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Four-Week Omega-3 Supplementation in Carriers of the Prosteatotic PNPLA3 p.I148M Genetic Variant: An Open-Label Study.
Kuttner, CS, Mancina, R, Wagenpfeil, G, Lammert, F, Stokes, CS
Lifestyle genomics. 2019;(1-6):10-17
Abstract
BACKGROUND/AIMS: The PNPLA3 loss-of-function variant p.I148M is a strong genetic determinant of nonalcoholic fatty liver disease. The PNPLA3 protein functions as an intracellular lipase in the liver, with a greater activity on unsaturated fatty acids. This study aimed to determine whether short-term supplementation with omega-3 fatty acids impacts hepatic steatosis differently in PNPLA3 p.148I wild-type individuals as compared to homozygous carriers of the PNPLA3 p.148M variant. METHODS Twenty subjects with hepatic steatosis (50% women, age 18-77 years) were included. Ten subjects homozygous for the PNPLA3 148M variant were matched to 10 wild-type individuals. The subjects received 4 g omega-3 fatty acids (1,840 mg eicosapentaenoic acid and 1,520 mg docosahexaenoic acid) a day for 4 weeks. Transient elastography with a controlled attenuation parameter (CAP) was used to quantify liver fat before and after the intervention. Body composition, fibrosis, liver function tests, serum free fatty acids (FFA) and glucose markers were compared. RESULTS Patients homozygous for the PNPLA3 p.148M variant (risk group) demonstrated no significant changes in CAP compared to baseline (284 ± 55 vs. 287 ± 65 dB/m) as did the control group (256 ± 56 vs. 262 ± 55 dB/m). While serum liver enzyme activities remained unchanged in both groups, the risk group displayed significantly (p = 0.02) lower baseline FFA concentrations (334.5 [range 281.0-431.0] vs. 564.5 [range 509.0-682.0] μmol/L), which markedly increased by 9.1% after the intervention. In contrast, FFA concentrations decreased significantly (p = 0.01) by 28.3% in the wild-type group. CONCLUSIONS Short-term omega-3 fatty acid supplementation did not significantly alter hepatic steatosis. The nutrigenomic and metabolic effects of omega-3 fatty acids should be investigated further in carriers of the PNPLA3 148M risk variant.
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Primary vitamin D receptor target genes as biomarkers for the vitamin D3 status in the hematopoietic system.
Wilfinger, J, Seuter, S, Tuomainen, TP, Virtanen, JK, Voutilainen, S, Nurmi, T, de Mello, VD, Uusitupa, M, Carlberg, C
The Journal of nutritional biochemistry. 2014;(8):875-84
Abstract
Vitamin D(3) belongs to the few nutritional compounds that has, via the binding of its metabolite 1α,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) to the transcription factor vitamin D receptor (VDR), a direct effect on gene regulation. The relation of thousands of genomic VDR-binding sites to a few hundred primary 1,25(OH)(2)D(3) target genes is still largely unresolved. We studied chromatin domains containing genes for the adhesion molecules CD97 and LRRC8A, the glucose transporter SLC37A2 and the coactivator NRIP1. These domains vary significantly in size (7.3 to 956 kb) but contain each one major VDR-binding site. In monocytic cells these four sites are associated with open chromatin and occupied by VDR, while in macrophage-like cells only the sites of LRRC8A, SLC37A2 and NRIP1 are accessible and receptor bound. The VDR site of CD97 does, in contrast to the three other loci, not carry any DR3-type binding sequence. CD97, LRRC8A, SLC37A2 and NRIP1 are early responding 1,25(OH)(2)D(3) target genes in monocytic cells, while in macrophage-like cells they respond less and, in part, delayed. In primary human peripheral blood mononuclear cells from 71 prediabetic subjects of a vitamin D(3) intervention study (VitDmet) CD97, LRRC8A, SLC37A2 and NRIP1 can be used as transcriptomic biomarkers for classifying human individuals for their possible benefit from vitamin D(3) supplementation. In particular, NRIP1 exceeds the potential of the previously identified marker CD14 by more than 40% and seems to be a well-suited molecular marker for the vitamin D(3) status in the hematopoietic system.
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EGCG-rich green tea extract stimulates sRAGE secretion to inhibit S100A12-RAGE axis through ADAM10-mediated ectodomain shedding of extracellular RAGE in type 2 diabetes.
