Biomedical subjects

X M Yuan

Publications and source records attributed to X M Yuan.

16 recordsLinked to original sources

PubMed2001

Transdifferentiation of neoplastic cells.

Transdifferentiation is a process in which a stable cell's phenotype changes to that of a distinctly different cell type. It occurs during certain physiological processes and leads to transition of tumor cell phenotypes. The latter process includes neoplastic epithelial-epithelial transition, neoplastic epithelial-mesenchymal transition, neoplastic mesenchymal-epithelial transition and transition between non-neural and neural neoplastic cell. This phonomenon is exemplified in some origin-debated tumors, such as carcinosarcoma, pleomorphic adenoma, synovial sarcoma, Ewing's/pPNET, and malignant fibrohistiocytoma. We propose that differentiation disturbance of cancer cells should include not only undifferentiation and dedifferentiation, but also transdifferentiation as well. Tumor cell transdifferentiation may be influenced or determined by cellular genetic instabilities, proliferation and apoptosis, as well as by extracellular matrix and growth factors.

Animals↗

PubMed2001

Apoptotic death of inflammatory cells in human atheroma.

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.

Apoptosis↗

PubMed2001

Transdifferentiation in neoplastic development and its pathological implication.

Transdifferentiation is a process in which a cell committed to a particular specialization changes to another quite distinct type. It occurs during embryological development and some pathological processes, and causes the tumor cells to express a phenotype different from that of their normal progenitors. Neoplastic transdifferentiation involves pathogenesis of cancer subtype, transition between neoplastic epithelia and neuroendocrine cell, transition between neoplastic epithelia and mesenchyme, as well as transition between non-neuroectodermal and neuroectodermal cells. We propose that differentiation disturbance of cancer cells should include not only lower-, un-, or de-differentiation, but also transdifferentiation. Tumor cell transdifferentiation results from genetic instabilities. In some type of neoplastic transition, the initiation may be induced by extracellular matrix and growth factors.

Animals↗

PubMed2000

Lysosomal destabilization during macrophage damage induced by cholesterol oxidation products.

We have previously shown that oxidized low-density lipoprotein (LDL) induces damage to the macrophage lysosomal membranes, with ensuing leakage of lysosomal contents and macrophage cell death. Cholesterol oxidation products (ChOx) have been reported to be the major cytotoxic components of oxidized LDL/LDL- and also to stimulate cholesterol accumulation in vascular cells. In the present study, we characterized the initial events during macrophage damage induced by cholesterol oxidation products (ChOx). Within 24 h of exposure, ChOx caused lysosomal destabilization, release to the cytosol of the lysosomal marker-enzyme cathepsin D, apoptosis, and postapoptotic necrosis. Enhanced autophagocytosis and chromatin margination was found 12 h after the exposure to ChOx, whereas apoptosis and postapoptotic necrosis was pronounced 24 and 48 h after the exposure. Some lysosomal vacuoles were then filled with degraded cellular organelles, indicating phagocytosis of apoptotic bodies by surviving cells. Because caspase-3 activation was detected in the ChOx-exposed cells, lysosomal destabilization may associate with the leakage of lysosomal enzymes, and activation of the caspase cascade. MnSOD mRNA levels were markedly increased after 24 h of exposure to ChOx, suggesting associated induction of mitochondrial protection repair or turnover. We conclude that ChOx-induced damage to lysosomes and mitochondria are sequelae to the cascade of oxysterol cytotoxic events. The early disruption of lysosomes induced by ChOx, with resultant autophagocytosis may be a critical event in apoptosis and/or necrosis of macrophages/foam cells during the development of atherosclerotic lesions.

Animals↗

PubMed1999

Apoptotic macrophage-derived foam cells of human atheromas are rich in iron and ferritin, suggesting iron-catalysed reactions to be involved in apoptosis.

