| 1. |
- Daré, Elisabetta, et al.
(författare)
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Methylmercury and H2O2 provoke lysosomal damage in human astrocytoma D384 cells followed by apoptosis
- 2001
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Ingår i: Free Radical Biology & Medicine. - Linköping : Elsevier. - 0891-5849 .- 1873-4596. ; 30:12, s. 1347-1356
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Tidskriftsartikel (refereegranskat)abstract
- Methylmercury (MeHg) is a neurotoxic agent acting via diverse mechanisms, including oxidative stress. MeHg also induces astrocytic dysfunction, which can contribute to neuronal damage. The cellular effects of MeHg were investigated in human astrocytoma D384 cells, with special reference to the induction of oxidative-stress-related events. Lysosomal rupture was detected after short MeHg-exposure (1 μM, 1 h) in cells maintaining plasma membrane integrity. Disruption of lysosomes was also observed after hydrogen peroxide (H2O2) exposure (100 μM, 1 h), supporting the hypothesis that lysosomal membranes represent a possible target of agents causing oxidative stress. The lysosomal alterations induced by MeHg and H2O2 preceded a decrease of the mitochondrial potential. At later time points, both toxic agents caused the appearance of cells with apoptotic morphology, chromatin condensation, and regular DNA fragmentation. However, MeHg and H2O2 stimulated divergent pathways, with caspases being activated only by H2O2. The caspase inhibitor z-VAD-fmk did not prevent DNA fragmentation induced by H2O2, suggesting that the formation of high-molecular-weight DNA fragments was caspase independent with both MeHg and H2O2. The data point to the possibility that lysosomal hydrolytic enzymes act as executor factors in D384 cell death induced by oxidative stress.
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| 2. |
- Beral, V, et al.
(författare)
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Alcohol, tobacco and breast cancer - collaborative reanalysis of individual data from 53 epidemiological studies, including 58515 women with breast cancer and 95067 women without the disease
- 2002
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Ingår i: British Journal of Cancer. - : Springer Science and Business Media LLC. - 1532-1827 .- 0007-0920. ; 87, s. 1234-45
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Tidskriftsartikel (refereegranskat)abstract
- Alcohol and tobacco consumption are closely correlated and published results on their association with breast cancer have not always allowed adequately for confounding between these exposures. Over 80% of the relevant information worldwide on alcohol and tobacco consumption and breast cancer were collated, checked and analysed centrally. Analyses included 58515 women with invasive breast cancer and 95067 controls from 53 studies. Relative risks of breast cancer were estimated, after stratifying by study, age, parity and, where appropriate, women's age when their first child was born and consumption of alcohol and tobacco. The average consumption of alcohol reported by controls from developed countries was 6.0 g per day, i.e. about half a unit/drink of alcohol per day, and was greater in ever-smokers than never-smokers, (8.4 g per day and 5.0 g per day, respectively). Compared with women who reported drinking no alcohol, the relative risk of breast cancer was 1.32 (1.19 - 1.45, P < 0.00001) for an intake of 35 - 44 g per day alcohol, and 1.46 (1.33 - 1.61, P < 0.00001) for greater than or equal to 45 g per day alcohol. The relative risk of breast cancer increased by 7.1% (95% CI 5.5-8.7%; P<0.00001) for each additional 10 g per day intake of alcohol, i.e. for each extra unit or drink of alcohol consumed on a daily basis. This increase was the same in ever-smokers and never-smokers (7.1 % per 10 g per day, P < 0.00001, in each group). By contrast, the relationship between smoking and breast cancer was substantially confounded by the effect of alcohol. When analyses were restricted to 22 255 women with breast cancer and 40 832 controls who reported drinking no alcohol, smoking was not associated with breast cancer (compared to never-smokers, relative risk for ever-smokers= 1.03, 95% CI 0.98 - 1.07, and for current smokers=0.99, 0.92 - 1.05). The results for alcohol and for tobacco did not vary substantially across studies, study designs, or according to 15 personal characteristics of the women; nor were the findings materially confounded by any of these factors. If the observed relationship for alcohol is causal, these results suggest that about 4% of the breast cancers in developed countries are attributable to alcohol. In developing countries, where alcohol consumption among controls averaged only 0.4 g per day, alcohol would have a negligible effect on the incidence of breast cancer. In conclusion, smoking has little or no independent effect on the risk of developing breast cancer; the effect of alcohol on breast cancer needs to be interpreted in the context of its beneficial effects, in moderation, on cardiovascular disease and its harmful effects on cirrhosis and cancers of the mouth, larynx, oesophagus and liver. (C) 2002 Cancer Research UK.
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| 3. |
- Hardling, Mats, et al.
