal distribution of histone H4 hyperacetylation. Both histone modifications are associated with the c-fos gene promoter after kainate stimulation, while only histone acetylation with the c-jun gene. Pretreatment with curcumin, which has a HAT inhibitory activity specific for CBP/p300, attenuates histone modifications, IEGs expression and also the severity of status epilepticus after kainate treatment. Histone modifications may have a crucial role in the development of epilepsy induced by kainate.
- PublicationOpen AccessComparison of MR images and histochemical localization of intra-arterially administered microglia surrounding ß-amyloid deposits in the rat brain(Murcia : F. Hernández, 2006) Song, Y.; Morikawa, S.; Morita, M.; Inubushi, T.; Takada, T.; Torii, R.; Kitamura, Y.; Taniguchi, T.; Tooyama, I.The therapeutic use of microglial cells has recently received some attention for the treatment of Alzheimer disease (AD), but few non-invasive techniques exist for monitoring the cells after administration. Here we present a magnetic resonance imaging (MRI) technique for tracking microglia injected intra-arterially in vivo. We micro-injected Aß42 into the left hippocampus and saline into the right hippocampus of rats. We then administered microglia, which were labeled with enhanced green fluorescent protein (EGFP) gene and Resovist, into the carotid artery. After monitoring exogenously administered microglia using MRI, we compared the MR images and the histochemical localization of administered microglia. MRI revealed clear signal changes attributable to Resovist-containing microglia in Aß-injected areas. Histochemistry demonstrated that EGFP-positive microglia accumulated around Aß deposits and internalized the peptide. This study demonstrates the usefulness of MRI for non-invasive monitoring of exogenous microglia, and suggests a promising future for microglia/macrophages as therapeutic tools for AD.
- PublicationOpen AccessQuantitative cell-cycle protein expression in oral cancer assessed by computer-assisted system(Murcia : F. Hernández, 2006) Soares, C.P.; Zuanon, J.A.S.; Teresa, D.B.; Fregonezi, P.A.; Neto, C.B.; Oliveira, M.R.B.; Donadi, E.A.; Martinelli-Kläy, C.P.; Soares, E.G.The knowledge of cell-cycle control has shown that the capacity of malignant growth is acquired by the stepwise accumulation of defects in specific genes regulating cell growth. Histologic diagnosis might be improved by a quantitative evaluation of more specific diagnosis biomarkers, which could help to precisely identify pre-malignant and malignant oral lesions. The aim of the present study is to evaluate whether computer-based quantitative assessment of p53, PCNA and Ki-67 immunohistochemical expression, could be used clinically to foresee the risk of oral malignant transformation. This retrospective study was carried out in ninety-five oral biopsies, 27 were classified as fibrous inflammatory hyperplasia, 40 as leukoplakia and 28 as oral squamous cell carcinoma. Sixteen out of the 40 leukoplakia were diagnosed as non-dysplastic leukoplakia, the other 24 being dysplastic leukoplakia, of which 50.0% were classified as moderate to severe dysplasia. Comparison of the four groups of oral tissues showed significant rises in p53 and Ki-67 positivity index, which increased steadily in the order benign, premalignant, and malignant. In contrast, it was not possible to relate higher PCNA levels with pre-malignant and malignant oral lesions. We therefore conclude that PCNA immunohistochemistry expression is probably an inappropriate marker to identify oral carcinogenesis, whereas joint quantitative evaluation of p53 and Ki-67, appears to be useful as a tumor marker, providing a prediagnostic estimate of the potential for cell-cycle deregulation of the oral proliferate status.
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