Huang, SM, Chang, YH, Chao, YC, Lin, JA, Wu, CH, Lai, CY, Chan, KC, Tseng, ST, Yen, GC
Molecular nutrition & food research. 2013;(12):2264-8
Abstract
The receptor for advanced glycation of end products (RAGE) plays a critical role in the progression of type 2 diabetes (T2D). Soluble RAGE (sRAGE) is one of the RAGE variants, which acts as a decoy domain receptor and competes with RAGE, thus contributing to prevention of T2D. In this study, we conducted clinical trials of (-)-epigallocatechin-3-gallate (EGCG) rich green tea extract (300-900 mg/day) to investigate the effect of EGCG on relationship between S100A12 RAGE ligand and diverse sRAGE in T2D. Moreover, mechanism of sRAGE production also confirmed in vitro. Our data indicated that EGCG could stimulate sRAGE circulation but inhibited RAGE ligand in T2D, and ADAM10-mediated ectodomain shedding of extracellular RAGE was mainly involved in EGCG-stimulated sRAGE circulation. The present evidence indicates that EGCG has a potential to block S100A12-RAGE axis by stimulating sRAGE production through ADAM10-mediated ectodomain shedding of extracellular RAGE. Therefore, EGCG contributes to nutritional strategies for diabetes, not only because of its efficient antioxidant activity to scavenge free radicals, but also because of its ability stimulating sRAGE release in the circulation. Additionally, ADAM10-induced ectodomain shedding of extracellular RAGE leading to sRAGE circulation should be a potential of passive mechanism of sRAGE production to block S100A12-RAGE axis-related pathogenesis of proinflammation and diabetes.
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Acetaminophen selectively suppresses peripheral prostaglandin E2 release and increases COX-2 gene expression in a clinical model of acute inflammation.
Lee, YS, Kim, H, Brahim, JS, Rowan, J, Lee, G, Dionne, RA
Pain. 2007;(3):279-286
Abstract
Acetaminophen is widely used for pain management as an alternative to NSAIDs and selective COX-2 inhibitors, but its action at a molecular level is still unclear. We evaluated acetaminophen's effect on PG release and the expression patterns of genes related to PG production in a clinical model of tissue injury and acute inflammation. Subjects (119 outpatients) received either 1000 mg acetaminophen, 50 mg rofecoxib (a selective COX-2 inhibitor), 30 mg ketorolac (a dual COX-1/COX-2 inhibitor), or placebo before the surgical removal of two impacted mandibular third molars. Microdialysis was used to collect inflammatory transudate from the surgical site for measurement of PGE2 and TXB2 levels at the site of injury. Biopsies were collected to investigate the expression patterns of genes related to PG production at baseline prior to surgery and at 3 or 24 h following surgery. PGE2 release was suppressed by ketorolac, rofecoxib and acetaminophen compared to placebo at 3 h coincident with increased COX-2 gene expression in biopsies collected from the surgical site. TXB2 release was suppressed only by ketorolac. COX-2 gene expression remained elevated at 24 h with continued ketorolac and acetaminophen treatment. COX-1 gene expression was significantly down-regulated at 24 h by ketorolac, rofecoxib and acetaminophen. Acetaminophen suppression of PGE2 without inhibiting TXB2 release, when COX-2 gene expression is up-regulated, suggests that acetaminophen is a selective COX-2 inhibitor in vivo. The up-regulation of COX-2 gene and down-regulation of COX-1 gene expression suggests that acetaminophen may result in changes in COX-derived prostanoids with repeated doses.
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Contribution of cyclooxygenase-2 to elevated biosynthesis of thromboxane A2 and prostacyclin in cigarette smokers.
McAdam, BF, Byrne, D, Morrow, JD, Oates, JA
Circulation. 2005;(7):1024-9
Abstract
BACKGROUND Cigarette smoking is highly pathogenic to the vasculature. In smokers, the biosynthesis of both thromboxane (Tx) A2 and prostacyclin is increased. We hypothesized that the excess in prostacyclin biosynthesis in smokers was derived from the inducible cyclooxygenase-2 (COX-2). We further hypothesized that if the overproduction of prostacyclin in smokers were restraining platelet activation, then inhibition of COX-2 would lead to an increase in the activation of platelets, with a corresponding increase in the biosynthesis of TxA2. METHODS AND RESULTS Smokers and nonsmokers received rofecoxib 25 mg twice daily or placebo for 1 week each in random sequence. The systemic biosynthesis of TxA2 and prostacyclin was assessed by analysis of their respective urinary metabolites, 11-dehydrothromboxane B2 (Tx-M) and 2'3-donor-6-keto-PGF(1alpha) (PGI-M). Serum TxB2 was measured as an indicator of platelet COX-1 activity. Results are expressed as mean+/-SE with median and range. The elevated PGI-M in smokers (189+/-25, median 174, range 85 to 390 pg/mg creatinine) was reduced by rofecoxib to 78+/-27, median 71.5, range 50 to 135 pg/mg creatinine (P=0.002), and in nonsmokers, PGI-M at baseline (115+/-10, median 107, range 67 to 198 pg/mg creatinine) fell to 56+/-15, median 50, range 34 to 125 pg/mg creatinine (P=0.001) with rofecoxib. The increased excretion of Tx-M in smokers (284+/-26, median 252, range 200 to 569 pg/mg creatinine) was reduced by 21% to 223+/-16, median 206, range 154 to 383 pg/mg creatinine by rofecoxib (P=0.04) but was not changed in nonsmokers. Levels of serum TxB2 were not different in smokers and nonsmokers and were unaffected by rofecoxib. CONCLUSIONS The increased prostacyclin biosynthesis in smokers is derived largely from the inducible COX-2. COX-2 also contributes to the increased biosynthesis of TxA2 in smokers, most likely from inflammatory cells.