Influence of ischemia-reperfusion injury on liver cancer and related mechanism / 临床肝胆病杂志

In the process of the surgical treatment of liver cancer, blood flow occlusion at the porta hepatis is an important method to reduce intraoperative bleeding, and ischemia-reperfusion injury (IRI) resulting from such occlusion has an important effect on tumor cell. IRI can not only lead to tumor recurrence and metastasis, but also exert an inhibitory effect on tumor. Such influence is associated with various factors including free radicals, nitric oxide, inflammatory cytokines, and enzymes. An understanding of such effect and related mechanisms is of great importance to the research on the association between IRI and liver cancer and the selection of treatment methods for liver cancer.

Advances in molecular chaperones regulating yeast prion [ PSI+] propagation / 军事医学

The finding and research on yeast prion are of great values for biology and medical sciences.Research advances in molecular chaperones, especially in Hsp104p, Hsp70p and Hsp40p, regulating yeast prion [PSI+] propaga-tion,are reviewed.

Estudo da degradação da proteína Tau hiperfosforilada por vias independentes do proteassoma, em modelo experimental de neurodegeneração / Study of hyperphosphorylated Tau protein degradation by proteasome-independent pathways, in an experimental model of neurodegeneration

O desenvolvimento das doenças neurodegenerativas, como a doença de Alzheimer, está associado à presença de agregados proteicos contendo Tau hiperfosforilada (p-Tau). Esta disfunção da Tau leva a prejuízos na homeostase celular. Um mecanismo chave para diminuir e/ou prevenir os danos promovidos pelos agregados contendo Tau seria o estímulo de sua degradação. Neste sentido, a proposta do presente estudo foi analisar a degradação da proteína Tau após aumento da expressão exógena da cochaperona Bag-2, a qual influencia o sistema proteassomal de degradação; bem como avaliar a ativação dos sistemas de degradação, a fim de correlacionar estes sistemas em cultura de células primárias e organotípica do hipocampo de ratos. Os resultados mostraram que a rotenona foi capaz de aumentar os níveis de p-Tau e que a superexpressão de Bag-2, foi eficiente em prevenir e degradar a p-Tau. O mecanismo envolvido neste processo envolve a coordenação dos sistemas proteassomal e lisossomal, já que a Rab7 e a Rab24 (envolvidas na via lisossomal) mostraram-se diminuídas na fase que antecede a agregação proteica, enquanto houve aumento da Rab24 na presença dos agregados proteicos. Com relação ao peptídeo beta amiloide, foi demonstrado tendência de aumento de p-Tau acompanhado de diminuição da atividade proteassomal e lisossomal. O tratamento com PADK (ativador lisossomal) foi capaz de reverter este efeito nestas diferentes condições. A análise da interrelação entre os sistemas mostrou que uma inibição do proteassoma favorece a via lisossomal e que o inverso não se repete. Os resultados sugerem que a modulação das vias de degradação pode ser interessante para o estudo, prevenção e tratamento das doenças neurodegenerativas associadas à agregação de proteínas...

Neurodegenerative diseases, such as Alzheimer's, are associated to protein inclusions containing hyperphosphorylated Tau (p-Tau). It is well established that Tau dysfunction impairs cell homeostasis. A key mechanism to prevent and/or reduce the damage promoted by aggregates of Tau might be its degradation. In view of this, the aims of the present study are to evaluate p- Tau clearance following exogenous expression of Bag-2, which stimulates proteasome; as well as to analyze the activation of both lysosome and proteasome pathways in order to understand the crosstalk between these two systems in primary and organotypic cultures of rat hippocampus. Results showed that rotenone was able of increasing p-Tau that was prevented and degraded by Bag-2 overexpression. Mechanisms involved in this process involve the coordination of cell degradation systems, depending upon aggregation status, since Rab7 and Rab24 (involved in lysosomal pathway) were decreased before protein aggregation, while Rab24 increased in the presence of protein inclusions. Amyloid-beta peptide also increased p-Tau accompanied by decreased proteasome and lysosome activity. PADK (lysosomal activator) treatment reverted the inhibition promoted by amyloidbeta peptide. Inhibition of proteasome leads to activation of lysosome, but lysosome inhibition does not affect proteasome. Overall, results suggest that targeting degradation pathways might be useful to understand, prevent and treat neurodegenerative diseases associated with protein deposits...

