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Background Quercetin (QE) is an antioxidant, anti-inflammatory, flavonoid compound. It was shown that islets are susceptible to oxidative stress due to their inherent low antioxidant capacity. In the present study, we investigated whether treatment of mouse islets with QE could enhance their function before transplantation. Methods Balb/c mouse islets were treated with various concentrations of QE and their viability, function, and nitric oxide (NO) and the expression of inducible NO synthase (iNOS) were determined before and after cytokine treatment. The expression of antioxidant genes was determined. Apoptosis and apoptosis-associated gene expression was measured using INS-1 cells with or without QE treatment before and after cytokine treatment. Results The QE-treated islets and INS-1 cells showed higher cell function compared to untreated control. The expression of heme oxygenase-1, manganese-dependent superoxide dismutase, and B-cell lymphoma-2 (Bcl-2) were enhanced, and the expression of NO, iNOS, and Bcl-2-associated X protein were reduced before and after cytokine treatment. Conclusions Our results show that QE could enhance the viability and reduce apoptosis of mouse islets and improve their function before transplantation.

Background Calcineurin inhibitors are effective immunosuppressive agents, but associated adverse effects such as nephrotoxicity may limit efficacy. Tacrolimus (FK506) is an immunosuppressive drug used mainly to lower the risk of organ rejection after allogeneic organ transplant. Adverse effects of FK-506 can prompt patients to end treatment despite the efficacy. In the present study, we investigated the protective effect and mechanism of tetrahydrocurcumin (THC) on FK506-induced renal damage, apoptosis, and oxidative stress to evaluate its possible use for kidney protection. Materials and Methods The effect of THC on FK506-induced kidney cell damage was investigated in LLC-PK1 cells. LLC-PK1 cells were pretreated with THC at concentrations of dose for 2 hours followed by addition of FK506 for 24 hours. LLC-PK1 cells were treated with FK506 and THC, and cell viability and glutathione was measured. The number of apoptotic cells was measured using an annexin V/propidium iodide staining with flow cytometry. The effect of apoptosis by THC in LLC-PK1 cells was determined by measuring the caspase-9, caspase-3, B-cell lymphoma-2 (Bcl-2), and Bcl-2-associated X protein levels using Western blotting analyses. Results FK506-induced LLC-PK1 renal cell damage was markedly ameliorated by THC treatment. THC protected LLC-PK1 cells by preventing FK506-induced glutathione decrease. THC protects against FK506-induced apoptosis in LLC-PK1 cells. Apoptosis was significantly decreased, and Bcl-2 was elevated in the THC-treated group. Bcl-2-associated X protein, caspase-3, and caspase-9 were decreased in the THC-treated group. Conclusion These results collectively provide therapeutic evidence that THC ameliorates the FK506-induced renal damage via antioxidant effect and apoptosis inhibition.

Background The transplantation of isolated pancreatic islets is a promising treatment for diabetes. Curcumin has been used for its pharmacologic effects, such as antidiabetic and anti-inflammatory activities. Tetrahydrocurcumin (THC), one of the major metabolites of curcumin, has been reported to have antioxidant and anti-inflammatory activities. This study examines the hypothesis that preoperative THC treatment can attenuate ischemic damage and apoptosis before islet transplantation. Methods Islets isolated from Balb/c mice were randomly divided into 2 groups and cultured in medium supplemented with or without THC. In vitro islet viability and function were assessed. After treatment with a cytokine cocktail consisting of tumor necrosis factor-α, interferon-β, and interleukin-1β, islet cell viability, function, and apoptotic status were determined. Proteins related to apoptosis were analyzed using INS-1 cell after streptozocin treatment. Results There was no difference in cell viability between the 2 groups. Islets cultured in the medium supplemented with THC showed 1.3-fold higher glucose-induced insulin secretion than the islets cultured in the medium without THC. After treatment with a cytokine cocktail, glucose-induced insulin release, and NO of the islets were significantly improved in THC-treated islets compared with islets not treated with THC. Apoptosis was significantly decreased, and B-cell lymphoma-2 was elevated in the THC-treated group. The streptozocin-treated INS-1 cell produced significantly higher levels of and B-cell lymphoma-2-associated X protein, caspase-3, and caspase-9 than INS-1 treated with THC. Conclusions These results suggest that preoperative THC administration enhances islet function before transplantation and attenuates the cytokine-induced damage associated with apoptosis.

