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1.
Charys Palmer Fabio A Facchini Richard PO Jones Frank Neumann Francesco Peri Grisha Pirianov 《Innate immunity》2021,27(3):275
TLRs, including TLR4, play a crucial role in inflammatory-based diseases, and TLR4 has been identified as a therapeutic target for pharmacological intervention. In previous studies, we investigated the potential of FP7, a novel synthetic glycolipid active as a TLR4 antagonist, to inhibit haematopoietic and non-haematopoietic MyD88-dependent TLR4 pro-inflammatory signalling. The main aim of this study was to investigate the action of FP7 and its derivative FP12 on MyD88-independent TLR4 signalling in THP-1 derived macrophages. Western blotting, Ab array and ELISA approaches were used to explore the effect of FP7 and FP12 on TRIF-dependent TLR4 functional activity in response to LPS and other endogenous TLR4 ligands in THP-1 macrophages. A different kinetic in the inhibition of endotoxin-driven TBK1, IRF3 and STAT1 phosphorylation was observed using different LPS chemotypes. Following activation of TLR4 by LPS, data revealed that FP7 and FP12 inhibited TBK1, IRF3 and STAT1 phosphorylation which was associated with down-regulation IFN-β and IP-10. Specific blockage of the IFN type one receptor showed that these novel molecules inhibited TRIF-dependent TLR4 signalling via IFN-β pathways. These results add novel information on the mechanism of action of monosaccharide FP derivatives. The inhibition of the TRIF-dependent pathway in human macrophages suggests potential therapeutic uses for these novel TLR4 antagonists in pharmacological interventions on inflammatory diseases. 相似文献
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O. B. Vasilyeva M. A. Nazarova P. O. Ripatti N. N. Nemova 《Contemporary Problems of Ecology》2016,9(2):177-187
We studied the growth performance and lipid composition of liver, muscles and visceral fat in rainbow trout Parasalmo mykiss (Walbaum, 1792) and the diets used in its cultivation during the spring-summer season. The differences in dietary lipid composition determined modifications in the biochemical composition of tissues of rainbow trout and had an effect on the weight and growth rate of the fish. Trophic and seasonal factors also had their influence on the studied parameters. The degree of influence depended on the functional characteristics of tissues and organs of rainbow trout. 相似文献
3.
Computer simulations (by the Monte Carlo method) of unperturbed linear hydrocarbon chains of 18-22 carbon atoms with methylene-interrupted cis-double bonds (18:0, 20:0, 22:0, 18:1delta11cis, 18:2delta9, 12cis, 18:3delta9, 12, 15cis, 20:3delta5, 8, 11cis, 20:4delta5, 8, 11, 14cis, 20:5delta5, 8, 11, 14, 17cis, 22:6delta4, 7, 10, 13, 16, 19cis), typical components of natural lipids, at a temperature of 298 K have been carried out. The conformations generated with continuous variation of all single C-C bond rotation angles within the (0, 360 degrees) range have been considered. The energy of nonbonded interactions and torsion and electrostatic terms have been taken into account. The intramolecular bond order parameters S(CC) and S(CH) about the axes along inertia tensor eigenvectors and bond orientation distributions rho(theta) with respect to the maximum molecule span axis (theta is the angle between the bond and the axis) have been calculated. The relation of the bond orientation distributions rho(theta) to the order parameters S are analyzed in terms of angles thetamax (a "geometric" factor, rho(thetamax) = max) and widths deltatheta of the distributions (factor of "fluctuations"). The results indicate that fluctuation factors depend on both the segment chemical structure and location in the chain; fluctuations increase from the centre of the chain towards the terminals, all things being equal. The two deltatheta values of C-H bonds flanking the cis-double bond are smaller than that obtained for adjacent CH2 groups by a factor of 1.5-2. Defining these properties is a necessary step to gaining a more complete understanding of polyunsaturated lipid hydrocarbon chains significance. The mean molecule magnitudes of ?S(CH)? decrease when unsaturation increases. The cis-double bond parameters S(CC) are found to be higher than those of adjacent single C-C bonds: the parameter S(CC) odd-even effect in the polyunsaturated molecules of such structure changes the "sign" between double bonds. The order parameter profiles -S(CH) of cis-18:1 and cis-18:2 obtained from the simulations (at the portion which corresponds to the double bonds location) are in qualitative agreement with experimental data on bilayers in the liquid-crystal phase. This has made possible the quantitative prognosis of the ordering properties of experimentally uninvestigated unsaturated lipids. 相似文献
4.
