Induction of heat shock protein 70 and glial fibrillary acidic protein in the postischemic gerbil hippocampus

Immunohistochemical changes of heat shock protein 70 (HSP 70) and glial fibrillary acidic protein (GFAP) were investigated in the gerbil hippocampus 1 h-7 days after 10 min of cerebral ischemia. Transient cerebral ischemia caused HSP 70 expression in GFAP-positive astrocytes in a delayed fashion, as compared with a rapid induction in vulnerable neurons such as hilar neurons. The present results may offer clues to elucidate the mechanisms of ischemic neuronal damage.     

A non-toxic heat shock protein 70 inducer, geranylgeranylacetone, suppresses apoptosis of cultured rat hepatocytes caused by hydrogen peroxide and ethanol

BACKGROUND/AIMS: A stress-inducible heat shock protein 70 (HSP70) is one of the best-known endogenous factors protecting cell injury under various pathological conditions. The aim of this study was to examine anti-apoptotic actions of a non-toxic HSP70 inducer, geranylgeranylacetone (GGA), on hepatocytes exposed to hydrogen peroxide (H2O2) or ethanol. METHODS: Primary cultures of rat hepatocytes were treated with different concentrations of GGA and exposed to 0.5 mM H202 or 100 mM ethanol. The heat shock response was assessed by measuring the activation of heat shock factor 1 (HSF1), HSP70 mRNA expression, and accumulations of HSP70, HSP90, and HSP27. Apoptosis was evaluated by DNA fragmentation. RESULTS: Pretreatment with 1 microM GGA for 2 h enhanced nuclear translocation and phosphorylation of HSF1, HSF1-DNA binding, HSP70 mRNA expression, and its accumulation, when the cells were exposed to H202 or ethanol. In association with this accelerated response, GGA suppressed the insult-induced activation of c-Jun N-terminal kinases, caspase 9, and caspase 3-like proteases, leading to significant inhibition of apoptosis. CONCLUSIONS: GGA exerted anti-apoptotic actions, at least in part, by priming hepatocytes for enhanced HSP70 induction. Our results suggest that GGA may have a potential benefit for the treatment of alcoholic and ischemia-reperfusion liver injuries.     

热休克蛋白70系列与应激性溃疡之间的相互关系

生物细胞在受到各种理化因素刺激后,可以产生一系列的应激反应,诱导热休克蛋白(heat shock protein,HSP)表达.在众多的HSP中,HSP70家族是生物进化过程中最为保守也是目前人们研究最多的一组蛋白.应激可以诱导机体胃黏膜的损伤并可以降低胃黏膜的屏障保护作用,进而导致应激性溃疡的产生,同时加速热休克蛋白的合成,而热休克蛋白反过来又可预防应激性溃疡的发生,抑制胃黏膜细胞凋亡,促进胃溃疡的愈合.本文综述了主要的热休克蛋白分子的分类、调节以及在应激性溃疡中的表达和应用,并简要论述了通过诱导热休克蛋白表达而作为胃黏膜保护剂的几种药物.     

银杏叶提取物对大鼠脑缺血再灌注损伤热休克蛋白70表达的影响

目的探讨银杏叶提取物对大鼠缺血再灌注损伤热休克蛋白70表达的影响。方法42只大鼠随机分为3组:假手术组、单纯缺血再灌注组、缺血再灌注+银杏叶提取物组,每组14只。通过免疫组织化学方法和原位末端标记法(TUNEL)检测热休克蛋白70表达及凋亡细胞数,TTC染色观察梗死体积。结果3组均可检测到热休克蛋白70的表达,单纯缺血再灌注组热休克蛋白70的表达较假手术组增强(P<0.01),缺血再灌注+银杏叶提取物组较缺血再灌注组表达增强(P<0.05)。缺血再灌注+银杏叶提取物组梗死体积及凋亡细胞数明显少于缺血再灌注组(P<0.01)。结论银杏叶提取物可能通过上调缺血缺氧后热休克蛋白70的表达减少神经细胞凋亡。     

Radiofrequency ablation,heat shock protein 70 and potential anti-tumor immunity in hepatic and pancreatic cancers:a minireview

BACKGROUND: Radiofrequency ablation (RFA) is a minimally invasive surgical procedure which has widespread popularity in the treatment of hepatic and pancreatic cancers. Increased evidence indicates that RFA stimulates anti-tumor immunity, possibly through the induction heat shock protein 70 (HSP70) expression. HSP70 has the capacity to affect the immunogenicity of tumor cells, to chaperone antigenic peptides and deliver these into antigen presentation pathways within antigen-presenting cells, and to activat...     

