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Cerebral malaria (CM) is one of the most severe complications of malaria infection characterized by coma and neurological effects. Despite standardized treatment of malaria infection with artemisinin-based combination therapies (ACT), the mortality rate is still high, and it primarily affects pediatric patients. ACT reduces parasitemia but fails to adequately target the pathogenic mechanisms underlying CM, including blood-brain-barrier (BBB) disruption, endothelial activation/dysfunction, and hyperinflammation. The need for adjunctive therapies to specifically treat this form of severe malaria is critical as hundreds of thousands of people continue to die each year from this disease. Here we present a summary of some potential promising therapeutic targets and treatments for CM, as well as some that have been tested and deemed ineffective or, in some cases, even deleterious. Further exploration into these therapeutic agents is warranted to assess the effectiveness of these potential treatments for CM patients. [ABSTRACT FROM AUTHOR]

Cerebral malaria is characterized by cytoadhesion of Plasmodium falciparum-infected red blood cells (Pf-iRBCs) to endothelial cells in the brain, disruption of the blood-brain barrier, and cerebral microhemorrhages. No available antimalarial drugs specifically target the endothelial disruptions underlying this complication, which is responsible for the majority of malaria-associated deaths. Here, we have demonstrated that ruptured Pf-iRBCs induce activation of β-catenin, leading to disruption of inter-endothelial cell junctions in human brain microvascular endothelial cells (HBMECs). Inhibition of β- catenin-induced TCF/LEF transcription in the nucleus of HBMECs prevented the disruption of endothelial junctions, confirming that β-catenin is a key mediator of P. falciparum adverse effects on endothelial integrity. Blockade of the angiotensin II type 1 receptor (AT1) or stimulation of the type 2 receptor (AT2) abrogated Pf-iRBC-induced activation of β-catenin and prevented the disruption of HBMEC monolayers. In a mouse model of cerebral malaria, modulation of angiotensin II receptors produced similar effects, leading to protection against cerebral malaria, reduced cerebral hemorrhages, and increased survival. In contrast, AT2-deficient mice were more susceptible to cerebral malaria. The interrelation of the β-catenin and the angiotensin II signaling pathways opens immediate host-targeted therapeutic possibilities for cerebral malaria and other diseases in which brain endothelial integrity is compromised., Introduction Cerebral malaria is a multifactorial syndrome involving the interaction between Plasmodium falciparum-infected red blood cells (Pf-iRBCs) and host cerebral microvascular endothelial cells (1). P. falciparum erythrocyte membrane protein-1 (PfEMP1) [...]

There is significant evidence that brain-infiltrating CD8+ T cells play a central role in the development of experimental cerebral malaria (ECM) during Plasmodium berghei ANKA infection of C57BL/6 mice. However, the mechanisms through which they mediate their pathogenic activity during malaria infection remain poorly understood. Utilizing intravital two-photon microscopy combined with detailed ex vivo flow cytometric analysis, we show that brain-infiltrating T cells accumulate within the perivascular spaces of brains of mice infected with both ECM-inducing (P. berghei ANKA) and non-inducing (P. berghei NK65) infections. However, perivascular T cells displayed an arrested behavior specifically during P. berghei ANKA infection, despite the brain-accumulating CD8+ T cells exhibiting comparable activation phenotypes during both infections. We observed T cells forming long-term cognate interactions with CX3CR1-bearing antigen presenting cells within the brains during P. berghei ANKA infection, but abrogation of this interaction by targeted depletion of the APC cells failed to prevent ECM development. Pathogenic CD8+ T cells were found to colocalize with rare apoptotic cells expressing CD31, a marker of endothelial cells, within the brain during ECM. However, cellular apoptosis was a rare event and did not result in loss of cerebral vasculature or correspond with the extensive disruption to its integrity observed during ECM. In summary, our data show that the arrest of T cells in the perivascular compartments of the brain is a unique signature of ECM-inducing malaria infection and implies an important role for this event in the development of the ECM-syndrome. [ABSTRACT FROM AUTHOR]

Tight blood pressure control decreases apoptosis during renal damage. Background. An excess rate of apoptosis could lead to the gradual loss of renal mass. In this study, we investigated the role of apoptosis in the renal damage secondary to hypertension. Methods. Spontaneously hypertensive rats with 5/6 renal mass reduction (subtotal nephrectomy) were distributed to receive no-treatment, 200 mg/L quinapril, 360 mg/L losartan, or triple therapy (200 mg/L hydralazine, 4 mg/L reserpine, and 100 mg/L hydrochlorothiazide) for 5 weeks. Sham-operated spontaneously hypertensive rats served as controls. Age-matched Wistar-Kyoto (WKY) rats, with or without subtotal nephrectomy, were also studied. Results. Nontreated spontaneously hypertensive rats + subtotal nephrectomy developed proteinuria, glomerular sclerosis, and tubulointerstitial lesions. In comparison to spontaneously hypertensive rats, an increment in the number of [proliferating cell nuclear antigen (PCNA)]-positive and apoptotic [terminal deoxynucleotidyl transferase (Tdt)-mediated deoxyuridine triphosphate biotin nick end labeling (TUNEL)]-positive tubular and glomerular cells was observed. By contrast, WKY + subtotal nephrectomy rats showed less severe morphologic lesions, and only the number of proliferating cells increased. By Western blot, an up-regulation of renal Bax (apoptosis inducer) was noted both in spontaneously hypertensive rats + subtotal nephrectomy and WKY + subtotal nephrectomy rats. By contrast, Bcl-xL (apoptosis protector) was up-regulated in WKY + subtotal nephrectomy rats but not in spontaneously hypertensive rats + subtotal nephrectomy. The administration of appropriate doses of quinapril, losartan, or triple therapy to spontaneously hypertensive rats + subtotal nephrectomy normalized systolic blood pressure, partially prevented proteinuria, renal lesions and apoptosis, and decreased Bax, but no changes were noted in Bcl-xL. The Bax/Bcl-xL index was significantly increased in spontaneously hypertensive rats + subtotal nephrectomy compared to sham-operated spontaneously hypertensive rats and decreased in treated groups. Conclusion. The combination of renal mass reduction and hypertension caused severe renal lesions associated to an increment of apoptosis rate, mainly in tubular epithelial cells. Tight blood pressure control decreased the apoptosis rate and morphologic lesions. These studies suggest that changes in the expression of apoptosis-regulatory genes contribute to the progressive damage in hypertensive rats with renal mass reduction. [ABSTRACT FROM AUTHOR]

With the increasing incidence of cardiovascular diseases worldwide, specifically atherosclerosis and heart failure, the search for novel biomarkers remains a priority. As opposed to complex diagnostic techniques that may not be suitable to be applied to the wider population, biomarkers are useful for population screening. The search for novel biomarkers is based on knowledge of the molecular and cellular processes that take place in the development of a specific disease. Atherosclerosis and heart failure are characterized by a long period of silent disease progression, allowing early diagnosis and the potential of early therapeutic intervention. The use of the so-called proteomic techniques allows not only protein identification but partial characterization, which includes expression and also post-translational modification of these proteins. This allows for the discovery of previously unknown proteins involved in cardiovascular diseases, including some that may be suitable to be used as biomarkers. However, to approach this issue, we have to overcome difficulties such as tissue heterogeneity (vessel wall or myocardium) and the lack of fresh human samples. We discuss the proteomic study of human plaques, secreted proteins by pathologic and normal vessel wall, and left ventricular hypertrophy as potential sources of new biologic markers of cardiovascular disease.