| 1. |
- Artursson, Magnus, et al.
(författare)
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Aspekter på samhällsutveckling
- 2005
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Ingår i: Bronsåldersbygd 2300-500 f. Kr.. - 1650-2787. - 9172093765 ; , s. 496-547
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- ... Den förändringsprocess som vi här har försökt åskådliggöra är nära knuten till en förändring av ideologi och mentalitet, där den tidigare kollektivt präglade ideologin försvagades och successivt öppnade upp för en ökad stratifiering av samhället. Det finns tydliga tendenser i det arkeologiska materialet mot en ökad betoning och uppvisning av politisk, ekonomisk och militär makt. Denna demonstration av makt når sitt maximum under bronsålderns period II, 1500-1300 f. Kr., då de materiella lämningarna visar att man lagt en stor betydelse vid visuell och rituell uppvisning av hög social position ...
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| 2. |
- Borhade, Sanjay R., et al.
(författare)
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Preclinical Characterization of Acyl Sulfonimidamides : Potential Carboxylic Acid Bioisosteres with Tunable Properties
- 2015
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Ingår i: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 10:3, s. 455-460
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Tidskriftsartikel (refereegranskat)abstract
- Herein we present the preclinical characterization of novel compounds containing the linear acyl sulfonimidamide functionality. Specifically, we studied the pK(a), lipophilicity, in vitro metabolic stability, plasma protein binding, Caco-2 permeability, and aqueous solubility for nine aryl acyl sulfonimidamides. In comparison with widely used carboxylic acid bioisosteres, the acyl sulfonimidamides were found to be less acidic and more lipophilic depending on the substitution pattern in the studied compounds. Importantly, the pKa values (5.9-7.6) were significantly influenced by substituents on the nitrogen atom and the aryl substituents. Moreover, the acyl sulfonimidamides displayed membrane permeabilities ranging from moderate to very high, which correlated with decreased pKa and low to negligible efflux ratios. We foresee that the chiral sulfur center and the two handles for structural diversity of linear acyl sulfonimidamides will offer new opportunities for drug design and for improving the oral bioavailability of acidic drug candidates.
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| 3. |
- Bose, Partha Pratim, et al.
(författare)
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In vitro ADMET and physicochemical investigations of poly-N-methylated peptides designed to inhibit Aβ aggregation
- 2010
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Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896 .- 1464-3391. ; 18:16, s. 5896-5902
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Tidskriftsartikel (refereegranskat)abstract
- N-Methylation is a common strategy for improving oral bioavailability of peptide-based lead structures. Herein, we present a detailed study on how the degree of N-methylation affects the absorption-distribution-metabolism-excretion-toxicity (ADMET) properties such as solubility, membrane transport, proteolytic stability, and general cell toxicity of the investigated peptides. As representative structures we chose hexapeptides 1-8. These peptides, corresponding to N-methylated analogues of residues 16-21 and 32-37 of the Abeta-peptide, pathological hallmark of Alzheimer's disease (AD), have previously been shown to inhibit aggregation of Abeta fibrils in vitro. This study suggests that poly-N-methylated peptides are non-toxic and have enhanced proteolytic stability over their non-methylated analogues. Furthermore, solubility in aqueous solution is seen to increase with increased degree of N-methylation, while membrane transport was found to be low for all investigated hexapeptides. The present results, together with those reported in the literature, suggest that poly-N-methylated peptides, especially shorter or equal to six residues, can be suitable candidates for drug design.
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| 4. |
- Caraballo, Remi, et al.
(författare)
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Structure-activity relationships for lipoprotein lipase agonists that lower plasma triglycerides in vivo
- 2015
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Ingår i: European Journal of Medicinal Chemistry. - : Elsevier. - 0223-5234 .- 1768-3254. ; 103, s. 191-209
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Tidskriftsartikel (refereegranskat)abstract
- The risk of cardiovascular events increases in individuals with elevated plasma triglyceride (TG) levels, therefore advocating the need for efficient TG-lowering drugs. In the blood circulation, TG levels are regulated by lipoprotein lipase (LPL), an unstable enzyme that is only active as a non-covalently associated homodimer. We recently reported on a N-phenylphthalimide derivative (1) that stabilizes LPL in vitro, and moderately lowers triglycerides in vivo (Biochem. Biophys. Res. Common. 2014, 450, 1063). Herein, we establish structure activity relationships of 51 N-phenylphthalimide analogs of the screening hit 1. In vitro evaluation highlighted that modifications on the phthalimide moiety were not tolerated and that lipophilic substituents on the central phenyl ring were functionally essential. The substitution pattern on the central phenyl ring also proved important to stabilize LPL However, in vitro testing demonstrated rapid degradation of the phthalimide fragment in plasma which was addressed by replacing the phthalimide scaffold with other heterocyclic fragments. The in vitro potency was retained or improved and substance 80 proved stable in plasma and efficiently lowered plasma TGs in vivo. 2015 The Authors. Published by Elsevier Masson SAS.
