Post treatment with mangiferin successfully suppressed all these mitochondrial dependent pathophysiological processes

To investigate the molecular mechanism underlying the protective action of mangiferine, we explored whether one or more members of this family plays any role in Pb-induced oxidative stress and cellular dysfunction in liver as well as in hepatocytes. We observed a noticeable increase in protein content of phospho-JNK, p38 and ERK without any alteration in total protein content of these MAPKs family LOUREIRIN-B proteins in Pb-induced liver toxicity. Similar results were also obtained when an in vitro study was conducted using hepatocytes as the working model. Earlier studies also suggest that in addition to MAPKs activation, NF-kB pathway is also involved in Pb induced organ pathophysiology. NF-kB is known to be a rapidly induced transcription factor among many involved in the stressresponsive intracellular signaling pathways and is highly sensitive to the alterations of cellular oxidative status, cell transformation, and apoptosis. Activation of this transcription factor could be regulated by the phosphorylation of its p65 subunits and degradation of its inhibitor-kB via phosphorylation of IKKa/b resulting its translocation into the nucleus. In our study, we also found the up-regulation of the phospho NF-kB in response to Pb induced liver damage and hepatocytes cytotoxicity signifying its pro-apoptotic role. These results also supported the fact in the existing literature. Mangiferin, on the other hand, successfully suppressed the Pb induced upregulation of MAPKs family proteins and phospho NF-kB both in vivo and in vitro. So, it can be concluded that at least a part of the beneficial effects of mangiferin in Pb induced hepatic pathophysiology is due to the inhibition of the MAPKs-NF-kB pathways. There exist a balance between the proapoptotic and antiapoptotic members of the Bcl-2 family proteins and their up and down regulations usually determine the fate of the cells either to undergo apoptosis or to survive in an organ pathophysiology. In addition, these proteins are the upstream regulators of mitochondrial membrane potential and release of cytochrome C into cytosol. Mitochondria play an important role in apoptosis or programmed cell death pathway. A number of studies suggest that the change in mitochondrial membrane potential is able to switch the committed cells to apoptotic death with oxidative stress as the mediator. Throughout this process, the electrochemical gradient 4-(Benzyloxy)phenol across the mitochondrial membrane collapse. Mitochondria have been expressed as the sensor of oxidative stress and loss of its membrane potential or formation of a pore in the mitochondrial membrane all together can show the way of cell death through the release of cytochrome C. Once cytochrome C is released into the cytosol it is able to interact with a protein called Apaf-1. This leads to the recruitment of procaspase 9 into a multi-protein complex with cytochrome C and Apaf-1 called the apoptosome. Formation of the apoptosome leads to activation of initiator caspase as well as the effector caspase and induces apoptosis. In the present study, we found that Pb up regulated the expression of Bax in addition to a down regulation of the expression of Bcl-2 in both the liver tissue and hepatocytes, reduced the mitochondrial membrane potential, enhanced the release of cytochrome C in the cytosol, down regulated Apaf-1 and activated caspases both in vivo and in vitro.

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