The cell surface expression and functional status of the CD95/Fas antigen on primitive hematopoietic progenitors isolated from human cord blood (CB) were studied. The CD34 + cells freshly isolated from CB displayed ...The cell surface expression and functional status of the CD95/Fas antigen on primitive hematopoietic progenitors isolated from human cord blood (CB) were studied. The CD34 + cells freshly isolated from CB displayed low CD95 expression. The combinations of cytokines such as SCF+FL could up regulate the expression of CD95 in vitro culture and tumor necrosis factor α (TNF α) and interon γ (IFN γ) further increased the CD95 expression induced by positive cytokines. The functional status of CD95 mediated apoptosis were analyzed by incubation of CD34 +CB cells in the presence of anti CD95 monoclonal antibodies (McAbs). The effects of anti CD95 McAbs were measured by viable cell counting, flow cytometry, LTIC and CFU C assays. A decrease of viable cells, CFU C and LTIC numbers were observed in the presence of anti CD95 McAbs and TNF α or IFN γ. However, growth factor deprivation or the early acting cytokine such as SCF and FL cross linking to CD95 caused low apoptosis of CD34 + cells. The correlation of increased intracytoplasmic levels of bcl 2 and the presence of CD95 on fresh CB CD34 + cells suggested that bcl 2 might be involved in protecting against CD95 mediated apoptosis of CB CD34 + cells.展开更多
The balance between cell proliferation and cell growth characterizes tissue homeostasis on one side and cell death on the other side. Fas receptor-mediated apoptosis is a control mechanism for tissue homeostasis, and ...The balance between cell proliferation and cell growth characterizes tissue homeostasis on one side and cell death on the other side. Fas receptor-mediated apoptosis is a control mechanism for tissue homeostasis, and avoiding this death pathway predisposes to many human diseases, including cancer. Current therapies for this disease are invasive and do not have the desired effect in the control of the disease. In this context, the search for new drugs that contribute to a better treatment is gaining more relevance. 4-tert-butyl-bis-(2,6-thiomorpholin-4-ylmethyl)-1-phenol (LQM319) [1,2] is a drug currently in preclinical stage, and we have shown that it has a hypertensive effect, similar to captopril, in a hypertensive rat model. Different studies have shown that some chemicals that are used as antihypertensive agents have an antineoplastic effect against certain types of cancer, as is the case of hydralazine [3], and captopril [4], among others [5]. On the other hand, it has been reported that morpholine derivatives may activate Fas (CD95)-mediated apoptosis. The aim of the present study was to show the interaction between CD95 (receptor) and thiomorpholine derivatives (ligand) using molecular modeling and docking studies, and to elucidate the possible action mechanism of 4-tert-butyl-bis-(2,6-thiomorpholin-4-ylmethyl)-1-phenol.展开更多
Over-expression of bcl-2 in lymphocytes has an important role in some immunological and inflammatory diseases. Fas (CD95) is a cell surface molecule that mediates receptor-triggered apoptosis in various cells includin...Over-expression of bcl-2 in lymphocytes has an important role in some immunological and inflammatory diseases. Fas (CD95) is a cell surface molecule that mediates receptor-triggered apoptosis in various cells including autoreactive T cells. In this study we investigated bcl-2 and Fas (CD95) expression in dermal lymphocytes in active skin lesions of Beh et s disease (BD) and in skin biopsy samples with chronic, non-specific inflammations. Tissue sections of 29 skin lesions of Beh et s disease and of 10 chronic non-spesific inflammatory process cases from the archives of the Ondokuz Mayis University s Pathology Department were immunohistochemically stained for bcl-2 and Fas (CD95), and lymphocytes in the dermal infiltrate were evaluated for cytoplasmic staining, bcl-2 staining was observed in the skin lesions of 22 cases (75.8% ) of Beh et s disease. bcl-2 staining was detected in two (20% ) control skin biopsy samples with non-specific chronic inflammation. Fas (CD95) positivity was not detected in lymphocytes in Beh et s disease-related skin lesions. Fas (CD9) staining was observed in only three skin biopsy samples with non-specific chronic in-flammation. bcl-2 and Fas (CD95) staining values in Beh et s and non-specific inflammation groups were significantly different (P<0.01); differences in the bcl-2 staining values between Behc?et s patients with mucocutaneous involvement only and mucocutaneous and other systemic involvements were not significant (P >0.05) . Expression of bcl-2 and loss of Fas (CD95) expression in dermal lymphocytesmay play a role in the development of skin lesions and may account for the chronic course with periodic exacerbations in BD.展开更多