Background Crepidiastrum denticulatum (CD) is a well-known, traditionally consumed vegetable in Korea, which was recently reported to contain bioactive compounds with detoxification and antioxidant properties. Ischemia-reperfusion injury (IRI) is a major problem after renal transplantation. Furthermore, inflammatory responses to IRI exacerbate the resultant renal injury. In the present study, we investigated whether CD extract exhibits renoprotective effects against IR-induced acute kidney injury in mice. Materials and methods Renal IRI was induced in male C57BL/6 mice by bilateral renal pedicle occlusion for 30 minutes followed by reperfusion for 48 hours. CD extract (75 mg/kg) was administered orally 5 days before IRI. Results Treatment with CD extract significantly decreased blood urea nitrogen and serum creatinine levels as well as kidney tubular injury. CD also prevented IRI-induced renal glutathione depletion and increased malondialdehyde levels. Western blotting and reverse transcriptase polymerase chain reaction indicated that CD extract significantly attenuates inducible nitric oxide synthase and toll-like receptor 2/4 protein levels 48 h after IRI. The expression of tumor necrosis factor-α and interleukin-1β was significantly decreased in the CD extract treatment group. Conclusion CD extract improved acute renal IRI through its antioxidant and anti-inflammatory effects. These findings suggest that CD extract is a potential therapeutic agent for acute ischemia-induced renal damage.

Background Transplantation of isolated islets is a promising treatment for diabetes. Red ginseng (RG) is steamed ginseng and has been reported to enhance insulin secretion–stimulating and anti-apoptotic activities in pancreatic β-cells. In this study, we examined the hypothesis that pre-operative RG treatment enhances islet cell function and anti-apoptosis and investigated whether RG improves islet engraftment by transplant of a marginal mass of syngeneic islets pretreated with RG in diabetic mice. Methods Balb/c mice were randomly divided into 2 groups, and 1 group was administered RG (400 mg/kg/day orally) for 7 days before islet isolation. In vitro islet viability and function were assessed. After cytokine treatment, cell viability, function, and apoptosis of islet cells were analyzed. Furthermore, we studied the effects of RG in a syngeneic islet graft model. A marginal mass of syngeneic mouse islets was transplanted into diabetic hosts. Results Islet pretreatment with RG showed 1.4-fold higher glucose-induced insulin secretion than did control islets. RG pretreatment upregulated B-cell lymphoma 2 (Bcl-2) expression and downregulated Bcl-associated X protein (BAX), caspase-3, and inducible nitric oxide synthase (iNOS) expression. Glucose-induced insulin release, NO, and apoptosis were significantly improved in RG-pretreated islets compared with cytokine-treated islets. RG-pretreated mice exhibited improved marginal mass islet graft survival compared with controls. Conclusions These results suggest that pre-operative RG administration enhanced islet function before transplantation and attenuated cytokine-induced damage associated with apoptosis. These studies indicate that inhibition of apoptosis by RG significantly improved islet cell and graft function after isolation and transplantation, respectively.

Background Eupatilin, a pharmacologically active flavone derived from Artemisia species, is known to have antioxidant and antiinflammatory activities. Ischemia-reperfusion injury (IRI) is a major critical event that commonly occurs after liver transplantation and resection. Furthermore, inflammatory responses to IRI exacerbate the resultant hepatic injury. In this study, we investigated whether eupatilin protects against IR-induced acute liver injury in mice. Materials and Methods Partial (70%) hepatic IRI was induced in male C57BL/6 mice by portal triad pedicle occlusion for 90 minutes followed by reperfusion for 6 hours. Eupatilin (10 mg/kg body weight, oral) was administered 4 days before the IRI. Results Treatment with eupatilin significantly decreased serum alanine aminotransferase and serum aspartate aminotransferase as well as liver histologic changes. Eupatilin also prevented hepatic glutathione depletion and increased malondialdehyde levels induced by IRI. Western blotting indicated that eupatilin significantly increased the levels of heat shock protein and B-cell lymphoma 2 protein, attenuated inducible nitric oxide synthase, and cleaved caspase-3 levels 6 hours after IRI. The expression of the Toll-like receptor 2/4, and phosphorylated nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor was significantly decreased in the eupatilin pretreatment group. Conclusions Eupatilin improved the acute hepatic IRI by reducing inflammation and apoptosis. These findings suggest that eupatilin is a promising therapeutic agent against acute IR-induced hepatic damage.

Background The transplantation of isolated islets is thought to be an attractive approach for curative treatment of diabetes mellitus. Panax ginseng has been used in oriental countries for its pharmacologic effects, such as antidiabetic and antiinflammatory activities. 20(S)-ginsenoside Rg3 (Rg3), an active ingredient of ginseng saponins, has been reported to enhance insulin secretion–stimulating and antiapoptotic activities in pancreatic beta cells. We performed this study to examine the hypothesis that preoperative Rg3 administration can enhance islet cell function and antiapoptosis before islet transplantation. Methods Balb/c mice were randomly divided into 2 groups according to the administration of Rg3 after islet isolation. Mouse islets were cultured in medium supplemented with or without Rg3. In vitro, islet viability and function were assessed. After treatment of islets with a cytokine cocktail (tumor necrosis factor α, interferon-γ, and interleukin-1β), cell viability, function, and apoptosis were assessed. Results Cell viability was similar between the 2 groups. Islets cultured in medium supplemented with Rg3 showed 2.3-fold higher glucose-induced insulin secretion than islets cultured in medium without Rg3. After treatment with a cytokine cocktail, glucose-induced insulin release, total insulin content of islets, and apoptosis were significantly improved in Rg3-treated islets compared with cytokine-treated islets. Cytokine-treated islets produced significantly higher levels of nitric oxide (NO) than islets treated with Rg3. Conclusions These results suggest that preoperative Rg3 administration enhanced islet function before islet transplantation and attenuated both cytokine-induced damage associated with NO production and apoptosis. Rg3 administration might be a prospective management to enhanced islet function and ameliorate early inflammation after transplantation.