We investigated the presence of low-molecular-weight iron and ferritin in human atheromas, and their possible relation to the apoptotic process. Arterial wall segments with fatty streaks were collected from coronary arteries and thoracic aortas of 12 clinical autopsy cases with general atherosclerosis. Normal appearing regions from the same cases together with normal coronary arteries from seven young forensic autopsy cases, without any sign of atherosclerosis, were used for comparison. Anti-CD68 (macrophage marker) and anti-ferritin antibodies were applied to serial sections of the arterial wall segments, fixed in formadehyde and embedded in paraffin wax, using an avidin-biotin complex (ABC) technique. Similarly, apoptotic cells were assayed by the TUNEL technique, while low-molecular-weight iron was cytochemically detected by autometallography. Cell counting and computerised image analysis were performed to compare the distribution of macrophages, ferritin- and iron-rich cells, and apoptotic cells in the intima, media, and adventitia of the arteries. Pronounced ferritin accumulation, occurrence of lysosomal low-molecular-weight iron, and apoptosis mainly concerned CD68-positive cells (macrophages) in the atherosclerotic lesions. No ferritin- or CD68-positivity was found in normal coronary arteries from the young forensic-autopsy cases, while a moderate number of such cells were observed in the intima of normal looking vessel areas from the control cases. In the intima, cytosolic ferritin and low-molecular-weight iron with a lysosomal type distribution were found in many CD68-positive macrophages which frequently were surrounded by erythrocytes. A substantial number of apoptotic cells within the intima, media, and adventitia were registered in all atherosclerotic lesions examined, although mainly in the vulnerable macrophage-enriched areas of the atheroma shoulder. We suggest that iron may occur within the cytosol, mainly bound in ferritin, but also in low-molecular weight, redox-active form within the acidic vacuolar apparatus of macrophages and macrophage-derived foam cells following erythrophagocytosis or phagocytosis of apoptotic cells. Low-molecular-weight iron within lysosomes, present due to degradation of iron-containing structures, such as ferritin, may partially become exocytosed and contribute to cell-mediated LDL-oxidation. Moreover, such lysosomal iron may also sensitise lysosomes to oxidative stress and induce apoptosis of macrophage/foam-cells that may result in instability and rupture of atherosclerotic plaques.

Adult↗

PubMed1998

OxLDL-induced macrophage cytotoxicity is mediated by lysosomal rupture and modified by intralysosomal redox-active iron.

Oxidized low density lipoprotein (oxLDL) is believed to play a central role in atherogenesis. LDL is oxidized in the arterial intima by mechanisms that are still only partially understood. OxLDL is then taken up by macrophages through scavenger receptor-mediated endocytosis, which then leads to cellular damage, including apoptosis. The complex mechanisms by which oxLDL induces cell injury are mostly unknown. This study has demonstrated that oxLDL-induced damage of macrophages is associated with iron-mediated intralysosomal oxidative reactions, which cause partial lysosomal rupture and ensuing apoptosis. This series of events can be prevented by pre-exposing cells to the iron-chelator, desferrioxamine (DFO), whereas it is augmented by pretreating the cells with a low molecular weight iron complex. Since both DFO and the iron complex would be taken up by endocytosis, and thus directed to the lysosomal compartment, the results suggest that the normal contents of lysosomal low molecular weight iron may play an important role in oxLDL-induced cell damage, presumably by catalyzing intralysosomal fragmentation of lipid peroxides and the formation of toxic aldehydes and oxygen-centered radicals.

Animals↗

PubMed1998

Iron and LDL-oxidation in atherogenesis.

It has been proposed that the development of atherosclerosis may be linked to the size of the body iron stores. The exact role of iron in the initiation and progression of atherogenesis is, however, still unknown. As a result of increasing support for the LDL-oxidation hypothesis, much additional knowledge about the relation between iron and atherosclerosis has recently been gained. This review presents the current evidence on the role of iron--being a potent catalyst of oxidative reactions--and macrophage-mediated LDL-oxidation in atherogenesis. The authors hypothesize that iron, as a possible central intermediary, may play an important role in cell-mediated LDL-oxidation.

