共查询到20条相似文献,搜索用时 31 毫秒
1.
Sayuri Sales Rodrigo Portes Ureshino Renato Tavares dos Santos Pereira Milene Schmidt Amaral Luna Marcelo Pires de Oliveira Norma Yamanouye Rosely Oliveira Godinho Soraya Soubhi Smaili Catarina Segreti Porto Fernando Maurício Francis Abdalla 《Life sciences》2010,86(21-22):832-838
AimsThe aim of the present study was to investigate the effects of different periods of ovariectomy and 17β-estradiol replacement on apoptotic cell death and expression of members of the Bcl-2 family in the rat hippocampus.Main methodsHippocampi were obtained from rats in proestrus, ovariectomized (15 days, 21 days and 36 days), ovariectomized for 15 days and then treated with 17β-estradiol for 7 or 21 days, and rats ovariectomized and immediately treated with 17β-estradiol for 21 days.The expression of Bcl-2 and Bax and the number of apoptotic cells were determined.Key findingsOvariectomy decreased Bcl-2 expression and increased Bax expression and the number of apoptotic cells. Replacement with 17β-estradiol (21 days) throughout the post-ovariectomy period reduced the number of apoptotic cells to the control levels, and prevented the effects of ovariectomy on Bax expression, but only partially restored the Bcl-2 expression. After 15 days of ovariectomy, the replacement with 17β-estradiol for 21 days, but not for 7 days, restored the Bcl-2 and Bax expression and the percentage of apoptotic cells to the levels found in the proestrus control.SignificanceThe present results show that a physiological concentration of 17β-estradiol may help maintain long-term neuronal viability by regulating the expression of members of the Bcl-2 family. Even after a period of hormonal deprivation, treatment with 17β-estradiol is able to restore the expression of Bax and Bcl-2 to control levels, but the duration of the treatment is a key factor to obtain the desired effect. These data provide new understanding into the mechanisms contributing to the neuroprotective action of estrogen. 相似文献
2.
Dongshu Du Xiaobo Ma Jianfu Zhang Yongmei Zhang Xiaoyan Zhou Yu Li 《Life sciences》2010,86(1-2):30-38
AimsTo investigate the protective effects of 17β-estradiol postconditioning against ischemia/reperfusion (I–R)-induced gastric mucosal injury in rats.Main methodsThe animal model of gastric ischemia/reperfusion was established by clamping of the celiac artery for 30 min and reperfusion for 30 min, 1 h, 3 h, 6 h, 12 h or 24 h. 17β-estradiol at doses of 5, 50 or 100 μg/kg (rat) was administered via peripheral veins 2 min before reperfusion. In a subgroup of rats, the estrogen receptor antagonist fulvestrant (Ful, 2 mg/kg) was intravenously injected prior to 17β-estradiol administration. Histological and immunohistochemical methods were employed to assess the gastric mucosal injury index and gastric mucosal cell apoptosis and proliferation. The malondialdehyde (MDA) concentration, superoxide dismutase (SOD) activity, xanthine oxidase (XOD) activity and hydroxyl free radical (–OH) inhibitory ability were determined by colorimetric assays. Subsequently, the expression of Bcl-2 and Bax in rat gastric mucosa was examined by western blotting.Key findings17β-estradiol dose-dependently inhibited gastric I–R (GI–R) injury, and 17β-estradiol (50 μg/kg) markedly attenuated GI–R injury 1 h after reperfusion. 17β-estradiol inhibited gastric mucosal cell apoptosis and promoted gastric mucosal cell proliferation in addition to increasing SOD activity and –OH inhibitory ability and decreasing the MDA content and XOD activity. The Bax protein level increased 1 h after GI–R and was markedly reduced by intravenous administration of 17β-estradiol. In contrast, the level of Bcl-2 protein decreased 1 h after GI–R and was restored to normal levels by intravenous administration of 17β-estradiol. These effects of 17β-estradiol were inhibited by pretreatment with fulvestrant.Significance17β-estradiol postconditioning should be investigated further as a possible strategy against gastric mucosal injury. 相似文献
3.