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| 5. |
- Hubatsch, Ina, et al.
(författare)
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Beta- and gamma-di- and tripeptides as potential substrates for the oligopeptide transporter hPepT1
- 2007
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 50:21, s. 5238-5242
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Tidskriftsartikel (refereegranskat)abstract
- The hPepT1-mediated transport properties of a series of 11 synthesized beta- and gamma-peptides have been studied in Caco-2 cells. The results show that several of the compounds interact with the peptide transporter, but only two beta-dipeptides act as substrates and are transported across the cell monolayers. These two are less-efficient substrates than alfa-peptides. Larger derivatives than beta-dipeptides do not act as hPepT1 substrates, but instead, they appear to be substrates for P-glycoprotein efflux.
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| 6. |
- Lundquist, Patrik, et al.
(författare)
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Barriers to the Intestinal Absorption of Four Insulin-Loaded Arginine-Rich Nanoparticles in Human and Rat
- 2022
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Ingår i: ACS Nano. - : American Chemical Society (ACS). - 1936-0851 .- 1936-086X. ; 16:9, s. 14210-14229
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Tidskriftsartikel (refereegranskat)abstract
- Peptide drugs and biologics provide opportunities for treatments of many diseases. However, due to their poor stability and permeability in the gastrointestinal tract, the oral bioavailability of peptide drugs is negligible. Nanoparticle formulations have been proposed to circumvent these hurdles, but systemic exposure of orally administered peptide drugs has remained elusive. In this study, we investigated the absorption mechanisms of four insulin-loaded arginine-rich nanoparticles displaying differing composition and surface characteristics, developed within the pan-European consortium TRANS-INT. The transport mechanisms and major barriers to nanoparticle permeability were investigated in freshly isolated human jejunal tissue. Cytokine release profiles and standard toxicity markers indicated that the nanoparticles were nontoxic. Three out of four nanoparticles displayed pronounced binding to the mucus layer and did not reach the epithelium. One nanoparticle composed of a mucus inert shell and cell-penetrating octarginine (ENCP), showed significant uptake by the intestinal epithelium corresponding to 28 ± 9% of the administered nanoparticle dose, as determined by super-resolution microscopy. Only a small fraction of nanoparticles taken up by epithelia went on to be transcytosed via a dynamin-dependent process. In situ studies in intact rat jejunal loops confirmed the results from human tissue regarding mucus binding, epithelial uptake, and negligible insulin bioavailability. In conclusion, while none of the four arginine-rich nanoparticles supported systemic insulin delivery, ENCP displayed a consistently high uptake along the intestinal villi. It is proposed that ENCP should be further investigated for local delivery of therapeutics to the intestinal mucosa.
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| 7. |
- Taipalensuu, Jan, et al.
(författare)
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Correlation of gene expression of ten drug efflux proteins of the ATP-binding cassette transporter family in normal human jejunum and inhuman intestinal epithelial Caco-2 cell monolayers
- 2001
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Ingår i: Journal of Pharmacology and Experimental Therapeutics. - 0022-3565 .- 1521-0103. ; 299:1, s. 164-170
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Tidskriftsartikel (refereegranskat)abstract
- This investigation describes the expression and interindividual variability in transcript levels of multiple drug efflux systems in the human jejunum and compares the expression profiles in these cells with that of the commonly used Caco-2 cell drug absorption model. Transcript levels of ten-drug efflux proteins of the ATP-binding cassette (ABC) transporter family [MDR1, MDR3, ABCB5, MRP1-6, and breast cancer resistance protein (BCRP)], lung resistance-related protein (LRP), and CYP3A4 were determined using quantitative polymerase chain reaction in jejunal biopsies from 13 healthy human subjects and in Caco-2 cells. All genes except ABCB5 were expressed, and transcript levels varied between individuals only by a factor of 2 to 3. Surprisingly, BCRP and MRP2 transcripts were more abundant in jejunum than MDR1 transcripts. Jejunal transcript levels of the different ABC transporters spanned a range of three log units with the rank order: BCRP approximately MRP2 > MDR1 approximately MRP3 approximately MRP6 approximately MRP5 approximately MRP1 > MRP4 > MDR3. Furthermore, transcript levels of 9 of 10 ABC transporters correlated well between jejunum and Caco-2 cells (r2 = 0.90). However, BCRP exhibited a 100-fold lower transcript level in Caco-2 cells compared with jejunum. Thus, the expression of a number of efflux protein transcripts in jejunum are equal to, or even higher than, that of MDR1, suggesting that the roles of these proteins (in particular BCRP and MRP2) in intestinal drug efflux have been underestimated. Also, we tentatively conclude that the Caco-2 cell line is a useful model of jejunal drug efflux, if the low expression of BCRP is taken into account.
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| 8. |
- Tremmel, Roman, et al.