The immune modulating properties of the heat shock proteins after brain injury / 대한해부학회지

Inflammation within the central nervous system often accompanies ischemia, trauma, infection, and other neuronal injuries. The immune system is now recognized to play a major role in neuronal cell death due to microglial activation, leukocyte recruitment, and cytokine secretion. The participation of heat shock proteins (Hsps) in the immune response following in brain injury can be seen as an attempt to correct the inflammatory condition. The Hsps comprise various families on the basis of molecular size. One of the most studied is Hsp70. Hsp70 is thought to act as a molecular chaperone that is present in almost intracellular compartments, and function by refolding misfolded or aggregated proteins. Hsps have recently been studied in inflammatory conditions. Hsp70 can both induce and arrest inflammatory reactions and lead to improved neurological outcome in experimental brain injury and ischemia. In this review, we will focus on underlying inflammatory mechanisms and Hsp70 in acute neurological injury.

Up-regulation of glucose regulated protein 78 induced by 2-deoxyglnoose plays a protective role for fetal rat cerebral neuron following intrauterine distress / 中华妇产科杂志

Objective To evaluate the influence of up-regulation of glucose regulated protein 78 (GRP 78)induced by 2-deoxyglucose(2DG)on fetal rat cerebral neuron apoptosis following intrauterine distress and the unification of endoplasmic reticulum and mitochondrium.Methods (1) Fetal rat intrauterine distress model was established and rats were divided into normal group(n=10),ischemiareperfusion(IR) group( n = 40) and treatment group ( n = 40, injection of 2DG into pregnant rats' abdomen after operation ). (2) Neuron apoptosis and the influence of 2DG on apoptosis was detected by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) staining. The expression of GRP78, caspase-9,-12,and cytoron C protein were detected by western blot technique. Results (1) The number of TUNEL positive neuron in normal group was 4. 3±1. 8 /mm2. The expression of GRP78,caspase-9,-12, cytoron C in cytoplasm were 0.012±0.003, 0.004±0.003, 0.006±0.002, 0.012±0. 005, respectively. (2) The number of TUNEL positive neuron in the IR group were 43.6±11.4/mm2( reperfusion 3 h), 64. 4±9. 3/mm2 (repeffusion 6 h), 74. 2±12. 1/mm2 ( repeffusion 12 h), 97. 3±8. 9 /mm2 (reperfusion 24 h), respectively. They were significantly more than that in normal group(P ＜0. 05).The expression of GRP78 at corresponding times in IR group were 0. 092±0. 008 ( reperfusion 3 h), 0. 078±0.006 (reperfusion 6 h), 0.054±0.009 (reperfusion 12 h), 0.038±0.007 (reperfusion 24 h),respectively. The expression of cytoren C in cytoplasm at corresponding times in IR group were 0. 040±0. 006 (repeffusion 3 h), 0. 076±0. 009 (reperfusion 6 h), 0. 108±0. 005 (reperfusion 12 h), 0. 089±0. 008 (reperfusion 24 h), respectively. The expression of caspase-9 at corresponding times in IR group were 0. 042±0. 003 ( reperfusion 3 h), 0. 086±0. 007 ( reperfusion 6 h ), 0. 142±0. 006 ( reperfusion 12 h), 0. 112±0. 009 ( reperfusion 24 h), respectively. The expression of caspase-12 at corresponding times in IR group were 0. 076±0. 006 (reperfusion 3 h), 0. 113±0. 010 (reperfusion 6 h), 0. 125±0. 005 (reperfusion 12 h), 0. 057±0. 008 (reperfusion 24 h), respectively. They were significantly higher than that in normal group(P＜0. 05). (3) The number of TUNEL positive neuron in the treatment group were 19.4±10. 6/mm2 ( reperfusion 3 h), 26. 4±12. 3/mm2 ( repeffusion 6 h), 39. 3±13.3/mm2 ( reperfusion 12 h), 49. 3±13. 6/mm2 (reperfusion 24 h), respectively. They were significantly lower than that in IR group, but more than that in normal group(P＜0. 05). The expression of GRP78 at corresponding times in the treatment group were 0. 158±0.012 (repeffusion 3 h), 0. 175±0. 005 (reperfusion 6 h), 0. 125±0. 013 (reperfusion 12 h), 0. 079±0. 004 (reperfusion 24 h), respectively. They were significantly higher than that in IR group and normal group (P＜0. 05 ). The expression of cytoron C in cytoplasm at corresponding times in IR group were 0. 026±0. 002 (reperfusion 3 h), 0. 042±0. 008 (repeffusion 6 h),0. 062±0. 007 ( reperfusion 12 h), 0. 045±0. 004 ( reperfusion 24 h), respectively. The expression of caspase-9 at corresponding times in IR group were 0. 033±0. 002 ( reperfusion 3 h), 0. 063±0. 005(reperfusion 6 h), 0. 092±0. 005 (reperfusion 12 h), 0. 068±0. 008 (reperfusion 24 h), respectively.The expression of caspase-12 at corresponding times in IR group were 0. 061±0. 004 ( reperfusion 3 h),0. 068±0. 009 ( reperfusion 6 h), 0. 072±0. 007 ( reperfusion 12 h), 0. 054±0. 005 ( repedusion 24 h),respectively. They were significantly lower than that in IR group, but higher than that in normal group(P＜0. 05). Conclusions Fetal rat cerebral neuron apoptosis following intrauterine distress is associated with the action of endoplasmic reticulum and mitochondrium. Up-regulation of GRP78 induced by 2DG counteracts primary cellular damage caused by endoplasmic reticulum stress. 2DG plays a protective role for fetal rat cerebral neuron following intrauterine distress.