Background Polydeoxyribonucleotide (PDRN) is an A2A receptor agonist that induces vascular endothelial growth factor (VEGF) production during the pathological condition of low tissue perfusion. Ischemia-reperfusion injury (IRI) is a major problem after renal transplantation. In the present study, we investigated whether PDRN exhibits reno-protective effects against ischemia-reperfusion–induced acute kidney injury in mice. Methods Renal ischemia-reperfusion injury was induced in male C57BL/6 mice by bilateral renal pedicle occlusion for 30 minutes, followed by reperfusion for 48 hours. PDRN (8 mg/kg body weight intraperitoneally) was administered 30 minutes before IRI. Results Treatment with PDRN significantly decreased neutrophil gelatinase-associated lipocalin levels in the urine, blood urea nitrogen level, and serum creatinine levels as well as kidney tubular injury. Western blotting showed that PDRN significantly increased the levels of vascular endothelial growth factor and B-cell lymphoma protein and attenuated p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, inducible nitric oxide synthase, and Bcl-2–associated X protein levels 48 hours after IRI. Conclusions Our findings suggest that PDRN is a potential therapeutic agent for acute ischemia-induced renal damage.

Background The transplantation of isolated pancreatic islets is a promising treatment for diabetes. 5,7-dihydroxy-3,4,6-trimethoxyflavone (Eupatilin), a pharmacologically active flavone derived from the Artemisia plant species, has been reported to have antioxidant and anti-inflammatory activities. This study examines the hypothesis that preoperative eupatilin treatment can attenuate ischemic damage and apoptosis before islet transplantation. Methods Islets isolated from Balb/c mice were randomly divided into 2 groups, and cultured in medium supplemented with or without eupatilin. In vitro islet viability and function were assessed. After treatment with a cytokine cocktail consisting of tumor necrosis factor (TNF)-α, interferon (INF)-γ, and interleukin (IL)-1β, islet cell viability, function, and apoptotic status were determined. The glutathione (GSH) and nitrous oxide (NO) levels were also measured. Proteins related to apoptosis were analyzed using Western blotting. Results There was no difference in cell viability between the 2 groups. Islets cultured in the medium supplemented with eupatilin showed 1.4-fold higher glucose-induced insulin secretion than the islets cultured in the medium without eupatilin. After treatment with a cytokine cocktail, glucose-induced insulin release and the total insulin content of the islets were significantly improved in eupatilin-pretreated islets compared with islets not treated with eupatilin. Apoptosis was significantly decreased, and GSH levels were elevated in the eupatilin-pretreated group. Cytokine-only treated islets produced significantly higher levels of NO, iNOS, and caspase-3 than islets pretreated with eupatilin before cytokine treatment. Conclusions These results suggest that preoperative eupatilin administration enhances islet function before transplantation and attenuates the cytokine-induced damage associated with NO production and apoptosis.

Background Eupatilin, a pharmacologically active flavone derived from Artemisia species, is known to have antioxidant and anti-inflammatory activities. Ischemia-reperfusion injury (IRI) is a major complication after renal transplantation, with inflammatory responses to IRI exacerbating the resultant renal injury. In the present study, we investigated whether eupatilin exhibits renoprotective activities against ischemia-reperfusion-induced acute kidney injury in mice. Materials and Methods Renal IRI was induced in male C57BL/6 mice by bilateral renal pedicle occlusion for 30 minutes followed by reperfusion for 48 hours. Eupatilin (10 mg/kg body weight p.o.) was administered 4 days before IRI. Results Treatment with eupatilin significantly decreased neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 levels in urine, blood urea nitrogen level, and serum creatinine levels, as well as kidney tubular injury. Western blotting indicated that eupatilin significantly increased the levels of heat shock protein 70 and B-cell lymphoma protein, and it attenuated inducible nitric oxide synthase, Bcl-2–associated X protein, and caspase-3 levels 48 hours after IRI. Conclusion Our findings suggest that eupatilin is a promising therapeutic agent against acute ischemia-induced renal damage.