(författare)
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Serial monitoring of BCR-ABL transcripts in chronic myelogenous leukemia (CML) treated with imatinib mesylate
- 2004
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Ingår i: Med Oncol. - 1357-0560. ; 21:4, s. 349-58
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Tidskriftsartikel (refereegranskat)abstract
- Survival among chronic myelogenous leukemia (CML) patients can be linked to the reduction in leukemic cell burden. Treatment with imatinib mesylate results in a high frequency of complete cytogenetic response, which can be further stratified using quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR). We have serially monitored peripheral blood and bone marrow BCR-ABL transcripts using qRT-PCR in CML patients commencing imatinib therapy, and compared the results with bone marrow cytogenetics. Seventeen patients (aged 25-74 yr) with Philadelphia chromosome positive CML in first chronic phase were treated with imatinib targeting a dose of 400 mg/d. The median follow up is 30 mo (range 9-33 mo). Every third month the product of the BCR-ABL fusion gene was evaluated in both blood and bone marrow specimens by real-time RT-PCR using the TaqMan probe system. In 113 simultaneously obtained blood and bone marrow samples, the BCR-ABL transcript values agreed well with cytogenetic data. Blood and bone marrow specimens gave comparable values for BCR-ABL transcripts. Before start of imatinib therapy there was a considerable variation in BCR-ABL transcripts among the patients, ranging approximately one log (base 10). Similarly, patients with a complete cytogenetic response following imatinib therapy had variable BCR-ABL transcript levels, ranging at least three logs (base 10). The major decline in BCR-ABL transcripts occurred within 6 mo after start of imatinib therapy. The decline in BCR-ABL transcripts, following imatinib therapy, appears to level off at 12-15 mo. Two late responders were identified with a still decreasing level in BCR-ABL transcripts after 24 mo of treatment. It is concluded that BCR-ABL mRNA quantification in peripheral blood is suitable for routine monitoring of the response to treatment and long-term disease status in CML, especially in patients who have achieved a complete cytogenetic response. A plateau in BCR-ABL transcripts seems to have been reached after 12-15 mo of imatinib treatment; however, some "late responders" are seen.
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| 4. |
- Li, Wei, et al.
(författare)
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3-Aminopropanal, formed during cerebral ischaemia, is a potent lysosomotropic neurotoxin
- 2003
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Ingår i: Biochemical Journal. - 0264-6021 .- 1470-8728. ; 371:2, s. 429-436
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Tidskriftsartikel (refereegranskat)abstract
- Cytotoxic polyamine-derived amino aldehydes, formed during cerebral ischaemia, damage adjacent tissue (the so-called 'penumbra') not subject to the initial ischaemic insult. One such product is 3-aminopropanal (3-AP), a potent cytotoxin that accumulates in ischaemic brain, although the precise mechanisms responsible for its formation are still unclear. More relevant to the present investigations, the mechanisms by which such a small aldehydic compound might be cytotoxic are also not known, but we hypothesized that 3-AP, having the structure of a weak lysosomotropic base, might concentrate within lysosomes, making these organelles a probable focus of initial toxicity. Indeed, 3-AP leads to lysosomal rupture of D384 glioma cells, a process which clearly precedes caspase activation and apoptotic cell death. Immunohistochemistry reveals that 3-AP concentrates in the lysosomal compartment and prevention of this accumulation by the lysosomotropic base ammonia, NH3, protects against 3-AP cytotoxicity by increasing lysosomal pH. A thiol compound, N-(2-mercaptopropionyl)glycine, reacts with and neutralizes 3-AP and significantly inhibits cytoxocity. Both amino and aldehyde functions of 3-AP are necessary for toxicity: the amino group confers lysosomotropism and the aldehyde is important for additional, presently unknown, reactions. We conclude that 3-AP exerts its toxic effects by accumulating intralysosomally, causing rupture of these organelles and releasing lysosomal enzymes which initiate caspase activation and apoptosis (or necrosis if the lysosomal rupture is extensive). These results may have implications for the development of new therapeutics designed to lessen secondary damage arising from focal cerebral ischaemia.
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| 5. |
- Li, Wei, 1962-, et al.
