Excessive reactive oxygen species (ROS) generation by inflammation and glycation contributes to various aging-related changes in the body. Therefore, inhibiting ROS production can prevent wrinkles, ...maculae, dullness, and slackness in skin. To assess the anti-aging effects of two polyoxometalates (PMs: VB2 and VB3) on skin, this study investigated whether they ameliorated the anti-aging responses of normal human dermal fibroblasts (NHDF) to oxidative stress due to ad-vanced glycation end products (AGEs) or H2O2 exposure. Compared with the mRNA expression levels of AGE receptors in cells exposed to AGEs alone, an additional treatment with VB2 or VB3 significantly increased the expression levels of FEEL-1, FEEL-2, and RAGE. Under AGE-induced stress conditions, the expression levels of five heat shock proteins were markedly increased by the VB treatments. Conversely, VBs suppressed the induction of cell death and intracellular ROS production. VBs also exerted prophylactic effects on these harmful events under stress conditions. Furthermore, VB treatments were found to prevent both the suppression of AQP-1/AQP-3 expression and the suppression of hyaluronan and elastin production induced via H2O2 exposure. These results show the potential of VB2 and VB3 as anti-aging agents.
Di(2-ethylhexyl) phthalate (DEHP) is a widely used plasticizer that is rapidly metabolized to mono(2-ethylhexyl) phthalate (MEHP), an active metabolite, in mammals. In the present study, the ...hydrolysis of DEHP by the liver and intestinal microsomes of humans, monkeys, dogs, rats, and mice was examined. The kinetics of liver microsomes fit the Michaelis-Menten model for humans, monkeys, and rats, and the Hill model for dogs and mice. Km or S50 values were similar among species, whereas Vmax exhibited species differences of approximately 9-fold. CLint or CLmax values were in the order of mice > dogs > monkeys ≥ rats > humans. Hydrolytic activity towards DEHP was not detected in the intestinal microsomes of humans or dogs. The kinetics of monkeys, rats, and mice followed the Hill model. In comparisons of the liver microsomes of each species, S50 values were similar, while Vmax and CLmax values (mice > rats > monkeys) were considerably lower (approximately 5–25%). These results suggest that hydrolytic activity towards DEHP in the liver and intestines markedly differ among humans and non-rodent and rodent experimental animals, and imply that species differences are closely associated with the toxicity of DEHP.
•DEHP hydrolysis in humans and experimental animals was examined in an in vitro system.•Hepatic hydrolysis activities were mice > dogs > monkeys ≥ rats > humans.•Intestinal hydrolysis activities were not detected in humans and dogs.•Intestinal hydrolysis activities were mice > rats > monkeys.
Calcium has a pivotal role in biological functions, and serum calcium levels have been associated with numerous disorders of bone and mineral metabolism, as well as with cardiovascular mortality. ...Here we report results from a genome-wide association study of serum calcium, integrating data from four independent cohorts including a total of 12,865 individuals of European and Indian Asian descent. Our meta-analysis shows that serum calcium is associated with SNPs in or near the calcium-sensing receptor (CASR) gene on 3q13. The top hit with a p-value of 6.3 x 10(-37) is rs1801725, a missense variant, explaining 1.26% of the variance in serum calcium. This SNP had the strongest association in individuals of European descent, while for individuals of Indian Asian descent the top hit was rs17251221 (p = 1.1 x 10(-21)), a SNP in strong linkage disequilibrium with rs1801725. The strongest locus in CASR was shown to replicate in an independent Icelandic cohort of 4,126 individuals (p = 1.02 x 10(-4)). This genome-wide meta-analysis shows that common CASR variants modulate serum calcium levels in the adult general population, which confirms previous results in some candidate gene studies of the CASR locus. This study highlights the key role of CASR in calcium regulation.
Previously, we have shown that the SNP rs10932201 genotype of the cyclic AMP responsive element binding protein 1 gene (
) contributes to individual differences in executive and memory function at ...the neural system and behavioral levels in healthy, young adults. However, longitudinal effects of
genotypes on cognition have not yet been addressed. Furthermore we were interested in replicating associations between
genotypes and human cognition in previous cross-sectional studies and explore whether APOE𝜀4 status might modify these relations.
We investigated whether common, independent tag SNPs within
(rs2253206, rs10932201, rs6785) influence individual differences in age-related longitudinal change and level of executive function and memory performance independent of baseline age, sex, APOE𝜀4 status, and education. Our analysis included data from cognitively unimpaired older adults participating in the Baltimore Longitudinal Study of Aging. Eleven measures from six cognitive tests (sample sizes range 617-786) were analyzed using linear mixed effects and generalized estimating equations models. Mean baseline age ranged from 50 to 69 years and mean time of follow-up (interval) ranged from 8 to 22 years.
