Browsing by Subject "TRANSPORTER"

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  • Leino, Sakari; Koski, Sini K.; Hänninen, Raisa; Tapanainen, Tuukka; Rannanpää, Saara; Salminen, Outi (2018)
    Preclinical studies suggest the involvement of various subtypes of nicotinic acetylcholine receptors in the pathophysiology of Parkinson's disease, a neurodegenerative disorder characterized by the death of dopaminergic neurons in the substantia nigra pars compacta (SNC). We studied for the first time the effects of alpha 5 nicotinic receptor subunit gene deletion on motor behavior and neurodegeneration in mouse models of Parkinson's disease and levodopa-induced dyskinesia. Unilateral dopaminergic lesions were induced in wild-type and alpha 5-KO mice by 6-hydroxydopamine injections into the striatum or the medial forebrain bundle. Subsequently, rotational behavior induced by dopaminergic drugs was measured. A subset of animals received chronic treatments with levodopa and nicotine to assess levodopa-induced dyskinesia and antidyskinetic effects by nicotine. SNC lesion extent was assessed with tyrosine hydroxylase immunohistochemistry and stereological cell counting. Effects of alpha 5 gene deletion on the dopaminergic system were investigated by measuring ex vivo striatal dopamine transporter function and protein expression, dopamine and metabolite tissue concentrations and dopamine receptor mRNA expression. Hemiparkinsonian alpha 5-KO mice exhibited attenuated rotational behavior after amphetamine injection and attenuated levodopa-induced dyskinesia. In the intrastriatal lesion model, dopaminergic cell loss in the medial cluster of the SNC was less severe in alpha 5-KO mice. Decreased striatal dopamine uptake in alpha 5-KO animals suggested reduced dopamine transporter function as a mechanism of attenuated neurotoxicity. Nicotine reduced dyskinesia severity in wild-type but not alpha 5-KO mice. The attenuated dopaminergic neurodegeneration and motor dysfunction observed in hemiparkinsonian alpha 5KO mice suggests potential for alpha 5 subunit-containing nicotinic receptors as a novel target in the treatment of Parkinson's disease. (C) 2018 The Authors. Published by Elsevier Ltd.
  • Eskian, Mahsa; Alavi, Abass; Khorasanizadeh, MirHojjat; Viglianti, Benjamin L.; Jacobsson, Hans; Barwick, Tara D.; Meysamie, Alipasha; Yi, Sun K.; Iwano, Shingo; Bybel, Bohdan; Caobelli, Federico; Lococo, Filippo; Gea, Joaquim; Sancho-Munoz, Antonio; Schildt, Jukka; Tatci, Ebru; Lapa, Constantin; Keramida, Georgia; Peters, Michael; Boktor, Raef R.; John, Joemon; Pitman, Alexander G.; Mazurek, Tomasz; Rezaei, Nima (2019)
    Objectives To evaluate the effect of pre-scan blood glucose levels (BGL) on standardized uptake value (SUV) in F-18-FDG-PET scan. Methods A literature review was performed in the MEDLINE, Embase, and Cochrane library databases. Multivariate regression analysis was performed on individual datum to investigate the correlation of BGL with SUVmax and SUVmean adjusting for sex, age, body mass index (BMI), diabetes mellitus diagnosis, F-18-FDG injected dose, and time interval. The ANOVA test was done to evaluate differences in SUVmax or SUVmean among five different BGL groups (200 mg/dl). Results Individual data for a total of 20,807 SUVmax and SUVmean measurements from 29 studies with 8380 patients was included in the analysis. Increased BGL is significantly correlated with decreased SUVmax and SUVmean in brain (p <0.001, p <0.001,) and muscle (p <0.001, p <0.001) and increased SUVmax and SUVmean in liver (p = 0.001, p = 0004) and blood pool (p=0.008, p200 mg/dl had significantly lower SUVmax. Conclusion If BGL is lower than 200mg/dl no interventions are needed for lowering BGL, unless the liver is the organ of interest. Future studies are needed to evaluate sensitivity and specificity of FDG-PET scan in diagnosis of malignant lesions in hyperglycemia.