Anu Loukola Jadwiga Buchwald Richa Gupta Teemu Palviainen Jenni H?llfors Emmi Tikkanen Tellervo Korhonen Miina Ollikainen Antti-Pekka Sarin Samuli Ripatti Terho Lehtim?ki Olli Raitakari Veikko Salomaa Richard J. Rose Rachel F. Tyndale Jaakko Kaprio 《PLoS genetics》2015,11(9)
Individuals with fast nicotine metabolism typically smoke more and thus have a greater risk for smoking-induced diseases. Further, the efficacy of smoking cessation pharmacotherapy is dependent on the rate of nicotine metabolism. Our objective was to use nicotine metabolite ratio (NMR), an established biomarker of nicotine metabolism rate, in a genome-wide association study (GWAS) to identify novel genetic variants influencing nicotine metabolism. A heritability estimate of 0.81 (95% CI 0.70–0.88) was obtained for NMR using monozygotic and dizygotic twins of the FinnTwin cohort. We performed a GWAS in cotinine-verified current smokers of three Finnish cohorts (FinnTwin, Young Finns Study, FINRISK2007), followed by a meta-analysis of 1518 subjects, and annotated the genome-wide significant SNPs with methylation quantitative loci (meQTL) analyses. We detected association on 19q13 with 719 SNPs exceeding genome-wide significance within a 4.2 Mb region. The strongest evidence for association emerged for CYP2A6 (min p = 5.77E-86, in intron 4), the main metabolic enzyme for nicotine. Other interesting genes with genome-wide significant signals included CYP2B6, CYP2A7, EGLN2, and NUMBL. Conditional analyses revealed three independent signals on 19q13, all located within or in the immediate vicinity of CYP2A6. A genetic risk score constructed using the independent signals showed association with smoking quantity (p = 0.0019) in two independent Finnish samples. Our meQTL results showed that methylation values of 16 CpG sites within the region are affected by genotypes of the genome-wide significant SNPs, and according to causal inference test, for some of the SNPs the effect on NMR is mediated through methylation. To our knowledge, this is the first GWAS on NMR. Our results enclose three independent novel signals on 19q13.2. The detected CYP2A6 variants explain a strikingly large fraction of variance (up to 31%) in NMR in these study samples. Further, we provide evidence for plausible epigenetic mechanisms influencing NMR. 相似文献
5.
Jarkko Soronen Pirkka-Pekka Laurila Jussi Naukkarinen Ida Surakka Samuli Ripatti Matti Jauhiainen Vesa M Olkkonen Hannele Yki-Järvinen 《BMC medical genomics》2012,5(1):1-13
Background
To elucidate gene expression associated with copy number changes, we performed a genome-wide copy number and expression microarray analysis of 25 pairs of gastric tissues.Methods
We applied laser capture microdissection (LCM) to obtain samples for microarray experiments and profiled DNA copy number and gene expression using 244K CGH Microarray and Human Exon 1.0 ST Microarray.Results
Obviously, gain at 8q was detected at the highest frequency (70%) and 20q at the second (63%). We also identified molecular genetic divergences for different TNM-stages or histological subtypes of gastric cancers. Interestingly, the C20orf11 amplification and gain at 20q13.33 almost separated moderately differentiated (MD) gastric cancers from poorly differentiated (PD) type. A set of 163 genes showing the correlations between gene copy number and expression was selected and the identified genes were able to discriminate matched adjacent noncancerous samples from gastric cancer samples in an unsupervised two-way hierarchical clustering. Quantitative RT-PCR analysis for 4 genes (C20orf11, XPO5, PUF60, and PLOD3) of the 163 genes validated the microarray results. Notably, some candidate genes (MCM4 and YWHAZ) and its adjacent genes such as PRKDC, UBE2V2, ANKRD46, ZNF706, and GRHL2, were concordantly deregulated by genomic aberrations.Conclusions
Taken together, our results reveal diverse chromosomal region alterations for different TNM-stages or histological subtypes of gastric cancers, which is helpful in researching clinicopathological classification, and highlight several interesting genes as potential biomarkers for gastric cancer. 相似文献6.