基金This project was supported by a grant from National Na-ture Science Foundation of China (No.3992 80 10 )
文摘The cell surface expression and functional status of the CD95/Fas antigen on primitive hematopoietic progenitors isolated from human cord blood (CB) were studied. The CD34 + cells freshly isolated from CB displayed low CD95 expression. The combinations of cytokines such as SCF+FL could up regulate the expression of CD95 in vitro culture and tumor necrosis factor α (TNF α) and interon γ (IFN γ) further increased the CD95 expression induced by positive cytokines. The functional status of CD95 mediated apoptosis were analyzed by incubation of CD34 +CB cells in the presence of anti CD95 monoclonal antibodies (McAbs). The effects of anti CD95 McAbs were measured by viable cell counting, flow cytometry, LTIC and CFU C assays. A decrease of viable cells, CFU C and LTIC numbers were observed in the presence of anti CD95 McAbs and TNF α or IFN γ. However, growth factor deprivation or the early acting cytokine such as SCF and FL cross linking to CD95 caused low apoptosis of CD34 + cells. The correlation of increased intracytoplasmic levels of bcl 2 and the presence of CD95 on fresh CB CD34 + cells suggested that bcl 2 might be involved in protecting against CD95 mediated apoptosis of CB CD34 + cells.
文摘The balance between cell proliferation and cell growth characterizes tissue homeostasis on one side and cell death on the other side. Fas receptor-mediated apoptosis is a control mechanism for tissue homeostasis, and avoiding this death pathway predisposes to many human diseases, including cancer. Current therapies for this disease are invasive and do not have the desired effect in the control of the disease. In this context, the search for new drugs that contribute to a better treatment is gaining more relevance. 4-tert-butyl-bis-(2,6-thiomorpholin-4-ylmethyl)-1-phenol (LQM319) [1,2] is a drug currently in preclinical stage, and we have shown that it has a hypertensive effect, similar to captopril, in a hypertensive rat model. Different studies have shown that some chemicals that are used as antihypertensive agents have an antineoplastic effect against certain types of cancer, as is the case of hydralazine [3], and captopril [4], among others [5]. On the other hand, it has been reported that morpholine derivatives may activate Fas (CD95)-mediated apoptosis. The aim of the present study was to show the interaction between CD95 (receptor) and thiomorpholine derivatives (ligand) using molecular modeling and docking studies, and to elucidate the possible action mechanism of 4-tert-butyl-bis-(2,6-thiomorpholin-4-ylmethyl)-1-phenol.
文摘Over-expression of bcl-2 in lymphocytes has an important role in some immunological and inflammatory diseases. Fas (CD95) is a cell surface molecule that mediates receptor-triggered apoptosis in various cells including autoreactive T cells. In this study we investigated bcl-2 and Fas (CD95) expression in dermal lymphocytes in active skin lesions of Beh et s disease (BD) and in skin biopsy samples with chronic, non-specific inflammations. Tissue sections of 29 skin lesions of Beh et s disease and of 10 chronic non-spesific inflammatory process cases from the archives of the Ondokuz Mayis University s Pathology Department were immunohistochemically stained for bcl-2 and Fas (CD95), and lymphocytes in the dermal infiltrate were evaluated for cytoplasmic staining, bcl-2 staining was observed in the skin lesions of 22 cases (75.8% ) of Beh et s disease. bcl-2 staining was detected in two (20% ) control skin biopsy samples with non-specific chronic inflammation. Fas (CD95) positivity was not detected in lymphocytes in Beh et s disease-related skin lesions. Fas (CD9) staining was observed in only three skin biopsy samples with non-specific chronic in-flammation. bcl-2 and Fas (CD95) staining values in Beh et s and non-specific inflammation groups were significantly different (P<0.01); differences in the bcl-2 staining values between Behc?et s patients with mucocutaneous involvement only and mucocutaneous and other systemic involvements were not significant (P >0.05) . Expression of bcl-2 and loss of Fas (CD95) expression in dermal lymphocytesmay play a role in the development of skin lesions and may account for the chronic course with periodic exacerbations in BD.