Animals↗

PubMed1998

Uptake of oxidized LDL by macrophages results in partial lysosomal enzyme inactivation and relocation.

The cytotoxicity of oxidized LDL (oxLDL) to several types of artery wall cells might contribute to atherosclerosis by causing cell death, presumably by both apoptosis and necrosis. After its uptake into macrophage lysosomes by receptor-mediated endocytosis, oxLDL is poorly degraded, resulting in ceroid-containing foam cells. We studied the influence ofoxLDL on lysosomal enzyme activity and, in particular, on lysosomal membrane stability and the modulation of these cellular characteristics by HDL and vitamin E (vit-E). Unexposed cells and cells exposed to acetylated LDL (AcLDL) were used as controls. The lysosomal marker enzymes cathepsin L and N-acetyl-beta-glucosaminidase (NAbetaGase) were biochemically assayed in J-774 cells after fractionation. Lysosomal integrity in living cells was assayed by the acridine orange (AO) relocation test. Cathepsin D was immunocytochemically demonstrated in J-774 cells and human monocyte-derived macrophages. We found that the total activities of NAbetaGase and cathepsin L were significantly decreased, whereas their relative cytosolic activities were enhanced, after oxLDL exposure. Labilization of the lysosomal membranes was further proven by decreased lysosomal AO uptake and relocation to the cytosol of cathepsin D, as estimated by light and electron microscopic immunocytochemistry. HDL and vit-E diminished the cytotoxicity of oxLDL by decreasing the lysosomal damage. The results indicate that endocytosed oxLDL not only partially inactivates lysosomal enzymes but also destabilizes the acidic vacuolar compartment, causing relocation of lysosomal enzymes to the cytosol. Exposure to AcLDL resulted in its uptake with enlargement of the lysosomal apparatus, but the stability of the lysosomal membranes was not changed.

Acridine Orange↗

PubMed1997

The toxicity to macrophages of oxidized low-density lipoprotein is mediated through lysosomal damage.

Oxidized low-density lipoprotein (ox-LDL) has been shown to degrade poorly within the secondary lysosomes of macrophages but its possible effect on lysosomal integrity has received less attention. The effect of ultraviolet-C oxidized LDL (UVox-LDL) on cellular viability, and lysosomal membrane stability, was examined on cultured murine J-774 cells and human monocyte-derived macrophages (HMDMs). The acridine orange (AO) relocalization test was applied to study the lysosomal integrity of living cells. UVox-LDL dramatically reduced J-774 cell proliferation at a concentration of 25 microg/ml. Incubation with 5 microM copper alone, normally used to induce LDL oxidation, was also toxic. In contrast to the effects of ox-LDL, in concentrations up to 75 microg/ml, native LDL (nLDL) rather stimulated J-774 cell replication. Incubation with UVox-LDL (25-75 microg/ml) also altered cellular AO uptake, depending on time and dose: its lysosomal accumulation decreased and its cytosolic accumulation increased. This shift indicates damaged lysosomal membranes with decreased intralysosomal, and increased cytosolic, H+ concentration. Many J-774 cells exposed to UVox-LDL initially transformed into foam cells and then assumed an apoptotic-type morphology with TUNEL-positive nuclei. We conclude that ox-LDL is cytotoxic to macrophages due to oxidative damage of lysosomal membranes, with ensuing destabilization and leakage to the cytosol of lysosomal contents, such as hydrolytic enzymes, causing degeneration of apoptotic type.

Animals↗

PubMed1997

[Synthesis and biological activity of substance P analogs].