  • Ala-Mutka, Eero M.; Rimpelä, Jenni M.; Fyhrquist, Frej; Kontula, Kimmo K.; Hiltunen, Timo P. (2018)
    Aim: To recognize genetic associations of hydrochlorothiazide-induced change in serum uric acid (SUA) concentration. Patients & methods: We conducted a genome-wide association study on hydrochlorothiazide-induced change in SUA in 214 Finnish men from the GENRES study. Replication analyses were performed in 465 Finns from the LIFE study. Results: In GENRES, we identified 31 loci associated with hydrochlorothiazide-induced change in SUA at p <5 x 10(-5). rs1002976 near VEGFC associated with the change in GENRES and in LIFE. rs950569 near BRINP3 associated with the change in SUA in GENRES and LIFE. The analysis of previously reported SNPs and candidate genes provided some proof for PADI4 and ABCC4. Conclusion: We report genetic markers that may predict the increase in SUA concentration during thiazide treatment.
  • Lehtisalo, Minna; Keskitalo, Jenni E.; Tornio, Aleksi; Lapatto-Reiniluoto, Outi; Deng, Feng; Jaatinen, Taina; Viinamäki, Jenni; Neuvonen, Mikko; Backman, Janne T.; Niemi, Mikko (2020)
    Xanthine oxidase inhibitors febuxostat and allopurinol are commonly used in the treatment of gout. Febuxostat inhibits the breast cancer resistance protein (BCRP) in vitro. Rosuvastatin is a BCRP substrate and genetic variability in BCRP markedly affects rosuvastatin pharmacokinetics. In this study, we investigated possible effects of febuxostat and allopurinol on rosuvastatin pharmacokinetics. In a randomized crossover study with 3 phases, 10 healthy volunteers ingested once daily placebo for 7 days, 300 mg allopurinol for 7 days, or placebo for 3 days, followed by 120 mg febuxostat for 4 days, and a single 10 mg dose of rosuvastatin on day 6. Febuxostat increased the peak plasma concentration and area under the plasma concentration-time curve of rosuvastatin 2.1-fold (90% confidence interval 1.8-2.6; P = 5 x 10(-5)) and 1.9-fold (1.5-2.5; P = 0.001), but had no effect on rosuvastatin half-life or renal clearance. Allopurinol, on the other hand, did not affect rosuvastatin pharmacokinetics. In vitro, febuxostat inhibited the ATP-dependent uptake of rosuvastatin into BCRP-overexpressing membrane vesicles with a half-maximal inhibitory concentration of 0.35 mu M, whereas allopurinol showed no inhibition with concentrations up to 200 mu M. Taken together, the results suggest that febuxostat increases rosuvastatin exposure by inhibiting its BCRP-mediated efflux in the small intestine. Febuxostat may, therefore, serve as a useful index inhibitor of BCRP in drug-drug interaction studies in humans. Moreover, concomitant use of febuxostat may increase the exposure to BCRP substrate drugs and, thus, the risk of dose-dependent adverse effects.
  • Dichlberger, Andrea; Zhou, Kecheng; Bäck, Nils; Nyholm, Thomas; Backman, Anders; Mattjus, Peter; Ikonen, Elina; Blom, Tomas (2021)
    Lysosome Associated Protein Transmembrane 4B (LAPTM4B) is a four-membrane spanning ceramide interacting protein that regulates mTORC1 signaling. Here, we show that LAPTM4B is sorted into intraluminal vesicles (ILVs) of multivesicular endosomes (MVEs) and released in small extracellular vesicles (sEVs) into conditioned cell culture medium and human urine. Efficient sorting of LAPTM4B into ILV membranes depends on its third transmembrane domain containing a sphingolipid interaction motif (SLim). Unbiased lipidomic analysis reveals a strong enrichment of glycosphingolipids in sEVs secreted from LAPTM4B knockout cells and from cells expressing a SLim-deficient LAPTM4B mutant. The altered sphingolipid profile is accompanied by a distinct SLim-dependent co-modulation of ether lipid species. The changes in the lipid composition of sEVs derived from LAPTM4B knockout cells is reflected by an increased stability of membrane nanodomains of sEVs. These results identify LAPTM4B as a determinant of the glycosphingolipid profile and membrane properties of sEVs.
