Minja D.T.R.,National Institute for Medical Research |
Minja D.T.R.,Copenhagen University |
Schmiegelow C.,Copenhagen University |
Mmbando B.,National Institute for Medical Research |
And 13 more authors.
Emerging Infectious Diseases | Year: 2013
Intermittent preventive treatment during pregnancy with sulfadoxine-pyrimethamine (IPTp-SP) is a key strategy in the control of pregnancy-associated malaria. However, this strategy is compromised by widespread drug resistance from single-nucleotide polymorphisms in the Plasmodium falciparum dihydrofolate reductase and dihydropteroate synthetase genes. During September 2008-October 2010, we monitored a cohort of 924 pregnant women in an area of Tanzania with declining malaria transmission. P. falciparum parasites were genotyped, and the effect of infecting haplotypes on birthweight was assessed. Of the genotyped parasites, 9.3%, 46.3%, and 44.4% had quadruple or less, quintuple, and sextuple mutated haplotypes, respectively. Mutant haplotypes were unrelated to SP doses. Compared with infections with the less-mutated haplotypes, infections with the sextuple haplotype mutation were associated with lower (359 g) birthweights. Continued use of the suboptimal IPTp-SP regimen should be reevaluated, and alternative strategies (e.g., intermittent screening and treatment or intermittent treatment with safe and effective alternative drugs) should be evaluated.
Shabalina I.G.,Wenner Gren Institute |
Kramarova T.V.,Wenner Gren Institute |
Mattsson C.L.,Wenner Gren Institute |
Petrovic N.,Wenner Gren Institute |
And 7 more authors.
Toxicological Sciences | Year: 2015
The environmental pollutants perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) cause a dramatic reduction in the size of the major adipose tissue depots and a general body weight decrease when they are added to the food of mice. We demonstrate here that this is mainly due to a reduction in food intake; this reduction was not due to food aversion. Remarkably and unexpectedly, a large part of the effect of PFOA/PFOS on food intake was dependent on the presence of the uncoupling protein 1 (UCP1) in the mice. Correspondingly, PFOA/PFOS treatment induced recruitment of brown adipose tissue mitochondria: increased oxidative capacity and increased UCP1-mediated oxygen consumption (thermogenesis). In mice pair-fed to the food intake during PFOA/PFOS treatment in wildtype mice, brown-fat mitochondrial recruitment was also induced. We conclude that we have uncovered the existence of a regulatory component of food intake that is dependent upon brown adipose tissue thermogenic activity. The possible environmental consequences of this novel PFOA/PFOS effect (a possible decreased fitness) are noted, as well as the perspectives of this finding on the general understanding of control of food intake control and its possible extension to combatting obesity. © The Author 2015.
Kalinovich A.V.,Wenner Gren Institute |
Kalinovich A.V.,Moscow State University |
Shabalina I.G.,Wenner Gren Institute |
Shabalina I.G.,Moscow State University
Biochemistry (Moscow) | Year: 2015
Obesity is associated with premature mortality, impaired quality of life, and large healthcare costs. However, treatment options remain quite limited. Here we studied potential anti-obesity effects of a novel cationic mitochondrial uncoupler, C4R1 (derivative of rhodamine 19) in C57Bl/6 mice. Obesity was induced by long-term (eight weeks) high fat diet feeding at thermoneutrality. The treated group of mice received consecutively two doses of C4R1 in drinking water (30 and 12-14 μmol/kg daily) during 30 days. Effects of C4R1 were dose-dependent. After six days of C4R1 treatment at dose 30 μmol/kg daily, food intake was reduced by 68%, body weight by 19%, and fat mass by 21%. Body weight decrease was explained partly by reduced food intake and partly by increased metabolism, likely resulting from uncoupling. Body fat reduction upon C4R1 treatment was associated with improved lipid utilization estimated from decrease in respiratory quotient to the minimal level (0.7). Interestingly, the classical uncoupler 2,4-dinitrophenol at similar dose (27 μmol/kg daily) did not have any effect. Our results are relevant to the search for substances causing mild uncoupling of mitochondria that could be a promising therapeutic strategy to treat obesity. © 2015 Pleiades Publishing, Ltd.
Kucerova L.,Wenner Gren Institute |
Kubrak O.I.,University of Stockholm |
Bengtsson J.M.,University of Stockholm |
Strnad H.,Academy of Sciences of the Czech Republic |
And 3 more authors.
