ABSTRACT
Malaria infection causes multiple organ-specific lethal pathologies, including cerebral malaria, and severe liver and lung pathologies by inducing strong inflammatory responses. Gene polymorphism studies suggest that TLR4 and TLR2 contribute to severe malaria, but the roles of these signaling molecules in malaria pathogenesis remain incompletely understood. We hypothesize that danger-associated molecular patterns produced in response to malaria activate TLR2 and TLR4 signaling and contribute to liver and lung pathologies. By using a mouse model of Plasmodium berghei NK65 infection, we show that the combined TLR2 and TLR4 signaling contributes to malaria liver and lung pathologies and mortality. Macrophages, neutrophils, natural killer cells, and T cells infiltrate to the livers and lungs of infected wild-type mice more than TLR2,4-/- mice. Additionally, endothelial barrier disruption, tissue necrosis, and hemorrhage were higher in the livers and lungs of infected wild-type mice than in those of TLR2,4-/- mice. Consistent with these results, the levels of chemokine production, chemokine receptor expression, and liver and lung pathologic markers were higher in infected wild-type mice than in TLR2,4-/- mice. In addition, the levels of HMGB1, a potent TLR2- and TLR4-activating danger-associated molecular pattern, were higher in livers and lungs of wild-type mice than TLR2,4-/- mice. Treatment with glycyrrhizin, an immunomodulatory agent known to inhibit HMGB1 activity, markedly reduced mortality in wild-type mice. These results suggest that TLR2 and TLR4 activation by HMGB1 and possibly other endogenously produced danger-associated molecular patterns contribute to malaria liver and lung injury via signaling mechanisms distinct from those involved in cerebral malaria pathogenesis.
Subject(s)
HMGB1 Protein , Malaria, Cerebral , Animals , Mice , Toll-Like Receptor 2/metabolism , HMGB1 Protein/metabolism , Toll-Like Receptor 4/metabolism , Malaria, Cerebral/pathology , Lung/pathology , Signal Transduction/genetics , Liver/metabolism , Mice, Inbred C57BL , Mice, KnockoutABSTRACT
Mixed lineage kinase 3 (MLK3) is a serine/threonine kinase family member of mitogen activated protein kinase kinase kinases (MAP3Ks). MLK3 has been implicated in the regulation of tumor cell proliferation, differentiation, migration, invasion, and apoptosis depending on the cellular contexts. Notwithstanding the involvement of MLK3 in several cancers, the precise roles of MLK3 are not completely understood. This review evaluates the molecular mechanisms and signaling pathways associated with MLK3, which play a major role in malignancies that include breast, cervical, colorectal, gastric and prostate cancer. Since early detection of cancer is critical, this review discusses the potential of MLK3 as a predictive biomarker, which could likely help in clinical decision-making. Importantly, the efficacy of targeting MLK3 via different therapeutic approaches is also explored.
Subject(s)
MAP Kinase Kinase Kinases , Neoplasms , Humans , MAP Kinase Kinase Kinases/metabolism , Protein Serine-Threonine Kinases , Serine , Mitogen-Activated Protein Kinase Kinase Kinase 11ABSTRACT
Swiprosin-1 or EFHD2, is a Ca2+ binding actin protein and its expression has been shown to be distinct in various cell types. The expression of swiprosin-1 is upregulated during the activation of immune cells, epithelial and endothelial cells. The expression of swiprosin-1 is regulated by diverse signaling pathways that are contingent upon the specific type of cells. The aim of this review is to summarize and provide an overview of the role of swiprosin-1 in pathophysiological conditions of cancers, cardiovascular diseases, diabetic nephropathy, neuropsychiatric diseases, and in the process of inflammation, immune response, and inflammatory diseases. Novel approaches for the targeting of swiprosin-1 as a biomarker in the early detection and prevention of various development of chronic diseases are also explored.