In Vivo Gene Expression Dynamics of Tumor-Targeted Bacteria.
In Vivo Gene Expression Dynamics of Tumor-Targeted Bacteria.
Filed under: Drug and Alcohol Rehabilitation
ACS Synth Biol. 2012 Oct 19; 1(10): 465-470
Danino T, Lo J, Prindle A, Hasty J, Bhatia SN
The engineering of bacteria to controllably deliver therapeutics is an attractive application for synthetic biology. While most synthetic gene networks have been explored within microbes, there is a need for further characterization of in vivo circuit behavior in the context of applications where the host microbes are actively being investigated for efficacy and safety, such as tumor drug delivery. One major hurdle is that culture-based selective pressures are absent in vivo, leading to strain-dependent instability of plasmid-based networks over time. Here, we experimentally characterize the dynamics of in vivo plasmid instability using attenuated strains of S. typhimurium and real-time monitoring of luminescent reporters. Computational modeling described the effects of growth rate and dosage on live-imaging signals generated by internal bacterial populations. This understanding will allow us to harness the transient nature of plasmid-based networks to create tunable temporal release profiles that reduce dosage requirements and increase the safety of bacterial therapies.
HubMed – drug
Artesunate Exerts a Direct Effect on Endothelial Cell Activation and NF-?B Translocation in a Mechanism Independent of Plasmodium Killing.
Filed under: Drug and Alcohol Rehabilitation
Malar Res Treat. 2012; 2012: 679090
Souza MC, Paixão FH, Ferraris FK, Ribeiro I, Henriques Md
Artemisinin and its derivates are an important class of antimalarial drug and are described to possess immunomodulatory activities. Few studies have addressed the effect of artesunate in the murine malaria model or its effect on host immune response during malaria infection. Herein, we study the effect of artesunate treatment and describe an auxiliary mechanism of artesunate in modulating the inflammatory response during experimental malaria infection in mice. Treatment with artesunate did not reduce significantly the parasitemia within 12?h, however, reduced BBB breakdown and TNF-? mRNA expression in the brain tissue of artesunate-treated mice. Conversely, mefloquine treatment was not able to alter clinical features. Notably, artesunate pretreatment failed to modulate the expression of LFA-1 in splenocytes stimulated with parasitized red blood cells (pRBCs) in vitro; however, it abrogated the expression of ICAM-1 in pRBC-stimulated endothelial cells. Accordingly, a cytoadherence in vitro assay demonstrated that pRBCs did not adhere to artesunate-treated vascular endothelial cells. In addition, NF-?B nuclear translocation in endothelial cells stimulated with pRBCs was impaired by artesunate treatment. Our results suggest that artesunate is able to exert a protective effect against the P. berghei-induced inflammatory response by inhibiting NF-?B nuclear translocation and the subsequent expression of ICAM-1.
HubMed – drug
Current perspectives on the neurobiology of drug addiction: a focus on genetics and factors regulating gene expression.
Filed under: Drug and Alcohol Rehabilitation
ISRN Neurol. 2012; 2012: 972607
Duncan JR
Drug addiction is a chronic, relapsing disorder defined by cyclic patterns of compulsive drug seeking and taking interspersed with episodes of abstinence. While genetic variability may increase the risk of addictive behaviours in an individual, exposure to a drug results in neuroadaptations in interconnected brain circuits which, in susceptible individuals, are believed to underlie the transition to, and maintenance of, an addicted state. These adaptations can occur at the cellular, molecular, or (epi)genetic level and are associated with synaptic plasticity and altered gene expression, the latter being mediated via both factors affecting translation (epigenetics) and transcription (non coding microRNAs) of the DNA or RNA itself. New advances using techniques such as optogenetics have the potential to increase our understanding of the microcircuitry mediating addictive behaviours. However, the processes leading to addiction are complex and multifactorial and thus we face a major contemporary challenge to elucidate the factors implicated in the development and maintenance of an addicted state.
HubMed – drug
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