Cytoprotective mechanism of heat shock protein 70 against hypoxia/reoxygenation injury

The role of heat shock protein 70 (HSP70) in the cytoprotection against hypoxia/reoxygenation injury was examined. Adult rat cardiomyocytes were isolated, subjected to hyperthermia at 42 degrees C for 15 min (heat shock treatment), and then incubated at 37 degrees C for 3 to 24 h (HSP production process). Heat shock treatment increased HSP70 production (80-260% increase); the peak increase was seen after 9 h of HSP production process. Thereafter, the cells were subjected to 120-min hypoxia and 15-min reoxygenation. Heat shock treatment increased the survival of the cells subjected to hypoxia/reoxygenation (1.5-2.5-fold); the maximal cytoprotection was observed after 12 h of HSP production process. Heat shock treatment increased HSP70 content in the nucleus when cells were subjected to 12 h of HSP production process. To examine the role of HSP70 accumulation in the nuclear fraction, the activity of poly(ADP-ribose) synthetase (PARS), which functions in the nucleus and consumes high-energy phosphates excessively in the reoxygenated state, were measured in the cells with heat shock and 12 h of HSP production process. Heat shock treatment attenuated the hypoxia/reoxygenation-induced increase in the PARS activity (50% decrease). Treatment of the cells with 3-aminobenzamide, an inhibitor of PARS, exerted the effects similar to those of heat shock treatment. These results suggest that attenuation of the PARS activity in the nucleus may play an important role in the cytoprotective effect of HSP70 on hypoxia/reoxygenation injury.     

Altered lymphocyte heat shock protein 70 expression in patients with HIV disease

Heat shock protein (HSP) expression in lymphocytes isolated from 20 patients with HIV disease and 15 age-matched controls was determined. Fold increases in lymphocyte hsp70 expression after heat shock were 4.52 +/- 2.97 in HIV-positive individuals compared with 2.60 +/- 1.29 for HIV-negative controls (P= 0.001). Given clear roles for HSP in the cross-presentation of antigens, alpha-defensin internalization and pro-inflammatory cytokine production, a further investigation of HSP in HIV patients is merited.     

Potentiation of baroreceptor reflex response by heat shock protein 70 in nucleus tractus solitarii confers cardiovascular protection during heatstroke

BACKGROUND: Whereas hypotension and bradycardia seen during the onset of heatstroke may be protected by prior induction of heat shock protein 70 (HSP70) in the brain, the underlying mechanism is not fully understood. We evaluated the hypothesis that HSP70 may confer cardiovascular protection during heatstroke by potentiating the baroreceptor reflex (BRR) control of peripheral hemodynamic performance. METHODS AND RESULTS: Adult male Sprague-Dawley rats subjected to a brief hyperthermic heat shock (HS; 42 degrees C for 15 minutes) induced discernible expression of HSP70 in the bilateral nucleus tractus solitarii (NTS), the terminal site in the brain stem for primary baroreceptor afferents. This HSP70 expression was detected at 8 hours, peaked at 24 hours, and returned to baseline by 48 hours after HS. Brief hyperthermia also significantly potentiated the BRR response in a temporal profile that correlated positively with changes in HSP70 expression at the NTS. Prior HS also appreciably alleviated hyperthermia, severe hypotension, and bradycardia manifested during the onset of heatstroke (45 degrees C for 60 minutes) elicited 24 hours later. Microinjection bilaterally of anti-HSP70 antiserum (1:20) into the NTS or denervation of the sinoaortic baroreceptor afferents significantly reversed the enhancement of BRR response and cardiovascular protection during heatstroke induced by prior HS. CONCLUSIONS: These results suggest that HS-induced expression of HSP70 in the NTS may alleviate severe hypotension and bradycardia exhibited during the onset of heatstroke by potentiating both the sensitivity and capacity of BRR response.     

Identification of cytosolic peroxisome proliferator binding protein as a member of the heat shock protein HSP70 family.