BMC Genomics | Year: 2015
Background: In models extensively used in studies of aging and extended lifespan, such as C. elegans and Drosophila, adult senescence is regulated by gene networks that are likely to be similar to ones that underlie lifespan extension during dormancy. These include the evolutionarily conserved insulin/IGF, TOR and germ line-signaling pathways. Dormancy, also known as dauer stage in the larval worm or adult diapause in the fly, is triggered by adverse environmental conditions, and results in drastically extended lifespan with negligible senescence. It is furthermore characterized by increased stress resistance and somatic maintenance, developmental arrest and reallocated energy resources. In the fly Drosophila melanogaster adult reproductive diapause is additionally manifested in arrested ovary development, improved immune defense and altered metabolism. However, the molecular mechanisms behind this adaptive lifespan extension are not well understood. Results: A genome wide analysis of transcript changes in diapausing D. melanogaster revealed a differential regulation of more than 4600 genes. Gene ontology (GO) and KEGG pathway analysis reveal that many of these genes are part of signaling pathways that regulate metabolism, stress responses, detoxification, immunity, protein synthesis and processes during aging. More specifically, gene readouts and detailed mapping of the pathways indicate downregulation of insulin-IGF (IIS), target of rapamycin (TOR) and MAP kinase signaling, whereas Toll-dependent immune signaling, Jun-N-terminal kinase (JNK) and Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways are upregulated during diapause. Furthermore, we detected transcriptional regulation of a large number of genes specifically associated with aging and longevity. Conclusions: We find that many affected genes and signal pathways are shared between dormancy, aging and lifespan extension, including IIS, TOR, JAK/STAT and JNK. A substantial fraction of the genes affected by diapause have also been found to alter their expression in response to starvation and cold exposure in D. melanogaster, and the pathways overlap those reported in GO analysis of other invertebrates in dormancy or even hibernating mammals. Our study, thus, shows that D. melanogaster is a genetically tractable model for dormancy in other organisms and effects of dormancy on aging and lifespan. © 2016 Kučerová et al.
Fotouhi A.,Wenner Gren Institute |
Cornella N.,Wenner Gren Institute |
Ramezani M.,Wenner Gren Institute |
Wojcik A.,Wenner Gren Institute |
Haghdoost S.,Wenner Gren Institute
Mutation Research - Genetic Toxicology and Environmental Mutagenesis | Year: 2015
The longer wave parts of UVR can increase the production of reactive oxygen species (ROS) which can oxidize nucleotides in the DNA or in the nucleotide pool leading to mutations. Oxidized bases in the DNA are repaired mainly by the DNA base excision repair system and incorporation of oxidized nucleotides into newly synthesized DNA can be prevented by the enzyme MTH1. Here we hypothesize that the formation of several oxidized base damages (from pool and DNA) in close proximity, would cause a high number of base excision repair events, leading to DNA double strand breaks (DSB) and therefore giving rise to cytogenetic damage. If this hypothesis is true, cells with low levels of MTH1 will show higher cytogenetic damage after the longer wave parts of UVR. We analyzed micronuclei induction (MN) as an endpoint for cytogenetic damage in the human lymphoblastoid cell line, TK6, with a normal and a reduced level of MTH1 exposed to UVR. The results indicate a higher level of micronuclei at all incubation times after exposure to the longer wave parts of UVR. There is no significant difference between wildtype and MTH1-knockdown TK6 cells, indicating that MTH1 has no protective role in UVR-induced cytogenetic damage. This indicates that DSBs induced by UV arise from damage forms by direct interaction of UV or ROS with the DNA rather than through oxidation of dNTP. © 2015 Elsevier B.V.
PubMed | Wenner Gren Institute
Type: Journal Article | Journal: Biochemistry. Biokhimiia | Year: 2015
Obesity is associated with premature mortality, impaired quality of life, and large healthcare costs. However, treatment options remain quite limited. Here we studied potential anti-obesity effects of a novel cationic mitochondrial uncoupler, C4R1 (derivative of rhodamine 19) in C57Bl/6 mice. Obesity was induced by long-term (eight weeks) high fat diet feeding at thermoneutrality. The treated group of mice received consecutively two doses of C4R1 in drinking water (30and 12-14mol/kg daily) during 30 days. Effects of C4R1 were dose-dependent. After six days of C4R1 treatment at dose 30mol/kg daily, food intake was reduced by 68%, body weight by 19%, and fat massby 21%. Body weight decrease was explained partly by reduced food intake and partly by increased metabolism, likely resulting from uncoupling. Body fat reduction upon C4R1 treatment was associated with improved lipid utilization estimated from decrease in respiratory quotient to the minimal level (0.7). Interestingly, the classical uncoupler 2,4-dinitrophenol at similar dose (27mol/kg daily) did not have any effect. Our results are relevant to the search for substances causing mild uncoupling of mitochondria that could be a promising therapeutic strategy to treat obesity.