5-fluorouracil (5-FU) is a chemotherapeutic agent commonly used for treatment of solid tumors, including colorectal cancer. However, chemoresistance against 5-fluorouracil (5-FU) often limits its success for chemotherapy and, therefore, finding out appropriate adjuvant(s) that might overcome chemoresistance against 5-FU bears a significant importance. In the present study, we have found that α-mangostin can sensitize 5-FU-resistant SNUC5/5-FUR colon cancer cells to apoptosis. Exposure of α-mangostin induced significant DNA damages and increased the intracellular 8-hydroxyguanosine (8-OH-G) and 4-hydroxynonenal (4-HNE) levels in SNUC5 and SNUC5/5-FUR cells. Western blot analysis illustrated that α-mangostin-induced apoptosis was mediated by the activation of the extrinsic and intrinsic pathways in SNUC5/5-FUR cells. In particular, we observed that Fas receptor (FasR) level was lower in SNUC5/5-FUR cells, compared with SNUC5 cells and that silencing FasR attenuated α-mangostin-mediated apoptosis in SNUC5/5-FUR cells. Together, our study illustrates that α-mangostin might be an efficient apoptosis sensitizer that can overcome chemoresistance against 5-FU by activating apoptosis pathway.
Antigens, CD95 ; Apoptosis* ; Blotting, Western ; Colon* ; Colonic Neoplasms* ; Colorectal Neoplasms ; DNA Damage ; Drug Therapy ; Fluorouracil

This study surveys the improvement characteristics in old-aged muscular mitochondria by bio-active materials coated fabric (BMCF). To observe the effects, the fabric (10 and 30%) was worn to old-aged rat then the oxygen consumption efficiency and copy numbers of mitochondria, and mRNA expression of apoptosis- and mitophagy-related genes were verified. By wearing the BMCF, the oxidative respiration significantly increased when using the 30% materials coated fabric. The mitochondrial DNA copy number significantly decreased and subsequently recovered in a dose-dependent manner. The respiratory control ratio to mitochondrial DNA copy number showed a dose-dependent increment. As times passed, Bax, caspase 9, PGC-1alpha and beta-actin increased, and Bcl-2 decreased in a dose-dependent manner. However, the BMCF can be seen to have had no effect on Fas receptor. PINK1 expression did not change considerably and was inclined to decrease in control group, but the expression was down-regulated then subsequently increased with the use of the BMCF in a dose-dependent manner. Caspase 3 increased and subsequently decreased in a dose-dependent manner. These results suggest that the BMCF invigorates mitophagy and improves mitochondrial oxidative respiration in skeletal muscle, and in early stage of apoptosis induced by the BMCF is not related to extrinsic death-receptor mediated but mitochondria-mediated signaling pathway.
Actins ; Animals ; Antigens, CD95 ; Apoptosis ; Caspase 3 ; Caspase 9 ; DNA, Mitochondrial ; Mitochondria* ; Mitochondrial Degradation ; Muscle, Skeletal ; Oxygen Consumption ; Rats* ; Respiration ; RNA, Messenger

Deregulation of soluble apoptosis stimulating fragment (sFas) plays an important role in glomerulonephritis (GN). The study assed the influence of immunosuppressive treatment on serum and urine sFas in patients with proliferative (PGN) and non-proliferative (NPGN) GN, and evaluated the potential of sFas measurements in predicting outcomes. Eighty-four patients with GN (45 males and 39 females) were included. Serum concentration (ng/mL) and urinary excretion (ng/mg of urinary creatinine) of sFas were measured before and after the treatment. After 12 months of therapy with steroids and cyclophosphamide, patients were divided into two subgroups according to the treatment results: Responders (R) and Non-Responders (NR). The sFas urinary excretion was reduced after treatment in both PGN and NPGN (from 17.12 +/- 15 to 5.3 +/- 4.2, P = 0.008 and from 10.11 +/- 6.1 to 3.4 +/- 3.0, P = 0.039; respectively) whereas the sFas serum concentration remained unchanged. In PGN, pre-treatment urinary sFas concentration was significantly lower in the Responders than in Non-Responders (2.3 +/- 3.1 vs 19.4 +/- 14.1, P = 0.003), and was lower still than in both R (P = 0.044) and NR (P = 0.042) subgroups with NPGN. The immunosuppressive treatment reduced sFas urinary excretion in proliferative and non-proliferative GN and results suggest that the lower urinary sFas may be linked with favorable therapy outcomes in patients with PGN.
Adult ; Antigens, CD95/blood/*urine ; Cyclophosphamide/therapeutic use ; Female ; Glomerulonephritis/*drug therapy/metabolism/pathology ; Humans ; Immunosuppressive Agents/*therapeutic use ; Male ; Middle Aged ; Steroids/therapeutic use ; Treatment Outcome

