ing the fact that there was no significant difference in free Heme level between CXC102/2 infected mice and non-infected controls, we postulated that HO-1 activation may not be required under this situation. 10670419” Animal models provide valuable biological information under controlled circumstances. However, different mice strains show variations in susceptibility to rodent malaria, this may reflect qualitative or quantitative differences in host immune response to the parasite and differences in the pathogenicity of purchase DMXB-A sub-strains of murine malaria parasite species. C57BL/6 infected with PBA shares many features similar to human CM. However, lung damage might not be severe enough to cause animal death. This may explain why the pathological manifestation in lung and kidney was modest our study. Our observation of Hb levels being lower in infected wild type mice is consistent with previous studies which showed that P.berghei ANKA infection in C57BL/6 results in anemia. CXCL10 gene deficiency prevents decrease in Hb levels. Since the level of free Heme is not increased, it is possible that this may occur through reduction of hemolysis of infected RBC. But the compromised clearance of uninfected RBCs or erythroid response could not be excluded as a possibility. A recent study in Ghanaian patients demonstrated an association between 
fatal CM and increased serum and cerebrospinal fluid levels of proinflammatory and proapoptotic factors including CXCL10, IL-1ra, sTNFR1, sTNFR2 and sFas and 15256538” decreased serum and CSF levels of neuroprotective angiogenic growth factors . Further investigation in Indian patients confirmed findings from Ghana, thus indicating STAT3 Activation in Severe Malaria that CXCL10, sTNFR2 and sFas are positively correlated, while angiogenic and anti-apoptotic factors, VEGF is negatively correlated with mortality associated with CM. Studies from a murine CM model also confirmed importance of CXCL10/ CXCR3 interactions in the pathogenesis of fatal CM through the recruitment and activation of pathogenic CD8 T cells. CXCL102/2 and CXCR32/2 mice are partially resistant to P. berghei-mediated CM. The animal studies demonstrate that high level of CXCL10 in tissues is associated with ECM in PBA infected mice, which is consistent with previous reports relating to human studies. Our studies to determine the mechanisms by which CXCL10 is up-regulated using in vitro cell culture models revealed that Heme regulates CXCL10 at the transcriptional level in vitro. Our results also suggest that CXCL10 is positively associated with HO-1 gene expression, and may be involved in the regulation of HO-1. Interestingly, an emerging body of evidence demonstrates that HO-1 gene also regulates CXCL10 9 STAT3 Activation in Severe Malaria expression. For instance, HO-1-mediated cytoprotection is mediated by suppression of CXCL10 during liver ischemia and reperfusion injury and kidney transplantation. Our results indicating that reduced HO-1 expression by siHO-1 increased CXCL10 expression support these previous findings. Additionally, HO-1 may enforce angiostatic action via CXCL10 during renal injury. This observation supports the views that a mutual signaling regulation loop exists between HO-1 and CXCL10. Detailed understanding of the characteristic signaling abnormalities could contribute to novel approaches in diagnosis and treatment of severe malaria. STAT3 can be activated by pro- and ant-inflammatory stimuli and cellular stresses, therefore STAT3 can be eit
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