AimThe aim of the present study was to assess and compare the effect of 17β-estradiol and two different selective estrogen receptor modulators (SERMs), tamoxifen and raloxifene, as well as a selective estrogen receptor alpha agonist, propyl-pyrazole-triol (PPT) and a selective estrogen receptor beta agonist, diarylpropionitrile (DPN), on behavioral and biochemical alterations in 6-hydroxydopamine (6-OHDA)-induced nigral dopaminergic cell death in rats.Main methods80 female Wister rats were used. Animals were divided into eight equal groups: Group I; Sham operated, Group II; subjected to ovariectomy (OVX), Group III; OVX rats received striatal injection of 6-OHDA, Groups IV–VIII; OVX rats received striatal injection of 6-OHDA and were injected daily with 17β-estradiol, tamoxifen, raloxifene, PPT and DPN respectively for 5 days before 6-OHDA and continued for further 2 weeks.Key findingsResults showed that striatal injection of 6-OHDA produced significant behavioral alteration suggestive of PD, together with significant decrease in striatal dopamine, homovanillic acid (HVA) and 3,4-dihydroxyphenyl acetic acid (DOPAC) concentrations. 6-OHDA-induced nigral dopaminergic cell death was characterized by oxidative stress, evidenced by significant decrease in striatal glutathione peroxidase activity, as well as apoptosis, evidenced by significant increase in nigral caspase-3 activity. Treatment with 17β-estradiol, raloxifene, PPT, but neither tamoxifen nor DPN, resulted in significant amelioration of the behavioral and biochemical alterations induced by 6-OHDA.SignificanceThese findings suggest that estrogen and some SERMs having estrogenic agonist activity in the brain, like raloxifene, might exert beneficial effect in PD. 相似文献
4.
White JP Calcott G Jenes A Hossein M Paule CC Santha P Davis JB Ma D Rice AS Nagy I 《Life sciences》2011,88(3-4):141-149
AimsXenon provides effective analgesia in several pain states at sub-anaesthetic doses. Our aim was to examine whether xenon may mediate its analgesic effect, in part, through reducing the activity of transient receptor potential vanilloid type 1 (TRPV1), a receptor known to be involved in certain inflammatory pain conditions.Main methodsWe studied the effect of xenon on capsaicin-evoked cobalt uptake in rat cultured primary sensory neurons and in human TRPV1 (hTRPV1)-expressing human embryonic kidney 293 (HEK293) cells. We also examined xenon's effect on the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) in the rat spinal dorsal horn evoked by hind-paw injection of capsaicin.Key findingsXenon (75%) reduced the number of primary sensory neurons responding to the TRPV1 agonist, capsaicin (100 nM–1 μM) by ~ 25% to ~ 50%. Xenon reduced the number of heterologously-expressed hTRPV1 activated by 300 nM capsaicin by ~ 50%. Xenon (80%) reduced by ~ 40% the number of phosporylated ERK1/2-expressing neurons in rat spinal dorsal horn resulting from hind-paw capsaicin injection.SignificanceXenon substantially reduces the activity of TRPV1 in response to noxious stimulation by the specific TRPV1 agonist, capsaicin, suggesting a possible role for xenon as an adjunct analgesic where hTRPV1 is an active contributor to the excitation of primary afferents which initiates the pain sensation. 相似文献
5.
Ferretti M Bertoni L Cavani F Benincasa M Sena P Carnevale G Zavatti M Viesti VD Zanoli P Palumbo C 《Life sciences》2012,90(3-4):161-168
AimsThe effects of chronic administration of Ferutinin (phytoestrogen found in the plants of genus Ferula), compared with those elicited by estradiol benzoate, were evaluated, following ovariectomy, on the uterus of ovariectomized rats as regard weight, size, structure and histomorphometry.Main methodsThe experimental study included 40 female Sprague–Dawley rats, assigned to two different protocols, i.e. preventive and recovering. In the preventive protocol, ferutinin (2 mg/kg/day) was orally administered for 30 days, starting from the day after ovariectomy; in the recovering protocol, ferutinin was administered, at the same dosage, for 30 days starting from the 60th day after ovariectomy, when osteoporosis was clearly established. Its effects were compared with those of estradiol benzoate (1.5 μg per rat twice a week, subcutaneously injected) vs. vehicle-treated ovariectomized controls and vehicle-treated sham-operated controls. Uteri were removed, weighed and analysed under both the structural and histomorphometrical points of view.Key findingsOur data show that ferutinin acts, similarly to estradiol benzoate, on the uterus stimulating endometrial and myometrial hypertrophy; this notwithstanding, the phytoestrogen ferutinin, in contrast to estrogen treatment, appears to increase apoptosis in uterine luminal and glandular epithelia.SignificanceFerutinin, used in osteoporosis treatment primarily for bone mass recovering, seems in line with an eventual protective function against uterine carcinoma, unlike estrogens so far employed in hormone replacement therapy (HRT). 相似文献
6.