Clofibrate and many of its structural analogues induce proliferation of peroxisomes in the hepatic parenchymal cells of rodents and certain nonrodent species including primates. This induction is tissue specific, occurring mainly in the liver parenchymal cells and to a lesser extent in the kidney cortical epithelium. The induction of peroxisomes is associated with a predictable pleiotropic response, characterized by hepatomegaly, and increased activities and mRNA levels of certain peroxisomal enzymes. Using affinity chromatography, we had previously isolated a protein that binds to clofibric acid. We now show that this protein is homologous with the heat shock protein HSP70 family by analysis of amino acid sequences of isolated peptides from trypsin-treated clofibric acid binding protein and by cross-reactivity with a monoclonal antibody raised against the conserved region of the 70-kDa heat shock proteins. The clofibric acid-Sepharose column could bind HSP70 proteins isolated from various species, which could then be eluted with either clofibric acid or ATP. Conversely, when a rat liver cytosol containing multiple members of the HSP70 family was passed through an ATP-agarose column, and eluted with clofibric acid, only P72 (HSC70) was eluted. These results suggest that clofibric acid, a peroxisome proliferator, preferentially interacts with P72 at or near the ATP binding site.     

Expression and significance of heat shock protein 70 and glucose-regulated protein 94 in human esophageal carcinoma

AIM: To investigate the expression and significance of heat shock protein 70 (HSP70) and glucose-regulated protein 94 (grp94) in human esophageai carcinoma and adjacent normal tissues. METHODS: The expression of HSP70 and grp94 in 78 human esophageai cancer and adjacent normal tissues was studied by immunohistochemistry and pathology photograph analysis. RESULTS: Both esophageai cancer and adjacent normal tissues could express HSP70 and grp94. Of the 78 cases of esophageai carcinoma, 95.0%(72/78) showed positive HSP70, mainly stained in nuclei, while grp94 was mainly stained in cell plasma, and the positive rate was 71.8% (56/78).There was a significant difference in the expression of HSP70 and grp94 between esophageai cancer and adjacent normal tissues (P<0.01). Compared with adjacent normal tissues, there was a significant difference between differential types and HSP70 expression (P<0.01). CONCLUSION: HSP70 and grp94 express differently in cell plasma and nuclei. The expression intensity of HSP70 is related to the differentiation of esophageai carcinoma.     

肝细胞癌组织HSP70、p53和PCNA的表达及其意义

目的探讨热休克蛋白70（HSP70）、p53和增殖细胞核抗原（PCNA）在肝细胞癌（HCC）组织中的表达及其意义。方法采用免疫组化法检测正常人、慢性乙型肝炎、肝硬化和HCC肝或癌组织HSP70、p53和PCNA的表达情况。结果 HCC组织HSP70、p53和PCNA表达阳性率明显高于非癌组织（x1^2=27.16x2^2=67.6,x3^2=40.6,P〈0.01）;HSP70在正常人、慢性乙型肝炎、肝硬化和HCC中的表达逐步增强;HSP70和p53在分化较好的HCC中的阳性率明显低于分化不良者（x1^2=6.8,P1〈0.01x2^2=6.1,P2〈0.05）,而PCNA表达与HCC组织分化程度无关（x2=2.4,P〉0.05）;HSP70表达强度与p53和PCNA表达关系密切（x1^2=41.3,x2^2=41.4,P〈0.01）。结论 HCC是HSP70高表达肿瘤。HSP70表达与p53和PCNA表达密切相关,因而在HCC发生和发展中起重要作用。     

Cross-sectional correlates of serum heat shock protein 70 in the community

BACKGROUND: Recent studies of referral samples suggest that heat shock proteins play a key role in the pathogenesis of high BP and cardiovascular diseases (CVD) including heart failure. It is unclear whether circulating heat shock protein 70 (HSP70) levels are related to CVD risk factors, echocardiographic indexes of left ventricular (LV) remodeling, and prevalent CVD in the population. METHODS: We evaluated the cross-sectional relations of serum HSP70 to established CVD risk factors (including hypertension), markers of oxidative stress (urinary 8-epi-PGF(2alpha)) and inflammation (plasma interleukin-6, C-reactive protein, monocyte chemoattractant protein-1 MCP-1, and soluble intercellular adhesion molecule sICAM-1), echocardiographic LV dimensions and prevalent CVD in 456 Framingham Offspring Study participants (mean age 61 years, 42% women). RESULTS: In multivariable analyses, serum HSP70 was not associated with age, sex, vascular risk factors (including hypertension), echocardiographic LV mass or prevalent CVD. Also, serum HSP70 was not related to any of the biomarkers evaluated (p> or = 0.10 for all). CONCLUSIONS: In our community-based sample, serum HSP70 was similar in men and women, and not significantly related to traditional or novel risk factors, to LV mass or to prevalent CVD. Our data suggest that blood levels may not adequately reflect the important role of heat shock proteins in prevalent CVD.     