Zearalenone (ZEA), a nonsteroidal estrogenic mycotoxin, is known to cause testicular toxicity in animals. In the present study, the effects of ZEA on spermatogenesis and possible mechanisms involved in germ cell injury were examined in rats. Ten-week-old Sprague-Dawley rats were treated with 5 mg/kg i.p. of ZEA and euthanized 3, 6, 12, 24 or 48 h after treatment. Histopathologically, spermatogonia and spermatocytes were found to be affected selectively. They were TUNEL-positive and found to be primarily in spermatogenic stages I-VI tubules from 6 h after dosing, increasing gradually until 12 h and then gradually decreasing. Western blot analysis revealed an increase in Fas and Fas ligand (Fas-L) protein levels in the ZEA-treated rats. However, the estrogen receptor (ER)alpha expression was not changed during the study. Collectively, our data suggest that acute exposure of ZEA induces apoptosis in germ cells of male rats and that this toxicity of ZEA is partially mediated through modulation of Fas and Fas-L systems, though ERalpha may not play a significant role.
Animals ; Antigens, CD95/*immunology ; Apoptosis/*drug effects/immunology ; Estrogens, Non-Steroidal/*toxicity ; Fas Ligand Protein/*immunology ; Histocytochemistry ; Immunoblotting ; In Situ Nick-End Labeling ; Male ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Spermatocytes/cytology/*drug effects/immunology ; Spermatogenesis/drug effects/immunology ; Spermatogonia/drug effects/immunology ; Testis/cytology/*drug effects/immunology ; Zearalenone/*toxicity

Mouse blastocysts were exposed to doses of 0, 1 and 10 mumol/L retinoic acid (RA) for 24 h and the cytotoxic effect of RA on the mouse blastocysts in vitro was observed. FITC-labeled terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL-FITC) assay was employed to stain apoptotic cells and immunohistochemical S-P staining method was used to detect the expression of Fas protein in mouse blastocysts in vitro. The results showed that RA could induce apoptosis and increase the expression of Fas proteins of trophectoderm (TE) and inner cell mass (ICM) cells in blastocysts. Compared with the findings for the control blastocysts, exposure to RA (10 mumol/L) resulted in a more significant apoptosis and higher expression level of Fas proteins (P<0.01). It was concluded that RA could induce apoptosis, which may result in a significant reduction in the average number of total cells and the trophectoderm/inner cell mass in blastocysts and an increased expression of Fas protein, suggesting that RA had a cytotoxic effect on the growth and development of early embryos in mice.
Antigens, CD95/*biosynthesis ; Apoptosis/*drug effects ; Blastocyst/cytology ; Blastocyst/*metabolism ; Cell Culture Techniques/methods ; Cells, Cultured ; Gene Expression Regulation/*drug effects ; In Situ Nick-End Labeling ; RNA, Messenger/metabolism ; Tretinoin/*pharmacology

Neutrophils are also known to acquire the characteristics of dendritic cells (DCs) under the appropriate conditions. In this study, neutrophils were cultivated in vitro in the presence or absence of compounds modulating their survival in an attempt to characterize the expression profile of the DC markers. Higher MHC-II, CD80, CD86, CD83, and CD40 expression levels were detected on the surface of the cultured neutrophils for 24 h than on the freshly isolated cells. The annexin V-positive cells showed a higher expression level of the DC markers than the annexin V-negative cells. The population of neutrophils double stained with annexin V and the DC markers increased after being incubated with agonistic anti-Fas Ab. LPS, the anti-apoptotic compound, decreased the CD86 and MHC-II expression levels but 50-60% of the DC marker-positive cells were detected in the annexin V-positive cells. In contrast, CD80, CD86, CD83, and HLA-DR mRNA levels increased in the GM-CSF-treated neutrophils but not in the anti-Fas Ab-treated neutrophils. T cell proliferation was inhibited by co-culturing them with anti-Fas Ab- or LPS-treated neutrophils at a high neutrophil:T cell ratio. However, the superantigen-mediated T cell proliferation was increased by the LPS-treated neutrophils but decreased by the anti-Fas Ab-treated neutrophils. There was a lower level of interferon-gamma production in the T cells co-cultured with anti-Fas Ab-treated neutrophils than with the LPS-treated neutrophils. This suggests that apoptotic neutrophils express DC markers on their surface and the differential expression of DC markers might have a detrimental effect on the immune reaction.
Antigen Presentation ; Antigens, CD/biosynthesis ; Antigens, CD95/pharmacology ; Antigens, Differentiation/*biosynthesis ; *Apoptosis ; Cells, Cultured ; Dendritic Cells/*metabolism ; Humans ; Lipopolysaccharides/pharmacology ; Lymphocyte Activation ; Neutrophils/*metabolism/physiology ; T-Lymphocytes/immunology