Heat Shock Proteins as Molecular Chaperons in Neuropsychiatry

Recent researches have shown that important cellular-based autoprotective mechanisms are mediated by heat-shock proteins(HSPs), also called 'molecular chaperones'. HSPs as molecular chaperones are the primary cellular defense mechanism against damage to the proteome, initiating refolding of denatured proteins and regulating degradation after severe protein damage. HSPs also modulate multiple events within apoptotic pathways to help sustain cell survival following damaging stimuli. HSPs are induced by almost every type of stresses including physical and psychological stresses. Our nervous system in the brain are more vulnerable to stress and damage than any other tissues due to HSPs insufficiency. The normal function of HSPs is a key factor for endogenous stress adaptation of neural tissues. HSPs play an important role in the process of neurodevelopment, neurodegeneration, and neuroendocrine regulation. The altered function of HSPs would be associated with the development of several neuropsychiatric disorders. Therefore, an understanding of HSPs activities could help to improve autoprotective mechanism of our neural system. This paper will review the literature related to the significance of HSPs in neuropsychiatric field.

Heat shock protein 27 interacts with vimentin and prevents insolubilization of vimentin subunits induced by cadmium

Vimentin is an intermediate filament that regulates cell attachment and subcellular organization. In this study, vimentin filaments were morphologically altered, and its soluble subunits were rapidly reduced via cadmium chloride treatment. Cadmium chloride stimulated three major mitogen-activated protein kinases (MAPKs): extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38, and led apoptotic pathway via caspase-9 and caspase-3 activations. In order to determine whether MAPKs were involved in this cadmium-induced soluble vimentin disappearance, we applied MAPK- specific inhibitors (PD98059, SP600125, SB203580). These inhibitors did not abolish the cadmium-induced soluble vimentin disappearance. Caspase and proteosome degradation pathway were also not involved in soluble vimentin disappearance. When we observed vimentin levels in soluble and insoluble fractions, soluble vimentin subunits shifted to an insoluble fraction. As we discovered that heat- shock protein 27 (HSP27) was colocalized and physically associated with vimentin in unstressed cells, the roles of HSP27 with regard to vimentin were assessed. HSP27-overexpressing cells prevented morphological alterations of the vimentin filaments, as well as reductions of soluble vimentin, in the cadmium-treated cells. Moreover, HSP27 antisense oligonucleotide augmented these cadmium-induced changes in vimentin. These findings indicate that HSP27 prevents disruption of the vimentin intermediate filament networks and soluble vimentin disappearance, by virtue of its physical interaction with vimentin in cadmium-treated SK-N-SH cells.