(författare)
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Hepatic Expression of the Na+-Taurocholate Cotransporting Polypeptide Is Independent from Genetic Variation
- 2022
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Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 23:13
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Tidskriftsartikel (refereegranskat)abstract
- The hepatic Na+-taurocholate cotransporting polypeptide NTCP/SLC10A1 is important for the uptake of bile salts and selected drugs. Its inhibition results in increased systemic bile salt concentrations. NTCP is also the entry receptor for the hepatitis B/D virus. We investigated interindividual hepatic SLC10A1/NTCP expression using various omics technologies. SLC10A1/NTCP mRNA expression/protein abundance was quantified in well-characterized 143 human livers by real-time PCR and LC-MS/MS-based targeted proteomics. Genome-wide SNP arrays and SLC10A1 next-generation sequencing were used for genomic analyses. SLC10A1 DNA methylation was assessed through MALDI-TOF MS. Transcriptomics and untargeted metabolomics (UHPLC-Q-TOF-MS) were correlated to identify NTCP-related metabolic pathways. SLC10A1 mRNA and NTCP protein levels varied 44-fold and 10.4-fold, respectively. Non-genetic factors (e.g., smoking, alcohol consumption) influenced significantly NTCP expression. Genetic variants in SLC10A1 or other genes do not explain expression variability which was validated in livers (n = 50) from The Cancer Genome Atlas. The identified two missense SLC10A1 variants did not impair transport function in transfectants. Specific CpG sites in SLC10A1 as well as single metabolic alterations and pathways (e.g., peroxisomal and bile acid synthesis) were significantly associated with expression. Inter-individual variability of NTCP expression is multifactorial with the contribution of clinical factors, DNA methylation, transcriptional regulation as well as hepatic metabolism, but not genetic variation.
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| 9. |
- Tremmel, Roman, et al.
(författare)
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Non-genetic and epigenetic factors contribute to inter-individualvariability of the hepatic bile acid and drug transporter NTCP : Hepatic variability of the hepatic bile acid and drug transporter NTCP
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background and Purpose: The hepatic Na+-taurocholate cotransporting polypeptide NTCP/SLC10A1 plays an importantrole in the uptake of bile salts and drugs, and as key receptor for hepatitis B/D virus entry. NTCPinhibitors are investigated for treatment of HBV/HDV-infection. We performed a comprehensivemulti-omics approach to investigate underlying mechanisms of inter-individual variability ofNTCP expression in Caucasians.Experimental Approach: mRNA/protein expression of SLC10A1/NTCP was quantified in 143 well-characterized nontumorhuman liver samples by real-time PCR and LC-MS/MS-based targeted proteomics,respectively. Genetic variants were investigated using genome-wide SNP arrays and nextgenerationsequencing. DNA methylation of the SLC10A1 promoter region was investigatedthrough MALDI-TOF MS. Untargeted metabolomics of liver tissues was performed by UHPLC-QTOFMS.Key Results: The SLC10A1 mRNA expression showed a 44-fold variation in liver samples, whereas NTCPprotein expression varied 10.4-fold. Genome-wide association analyses and in-depth SLC10A1sequencing indicates that genetic variants either in SLC10A1 or other genes, cannot explainexpression variability. Only two missense SLC10A1 variants were identified. NTCP proteinexpression is significantly influenced by non-genetic factors (e.g. smoking, alcoholconsumption). DNA methylation analysis revealed a significant association of specific CpG-siteswith protein expression (p<0.05). Additionally, variable expression is associated with metabolicalterations determined through gene set enrichment and untargeted metabolomics. Findingswere validated partly in livers (n=50) from The Cancer Genome Atlas.Conclusion and Implications: Inter-individual variability of NTCP expression is multifactorial with a significant contribution ofDNA methylation. Functional genetic variants are negligible and may not limit targeting of NTCPby novel inhibitors for treatment of HBV/HDV-infection.
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| 10. |
- Unéus, Lars, 1971-, et al.
(författare)
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Evaluation of on-line flue gas measurements by MISiCFET and metal-oxide sensors in boilers
- 2005
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Ingår i: IEEE Sensors Journal. - 1530-437X .- 1558-1748. ; 5:1, s. 75-81
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Tidskriftsartikel (refereegranskat)abstract
- Metal insulator silicon carbide field-effect transistor sensors, metal-oxide sensors, and a linear Lambda sensor in an electronic nose was used to measure on-line in hot flue gases from a boiler. Flue gas from a 100-MW pellets-fuelled boiler has been used to feed the experimental setup. Several reference instruments, which measure the flue gases in parallel to the sensor array, are connected to the electronic nose. Data was collected during six weeks and then evaluated. Using principal component analysis as the data evaluation method, different operating modes for the boiler have been identified in the data set. The different modes could be described in terms of high or low O 2 and CO concentration. Furthermore, we have shown that it seems possible to use a sensor array to determine the operating mode of the boiler and, by partial least-squares models, measure the CO concentration when the boiler operates in its optimum mode.
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