(författare)
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Alpha-tocopherol and astaxanthin decrease macrophage infiltration, apoptosis and vulnerability in atheroma of hyperlipidaemic rabbits
- 2004
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Ingår i: Journal of Molecular and Cellular Cardiology. - : Elsevier BV. - 0022-2828 .- 1095-8584. ; 37:5, s. 969-978
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Tidskriftsartikel (refereegranskat)abstract
- The composition of atherosclerotic plaques, not just macroscopical lesion size, has been implicated in their susceptibility to rupture and the risk of thrombus formation. By focusing on the quality of lipids, macrophages, apoptosis, collagen, metalloproteinase expression and plaque integrity, we evaluated the possible anti-atherosclerotic effect of the antioxidants α-tocopherol and astaxanthin in Watanabe heritable hyperlipidemic (WHHL) rabbits. Thirty-one WHHL rabbits were divided into three groups and were fed a standard diet, as controls (N =10), or a standard diet with the addition of 500 mg α-tocopherol per kg feed (N =11) or 100 mg astaxanthin per kg feed (N =10) for 24 weeks. We found that both antioxidants, particularly astaxanthin, significantly decreased macrophage infiltration in the plaques although they did not affect lipid accumulation. All lesions in the astaxanthin-treated rabbits were classified as early plaques according to the distribution of collagen and smooth muscle cells. Both antioxidants also improved plaque stability and significantly diminished apoptosis, which mainly occurred in macrophages, matrix metalloproteinase three expressions and plaque ruptures. Although neither antioxidant altered the positive correlations between the lesion size and lipid accumulation, the lesion size and apoptosis were only positively correlated in the control group. Astaxanthin and α-tocopherol may improve plaque stability by decreasing macrophage infiltration and apoptosis in this atherosclerotic setting. Apoptosis reduction by α-tocopherol and astaxanthin may be a new anti-atherogenic property of these antioxidants. © 2004 Elsevier Ltd. All rights reserved.
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| 6. |
- Li, Wei, 1962-, et al.
(författare)
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Apoptotic Death of Inflammatory Cells in Human Atheroma
- 2001
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - : Ovid Technologies (Wolters Kluwer Health). - 1079-5642 .- 1524-4636. ; 21:7, s. 1124-1130
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Tidskriftsartikel (refereegranskat)abstract
- Although the accumulation of cholesterol and other lipidic material is unquestionably important in atherogenesis, the reasons why this material progressively accumulates, rather than being effectively cleared by phagocytic cells such as macrophages, are not completely understood. We hypothesize that atheromatous lesions may represent "death zones" that contain toxic materials such as oxysterols and in which monocytes/macrophages become dysfunctional and apoptotic. Indeed, cathepsins B and L, normally confined to the lysosomal compartment, are present in the cytoplasm and nuclei of apoptotic (caspase-3-positive) macrophages within human atheroma. The possible involvement of oxysterols is suggested by experiments in which cultured U937 and THP-1 cells exposed to 7-oxysterols similarly undergo marked lysosomal destabilization, caspase-3 activation, and apoptosis. Like macrophages within atheroma, intralysosomal cathepsins B and L are normally present in the cytoplasm and nuclei of these oxysterol-exposed cells. Lysosomal destabilization, cathepsin release, and apoptosis may be causally related, because inhibitors of cathepsins B and L suppress oxysterol-induced apoptosis. Thus, toxic materials such as 7-oxysterols in atheroma may impair the clearance of cholesterol and other lipidic material by fostering the apoptotic death of phagocytic cells, thereby contributing to further development of atherosclerotic lesions.
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| 7. |
- Li, Wei, et al.
(författare)
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Enhanced expression of natural resistance-associated macrophage protein 1 in atherosclerotic lesions may be associated with oxidized lipid-induced apoptosis
- 2004
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Ingår i: Annals of the New York Academy of Sciences. - : Wiley. - 0077-8923 .- 1749-6632. ; 1030, s. 202-207
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Tidskriftsartikel (refereegranskat)abstract
- The natural resistance-associated macrophage proteins (Nramps) can modulate inflammatory reactions. Nramps are not only responsible for intracellular divalent metal transport but also determine the macrophage functions in inflammatory processes. In the present study we tested whether Nramp1 is involved in macrophage apoptosis induced by oxidized lipids in atherogenesis. Arterial segments of Watanabe heritable hyperlipidemic rabbits were used for an examination of Nramp1 mRNA by in situ RT-PCR and macrophage immunohistochemistry. Annexin V/PI staining and terminal dUTP nick-end labeling (TUNEL) techniques were used for apoptosis detection. We found that, in macrophage-rich areas (positive to RMA-11) of the rabbit atherosclerotic aorta, there were lesion-dependent increases in Nramp1 mRNA, which are mainly apoptotic foamy macrophages that are positive to TUNEL staining. U937 cells were treated with 7 beta-hydroxycholesterol (7 beta-OH) in the presence or absence of the redox-active iron chelator desferrioxamine (DFO) or 1,10-phenanthroline. The cellular iron chelators considerably reduced, whereas iron compounds enhanced, 7 beta-OH-induced apoptosis and necrosis. DFO also decreased mRNA levels of Nramp1, whereas both iron compounds and 7 beta-OH dramatically enhanced the expression of Nramp1 mRNA, particularly among 7 beta-OH-induced apoptotic cells. We conclude that the enhanced expression of Nramp1 in macrophage regions of atherosclerotic lesions may be associated with ferrous iron-enhanced, oxidized lipid-induced apoptosis. This finding reveals a novel function of Nramp1 in atherogenesis.
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| 8. |
- Li, Wei, et al.