We found significant effects of all three
SNPs on performance level and/or longitudinal change in performance based on eight measures assessing semantic memory, episodic memory, or both executive function and semantic memory. SNP rs10932201 showed the most significant and largest effect (Cohen's
= -0.70,
< 0.01) on age-related longitudinal decline of semantic memory. Additionally, we show interactions between all three
SNPs and APOE𝜀4 status on age-related longitudinal declines and levels of memory and executive function.
Our results suggest that
genotypes independently and by interactions with APOE𝜀4 status contribute to individual differences in cognitive aging.
Daidzein, one of the major soy isoflavones, has a number of beneficial bioactivities for human health. It is mainly metabolized into 7- and/or 4′-glucuronides by UDP-glucuronosyltransferase (UGT) ...enzymes in mammals, including humans. The present study was conducted to examine the regioselective glucuronidation of daidzein at the 7- and 4′-hydroxyl groups in the liver and intestinal microsomes of humans, monkeys, rats, and mice. Daidzein glucuronidation activities at substrate concentrations of 1.0–200 µM were assessed, and Eadie–Hofstee plots were constructed. The kinetics for 7- and 4′-glucuronidation in the liver microsomes fit the Michaelis–Menten model, except for an atypical model for 7-glucuronidation in rats and a biphasic model for 4′-glucuronidation in monkeys. These kinetics in the intestinal microsomes followed the Michaelis–Menten model, except for a biphasic model for 7-glucuronidation in mice. The CL
int
values for 7-glucuronidation were in the order of monkeys (49) ≫ rats (5.3) > humans (1.0) > mice (0.7) for liver microsomes, and rats (2.4) ≥ monkeys (2.2) > humans (1.0) ≥ mice (0.8) for intestinal microsomes. On the other hand, the CL
int
values for 4′-glucuronidation were in the order of monkeys (4.0) > mice (1.0) ≈ humans (1.0) > rats (0.4) for liver microsomes, and humans (1.0) ≫ monkeys (0.08) ≥ mice (0.07) > rats (0.05) for intestinal microsomes. These results demonstrated that the metabolic abilities of UGT enzymes toward daidzein in the liver and intestines markedly differed among humans, monkeys, rats, and mice, and suggest that species and regioselective differences are closely associated with the bioactivities of soy isoflavones.
SCOPE: Tissue concentrations of omega‐3 fatty acids may reduce cardiovascular disease risk, and genetic variants are associated with circulating fatty acids concentrations. Whether dietary fatty ...acids interact with genetic variants to modify circulating omega‐3 fatty acids is unclear. We evaluated interactions between genetic variants and fatty acid intakes for circulating alpha‐linoleic acid, eicosapentaenoic acid, docosahexaenoic acid, and docosapentaenoic acid. METHODS AND RESULTS: We conducted meta‐analyses (N = 11 668) evaluating interactions between dietary fatty acids and genetic variants (rs174538 and rs174548 in FADS1 (fatty acid desaturase 1), rs7435 in AGPAT3 (1‐acyl‐sn‐glycerol‐3‐phosphate), rs4985167 in PDXDC1 (pyridoxal‐dependent decarboxylase domain‐containing 1), rs780094 in GCKR (glucokinase regulatory protein), and rs3734398 in ELOVL2 (fatty acid elongase 2)). Stratification by measurement compartment (plasma versus erthyrocyte) revealed compartment‐specific interactions between FADS1 rs174538 and rs174548 and dietary alpha‐linolenic acid and linoleic acid for docosahexaenoic acid and docosapentaenoic acid. CONCLUSION: Our findings reinforce earlier reports that genetically based differences in circulating fatty acids may be partially due to differences in the conversion of fatty acid precursors. Further, fatty acids measurement compartment may modify gene–diet relationships, and considering compartment may improve the detection of gene–fatty acids interactions for circulating fatty acid outcomes.
Uridine diphosphate (UDP)-glucuronosyltransferase 1A1 (UGT1A1) plays important roles in the glucuronidation of various drugs and endogenous substances. Minipigs have been used as experimental animals ...in pharmacological and toxicological studies, because many of their physiological characteristics are similar to those of humans. In this study, the similarities and differences in enzymatic properties of UGT1A1 between humans and minipigs were precisely identified. Minipig UGT1A1 (mpUGT1A1) cDNA was firstly cloned by the rapid amplification of cDNA ends (RACE) method, and the corresponding protein as well as human UGT1A1 (hUGT1A1) enzyme was expressed in insect cells. Then the kinetics of estradiol at 3-hydroxy position (E-3OH) and 7-ethyl-10-hydroxycamptothecin (SN-38) glucuronidation by recombinant UGT1A1s as well as human and minipig liver microsomes were analyzed. The homology between mpUGT1A1 and hUGT1A1 at the amino acid level was 80.9%. E-3OH and SN-38 glucuronidation by recombinant hUGT1A1 and mpUGT1A1 showed allosteric sigmoidal kinetics. The CLmax value (29.1 µL/min/mg protein) for E-3OH glucuronidation of mpUGT1A1 was significantly higher (1.4-fold) than that of hUGT1A1, whereas the CLmax value (0.83 µL/min/mg protein) for SN-38 glucuronidation was significantly lower (27%) than that of hUGT1A1; however, the kinetic models and parameter levels for E-3OH and SN-38 glucuronidation by human and minipig liver microsomes did not parallel those in the respective species. These findings suggest that the enzymatic properties of UGT1A1 are considerably different between humans and minipigs. The information on species differences in UGT1A1 function gained in this study should help with in vivo extrapolation of xenobiotic metabolism and toxicity.