Cameron G Tantiworawit A Halpenny M Letcher B Berrigan S Hindmarsh K Giftakis A Fortier J O'Hoski P Hogge D 《Cytotherapy》2011,13(7):856-863
Background aimsThe ability of hematopoietic progenitor cells–apheresis (HPC-A) that have been stored for many years after cryopreservation to reconstitute hematopoiesis following high-dose chemo/radiotherapy has not been well-documented.MethodsIn this retrospective study, eight Canadian centers contributed data from 53 autologous stem cell transplants (ASCT) performed using HPC-A that had undergone long-term storage (>2 years, range 2–7 years) and 120 ASCT using HPC-A stored for <6 months (short-term storage).ResultsThe doses of nucleated and CD34+ cells per kilogram recipient weight were similar between the short- (mean ± SD, 4.7 ± 4.9 × 108 and 6.8 ± 4.3 × 106, respectively) and long- (4.0 ± 4.9 × 108 and 6.1 ± 3.4 × 106, respectively) term storage groups. The median days to neutrophils (absolute neutrophil count; ANC) >0.5 × 109/L (median 11 days for both short- and long-term storage) and platelets >20 × 109/L (median 12 and 11 for short- and long-term storage, respectively) post-ASCT were not significantly different between the two groups. When ASCT performed with <5 × 106/kg CD34+ cells was compared there was also no difference in ANC or platelet recovery (median 12 days for both after short-term storage, and 12 and 11 days, respectively, after long-term storage). Fourteen HPC-A products stored for >5 years also showed similar count recoveries as the entire long-term storage group (median 11 days for both ANC and platelets).ConclusionsCryopreserved HPC-A can be stored for at least 5 years with no apparent loss in their ability to support hematopoietic reconstitution after high-dose chemotherapy. 相似文献
7.
AimsHuman amnion-derived cells have been used as in vitro models to test the release of inflammatory mediators, such as arachidonic acid (AA) and prostaglandin E2 (PGE2). We compared estrogen metabolites for their ability to induce AA release, to influence PGE2 production and to interact toward intracellular estrogen receptors (ERs).Main methodsMetabolite effects on AA and PGE2 release were examined by radiolabelled substrate incorporation and by colorimetric enzyme immunoassays, respectively. [3H]17-β-estradiol binding displacements were performed on Ro-20-1724 treated whole cells.Key findingsIn WISH cells, estrone, 2-hydroxy-estrone and estriol induced a rapid dose dependent release of AA that was not inhibited by cycloheximide. Estrone and 2-hydroxy-estrone showed biphasic dose–response curves of PGE2, whereas estriol and 16-α-hydroxy-estrone increased PGE2 levels at high concentrations. 2-methoxy-estrone, 4-hydroxy-estradiol and 4-hydroxy-estrone did not significantly affect PGE2 release. 2-methoxy-estradiol and 2-hydroxy-estradiol decreased the PGE2 release. Effects of metabolites on PGE2 were inhibited by cycloheximide and by the ER antagonist tamoxifen. In AV3 cells PGE2 production was poorly detectable. On Ro-20-1724 treated WISH cells the Ki of 17-β-estradiol was 29.2 ± 5.4 nM. Estrone, 2-methoxy-estrone and 2-methoxy-estradiol showed similar affinity values. The hydroxyl substituent at position 2, 4 and 16 decreased or markedly increased the affinity for estradiol or estrone derivatives, respectively.SignificanceThe estrogen metabolites induced nongenomic effects on AA release from WISH cells. The influence on PGE2 release was detectable only on WISH cells. These effects appeared genomic and mediated by intracellular ERs, whose properties seemed strongly dependent on intracellular cAMP levels. 相似文献
8.
