A few ruthenium based metal carbonyl complexes, e.g. CORM-2 and CORM-3, have therapeutic activity attributed to their ability to deliver CO to biological targets. In this work, a series of related complexes with the formula [Ru(CO)3Cl2L] (L = DMSO (3), L-H3CSO(CH2)2CH(NH2)CO2H) (6a); D,L-H3CSO(CH2)2CH(NH2)CO2H (6b); 3-NC5H4(CH2)2SO3Na (7); 4-NC5H4(CH2)2SO3Na (8); PTA (9); DAPTA (10); H3CS(CH2)2CH(OH)CO2H (11); CNCMe2CO2Me (12); CNCMeEtCO2Me (13); CN(c-C3H4)CO2Et) (14)) were designed, synthesized and studied. The effects of L on their stability, CO release profile, cytotoxicity and anti-inflammatory properties are described. The stability in aqueous solution depends on the nature of L as shown using HPLC and LC-MS studies. The isocyanide derivatives are the least stable complexes, and the S-bound methionine oxide derivative is the more stable one. The complexes do not release CO gas to the headspace, but release CO2 instead. X-ray diffraction of crystals of the model protein Hen Egg White Lysozyme soaked with 6b (4UWN) and 8 (4UWN) shows the addition of Ru(II)(CO)(H2O)4 at the His15 binding site. Soakings with 7(4UWN) produced the metallacarboxylate [Ru(COOH)(CO)(H2O)3](+) bound to the His15 site. The aqueous chemistry of these complexes is governed by the water-gas shift reaction initiated with the nucleophilic attack of HO(-) on coordinated CO. DFT calculations show this addition to be essentially barrierless. The complexes have low cytotoxicity and low hemolytic indices. Following i.v. administration of CORM-3, the in vivo bio-distribution of CO differs from that obtained with CO inhalation or with heme oxygenase stimulation. A mechanism for CO transport and delivery from these complexes is proposed.
Most founding events entail a reduction in population size, which in turn leads to genetic drift effects that can deplete alleles. Besides reducing neutral genetic variability, founder effects can in principle shift additive genetic variance for phenotypes that underlie fitness. This could then lead to different rates of adaptation among populations that have undergone a population size bottleneck as well as an environmental change, even when these populations have a common evolutionary history. Thus, theory suggests that there should be an association between observable genetic variability for both neutral markers and phenotypes related to fitness. Here, we test this scenario by monitoring the early evolutionary dynamics of six laboratory foundations derived from founders taken from the same source natural population of Drosophila subobscura. Each foundation was in turn three‐fold replicated. During their first few generations, these six foundations showed an abrupt increase in their genetic differentiation, within and between foundations. The eighteen populations that were monitored also differed in their patterns of phenotypic adaptation according to their immediately ancestral founding sample. Differences in early genetic variability and in effective population size were found to predict differences in the rate of adaptation during the first 21 generations of laboratory evolution. We show that evolution in a novel environment is strongly contingent not only on the initial composition of a newly founded population but also on the stochastic changes that occur during the first generations of colonization. Such effects make laboratory populations poor guides to the evolutionary genetic properties of their ancestral wild populations.
The discovery of the biological effects of carbon monoxide (CO) in recent years strongly suggests that CO could find applications as a therapeutic agent. CO is a highly toxic gas when used at industrial doses, due in part to its binding affinity to hemoglobin. Since hemoglobin binds CO with the highest affinity in vivo, it also constitutes a major barrier to the delivery of CO to tissues in need of therapy. A method of delivering CO that can bypass hemoglobin is the use of pro-drugs or CO carriers, called CO-releasing molecules (CO-RMs) that become activated and release CO in tissues in need of treatment. Organometallic carbonyl complexes are best suited to play the role of CO carriers, and indeed the natural CO carrier molecules hemoglobin and myoglobin belong to this class of chemical compounds. Here we describe the preparation of novel molybdenum CO-RMs of general formula Mo(CO) 3 (CNCR′R″CO 2 R‴) 3 (R′, R″ = H, Me, i Pr, CH 2 Ph, CO 2 Li, −CH 2 CH 2 −, −CH 2 (CH 2 ) 3 CH 2 −; R‴ = H, Li), which present favorable druglike characteristics, have low toxicity, and demonstrate specific CO delivery to the liver in the treatment of acetaminophen (APAP)-induced acute liver failure in mice.
The halotolerant green alga Dunaliella salina accumulates large amounts of beta-carotene when exposed to various stress conditions. Although several studies concerning accumulation and biotechnological production of beta-carotene have been published, the molecular basis and regulation of the genes involved in carotenoid biosynthesis in D. salina are still poorly known. In this paper, we report the isolation and regulation of the lycopene beta-cyclase (Lcy-beta) gene by abiotic stress. The function of this gene was determined by heterologous genetic complementation in E. coli. Gene expression and physiological analyses revealed that D. salina Lcy-beta steady-state transcript and carotenoid levels were up-regulated in response to all stress conditions tested (salt, light and nutrient depletion). The results presented here suggest that nutrient availability is a key factor influencing carotenogenesis as well as carotenoid biosynthesis-related gene expression in D. salina.
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