Oxidative stress plays an important role in the development of diabetes complications. Our results demonstrate that increased production of ROS is the central and major mediator of both diabetes and diabetic gastroparesis. It is intriguing, although the production of ROS is a common mechanism, however, the activation of JNK and p38 MAPK in pylorus is unique and specific to gastroparesis. While we did not observe any ROS-mediated activation of JNK and p38 MAPK pathways in pylorus, there are numerous reports demonstrate the activation of both the pathways in β-cells ( ). Thus, the two-faced character of ROS is clearly substantiated in our study.
Enhanced ROS production is followed by lipid peroxidation, protein oxidation, and DNA damage which …show more content…
The p38 MAPK signaling pathway virtually regulates many physiological functions depending on the stimulus and cell type. Recent report convincingly demonstrates that blockade of p38 MAPK pathway ameliorates delayed gastric emptying in diabetic rats ( ). In the line with this study, our results demonstrate the activation of this pathway in DM + GP rats further highlighting the importance of p38 MAPK pathway in gastric motility. Previous reports have shown that the p38 MAPK and JNK pathways are activated simultaneously and can crosstalk at several levels ( ). Therefore, the inhibition of these pathways has considerable potential for the treatment of gastric motility impairment. Interestingly, we found that the activation of MAPK pathways (p38 MAPK and JNK) per se is not simple on-off switch, and its level and duration is tightly regulated by MKP-1. Our results were further substantiated by an observation that JNK is involved in pancreatic β-cell death by STZ through inactivation of MKP-1 ( ). Off note, there is no change in the activation of JNK and p38 MAPK in DM rats presumably due the stabilization of MKP-1 protein. In support of our hypothesis, Zhou et al. ( ) found that ROS can up-regulate MKP-1 expression. The activity of MKP-1 is regulated at multiple levels including protein stabilization, catalytic activation, and transcriptional induction. In our study, the observed degradation of MKP-1 might be mediated by proteasome or impairment of de novo synthesis at the translational level. In support of our hypothesis, Choi et al. ( ) demonstrate that activation of PKC∆ triggers the degradation of MKP-1 through the ubiquitin-proteasome pathway. However, the more definitive evidence is needed in linking JNK/p38 signaling axis and
Enhanced ROS production is followed by lipid peroxidation, protein oxidation, and DNA damage which …show more content…
The p38 MAPK signaling pathway virtually regulates many physiological functions depending on the stimulus and cell type. Recent report convincingly demonstrates that blockade of p38 MAPK pathway ameliorates delayed gastric emptying in diabetic rats ( ). In the line with this study, our results demonstrate the activation of this pathway in DM + GP rats further highlighting the importance of p38 MAPK pathway in gastric motility. Previous reports have shown that the p38 MAPK and JNK pathways are activated simultaneously and can crosstalk at several levels ( ). Therefore, the inhibition of these pathways has considerable potential for the treatment of gastric motility impairment. Interestingly, we found that the activation of MAPK pathways (p38 MAPK and JNK) per se is not simple on-off switch, and its level and duration is tightly regulated by MKP-1. Our results were further substantiated by an observation that JNK is involved in pancreatic β-cell death by STZ through inactivation of MKP-1 ( ). Off note, there is no change in the activation of JNK and p38 MAPK in DM rats presumably due the stabilization of MKP-1 protein. In support of our hypothesis, Zhou et al. ( ) found that ROS can up-regulate MKP-1 expression. The activity of MKP-1 is regulated at multiple levels including protein stabilization, catalytic activation, and transcriptional induction. In our study, the observed degradation of MKP-1 might be mediated by proteasome or impairment of de novo synthesis at the translational level. In support of our hypothesis, Choi et al. ( ) demonstrate that activation of PKC∆ triggers the degradation of MKP-1 through the ubiquitin-proteasome pathway. However, the more definitive evidence is needed in linking JNK/p38 signaling axis and