Mono(2-ethylhexyl) phthalate (MEHP) is an active metabolite of di(2-ethylhexyl) phthalate (DEHP), which is an endocrine-disrupting chemical. In the present study, MEHP glucuronidation in humans was ...studied using recombinant UDP-glucuronosyltransferases (UGTs) and microsomes of the liver and intestine. Among the recombinant UGTs examined, UGT1A3, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B4, and UGT2B7 glucuronidated MEHP. The kinetics of MEHP glucuronidation by UGT1A3, UGT1A7, UGT1A8, UGT1A10, UGT2B4, and UGT2B7 followed the Michaelis–Menten model, whereas that by UGT1A9 fit the negative allosteric model. CL
int
values were in the order of UGT1A9 > UGT2B7 > UGT1A7 > UGT1A8 ≥ UGT1A10 > UGT1A3 > UGT2B4. The kinetics of MEHP glucuronidation by liver microsomes followed the Michaelis–Menten model. Diclofenac (20 µM) and raloxifene (20 µM) decreased CL
int
values to 43 and 36 % that of native microsomes, respectively. The kinetics of MEHP glucuronidation by intestine microsomes fit the biphasic model. Diclofenac (150 and 450 µM) decreased CL
int
values to 32 and 13 % that of native microsomes for the high-affinity phase, and to 28 and 21 % for the low-affinity phase, respectively. Raloxifene (2.5 and 7.0 µM) decreased CL
int
values to 35 and 4.1 % that of native microsomes for the high-affinity phase, and to 48 and 53 % for the low-affinity phase, respectively. These results suggest that MEHP glucuronidation in humans is catalyzed by UGT1A3, UGT1A9, UGT2B4, and/or UGT2B7 in the liver, and by UGT1A7, UGT1A8, UGT1A9, UGT1A10, and/or UGT2B7 in the intestine, and also that these UGT isoforms play important and characteristic roles in the detoxification of DEHP.
The aim of this investigation is to clarify the types and concentrations of VOCs present in various commercial household water-based hand pump spray products used in Japan, and to estimate their ...average concentrations in indoor air when the spray product is used. We selected glycol and glycol ethers as the main target compounds, as these chemicals were detected at high frequencies and concentrations in a national survey of Japanese indoor air pollution. The extraction of these chemicals using graphite carbon cartridges was examined, with good recoveries and reproducibilities being obtained. Eighteen chemicals were analyzed in 54 commercial products and 8 chemicals were detected. More specifically, dipropylene glycol (DPG) was present in 44 samples (1.1 × 10
1
-1.8 × 10
4
μg/mL); propylene glycol (PG) was present in 22 samples (1.5 × 10
1
-2.9 × 10
4
μg/mL); diethylene glycol monoethyl ether (DGMEE) was found in 15 samples (trace amount-1.9 × 10
3
μg/mL); diethylene glycol (DEG) was present in 9 samples (1.0 × 10
1
-2.4 × 10
3
μg/mL); 1,3-butandiol (13BG) was found in 5 samples (trace amount-7.4 × 10
3
μg/mL); 2-ethyl-1-hexanol (2E1H) was detected in 5 samples (3.2 × 10
−1
-4.4 × 10
1
μg/mL); diethylene glycol monobutyl ether (DGMBE) was present in 4 samples (2.1 × 10
1
-7.1 × 10
1
μg/mL); and 3-methoxy-3-methylbutanol (MMB) was found in 2 samples (2.4 × 10
1
-4.7 × 10
2
μg/mL). In addition, the average concentrations of these chemicals in indoor air were estimated using their maximum concentrations observed in the spray product. The estimated average concentrations of the chemicals in indoor air were determined to range between 1.0 × 10
−2
and 1.0 mg/m
3
, with the exception of 2E1H and DGMBE. Furthermore, the estimated average concentrations of PG, 13BG, and DGMEE in indoor air were comparable to or higher than those reported in a national survey of Japanese indoor air pollution. It therefore appeared that household water-based hand pump sprays may contribute to the presence of these chemicals in indoor air. In contrast, estimated average concentrations of 2E1H in indoor air were low, its concentrations observed in a national survey of Japanese indoor air pollution are likely due to the use of plasticizers and paints.
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