Pharmacologic Inhibition of CXCL10 in Combination With Anti-Malarial Therapy Eliminates Mortality Associated With Murine Model of Cerebral Malaria.
Pharmacologic Inhibition of CXCL10 in Combination with Anti-malarial Therapy Eliminates Mortality Associated with Murine Model of Cerebral Malaria.
PLoS One. 2013; 8(4): e60898
Wilson NO, Solomon W, Anderson L, Patrickson J, Pitts S, Bond V, Liu M, Stiles JK
Despite appropriate anti-malarial treatment, cerebral malaria (CM)-associated mortalities remain as high as 30%. Thus, adjunctive therapies are urgently needed to prevent or reduce such mortalities. Overproduction of CXCL10 in a subset of CM patients has been shown to be tightly associated with fatal human CM. Mice with deleted CXCL10 gene are partially protected against experimental cerebral malaria (ECM) mortality indicating the importance of CXCL10 in the pathogenesis of CM. However, the direct effect of increased CXCL10 production on brain cells is unknown. We assessed apoptotic effects of CXCL10 on human brain microvascular endothelial cells (HBVECs) and neuroglia cells in vitro. We tested the hypothesis that reducing overexpression of CXCL10 with a synthetic drug during CM pathogenesis will increase survival and reduce mortality. We utilized atorvastatin, a widely used synthetic blood cholesterol-lowering drug that specifically targets and reduces plasma CXCL10 levels in humans, to determine the effects of atorvastatin and artemether combination therapy on murine ECM outcome. We assessed effects of atorvastatin treatment on immune determinants of severity, survival, and parasitemia in ECM mice receiving a combination therapy from onset of ECM (day 6 through 9 post-infection) and compared results with controls. The results indicate that CXCL10 induces apoptosis in HBVECs and neuroglia cells in a dose-dependent manner suggesting that increased levels of CXCL10 in CM patients may play a role in vasculopathy, neuropathogenesis, and brain injury during CM pathogenesis. Treatment of ECM in mice with atorvastatin significantly reduced systemic and brain inflammation by reducing the levels of the anti-angiogenic and apoptotic factor (CXCL10) and increasing angiogenic factor (VEGF) production. Treatment with a combination of atorvastatin and artemether improved survival (100%) when compared with artemether monotherapy (70%), p<0.05. Thus, adjunctively reducing CXCL10 levels and inflammation by atorvastatin treatment during anti-malarial therapy may represent a novel approach to treating CM patients. HubMed – drug
Novel insights into obesity and diabetes through genome-scale metabolic modeling.
Front Physiol. 2013; 4: 92
Väremo L, Nookaew I, Nielsen J
The growing prevalence of metabolic diseases, such as obesity and diabetes, are putting a high strain on global healthcare systems as well as increasing the demand for efficient treatment strategies. More than 360 million people worldwide are suffering from type 2 diabetes (T2D) and, with the current trends, the projection is that 10% of the global adult population will be affected by 2030. In light of the systemic properties of metabolic diseases as well as the interconnected nature of metabolism, it is necessary to begin taking a holistic approach to study these diseases. Human genome-scale metabolic models (GEMs) are topological and mathematical representations of cell metabolism and have proven to be valuable tools in the area of systems biology. Successful applications of GEMs include the process of gaining further biological and mechanistic understanding of diseases, finding potential biomarkers, and identifying new drug targets. This review will focus on the modeling of human metabolism in the field of obesity and diabetes, showing its vast range of applications of clinical importance as well as point out future challenges. HubMed – drug
When the most potent combination of antibiotics selects for the greatest bacterial load: the smile-frown transition.
PLoS Biol. 2013 Apr; 11(4): e1001540
Pena-Miller R, Laehnemann D, Jansen G, Fuentes-Hernandez A, Rosenstiel P, Schulenburg H, Beardmore R
Conventional wisdom holds that the best way to treat infection with antibiotics is to ‘hit early and hit hard’. A favoured strategy is to deploy two antibiotics that produce a stronger effect in combination than if either drug were used alone. But are such synergistic combinations necessarily optimal? We combine mathematical modelling, evolution experiments, whole genome sequencing and genetic manipulation of a resistance mechanism to demonstrate that deploying synergistic antibiotics can, in practice, be the worst strategy if bacterial clearance is not achieved after the first treatment phase. As treatment proceeds, it is only to be expected that the strength of antibiotic synergy will diminish as the frequency of drug-resistant bacteria increases. Indeed, antibiotic efficacy decays exponentially in our five-day evolution experiments. However, as the theory of competitive release predicts, drug-resistant bacteria replicate fastest when their drug-susceptible competitors are eliminated by overly-aggressive treatment. Here, synergy exerts such strong selection for resistance that an antagonism consistently emerges by day 1 and the initially most aggressive treatment produces the greatest bacterial load, a fortiori greater than if just one drug were given. Whole genome sequencing reveals that such rapid evolution is the result of the amplification of a genomic region containing four drug-resistance mechanisms, including the acrAB efflux operon. When this operon is deleted in genetically manipulated mutants and the evolution experiment repeated, antagonism fails to emerge in five days and antibiotic synergy is maintained for longer. We therefore conclude that unless super-inhibitory doses are achieved and maintained until the pathogen is successfully cleared, synergistic antibiotics can have the opposite effect to that intended by helping to increase pathogen load where, and when, the drugs are found at sub-inhibitory concentrations. HubMed – drug