Streptozocin- and Alloxan-Induced H2O2 Generation and DNA Fragmentation in Pancreatic Islets: H2O2 as Mediator for DNA Fragmentation

Takasu, Nobuyuki; Komiya, Ichiro; Asawa, Takayuki; Nagasawa, Yoshitaka; Yamada, Takashi

doi:10.2337/diab.40.9.1141

Cited by 189 publications

(108 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The precise mechanism of action of STZ is unknown, but there is evidence that it interferes with cellular metabolite oxidative mechanisms (Okamoto, 1985). Generation of oxygen free radicals has been proposed to be a major mechanism involved in the cytotoxicity (Takasu et al, 1991). Pancreatic islets possess very low free radical scavenging enzyme and hence are vulnerable to The data are expressed in mean ± S.E.M.…”

Section: Discussionmentioning

confidence: 99%

Silymarin, a flavonoid antioxidant, protects streptozotocin-induced lipid peroxidation and β-Cell damage in rat pancreas

Sharma¹,

Anwer²,

Pillai³

et al. 2008

Oriental Pharmacy and Experimental Medicine

View full text Add to dashboard Cite

SUMMARYThe present study is aimed at finding the influence of silymarin (a flavonoid) (25 mg/kg & 50 mg/kg) in streptozotocin (STZ)-induced diabetic rats. Type 2 diabetes was induced by single intraperitoneal injection of STZ (100 mg/kg) to 3 days old rat pups. Silymarin was administered for 15 days after the animals were confirmed diabetic (75 days after STZ injection). Blood glucose, glycosylated hemoglobin (HbA levels, which were elevated by STZ, were lowered to physiological levels by the administration of silymarin. The levels of LPO were significantly increased in STZ-induced diabetic rats. Silymarin reduced the LPO levels in both pancreas and liver. GSH contents which were reduced significantly in pancreas and liver of STZ-induced diabetic rats were brought back to near normal levels by silymarin treatment. Multifocal necrotic and degenerative changes of pancreas in STZ-diabetic rats were minimized to near normal morphology by administration of silymarin as evident by histopathological examination. Silymarin showed a dose dependent protective effect on STZ-induced β-cell damage. It could be attributed to the antioxidative and free radicals scavenging properties of the flavonoid. Thus, it may be considered as a natural antioxidant with potential therapeutic application in the treatment of type 2 diabetes.

show abstract

Section: Discussionmentioning

confidence: 99%

Silymarin, a flavonoid antioxidant, protects streptozotocin-induced lipid peroxidation and β-Cell damage in rat pancreas

Sharma¹,

Anwer²,

Pillai³

et al. 2008

Oriental Pharmacy and Experimental Medicine

View full text Add to dashboard Cite

show abstract

“…STZ generates hydrogen peroxide and induces DNA oxidation and fragmentation (39). STZ markedly affects intracellular redox status, lowering levels of reduced glutathione in pancreatic (40) and other (41) cells.…”

Section: Discussionmentioning

confidence: 99%

Absence of a reductase, NCB5OR, causes insulin-deficient diabetes

Xie

Zhu

Larade

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

NCB5OR is a highly conserved NAD(P)H reductase that contains a cytochrome b5-like domain at the N terminus and a cytochrome b5 reductase-like domain at the C terminus. The enzyme is located in the endoplasmic reticulum (ER) and is widely expressed in organs and tissues. Targeted inactivation of this gene in mice has no impact on embryonic or fetal viability. At 4 weeks of age, Ncb5or؊͞؊ mice have normal blood glucose levels but impaired glucose tolerance. Isolated Ncb5or؊͞؊ islets have markedly impaired glucose-or arginine-stimulated insulin secretion. By 7 weeks of age, these mice develop severe hyperglycemia with markedly decreased serum insulin levels and nearly normal insulin tolerance. As the animals age, there is a progressive loss of beta cells in pancreatic islets, but there is no loss of alpha, delta, or PP cells. Electron microscopy reveals degranulation of beta cells and hypertrophic and hyperplastic mitochondria, some of which contain electron dense inclusions. Four-week-old Ncb5or؊͞؊ mice have enhanced sensitivity to the diabetogenic agent streptozotocin. NCB5OR appears to play a critical role in protecting pancreatic beta cells against oxidant stress.

show abstract

“…The precise mechanisms of the alloxan cytotoxicity are still not known in detail, although reactive oxygen species have been suggested to be important mediators during the cytotoxic process [3,4,7,10,[12][13][14][15][16][17][18][19][20]. The proposed cellular targets of alloxan cytotoxicity include plasma membranes [2,8], mitochondria [5], DNA [7] and lysosomes [12][13][14][15].…”

mentioning

confidence: 99%

Insulinoma cells in culture show pronounced sensitivity to alloxan-induced oxidative stress

1995

View full text Add to dashboard Cite

SummaryIn a model system of cultured J-774 cells we have previously shown that alloxan in moderate concentrations is toxic only in the presence of a reducing agent with the production of hydrogen peroxide. The cytotoxicity was found to involve lysosomal destabilization. In the present study the cytotoxic effects of (i) alloxan alone, (ii) a combination of alloxan and cysteine or (rio hydrogen peroxide were investigated in two established insulinoma cell lines (HIT-T15 and RINm5F), and compared with the effects on J-774 cells. The protective effects of desferrioxamine and catalase, and the intracellular levels of reduced glutathione and activities of the enzymes glutathione peroxidase, glutathione reductase and catalase were also studied. HIT and RIN cells showed about 10 times greater sensitivity than J-774 cells against exposure to either alloxan and cysteine, or hydrogen peroxide. All cell types were relatively insensitive to alloxan alone. Preincubation with desferrioxamine and addition of catalase provided efficient protection against cytotoxicity and lysosomal destabilization. HIT and RIN cells had less capacity to degrade hydrogen peroxide and lower levels of glutathione peroxidase than J-774 cells. The lysosomal stability in all three cell lines was directly correlated to their viability. We conclude that HIT and RIN cells have weak antioxidative defence systems resulting in enhanced lysosomal vulnerability when they are exposed to alloxan and cysteine, which produce hydrogen peroxide extracellularly. The degree of cytotoxicity seems to be dependent on cellular capacity to degrade hydrogen peroxide and the lysosomal content of reactive iron. [Diabetologia (1995) 38: 635-641]

show abstract

Streptozocin- and Alloxan-Induced H2O2 Generation and DNA Fragmentation in Pancreatic Islets: H2O2 as Mediator for DNA Fragmentation

Cited by 189 publications

References 10 publications

Silymarin, a flavonoid antioxidant, protects streptozotocin-induced lipid peroxidation and β-Cell damage in rat pancreas

Silymarin, a flavonoid antioxidant, protects streptozotocin-induced lipid peroxidation and β-Cell damage in rat pancreas

Absence of a reductase, NCB5OR, causes insulin-deficient diabetes

Insulinoma cells in culture show pronounced sensitivity to alloxan-induced oxidative stress

Contact Info

Product

Resources

About