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71.
72.
Previous studies in our laboratory had demonstrated that addition of alpha-naphthoflavone (ANF) to lymphocytes from smokers or polychlorinated biphenyls (PCB)s-exposed individuals caused an increase in sister chromatid exchange (SCE) frequency whereas lymphocytes from controls were relatively unaffected. In order to investigate the mechanism responsible, metabolism of ANF by uninduced and 2,3,7,8-tetrachlorodibenzodioxin (TCDD)-induced microsomes was studied as a function of microsomal protein concentration and incubation time. Nonpolar metabolites were analyzed and the amount of conjugated (polar) and protein-bound metabolites determined. The initial ANF-metabolism rate was 10-fold higher in TCDD-induced microsomes (4.9 +/- 0.6 nmol/min per mg TCDD-induced microsomal protein vs. 0.5 +/- 0.2 nmol/min per mg uninduced microsomal protein) than in uninduced microsomes. Moreover, uninduced microsomes no longer metabolize ANF after 30-40 min while TCDD-induced microsomes metabolize ANF for longer than 2 h or until all the ANF is gone. In addition to the metabolites formed by uninduced microsomes [7,8-dihydro-7,8-dihydroxy-ANF (7,8-dihydrodiol); 5,6-dihydro-5,6-dihydroxy-ANF (5,6-dihydrodiol); 5,6-oxide-ANF and 6-hydroxy-ANF], TCDD-induced microsomes from unidentified metabolites. When TCDD-induced microsomes and 40 microM ANF were added to Chinese hamster ovary (CHO) cells, we found a correlation between the concentration of 5,6-oxide-ANF and clastogenicity to CHO cells. However, purified 5,6-oxide-ANF did not induce SCEs in CHO cells in the absence or presence of TCDD-induced microsomes. However, a minor metabolite (identified as the 9,10-dihydro-9,10-dihydroxy-ANF by acid dehydration) formed with TCDD-induced microsomes produces clastogenicity in CHO cells. These data indicate that a minor metabolite of ANF is a potent clastogen which suggests that this metabolite may be responsible for the ANF-mediated increases in SCE frequency in lymphocytes from smokers or PCB-exposed individuals. 相似文献
73.
74.
75.
Wim Derave Mahir S Ozdemir Roger C Harris Andries Pottier Harmen Reyngoudt Katrien Koppo John A Wise Eric Achten 《Journal of applied physiology》2007,103(5):1736-1743
Carnosine (beta-alanyl-l-histidine) is present in high concentrations in human skeletal muscle. The ingestion of beta-alanine, the rate-limiting precursor of carnosine, has been shown to elevate the muscle carnosine content. We aimed to investigate, using proton magnetic resonance spectroscopy (proton MRS), whether oral supplementation with beta-alanine during 4 wk would elevate the calf muscle carnosine content and affect exercise performance in 400-m sprint-trained competitive athletes. Fifteen male athletes participated in a placebo-controlled, double-blind study and were supplemented orally for 4 wk with either 4.8 g/day beta-alanine or placebo. Muscle carnosine concentration was quantified in soleus and gastrocnemius by proton MRS. Performance was evaluated by isokinetic testing during five bouts of 30 maximal voluntary knee extensions, by endurance during isometric contraction at 45% maximal voluntary contraction, and by the indoor 400-m running time. beta-Alanine supplementation significantly increased the carnosine content in both the soleus (+47%) and gastrocnemius (+37%). In placebo, carnosine remained stable in soleus, while a small and significant increase of +16% occurred in gastrocnemius. Dynamic knee extension torque during the fourth and fifth bout was significantly improved with beta-alanine but not with placebo. Isometric endurance and 400-m race time were not affected by treatment. In conclusion, 1) proton MRS can be used to noninvasively quantify human muscle carnosine content; 2) muscle carnosine is increased by oral beta-alanine supplementation in sprint-trained athletes; 3) carnosine loading slightly but significantly attenuated fatigue in repeated bouts of exhaustive dynamic contractions; and 4) the increase in muscle carnosine did not improve isometric endurance or 400-m race time. 相似文献
76.