  • Korchynska, Solomiia; Krassnitzer, Maria; Malenczyk, Katarzyna; Prasad, Rashmi B.; Tretiakov, Evgenii O.; Rehman, Sabah; Cinquina, Valentina; Gernedl, Victoria; Farlik, Matthias; Petersen, Julian; Hannes, Sophia; Schachenhofer, Julia; Reisinger, Sonali N.; Zambon, Alice; Asplund, Olof; Artner, Isabella; Keimpema, Erik; Lubec, Gert; Mulder, Jan; Bock, Christoph; Pollak, Daniela D.; Romanov, Roman A.; Pifl, Christian; Groop, Leif; Hokfelt, Tomas G. M.; Harkany, Tibor (2020)
    Maternal drug abuse during pregnancy is a rapidly escalating societal problem. Psychostimulants, including amphetamine, cocaine, and methamphetamine, are amongst the illicit drugs most commonly consumed by pregnant women. Neuropharmacology concepts posit that psychostimulants affect monoamine signaling in the nervous system by their affinities to neurotransmitter reuptake and vesicular transporters to heighten neurotransmitter availability extracellularly. Exacerbated dopamine signaling is particularly considered as a key determinant of psychostimulant action. Much less is known about possible adverse effects of these drugs on peripheral organs, and if in utero exposure induces lifelong pathologies. Here, we addressed this question by combining human RNA-seq data with cellular and mouse models of neuroendocrine development. We show that episodic maternal exposure to psychostimulants during pregnancy coincident with the intrauterine specification of pancreatic beta cells permanently impairs their ability of insulin production, leading to glucose intolerance in adult female but not male offspring. We link psychostimulant action specifically to serotonin signaling and implicate the sex-specific epigenetic reprogramming of serotonin-related gene regulatory networks upstream from the transcription factor Pet1/Fev as determinants of reduced insulin production.
  • Zhou, Kecheng; Dichlberger, Andrea; Ikonen, Elina; Blom, Tomas (2020)
    Studies of lysosome associated protein transmembrane 4B (LAPTM4B) have mainly focused on the 35-kDa isoform and its association with poor prognosis in cancers. Here, by employing a novel monoclonal antibody, the authors found that the 24-kDa LAPTM4B isoform predominated in most, both healthy and malignant, human cells and tissues studied. LAPTM4B-24 lacks the extreme N-terminus and, contrary to LAPTM4B-35, failed to promote cell migration. The endogenous LAPTM4B-24 protein was subject to rapid turnover with a t(1/2) of approximately 1 hour. The protein was degraded by both lysosomal and proteasomal pathways, and its levels were increased by the availability of nutrients and lysosomal ceramide. These findings underscore the pathophysiological relevance of the LAPTM4B-24 isoform and identify it as a dynamically regulated effector in lysosomal nutrient signaling.
  • Huffman, Jennifer E.; Albrecht, Eva; Teumer, Alexander; Mangino, Massimo; Kapur, Karen; Johnson, Toby; Kutalik, Zoltn; Pirastu, Nicola; Pistis, Giorgio; Lopez, Lorna M.; Haller, Toomas; Salo, Perttu; Goel, Anuj; Li, Man; Tanaka, Toshiko; Dehghan, Abbas; Ruggiero, Daniela; Malerba, Giovanni; Smith, Albert V.; Nolte, Ilja M.; Portas, Laura; Phipps-Green, Amanda; Boteva, Lora; Navarro, Pau; Johansson, Asa; Hicks, Andrew A.; Polasek, Ozren; Esko, Tonu; Peden, John F.; Harris, Sarah E.; Murgia, Federico; Wild, Sarah H.; Tenesa, Albert; Tin, Adrienne; Mihailov, Evelin; Grotevendt, Anne; Gislason, Gauti K.; Coresh, Josef; D'Adamo, Pio; Ulivi, Sheila; Vollenweider, Peter; Waeber, Gerard; Campbell, Susan; Kolcic, Ivana; Fisher, Krista; Viigimaa, Margus; Metter, Jeffrey E.; Masciullo, Corrado; Trabetti, Elisabetta; Bombieri, Cristina; Sorice, Rossella; Doering, Angela; Reischl, Eva; Strauch, Konstantin; Hofman, Albert; Uitterlinden, Andre G.; Waldenberger, Melanie; Wichmann, H-Erich; Davies, Gail; Gow, Alan J.; Dalbeth, Nicola; Stamp, Lisa; Smit, Johannes