ed with 100 ng/ml TPA for the time period indicated, and phosphorylated Acknowledgments The authors thank Dr. Yihong Zhong in Department of Pathology, the Safety Assessment and Research Center for Drugs, Jiangsu Province, Nanjing Medical University for the assistance of immunohitochemistry analysis. Malaria infects 200 to 300 million Chebulinic acid people globally and kills approximately 900,000 every year. Current anti-malaria drugs, such as quinine and artemisinin derivatives can effectively clear malaria parasites in blood, however a significant numbers of severe malaria patients including CM patients die or develop severe sequelae regardless of treatment. It is not clear which factors exacerbate mortality among this subset of CM patients, therefore important questions remain to be answered concerning the mechanism of malaria pathogenesis and development of effective therapies. Existing anti-malaria therapy focus on clearance of parasites ” from blood. This strategy does not prevent secondary deleterious effects such as neurological disorders and cognitive problems caused by parasite derived factors. Recent studies have demonstrated that many pathological changes result from malaria-induced secondary effects which involve various signaling molecules and pathways in the host, indicating that malaria pathogenesis is highly complex and multifactorial,. Recently, it has been shown that increased level of free Heme produced during malaria infection induces inflammation that damages host vascular endothelium which is responsible for induction of fatal cerebral pathogenesis as well as acute lung injury /ARDS. Heme oxygenase is the rate-limiting step enzyme in the degradation of Heme groups to biliverdin, carbon monoxide and iron. Up-regulation of HO-1 protects against cellular stress including oxidative stress, heavy metal toxicity, UV radiation, and inflammation, thus preventing deleterious effects of Heme and mediating anti-inflammatory and anti-apoptotic functions. HO-1 induced by reactive oxygen species and nitric oxide, has recently been shown to STAT3 Activation in Severe Malaria be involved in regulation of angiogenesis. HO-1 may facilitate the repair of injured tissues through inhibition of infiltrating inflammatory cells. Severe malaria is associated with perturbation of inflammatory cytokines, chemokines, antiinflammatory cytokines and angiopoietic factors. Chemokine CXCL10 is 
a cytokine belonging to the CXC chemokine family. CXCL10 binds CXCR3 receptor to induce chemotaxis, apoptosis, cell growth and angiostasis. It is expressed early in mice infected with P. berghei ANKA as well as in human CM. Studies conducted in India and Ghana have identified CXCL10 as a serological marker highly linked with increased risk of fatal P. falciparum-mediated CM mortality in humans. Following our report of a role of CXCL10 in fatal human CM, several groups utilized gene knockout mice in ECM to confirm and demonstrate the role of CXCL10/CXCR3 interactions in the pathogenesis of fatal CM via the recruitment and activation of pathogenic CD8 T cells. In fact, survival of mice infected with the lethal strain of P. berghei ANKA CM increased to 80% in CXCL102/2 and CXCR32/2 mice when compared with the wild type within the observation period of 1012 days 15363972” post infection. In addition to genetic deletion of CXCL10 gene, Nie et al also reported that CXCL10 neutralization with specific antibodies protected against cerebral malaria infection and inflammation. Passive transf