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Titolo:
URSODEOXYCHOLIC ACID MAY INHIBIT DEOXYCHOLIC ACID-INDUCED APOPTOSIS BY MODULATING MITOCHONDRIAL TRANSMEMBRANE POTENTIAL AND REACTIVE OXYGENSPECIES PRODUCTION
Autore:
RODRIGUES CMP; FAN GS; WONG PY; KREN BT; STEER CJ;
Indirizzi:
UNIV MINNESOTA,SCH MED,DEPT MED,BOX 36 UMHC,420 DELAWARE ST SE MINNEAPOLIS MN 55455 UNIV MINNESOTA,SCH MED,DEPT MED MINNEAPOLIS MN 55455 UNIV MINNESOTA,SCH MED,DEPT CELL BIOL MINNEAPOLIS MN 55455 INST SUPER CIENCIAS SAUDE SUL MONTE DE CAPARICA PORTUGAL
Titolo Testata:
Molecular medicine
fascicolo: 3, volume: 4, anno: 1998,
pagine: 165 - 178
SICI:
1076-1551(1998)4:3<165:UAMIDA>2.0.ZU;2-F
Fonte:
ISI
Lingua:
ENG
Soggetto:
ELECTRON-TRANSPORT CHAIN; CELL-DEATH; PERMEABILITY TRANSITION; BILE-ACIDS; RAT-LIVER; DIFFERENTIAL REGULATION; BILIARY-CIRRHOSIS; CYCLOSPORINE-A; IN-VIVO; HEPATOCYTES;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
48
Recensione:
Indirizzi per estratti:
Citazione:
C.M.P. Rodrigues et al., "URSODEOXYCHOLIC ACID MAY INHIBIT DEOXYCHOLIC ACID-INDUCED APOPTOSIS BY MODULATING MITOCHONDRIAL TRANSMEMBRANE POTENTIAL AND REACTIVE OXYGENSPECIES PRODUCTION", Molecular medicine, 4(3), 1998, pp. 165-178

Abstract

Background: The hydrophilic bile salt ursodeoxycholate (UDCA) inhibits injury by hydrophobic bile acids and is used to treat cholestatic liver diseases. Interestingly, hepatocyte cell death from bile acid-induced toxicity occurs more frequently from apoptosis than from necrosis. However, both processes appear to involve the mitochondrial membrane permeability transition (MPT). In this study, we determined the inhibitory effect of UDCA on deoxycholic acid (DCA)-induced MPT in isolated mitochondria by measuring changes in transmembrane potential (Delta Psi(m)) and production of reactive oxy gen species (ROS). In addition, we examined the expression of apoptosis-associated proteins in mitochondria isolated from livers of bile acid-fed animals. Materials and Methods: Adult male rats were maintained on standard diet supplemented with DCA and/or UDCA for 10 days. Mitochondria were isolated from livers by sucrose/percoll gradient centrifugation and MPT was measured using spectrophotometric and fluorimetric assays. Delta Psi(m) and ROS generation were determined by FACScan analysis. Cytoplasmic and mitochondrial protein abundance were determined by Western blot analysis. Results: DCA increased mitochondrial swelling 25-fold over controls (p < 0.001); UDCA reduced the swelling by >40% (p < 0.001). Similarly, UDCA inhibited DCA-mediated release of calcein-loaded mitochondria by 50% (p <0.001). Delta Psi(m) was significantly decreased in mitochondria incubated with DCA but not with UDCA. Delta Psi(m) disruption was followedclosely by increased superoxide anion and peroxides production (p < 0.01). Coincubation of mitochondria with UDCA significantly inhibited the changes associated with DCA (p < 0.05). In vivo, DCA feeding was associated with a 4.5-fold increase in mitochondria-associated Bax protein levels (p < 0.001); combination feeding with UDCA almost totally inhibited this increase (p < 0.001). Conclusion: UDCA significantly reduces DCA-induced disruption of Delta Psi(m), ROS production, and Bax protein abundance in mitochondria, suggesting both short-and long-term mechanisms in preventing MPT. The results suggest a possible role for UDCA as a therapeutic agent in the treatment of both hepatic and nonhepatic diseases associated with high levels of apoptosis.

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Documento generato il 22/01/20 alle ore 06:43:42