Toxic epidermal necrolysis (TEN) is a rare, life-threatening, mucocutaneous drug reaction, which causes extensive epidermal detachment and serious complications involving ocular structures and internal organs. Recently, intravenous immunoglobulin (IVIG) was suggested to be effective in treating TEN through the blockage of Fas receptors which initiate keratinocyte apoptosis. Herein, we tried IVIG teratment (0.6 g/kg/day for 4 consecutive days) for a case of TEN. As a result, the progression of epidermal detachment was interrupted within 2 days and epithelialization was completed in 3 weeks without significant side effects.
Antigens, CD95 ; Apoptosis ; Immunoglobulins* ; Immunoglobulins, Intravenous ; Keratinocytes ; Stevens-Johnson Syndrome*

Toxic epidermal necrolysis (TEN) is a rare, life-threatening, mucocutaneous drug reaction, which causes extensive epidermal detachment and serious complications involving ocular structures and internal organs. Recently, intravenous immunoglobulin (IVIG) was suggested to be effective in treating TEN through the blockage of Fas receptors which initiate keratinocyte apoptosis. Herein, we tried IVIG teratment (0.6 g/kg/day for 4 consecutive days) for a case of TEN. As a result, the progression of epidermal detachment was interrupted within 2 days and epithelialization was completed in 3 weeks without significant side effects.
Antigens, CD95 ; Apoptosis ; Immunoglobulins* ; Immunoglobulins, Intravenous ; Keratinocytes ; Stevens-Johnson Syndrome*

BACKGROUND/AIMS: Apoptosis via Fas/FasL system is thought to be involved in the development of hepatocyte death in viral hepatitis B. In chronic hepatitis C, sFas/sFasL system was reported to control liver injury induced by Fas/FasL mediated apoptosis. To determine the role of sFas/sFasL system in chronic hepatitis B, we analyzed serum sFas/sFasL in 58 HBV patients and 29 healthy controls. METHODS: HBV patients were categorized into two groups; normal ALT (< or =40 IU/L) and elevated ALT (>40 IU/L). Serum sFas/sFasL levels in HBV patients were measured by ELISA and was compared with those in 29 healthy controls. Serum ALT levels, histological activity, and Fas/FasL expression of liver were compared. RESULTS: Chronic hepatitis B patients with elevated ALT had significantly higher serum sFas levels than those in healthy controls (P<0.01). Serum sFasL levels, however, were significantly lower than those in healthy controls (P<0.01). Patients with moderate to marked degree of inflammation and fibrosis had significantly higher serum sFas levels than those in healthy controls (P<0.05). Serum sFasL levels had no correlation with the hepatic histological activity. Serum sFas/sFasL levels also had no significant correlation with the Fas/FasL expression of liver. CONCLUSIONS: Serum sFas/sFasL levels play a possible role in the pathogenesis of chronic hepatitis B. These results suggest that serum sFas levels might serve as a marker for estimating the degree of hepatic histological activity.
Adult ; Antigens, CD95/analysis/*blood ; Fas Ligand Protein/analysis/*blood ; Female ; Hepatitis B virus/isolation & purification ; Hepatitis B, Chronic/*diagnosis ; Humans ; Male ; Middle Aged

Although the apoptosis of chondrocytes plays an important role in endochondral ossification, its mechanism has not been elucidated. In this study, we show that guanosine induces chondrocyte apoptosis based on the results of acridine orange/ ethidium bromide staining, caspase-3 activation, and sub-G1 fraction analysis. The potent inhibitory effect of dipyridamole, a nucleoside transporter blocker, indicates that extracellular guanosine must enter the chondrocytes to induce apoptosis. We found that guanosine promotes Fas-Fas ligand interaction which, in turn, leads to chondrocyte apoptosis. These findings indicate a novel mechanism for endochondral ossification via metabolic regulation.
Tumor Necrosis Factors/metabolism ; Signal Transduction/drug effects ; Receptors, Tumor Necrosis Factor/*metabolism ; Rats, Sprague-Dawley ; Rats ; Nucleoside Transport Proteins/metabolism ; Membrane Glycoproteins/metabolism ; Guanosine/*pharmacology/physiology ; Fas Ligand Protein ; Chondrocytes/*drug effects/metabolism ; Apoptosis/*drug effects ; Antigens, CD95 ; Animals