H.; Kirin, Mirna; Nagaraja, Ramaiah; Nauck, Matthias; Schurmann, Claudia; Budde, Kathrin; Farrington, Susan M.; Theodoratou, Evropi; Jula, Antti; Salomaa, Veikko; Sala, Cinzia; Hengstenberg, Christian; Burnier, Michel; Maegi, Reedik; Klopp, Norman; Kloiber, Stefan; Schipf, Sabine; Ripatti, Samuli; Cabras, Stefano; Soranzo, Nicole; Homuth, Georg; Nutile, Teresa; Munroe, Patricia B.; Hastie, Nicholas; Campbell, Harry; Rudan, Igor; Cabrera, Claudia; Haley, Chris; Franco, Oscar H.; Merriman, Tony R.; Gudnason, Vilmundur; Pirastu, Mario; Penninx, Brenda W.; Snieder, Harold; Metspalu, Andres; Ciullo, Marina; Pramstaller, Peter P.; van Duijn, Cornelia M.; Ferrucci, Luigi; Gambaro, Giovanni; Deary, Ian J.; Dunlop, Malcolm G.; Wilson, James F.; Gasparini, Paolo; Gyllensten, Ulf; Spector, Tim D.; Wright, Alan F.; Hayward, Caroline; Watkins, Hugh; Perola, Markus; Bochud, Murielle; Kao, W. H. Linda; Caulfield, Mark; Toniolo, Daniela; Voelzke, Henry; Gieger, Christian; Koettgen, Anna; Vitart, Veronique (2015)
    We tested for interactions between body mass index (BMI) and common genetic variants affecting serum urate levels, genome-wide, in up to 42569 participants. Both stratified genome-wide association (GWAS) analyses, in lean, overweight and obese individuals, and regression-type analyses in a non BMI-stratified overall sample were performed. The former did not uncover any novel locus with a major main effect, but supported modulation of effects for some known and potentially new urate loci. The latter highlighted a SNP at RBFOX3 reaching genome-wide significant level (effect size 0.014, 95% CI 0.008-0.02, P-inter= 2.6 x 10(-8)). Two top loci in interaction term analyses, RBFOX3 and ERO1LB-EDAR-ADD, also displayed suggestive differences in main effect size between the lean and obese strata. All top ranking loci for urate effect differences between BMI categories were novel and most had small magnitude but opposite direction effects between strata. They include the locus RBMS1-TANK (men, Pdifflean-overweight= 4.7 x 10(-8)), a region that has been associated with several obesity related traits, and TSPYL5 (men, Pdifflean-overweight= 9.1 x 10(-8)), regulating adipocytes-produced estradiol. The top-ranking known urate loci was ABCG2, the strongest known gout risk locus, with an effect halved in obese compared to lean men (Pdifflean-obese= 2 x 10(-4)). Finally, pathway analysis suggested a role for N-glycan biosynthesis as a prominent urate-associated pathway in the lean stratum. These results illustrate a potentially powerful way to monitor changes occurring in obesogenic environment.
  • Oeemig, Jesper S.; Ollila, O.H. Samuli; Iwaï, Hideo (2018)
    The TonB protein plays an essential role in the energy transduction system to drive active transport across the outer membrane (OM) using the proton-motive force of the cytoplasmic membrane of Gram-negative bacteria. The C-terminal domain (CTD) of TonB protein is known to interact with the conserved TonB box motif of TonB-dependent OM transporters, which likely induces structural changes in the OM transporters. Several distinct conformations of differently dissected CTDs of Escherichia coli TonB have been previously reported. Here we determined the solution NMR structure of a 96-residue fragment of Pseudomonas aeruginosa TonB (PaTonB-96). The structure shows a monomeric structure with the flexible C-terminal region (residues 338-342), different from the NMR structure of E. coli TonB (EcTonB-137). The extended and flexible C-terminal residues are confirmed by N-15 relaxation analysis and molecular dynamics simulation. We created models for the PaTonB-96/TonB box interaction and propose that the internal fluctuations of PaTonB-96 makes it more accessible for the interactions with the TonB box and possibly plays a role in disrupting the plug domain of the TonB-dependent OM transporters.
