Aims: Methionine sulfoxide reductase A (MsrA) and methionine metabolism are associated with oxidative stress, a principal cause of ischemia/reperfusion (I/R) injury. Herein, we investigated the protective role of MsrA against kidney I/R injury and the involvement of MsrA in methionine metabolism and the transsulfuration pathway during I/R. Results: We found that MsrA gene-deleted mice (MsrA -/ -) were more susceptible to kidney I/R injury than wild-type mice (MsrA +/+ ). Deletion of MsrA enhanced renal functional and morphological impairments, congestion, inflammatory responses, and oxidative stress under I/R conditions. Concentrations of homocysteine and H 2 S in the plasma of control MsrA -/ -mice were significantly lower than those in control MsrA +/+ mice. I/R reduced the levels of homocysteine and H 2 S in both MsrA +/+ and MsrA -/ -mice, and these reductions were significantly more profound in MsrA -/ -than in MsrA +/+ mice. I/R reduced the expression and activities of cystathionine-b-synthase (CBS) and cystathionine-c-lyase (CSE), both of which are H 2 S-producing enzymes, in the kidneys. These reductions were more profound in the MsrA -/ -mice than in the MsrA +/+ mice. Innovation: The data provided herein constitute the first in vivo evidence for the involvement of MsrA in regulating methionine metabolism and the trans-sulfuration pathway under normal and I/R conditions. Conclusion: Our data demonstrate that MsrA protects the kidney against I/R injury, and that this protection is associated with reduced oxidative stress and inflammatory responses. The data indicate that MsrA regulates H 2 S production during I/R by modulating the expression and activity of the CBS and CSE enzymes.

No abstract

Scoparone, which is a major constituent of Artemisia capillaries, has been identified as an anticoagulant, hypolipidemic, vasorelaxant, anti-oxidant and anti-inflammatory drug, and it is used for the traditional treatment of neonatal jaundice. Therefore, we hypothesized that scoparone could suppress the proliferation of VSMCs by interfering with STAT3 signaling. We found that the proliferation of these cells was significantly attenuated by scoparone in a dose-dependent manner. Scoparone markedly reduced the serum-stimulated accumulation of cells in the S phase and concomitantly increased the proportion of cells in the G0/G1 phase, which was consistent with the reduced expression of cyclin D1, phosphorylated Rb and survivin in the VSMCs. Cell adhesion markers, such as MCP-1 and ICAM-1, were significantly reduced by scoparone. Interestingly, this compound attenuated the increase in cyclin D promoter activity by inhibiting the activities of both the WT and active forms of STAT3. Similarly, the expression of a cell proliferation marker induced by PDGF was decreased by scoparone with no change in the phosphorylation of JAK2 or Src. On the basis of the immunofluorescence staining results, STAT3 proteins phosphorylated by PDGF were predominantly localized to the nucleus and were markedly reduced in the scoparone-treated cells. In summary, scoparone blocks the accumulation of STAT3 transported from the cytosol to the nucleus, leading to the suppression of VSMC proliferation through G1 phase arrest and the inhibition of Rb phosphorylation. This activity occurs independent of the form of STAT3 and upstream of kinases, such as Jak and Src, which are correlated with abnormal vascular remodeling due to the presence of an excess of growth factors following vascular injury. These data provide convincing evidence that scoparone may be a new preventative agent for the treatment of cardiovascular diseases.

Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely used antihyperglycemic agents for the treatment of type 2 diabetes mellitus. Recently, the pleiotropic actions of DPP-4 inhibitors have drawn much attention. In the present study, we aimed to examine whether gemigliptin, a recently developed DPP-4 inhibitor, could protect against cisplatin-induced nephrotoxicity. We showed that pretreatment with gemigliptin attenuated cisplatin-induced renal dysfunction, as shown by analysis of plasma creatinine levels and blood urea nitrogen and histological damage. Elevated plasma levels of active glucagon-like peptide-1 were observed in gemigliptin-pretreated mice after cisplatin treatment, compared to that in cisplatin alone-treated mice. Gemigliptin attenuated cisplatin-induced apoptotic cell death, as assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and Western blot analysis in the kidneys. Gemigliptin also decreased the plasma levels of tumor necrosis factor-α and monocyte chemoattractant protein-1 and attenuated nuclear staining of nuclear factor kappa-B p65 in the kidneys. In addition, gemigliptin increased the protein expression of heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO1) in the kidneys of cisplatin-treated mice. Taken together, these results suggest that pretreatment with gemigliptin protects against cisplatin-induced nephrotoxicity in mice, possibly via inhibition of apoptotic cell death and inflammatory responses through induction of HO-1 and NQO1 expression.

No abstract