Substance P (SP) and its three analogs were synthesized through solid-phase procedure. The fully-protected peptide-resin was cleaved with anhydrous HF.--SH of Cys in [Cys5,9] SP(4-11) was protected with Acm, then deprotected through Iodine oxidation method, the disulfide bridge cyclization was formed subsequently. The crude product was purified on C18 RP-HPLC. The results of guinea-pig isolated ileum test (GPI) showed that the potency of the analogs was as follows: [AcGln5, Pro9] SP(5-11) > SP > SP(4-11) > [Cys5,9] SP(4-11). They induced GPI to contract very fast and showed the characteristics of tachykinin. On the writing test in mice, the results showed: [Cys5,9] SP(4-11) > SP > SP(4-11) > [AcGln5, Pro9] SP(5-11). The biological tests showed that the SP analogs have some extent of selectivity.

Animals↗

PubMed1996

Iron in human atheroma and LDL oxidation by macrophages following erythrophagocytosis.

The oxidative modification of low density lipoprotein (LDL) has been implicated as an early step in the formation of atheromatous lesions. In vitro studies suggest it to be accelerated, or even initiated, by transition metals such as iron or copper in combination with a reducing agent. Even if such metals have been demonstrated in atheroma gruels, their origin and precise localisation within human atheroma are presently unknown. In the initial part of this study we applied Pearl's method, energy dispersive X-ray microanalysis, and a modified Timm sulphide silver method (SSM) to demonstrate the occurrence of iron in early atherosclerotic lesions from a number of consecutive autopsy cases with evident, general atheromatosis. With the very sensitive SSM, but not with the other techniques, we found foam cells to contain heavy metals with a mainly lysosomal localization. On the basis of the hypothesis that such a lysosomal accumulation of iron might be due to erythrophagocytosis by migrating tissue-bound macrophages that later develop into foam cells, we designed an in vitro model system where human monocyte-derived macrophages were exposed to artificially aged, UV-exposed erythrocytes. The macrophages were then exposed to LDL in serum-and iron-free RPMI medium, occasionally in the presence of the potent iron-chelator desferrioxamine. The capacity of macrophages to oxidise LDL was much enhanced following erythrophagocytosis, and the process was shown to involve secretion of iron. Consequently, LDL oxidation was greatly inhibited by desferrioxamine. We conclude that iron may be exocytosed by macrophages that previously had their lysosomal apparatus enriched with iron, e.g. due to erythrophagocytosis. Oxidation of LDL may result in ensuing foam cell-formation secondary to scavenger-receptor mediated endocytosis by macrophages.

Aged↗

PubMed1996

Antioxidants in the prevention of atherosclerosis.

Four antioxidant treatment modalities against atherosclerosis and coronary heart disease are scrutinized: probucol, beta-carotene, alpha-tocopherol and anti-iron treatment. A pattern seems to have emerged in which some treatments look promising, but others are disappointing. Most published studies of antioxidation in atherosclerosis have been ad-hoc in that the primary endpoint of the study has not been a diagnosis related to atherosclerosis; this may be misleading. The most promising antioxidant seems to be alpha-tocopherol, supported by the results of the Cambridge Heart Antioxidant Study. Probucol has the drawback of decreasing high density lipoprotein concentration and is therefore unlikely to influence atheroma in people. beta-Carotene has been repeatedly shown to be ineffective against coronary heart disease. Anti-iron treatment has not yet been tested in animal models or in man. More has to be learned of the role of antioxidation in atherosclerosis before the effectiveness of this treatment modality can be established.

Anticholesteremic Agents↗

PubMed1995

The establishment of two cell lines from a mouse uterine cervical carcinoma (U14) and their metastatic phenotype changes.