(författare)
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Increased expression and translocation of lysosomal cathepsins contribute to macrophage apoptosis in atherogenesis
- 2004
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Ingår i: Annals of the New York Academy of Sciences. - : Wiley. - 0077-8923 .- 1749-6632. ; 1030, s. 427-433
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Tidskriftsartikel (refereegranskat)abstract
- It has been recently reported that atherosclerotic lesions in both humans and mice express several lysosomal proteases, including cathepsins B, D, L, and S, which may affect plaque development and stability. The mechanisms responsible for the extralysosomal expression of lysosomal cathepsins and the related atherogenic implications remain unknown. We rind that the lesion-dependent expression of cathepsins B and L is mainly in macrophage-infiltrated areas of human carotid atheroma. These enzymes appear in the cytoplasm and nuclei of apoptotic macrophages (normally confined to the lysosomal compartment) and in the extracellular areas. After exposure to oxidized low-density lipoprotein (oxLDL) or 7 beta-hydroxycholesterol (7 beta-OH), macrophages initially transform into foam cells and then undergo apoptotic cell death. The oxidized lipids induce lysosomal destabilization, with leakage to the cytosol of lysosomal enzymes (cathepsins B, D, and L), as detected by cytochemistry and immunocytochemistry. A remarkable increase in cathepsin D mRNA levels was observed after 7 beta-OH exposure. Like macrophages within atheroma, intralysosomal cathepsins B and L are translocated to the cytoplasm and nuclei of 7B-OH-exposed cells. Our results suggest that endocytosed oxLDL and oxysterols not only destabilize the acidic vacuolar compartment but also cause the upregulation and translocation of lysosomal cathepsins, which may act as cleaving enzymes during the apoptotic process. The increased macrophage apoptosis and nuclear and matrix degradation by lysosomal enzymes in atheroma may play important roles in plaque development and rupture.
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| 9. |
- Li, Wei, 1962-, et al.
(författare)
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Induction of cell death by the lysosomotropic detergent MSDH
- 2000
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Ingår i: FEBS Letters. - 0014-5793 .- 1873-3468. ; 470:1, s. 35-39
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Tidskriftsartikel (refereegranskat)abstract
- Controlled lysosomal rupture was initiated in lysosome-rich, macrophage-like cells by the synthetic lysosomotropic detergent, O-methyl-serine dodecylamide hydrochloride (MSDH). When MSDH was applied at low concentrations, resulting in partial lysosomal rupture, activation of pro-caspase-3-like proteases and apoptosis followed after some hours. Early during apoptosis, but clearly secondary to lysosomal destabilization, the mitochondrial transmembrane potential declined. At high concentrations, MSDH caused extensive lysosomal rupture and necrosis. It is suggested that lysosomal proteases, if released to the cytosol, may cause apoptosis directly by pro-caspase activation and/or indirectly by mitochondrial attack with ensuing discharge of pro-apoptotic factors.
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| 10. |
- Li, Wei, et al.
(författare)
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Macrophage hemoglobin scavenger receptor and ferritin accumulation in human atherosclerotic lesions
- 2004
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Ingår i: Annals of the New York Academy of Sciences. - : Wiley. - 0077-8923 .- 1749-6632. ; 1030, s. 196-201
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Tidskriftsartikel (refereegranskat)abstract
- We previously proposed that erythrophagocytosis and iron metabolism by macrophages may contribute to iron-driven oxidative stress in atherogenesis. Recent studies have indicated that the macrophage hemoglobin scavenger receptor (HbSR/CD 163) is a key molecule in the process of removing hemoglobin released from senescent erythrocytes. In this study we investigated crythrophagocytosis and its relation to ferritin accumulation and the involvement of CD163 in ferritin induction in human atheroma lesions. Normal and atherosclerotic human arterial segments obtained at autopsy and surgery were collected for iron histochemistry, hemoglobin and ferritin immunohistochemistry, and computerized image analysis. The lesion-dependent accumulation of ferritin and hemoglobin was seen in atherosclerotic carotid and coronary arteries. The immunoreactivity of hemoglobin was significantly correlated to the same regions of ferritin immunoreactivity on serial sections. The staining intensity of hemoglobin and ferritin was also significantly correlated. Hemoglobin deposition is often associated with microvessels adjacent to the lipid core areas in advanced lesions, where most CD68-positive macrophages were. CD163 expression appeared in both early and advanced lesions. The accumulation of tissue iron and ferritin also frequently occurs in CD163-positive and vessel-rich regions in the advanced atheroma. Although they were not always correspondingly positive on the serial sections, tissue iron and ferritin were significantly correlated. We conclude that erythrophagocytosis and hemoglobin catabolism by macrophages contribute to iron deposition and ferritin induction in human atheroma. The involvement of CD163 during ferritin induction may play an important role in modulating inflammatory processes in atherogenesis.
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