br HO and cerebral malaria

HO-1 and cerebral malaria In a post-mortem evaluation of human cerebral (falciparum) malaria, strong HO-1 immunostaining was consistently noted in microglia/macrophages within and surrounding the pathognomonic Durck’s granulomas (Schluesener et al., 2001). As witnessed in cerebral trauma specimens (Section 13), microglial HMOX1 induction in the parasitized brains was particularly prominent in the vicinity of hemorrhages, whereas immunoreactive HO-1 was weak or nil in astrocytes and endothelial cells. Schluesener et al. conjectured that hemoglobin-derived heme, NO, pro-inflammatory cytokines and other ‘malaria toxins’ may contribute to cerebral HO-1 upregulation in these subjects. They speculated that CO released from heme may affect the outcome of this illness by influencing the biotransformation of anti-malaria drugs in a cytochrome P450-dependent manner (Schluesener et al., 2001).
HO-1 and cerebral neoplasms HO-1 mRNA and protein are variably upregulated in human cerebral neoplasms (Deininger et al., 2000; Hara et al., 1996). The HMOX1 induction may be secondary to deviations in redox homeostasis favouring sustained pro-oxidant conditions characteristic of transformed 6-Bnz-cAMP sodium salt (Policastro et al., 2004). The enzyme may also be synthesized as a paraprotein resulting from disorganized gene regulation in the cancer cells. HO-1 expression in human glial and other tumors reportedly correlates with the histopathological grade and aggressive clinical behavior of the malignancy (Deininger et al., 2000; Hara et al., 1996). Our laboratory demonstrated that transfection of HMOX1 cDNA into human M17 neuroblastoma and rat C6 glioma cells increases 3H-thymidine incorporation and cell proliferation, while suppressing growth in primary rat astrocyte cultures (Song et al., 2004). We also showed that silencing of HMOX1 expression with HO-1 shRNA or abrogation of enzymatic activity with the HO-1 specific inhibitor, OB-24 decreases oxidative stress, MAPK–ERK/p38 kinase activation, cell proliferation, survival and invasion and distant metastases in a mouse model of human prostate cancer, a lesion with a high propensity for neuraxial involvement (Alaoui-Jamali et al., 2009). The complex and frequently disparate effects of HO-1 on cytokinesis in normal and transformed cells, and the heme products considered to mediate these pleiotropic effects, are topics of an earlier review (Durante, 2003).
HO-1 and chronic brain disease: lessons learned In this section, conclusions are drawn from the work reviewed above concerning the untoward effects of sustained or repeated glial HMOX1 induction in brain development, aging and disease. The remainder of this article will highlight several key implications of the data for the pathogenesis and management of human chronic CNS afflictions.
Therapeutic considerations
Conflicts of interest
Acknowledgements The work reviewed herein was supported by grants to HMS from the Canadian Institutes of Health Research (MOP-68887), the Mary Katz Claman Foundation, ApoPharma Inc., and Immunotec Inc. The authors thank Mrs. Adrienne Liberman for assistance with the artwork.
Introduction Diabetes is a chronic disease characterized by elevated blood sugar levels resulting from either a lack of insulin production or resistance to insulin. The latest estimates revealed a global prevalence of 382 million patients with diabetes in 2013, expected to rise to 592 million by 2035. The etiological classification of diabetes is now widely accepted [1]. Being overweight or obese, major public health concerns worldwide, increases the risk of type 2 diabetes mellitus (T2DM) [2]. Early in the development of T2DM, insulin resistance (see Glossary) requires extra insulin production to maintain normal levels of blood glucose. Vascular dysfunction is a major mechanism in the development of cardiovascular disease in patients with abnormal glucose metabolism, and most diabetes-related deaths arise from vascular complications, such as myocardial infarction and cerebrovascular diseases.