Donjacour CE Kalsbeek A Overeem S Lammers GJ Pévet P Bothorel B Pijl H Aziz NA 《Chronobiology international》2012,29(3):356-362
Hypocretin deficiency causes narcolepsy. It is unknown whether melatonin secretion is affected in this sleep disorder. Therefore, in both narcolepsy patients and matched controls, the authors measured plasma melatonin levels hourly for 24 h before and after 5 days of sodium oxybate (SXB) administration. Although mean melatonin concentrations were similar between patients and controls, in narcoleptics the percentage of 24-h melatonin secreted during the daytime was significantly higher, and melatonin secretion exhibited a weaker coupling to sleep. SXB did not affect melatonin secretion. These findings suggest that hypocretin deficiency might disturb both the circadian control of melatonin release and its temporal association with sleep. 相似文献
77.
Gayet L Picault N Cazalé AC Beyly A Lucas P Jacquet H Suso HP Vavasseur A Peltier G Forestier C 《FEBS letters》2006,580(30):6891-6897
ABC transporters from the multidrug resistance-associated protein (MRP) subfamily are glutathione S-conjugate pumps exhibiting a broad substrate specificity illustrated by numerous xenobiotics, such as anticancer drugs, herbicides, pesticides and heavy metals. The engineering of MRP transporters into plants might be interesting either to reduce the quantity of xenobiotics taken up by the plant in the context of “safe-food” strategies or, conversely, in the development of phytoremediation strategies in which xenobiotics are sequestered in the vacuolar compartment. In this report, we obtained Arabidopsis transgenic plants overexpressing human MRP1. In these plants, expression of MRP1 did not increase plant resistance to antimony salts (Sb(III)), a classical glutathione-conjugate substrate of MRP1. However, the transporter was fully translated in roots and shoots, and targeted to the plasma membrane. In order to investigate the functionality of MRP1 in Arabidopsis, mesophyll cell protoplasts (MCPs) were isolated from transgenic plants and transport activities were measured by using calcein or Sb(III) as substrates. Expression of MRP1 at the plasma membrane was correlated with an increase in the MCPs resistance to Sb(III) and a limitation of the metalloid content in the protoplasts due to an improvement in Sb(III) efflux. Moreover, Sb(III) transport was sensitive to classical inhibitors of the human MRP1, such as MK571 or glibenclamide. These results demonstrate that a human ABC transporter can be functionally introduced in Arabidopsis, which might be useful, with the help of stronger promoters, to reduce the accumulation of xenobiotics in plants, such as heavy metals from multi-contaminated soils. 相似文献
78.
Segers VF Van Riet I Andries LJ Lemmens K Demolder MJ De Becker AJ Kockx MM De Keulenaer GW 《American journal of physiology. Heart and circulatory physiology》2006,290(4):H1370-H1377
Circulating stem cells home within the myocardium, probably as the first step of a tissue regeneration process. This step requires adhesion to cardiac microvascular endothelium (CMVE). In this study, we studied mechanisms of adhesion between CMVE and mesenchymal stem cells (MSCs). Adhesion was studied in vitro and in vivo. Isolated 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate-labeled rat MSCs were allowed to adhere to cultured CMVE in static and dynamic conditions. Either CMVE or MSCs were pretreated with cytokines [IL-1beta, IL-3, IL-6, stem cell factor, stromal cell-derived factor-1, or TNF-alpha, 10 ng/ml]. Control or TNF-alpha-treated MSCs were injected intracavitarily in rat hearts in vivo. In baseline in vitro conditions, the number of MSCs that adhered to CMVE was highly dependent on the flow rate of the superfusing medium but remained significant at venous and capillary shear stress amplitudes. Activation of both CMVE and MSCs with TNF-alpha or IL-1beta before adhesion concentration dependently increased adhesion of MSCs at each studied level of shear stress. Consistently, in vivo, activation of MSCs with TNF-alpha before injection significantly enhanced cardiac homing of MSCs. TNF-alpha-induced adhesion could be completely blocked by pretreating either CMVE or MSCs with anti-VCAM-1 monoclonal antibodies but not by anti-ICAM-1 antibodies. Adhesion of circulating MSCs in the heart appears to be an endothelium-dependent process and is sensitive to modulation by activators of both MSCs and endothelium. Inflammation and the expression of VCAM-1 but not ICAM-1 on both cell types have a regulatory effect on MSC homing in the heart. 相似文献
79.