Mandic O de Leeuw A Vuković B Krijgsman W Harzhauser M Kuiper KF 《Palaeogeography, Palaeoclimatology, Palaeoecology》2011,299(3-4):475-492
In the Early to Middle Miocene, a series of lakes, collectively termed the Dinaride Lake System (DLS), spread out across the north-western part of the Dinaride–Anatolian continental block. Its deposits, preserved in numerous intra-montane basins, allow a glimpse into the palaeoenvironmental, palaeobiogeographic and geodynamic evolution of the region. Lake Gacko, situated in southern Bosnia and Herzegovina, is one of the constituent lakes of the DLS, and its deposits are excellently exposed in the Gra?anica open-cast coal-mine. A detailed study of the sedimentary succession that addresses facies, sediment petrography, geophysical properties, and fossil mollusc palaeoecology reveals repetitive changes in lake level. These are interpreted to reflect changes in the regional water budget. First-order chronologic constraints arise from the integration of radio-isotopic and palaeomagnetic data. 40Ar/39Ar measurements on feldspar crystals from a tephra bed in the upper part of the sedimentary succession indicate a 15.31 ± 0.16 Ma age for this level. The reversed magnetic polarity signal that characterises the larger part of the investigated section correlates to chron C5Br of the Astronomically Tuned Neogene Timescale. Guided by these chronologic data and a detailed cyclostratigraphic analysis, the observed variations in lake-level, evident as two ~ 40-m and seven ~ 10-m scale transgression–regression cycles, are tuned to ~ 400-kyr and ~ 100-kyr eccentricity cycles. From the tuning, it can be inferred that the sediments in the Gacko Basin accumulated between ~ 15.8 and ~ 15.2 Ma. The economically valuable lignite accumulations in the lower part of the succession are interpreted to indicate the development of swamp forests in conjunction with lake-level falls corresponding to ~ 100-kyr eccentricity minima. Pedogenesis, rhizoliths and palustrine carbonate breccias in the upper part of the section reveal long-term aridity coinciding with a ~ 400-kyr eccentricity minimum. Eccentricity maxima are interpreted to trigger lake-level high-stands. These are accompanied by eutrophication events caused by enhanced denudation of the surrounding basement and increased detrital input into the basin. The presented age model proves that Lake Gacko arose during the Middle Miocene Climatic Optimum and that the optimum climatic conditions triggered the formation of this long-lived lake. 相似文献
9.
AimOur aim is to understand the molecular mechanisms of the selective nonsteroidal anti-inflammatory drugs (NSAID), cyclooxygenase-2 (COX-2) inhibitors', higher “priority” to reduce synthesis of the vascular protector, prostacyclin (PGI2), compared to that of nonselective NSAIDs.Main methodsCOX-1 or COX-2 was co-expressed with PGI2 synthase (PGIS) in COS-7 cells. The Km and initial velocity (½t Vmax) of the coupling reaction between COX-1 and COX-2 to PGIS were established. The experiment was further confirmed by a kinetics study using hybrid enzymes linking COX-1 or COX-2 to PGIS. Finally, COX-1 or COX-2 and PGIS were respectively fused to red (RFP) and cyanic (CFP) fluorescence proteins, and co-expressed in cells. The distances between COXs and PGIS were compared by FRET.Key findingsThe Km for converting arachidonic acid (AA) to PGI2 by COX-2 coupled to PGIS is ~ 2.0 μM; however, it was 3-fold more (~ 6.0 μM) for COX-1 coupled to PGIS. The Km and ½t Vmax for COX-2 linked to PGIS were ~ 2.0 μM and 20 s, respectively, which were 2–5 folds faster than that of COX-1 linked to PGIS. The FRET study found that the distance between COX-2-RFP and PGIS–CFP is shorter than that between COX-1-RFP and PGIS–CFP.SignificanceThe study provided strong evidence suggesting that the low Km, faster ½t Vmax, and closer distance are the basis for COX-2 dominance over COX-1 (coupled to PGIS) in PGI2 synthesis, and further demonstrated the mechanisms of selective COX-2 inhibitors with higher potential to reduce synthesis of the vascular protector, PGI2. 相似文献
10.
AimsWe tested the hypothesis that an in vivo gene delivery of the pro-survival protein XIAP (X-chromosome linked inhibitor of apoptosis protein) protects against myocardial apoptosis and infarction following ischemia/reperfusion.Main methodsNineteen rabbits were chronically instrumented with a hydraulic occluder placed around the circumflex coronary artery. Adenovirus harboring XIAP (Ad.XIAP; 1 × 1010 pfu/ml) or β-galactosidase (5 × 109 pfu/ml), as a control, was constructed and transfected into the heart using a catheter placed into the left ventricle accompanied by cross-clamping. 1–2 weeks after gene delivery, myocardial ischemia was induced by a 30-min occlusion followed by reperfusion for four days. Protein expression was determined by Western blot and apoptosis (% of myocytes) was quantified by TUNEL staining.Key findingsMyocardial infarct size, expressed as a fraction of the area at risk, was reduced in Ad.XIAP (n = 5) compared to control (n = 7) rabbits (21 ± 3% vs. 30 ± 2%, p < 0.05). Apoptosis was reduced in Ad.XIAP rabbits compared to control rabbits (2.96 ± 0.68% vs. 8.98 ± 1.84%, p < 0.01). This was associated with an approximate 60% decrease in the cleaved caspase-3 level in Ad.XIAP rabbits compared to control rabbits.SignificanceThe current findings demonstrate that overexpression of XIAP via in vivo delivery in an adenovirus can reduce both myocardial apoptosis and infarction following ischemia/reperfusion, at least in part, due to the ability of XIAP to inhibit caspase-3. These findings confirm previous work suggesting a link between myocardial apoptosis and infarction i.e., anti-apoptotic therapy was effective in reducing myocardial infarct size. 相似文献
11.