Expression of different members of heat shock protein 70 gene family in liver and hepatomas

The levels of expression of some genes of the HSP 70 family have been assessed in rat liver and in a series of transplantable hepatomas with different growth rates, subjected to heat shock in vivo. For this purpose, the mRNAs for the constitutive cognate HSC 73, the heat-inducible HSP 70 and the glucose-regulated GRP 78 have been analyzed by: (i) translation in reticulocyte lysates; (ii) hybrid-selected translation, and (iii) Northern blot analysis. In comparison with the liver, the fast-growing 3924A hepatoma has an increased constitutive amount of HSC 73 mRNA and a lower induction of HSP 70 mRNA after heat shock. The behavior of the 9618A slow-growing hepatoma is more similar to that of the liver, indicating that the changes detected in the fast-growing hepatoma are correlated to the high growth rate of the tumor rather than to carcinogenesis. This conclusion is reinforced by the results obtained with Yoshida AH-130 cells, growing at two different rates imposed by the environment in which they develop. When the Yoshida hepatoma grows rapidly in the peritoneal cavity, constitutive expression of HSC 73 mRNA is high and the inducibility of HSP 70 mRNA is poor: the opposite occurs when the tumor grows slowly in the subcutaneous compartment. The amount of GRP 78 mRNA increases progressively from the liver to the fast-growing hepatoma. The level of HSC 73 mRNA seems to correlate with the methylation state of the corresponding gene.     

慢性浅表性胃炎脾胃湿热证与热休克蛋白7O表达的关系

[目的]探讨慢性浅表性胃炎（CSG）脾胃湿热证与热休克蛋白70（HSP70）表达的关系。[方法]睽沿患者38例,其中脾胃湿热证22例、脾气虚证16例,另10例正常人为对照。胃镜下取胃窦黏膜,采用免疫组织化学检测HSP70蛋白表达情况。[结果]脾胃湿热证组和脾虚证组HSP70蛋白表达明显高于正常对照组（P〈0．01）}脾胃湿热证组各亚型中,HSP70表达水平呈热重于湿〉湿热并重〉湿重于热的趋势。[结论]HSP70属于人体“阳气”范畴,HSP70以热证表达最为明显,具有证的特异性;“热”与“湿”在脾胃湿热证中的比分会影响HSPT0在脾胃湿热证型中的表达：热邪提高HSP70表达,湿邪抑制HSP70表达。     

热休克蛋白70 mRNA在老年人胃癌中表达的意义

目的探讨热休克蛋白70 mRNA(HSP70 mRNA)在胃癌发生中的意义.方法取胃癌44例,癌旁不典型增生20例,单纯不典型增生16例,浅表性胃炎20例.采用核酸原位杂交技术(ISH)检测HSP70 mRNA表达状况.结果在胃癌、癌旁不典型增生和单纯不典型增生中HSP70 mRNA的阳性率分别为61.36(27/44)、55.00%(11/20)和31.25%(5/16);在浅表性胃炎组阳性率为5.00%(1/20).HSP70 mRNA表达与癌细胞浸润深度和淋巴结转移无明显相关性.结论 HSP70 mRNA在胃癌形成早期有较高表达,检测HSP70 mRNA可以作为胃癌早期诊断的指标.     

肺结核患者血浆中热休克蛋白70的表达及意义

目的通过检测肺结核患者外周血中热休克蛋白70(HSP70)的表达情况,旨在探讨HSP70与肺结核的关系。方法采用双抗体夹心ELISA法检测32例活动性肺结核组患者外周血中HSP70蛋白的表达情况,并与25例稳定性肺结核组及30例健康对照组进行对照分析。结果活动性肺结核患者血浆中HSP70蛋白表达水平为(7.5±1.3)ng/ml,显著高于稳定性肺结核组(5.5±1.7)ng/ml及健康对照组(5.3±0.8)ng/m(P<0.01);稳定性肺结核组与健康对照组比较差异无显著性(P>0.05)。结论活动性肺结核患者存在HSP70的过度表达,提示HSP70可能通过某些未明机制参与活动性肺结核的发病,并可辅助肺结核活动性的判断。