Valli-Jaakola K Suviolahti E Schalin-Jäntti C Ripatti S Silander K Oksanen L Salomaa V Peltonen L Kontula K 《Obesity (Silver Spring, Md.)》2008,16(9):2113-2119
The aim of this study was to investigate a series of single-nucleotide polymorphisms (SNPs) in the genes MC2R, MC3R, MC4R, MC5R, POMC, and ENPP1 for association with obesity. Twenty-five SNPs (2-7 SNPs/gene) were genotyped in 246 Finns with extreme obesity (BMI > or = 40 kg/m2) and in 481 lean subjects (BMI 20-25 kg/m2). Of the obese subjects, 23% had concomitant type 2 diabetes. SNPs and SNP haplotypes were tested for association with obesity and type 2 diabetes. Allele frequencies differed between obese and lean subjects for two SNPs in the ENPP1 gene, rs1800949 (P = 0.006) and rs943003 (P = 0.0009). These SNPs are part of a haplotype (rs1800949 C-rs943003 A), which was observed more frequently in lean subjects compared to obese subjects (P = 0.0007). Weaker associations were detected between the SNPs rs1541276 in the MC5R, rs1926065 in the MC3R genes and obesity (P = 0.04 and P = 0.03, respectively), and between SNPs rs2236700 in the MC5R, rs2118404 in the POMC, rs943003 in the ENPP1 genes and type 2 diabetes (P = 0.03, P = 0.02 and P = 0.02, respectively); these associations did not, however, remain significant after correction for multiple testing. In conclusion, a previously unexplored ENPP1 haplotype composed of SNPs rs1800949 and rs943003 showed suggestive evidence for association with adult-onset morbid obesity in Finns. In this study, we did not find association between the frequently studied ENPP1 K121Q variant, nor SNPs in the MCR or POMC genes and obesity or type 2 diabetes. 相似文献
7.
The Genome-wide Patterns of Variation Expose Significant Substructure in a Founder Population 总被引:2,自引:0,他引:2 下载免费PDF全文
Eveliina Jakkula Karola Rehnstrm Teppo Varilo Olli P.H. Pietilinen Tiina Paunio Nancy L. Pedersen Ulf deFaire Marjo-Riitta Jrvelin Juha Saharinen Nelson Freimer Samuli Ripatti Shaun Purcell Andrew Collins Mark J. Daly Aarno Palotie Leena Peltonen 《American journal of human genetics》2008,83(6):787-794
Although high-density SNP genotyping platforms generate a momentum for detailed genome-wide association (GWA) studies, an offshoot is a new insight into population genetics. Here, we present an example in one of the best-known founder populations by scrutinizing ten distinct Finnish early- and late-settlement subpopulations. By determining genetic distances, homozygosity, and patterns of linkage disequilibrium, we demonstrate that population substructure, and even individual ancestry, is detectable at a very high resolution and supports the concept of multiple historical bottlenecks resulting from consecutive founder effects. Given that genetic studies are currently aiming at identifying smaller and smaller genetic effects, recognizing and controlling for population substructure even at this fine level becomes imperative to avoid confounding and spurious associations. This study provides an example of the power of GWA data sets to demonstrate stratification caused by population history even within a seemingly homogeneous population, like the Finns. Further, the results provide interesting lessons concerning the impact of population history on the genome landscape of humans, as well as approaches to identify rare variants enriched in these subpopulations. 相似文献
8.
D. S. Pavlov Z. A. Nefedova A. E. Veselov N. N. Nemova T. R. Ruokolainen O. B. Vasil’eva P. O. Ripatti 《Journal of Ichthyology》2008,48(8):648-654
Mechanisms of formation of phenotypic groups of fingerlings of the Atlantic salmon are investigated, related to diversity of embryos and subsequent start possibilities of dispersion of larvae to microbiotopes differing in their life conditions. The fingerlings of salmon, which after hatching and dissolution of the yolk sac moved from the mainstream of the Varzuga River to mouths of its tributaries, had an increased level of triacylglycerols and a higher growth rate than the juveniles remaining in the coastal zone of the river. The revealed differences between the compared groups of fingerlings by the spectrum of stock and structural lipids are mainly connected with distinctions of feeding of juveniles of the same age. The found stable differences by lipid spectra in fingerlings of salmon from the investigated biotopes of the Varzuga in July, August, and October are considered as biochemical prerequisites of the origin of different phenotypic groups of juveniles. Subdivision of fingerlings into phenotypic groups may further on influence the oncoming of the smoltification time of juveniles at the age 2+, 3+, and 4+. Accordingly, this is reflected in formation of the complex age structure (by the number of years spent in the river and in the sea) of the Varzuga population of Atlantic salmon. 相似文献
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Krista Fischer Johannes Kettunen Peter Würtz Toomas Haller Aki S. Havulinna Antti J. Kangas Pasi Soininen T?nu Esko Mari-Liis Tammesoo Reedik M?gi Steven Smit Aarno Palotie Samuli Ripatti Veikko Salomaa Mika Ala-Korpela Markus Perola Andres Metspalu 《PLoS medicine》2014,11(2)