  • Mir, Sartaj Ahmad; Chen, Li; Burugupalli, Satvika; Burla, Bo; Ji, Shanshan; Smith, Adam Alexander T.; Narasimhan, Kothandaraman; Ramasamy, Adaikalavan; Tan, Karen Mei Ling; Huynh, Kevin; Giles, Corey; Mei, Ding; Wong, Gerard; Yap, Fabian; Tan, Kok Hian; Collier, Fiona; Saffery, Richard; Vuillermin, Peter; Bendt, Anne K.; Burgner, David; Ponsonby, Anne Louise; Lee, Yung Seng; Chong, Yap Seng; Gluckman, Peter D.; Eriksson, Johan G.; Meikle, Peter J.; Wenk, Markus R.; Karnani, Neerja (2022)
    Background: Lipids play a vital role in health and disease, but changes to their circulating levels and the link with obesity remain poorly characterized in expecting mothers and their offspring in early childhood. Methods: LC-MS/MS-based quantitation of 480 lipid species was performed on 2491 plasma samples collected at 4 time points in the mother-offspring Asian cohort GUSTO (Growing Up in Singapore Towards healthy Outcomes). These 4 time points constituted samples collected from mothers at 26–28 weeks of gestation (n=752) and 4–5 years postpartum (n=650), and their offspring at birth (n=751) and 6 years of age (n=338). Linear regression models were used to identify the pregnancy and developmental age-specific variations in the plasma lipidomic profiles, and their association with obesity risk. An independent birth cohort (n=1935), the Barwon Infant Study (BIS), comprising mother-offspring dyads of Caucasian origin was used for validation. Results: Levels of 36% of the profiled lipids were significantly higher (absolute fold change > 1.5 and Padj < 0.05) in antenatal maternal circulation as compared to the postnatal phase, with phosphatidylethanolamine levels changing the most. Compared to antenatal maternal lipids, cord blood showed lower concentrations of most lipid species (79%) except lysophospholipids and acylcarnitines. Changes in lipid concentrations from birth to 6 years of age were much higher in magnitude (log2FC=−2.10 to 6.25) than the changes observed between a 6-year-old child and an adult (postnatal mother) (log2FC=−0.68 to 1.18). Associations of cord blood lipidomic profiles with birth weight displayed distinct trends compared to the lipidomic profiles associated with child BMI at 6 years. Comparison of the results between the child and adult BMI identified similarities in association with consistent trends (R2=0.75). However, large number of lipids were associated with BMI in adults (67%) compared to the children (29%). Pre-pregnancy BMI was specifically associated with decrease in the levels of phospholipids, sphingomyelin, and several triacylglycerol species in pregnancy. Conclusions: In summary, our study provides a detailed landscape of the in utero lipid environment provided by the gestating mother to the growing fetus, and the magnitude of changes in plasma lipidomic profiles from birth to early childhood. We identified the effects of adiposity on the circulating lipid levels in pregnant and non-pregnant women as well as offspring at birth and at 6 years of age. Additionally, the pediatric vs maternal overlap of the circulating lipid phenotype of obesity risk provides intergenerational insights and early opportunities to track and intervene the onset of metabolic adversities. Clinical trial registration: This birth cohort is a prospective observational study, which was registered on 1 July 2010 under the identifier NCT01174875.
  • Ahola, Aila J.; Sandholm, Niina; Forsblom, Carol; Harjutsalo, Valma; Dahlstrom, Emma; Groop, Per-Henrik; FinnDiane Study Grp (2017)
    Previous studies have shown a relationship between uric acid concentration and progression of renal disease. Here we studied causality between the serum uric acid concentration and progression of diabetic nephropathy in 3895 individuals with type 1 diabetes in the FinnDiane Study. The renal status was assessed with the urinary albumin excretion rate and estimated glomerular filtration rate (eGFR) at baseline and at the end of the follow-up. Based on previous genomewide association studies on serum uric acid concentration, 23 single nucleotide polymorphisms (SNPs) with good imputation quality were selected for the SNP score. This score was used to assess the causality between serum uric acid and renal complications using a Mendelian randomization approach. At baseline, the serum uric acid concentration was higher with worsening renal status. In multivariable Cox regression analyses, baseline serum uric acid concentration was not independently associated with progression of diabetic nephropathy over a mean follow-up of 7 years. However, over the same period, baseline serum uric acid was independently associated with the decline in eGFR. In the cross-sectional logistic regression analyses, the SNP score was associated with the serum uric acid concentration. Nevertheless, the Mendelian randomization showed no causality between uric acid and diabetic nephropathy, eGFR categories, or eGFR as a continuous variable. Thus, our results suggest that the serum uric acid concentration is not causally related to diabetic nephropathy but is a downstream marker of kidney damage.
  • Dermadi, Denis; Valo, Satu; Ollila, Saara; Soliymani, Rabah; Sipari, Nina; Pussila, Marjaana; Sarantaus, Laura; Linden, Jere; Baumann, Marc; Nystrom, Minna (2017)
    Western-style diets (WD) high in fat and scarce in fiber and vitamin D increase risks of colorectal cancer. Here, we performed a long-term diet study in mice to follow tumorigenesis and characterize structural and metabolic changes in colon mucosa associated with WD and predisposition to colorectal cancer. WD increased colon tumor numbers, and mucosa proteomic analysis indicated severe deregulation of intracellular bile acid (BA) homeostasis and activation of cell proliferation. WD also in-creased crypt depth and colon cell proliferation. Despite increased luminal BA, colonocytes from WD-fed mice exhibited decreased expression of the BA transporters FABP6, OST beta, and ASBT and decreased concentrations of secondary BA deoxycholic acid and lithocholic acid, indicating reduced activity of the nuclear BA receptor FXR. Overall, our results suggest that WD increases cancer risk by FXR inactivation, leading to BA deregulation and increased colon cell proliferation. (C) 2017 AACR.