Joris M. Koene Kora Montagne-Wajer Dick Roelofs Andries Ter Maat 《Evolutionary ecology》2009,23(4):533-543
Multiple mating, sperm storage and internal fertilisation enhance sperm competition. The great pond snail can use stored sperm
for over three months, and frequently mates with different partners. This hermaphrodite, Lymnaea stagnalis, can also self-fertilise and often produces egg masses containing both selfed and outcrossed eggs. Hence, a sperm recipient
may exert considerable control over paternity. Using microsatellite markers, we show that when allosperm are present, all
genotyped eggs are cross-fertilised. We also find that sperm have the opportunity to compete, because double matings lead
on average to equal paternity for each sperm donor. This indicates that received sperm are randomly mixed in storage. To gain
further insight into the mechanisms underlying the process of sperm storage, digestion and utilisation, we investigated the
fate of donated sperm at different times after copulation. We find that within 3 h after transfer most sperm have been transported
into the sperm-digesting organ. Fluorescent labelling of sperm in histological sections further reveals that allosperm are
not stored in the fertilisation pouch, but upstream in either the hermaphroditic duct, seminal vesicles, or ovotestis. Besides
contributing to the understanding of the mechanisms underlying sperm competition and/or cryptic sperm choice, this study shows
that mixed mating cannot be treated as a separate issue in hermaphroditic animals. 相似文献
80.
Silvia Jansen Maria Andries Rita Derua Etienne Waelkens Mathieu Bollen 《The Journal of biological chemistry》2009,284(21):14296-14302
Autotaxin or NPP2 (nucleotide pyrophosphatase/phosphodiesterase 2) is a
secreted lysophospholipase-D that promotes metastasis and tumor growth by its
ability to generate lysophosphatidic acid. Considerable evidence suggests that
inhibitors of NPP2 can be used as a novel therapy for the treatment of cancer.
Although most attention is currently directed toward the development of
inhibitors of the catalytic site, we have explored whether NPP2 can also be
targeted through its non-catalytic nuclease-like domain. We demonstrate here
that the catalytic and nuclease-like domains are covalently linked by an
essential disulfide bridge between Cys413 and Cys805.
Within the nuclease-like domain, residues 829–850 are involved in the
secretion of NPP2, and Lys852 is required for the expression of
catalytic activity. These data show that the nuclease-like domain is crucial
for catalysis by NPP2 and is a possible target to generate inhibitors.NPP2 3 or autotaxin
is a secreted lysophospholipase-D that acts in a paracrine or autocrine
manner. The major substrate of NPP2 is lysophosphatidylcholine, which is
converted into choline and lysophosphatidic acid. The latter promotes
signaling through specific G-protein-coupled receptors that stimulate cell
proliferation, differentiation, and motility
(1). NPP2 functions in
processes as diverse as the homing of lymphocytes, blood vessel formation, and
wound healing but also promotes tumorigenesis
(2–6).
The metastasis-enhancing properties of NPP2 have been attributed to its
ability to promote the invasive properties of cancer cells and to stimulate
angiogenesis. Importantly, NPP2 is highly expressed by various cancers
including breast carcinoma (7),
Hodgkin lymphoma (8), and
glioblastoma multiforme (9),
and this correlates with an increased metastasis and angiogenesis. Therefore,
NPP2 is considered to be an attractive target for a novel anticancer therapy,
in particular because it acts extracellularly, and interfering drugs thus do
not need to be cell-permeable
(10).NPP2 is one of the seven mammalian members of the NPP-type family of
ectophosphodiesterases, belonging to the superfamily of
phospho-/sulfo-coordinating metalloenzymes
(11). These enzymes all have a
structurally related catalytic domain and the same catalytic mechanism but
show a different substrate specificity. For example, NPP1 only recognizes
nucleotide substrates, whereas NPP2 preferentially hydrolyzes
lysophospholipids. Interestingly, NPP1–3 share a C-terminal
non-catalytic domain, commonly referred to as the nuclease-like domain (NLD)
(12). The latter is related to
DNA/RNA-nonspecific endonucleases but lacks key residues that are necessary
for activity and is therefore believed to have a structural or regulatory
role. It is not known whether the NLD acts as a positive or negative regulator
of NPP activity, but swapping experiments of the NLD between NPP1 and NPP2
suggested that it harbors isoform-specific determinants for catalysis
(13).To examine the therapeutic potential of NPP2, in particular for the
treatment of cancer, a number of small molecule inhibitors have been developed
(14,
15). However, these inhibitors
are all directed against the catalytic site and may therefore also interfere
with other phospho-/sulfo-coordinating metalloenzymes. We report here that the
NLD is essential for the expression of catalytic activity and can be used as
an alternative target to inhibit NPP2. 相似文献