This paper studies the heterogeneity of metastatic potential of murine cervical carcinoma (U14). Two cell lines, P11-90 and L10-90, were established from a pulmonary metastatic substrain (U14AP11) and a lymphatic metastatic substrain (U14AL10), which were selected from U14 in vivo after 11 and 10 passages, respectively. The biologic differences between the two cell lines are as follows. (1) The cells of the P11-90 line grow more rapidly compared with the L10-90 line. From the 40th passage the medium pH was different. (2) The median number of chromosomes in P11-90 and L10-90 was 72 and 64, respectively; the rates of gap aberration were 88% and 78%, respectively. (3) The number of T lymphocytes and T helper lymphocytes in the peripheral blood from hosts with P11-90 were higher than that of hosts transplanted with L10-90, but the number of B lymphocytes in the latter was larger than that in the former. (4) The metastatic potential of each cell line partially decreased compared to the relative tumor substrain, but their organ preference still remained and the transplant locations, axillary or footpad, had a prominent influence on their metastatic behavior. To observe the effects of metastatic target organs on the metastatic phenotypes of tumor cells, as well as to explore a method for the establishment and maintenance of the metastatic organ preference of tumor cells, conditioned medium (CM) from pulmonary or lymphatic node diploid cells was added to the culture medium of P11-90 and L10-90. Two sublines, P + P11-90 and Ln + L10-90, were thus established. Using stereological methods we found that the majority of P + P11-90 cells became larger and their nuclei also increased in size compared with their parental lines, but the majority of Ln + L10-90 cells became smaller in size, though the nuclei were enlarged. The pulmonary metastatic rate and lymphatic metastatic rate of P + P11-90, as well as the lymphatic metastatic rate of Ln + L10-90, were restored dramatically. The results suggest that by taking advantage of the interaction between tumor cells and the CM of host cells the metastatic potential of tumor cell lines can be maintained in vitro. Our work may offer an experimental model for the manipulation of metastasis of cell lines coming from the same parent strain but with different metastatic potentials.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1995

Effects of iron- and hemoglobin-loaded human monocyte-derived macrophages on oxidation and uptake of LDL.

It is generally accepted that transition metals are required for cellular LDL oxidation. LDL may also be oxidized by iron and reducing agents in cell-free systems. We hypothesized that lysosomal iron may be exocytosed from macrophages that have been iron loaded by phagocytosis and degradation of iron-rich structures, eg, erythrocytes, and that such released iron may promote LDL oxidation and uptake by macrophages. Human monocyte-derived macrophages (HMDMs) were isolated and cultured for 7 days and then exposed to FeCl3, Fe-ADP, or Fe-EDTA (100 mumol/L) or hemoglobin (25 or 50 micrograms/mL) for 24 hours. After rinsing, LDL (50 to 150 micrograms/mL) was added in fresh culture medium without serum. After another 24 hours the media concentrations of iron and thiobarbituric acid-reacting substances as well as the electrophoretic mobility of LDL were increased, while the cells showed only minimal signs of decreased viability. Lipofuscin, neutral lipids, and phospholipids accumulated in a granular, lysosome-like pattern, and the cells acquired a foam cell-like morphology. There was a strong correlation (r = .87, P = .005) between the amount of iron added during the pre-exposure period and lipofuscin accumulation during the ensuing exposure to LDL in fresh, serum-free medium. Our results support our hypothesis and indicate that lysosomal iron may be exocytosed from HMDMs and promote oxidation and uptake of LDL and thus induce foam cell formation.

Cell Survival↗

PubMed1991

[Synthesis and analgesic activity of analogs of U-50488, an opiate kappa-agonist].

In this paper, we report the synthesis and analgesic activities in mouse hot plate test and writhing test of some analogs of U-50488, a kappa-agonist. Results showed that compounds in which the amino group was pyrrolinyl had higher kappa-agonist activity and the substitution of two chlorine atoms in 3 and 4-positions of the benzene nucleus was very important to kappa-activity. Furthermore, all of compounds in which the amino group was piperidyl, piperazinyl or morpholinyl exhibited very weak kappa-agonist activity.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1990

[Synthesis and analgesic activity of 4-N-propionyl analogs of 4-methoxycarbonyl fentanyl].

In the present paper, the synthesis and analgesic activities of some 4-N-propionyl analogs of 4-methoxycarbonyl fentanyl are reported. In mouse hot plate test, most of these compounds showed strong narcotic analgesic activity. The analgesic activities of compounds 1379, 1385 and 1387 were found to be more potent than that of 4-methoxycarbonyl fentanyl.

Analgesics↗