AimsTo investigate the role of the mitochondrial Ca2+-activated K+ channel in cardioprotection induced by limb remote ischemic preconditioning.Main methodsMale Sprague–Dawley rats (250–300 g) were randomized into control, ischemia/reperfusion (I/R), remote ischemic preconditioning (RPC), NS1619 (a specific mitochondrial Ca2+-activated K+ channel opener), and RPC + paxilline (a specific mitochondrial Ca2+-activated K+ channel inhibitor) groups. RPC was induced by 4 cycles of 5 min of ligation followed by 5 min of reperfusion of the left femoral artery. Myocardial I/R was achieved by ligation of the left anterior descending coronary artery for 30 min, followed by 120 min of reperfusion. Infarct size was determined by 2,3,5-triphenyltetrazolium chloride staining, the hemodynamics were monitored, and lactate dehydrogenase (LDH) levels in the coronary effluent, manganese superoxide dismutase (Mn-SOD) content in mitochondria and mitochondrial membrane potential were measured spectrophotometrically. The ultrastructure of cardiomyocyte mitochondria was assessed by electron microscopy.Key findingsNS1619 (10 μM) improved heart function, decreased infarct size, reduced LDH release, maintained mitochondrial structural integrity and mitochondrial membrane potential, and increased the mitochondrial content of Mn-SOD to the same degree as RPC treatment. However, paxilline (1 μM) eliminated the cardioprotective effect conferred by RPC.SignificanceThe mitochondrial Ca2+-activated K+ channel participates in the myocardial protection by limb remote ischemic preconditioning. 相似文献
12.
Åström-Olsson K Li L Olofsson CS Borén J Öhlin H Grip L 《Biochemical and biophysical research communications》2012,422(4):732-738
AimsTo establish a cardiac cell culture model for simulated ischemia and reperfusion and in this model investigate the impact of simulated ischemia and reperfusion on expression of the calcium handling proteins FKBP12 and FKBP12.6, and intracellular calcium dynamics.MethodsHL-1 cell cultures were exposed to normoxia (as control), hypoxia, simulated ischemia (HEDA) or HEDA + reactive oxygen species (ROS) for up to 24 h and after HEDA, with or without ROS, followed or not by simulated reperfusion (REPH) for 6 h. Viability was analyzed with a trypan blue exclusion method. Cell lysates were analyzed with real-time PCR and Western blot (WB) for FKBP12 and FKBP12.6. Intracellular Ca2+measurements were performed using dual-wavelength ratio imaging in fura-2 loaded cells.ResultsA time-dependent drop in viability was shown after HEDA (P < 0.001). Viability was not further influenced by addition of ROS or REPH. The general patterns of FKBP12 and FKBP12.6 mRNA expression showed upregulation after hypoxia, downregulation after ischemia and normalization after reperfusion, which was partially attenuated if ROS was added during HEDA. The protein contents were unaffected after hypoxia, tended to increase after ischemia and, for FKBP12.6, a further increase after reperfusion was shown. Hypoxia or HEDA, with or without REPH, resulted in a decreased amplitude of the Ca2+ peak in response to caffeine. In addition, cells subjected to HEDA for 3 h or HEDA for 3 h followed by 6 h of REPH displayed irregular Ca2+ oscillations with a decreased frequency.ConclusionA threshold for cell survival with respect to duration of ischemia was established in our cell line model. Furthermore, we could demonstrate disturbances of calcium handling in the sarcoplasmic reticulum as well as alterations in the expressions of the calcium handling proteins FKBP12 and FKBP12.6, why this model may be suitable for further studies on ischemia and reperfusion with respect to calcium handling of the sarcoplasmic reticulum. 相似文献
13.
AimsThis study tested the hypothesis that the inhibition of semicarbazide-sensitive amine oxidase (SSAO) after ischemia could attenuate myocardial ischemia–reperfusion (I/R) injury.Main methodsAnesthetized male Sprague–Dawley rats underwent myocardial I/R injury. Saline, semicarbazide (SCZ, 30 mg/kg), hydralazine (HYD, 10 mg/kg), or LJP 1207 (30 mg/kg) was administered intraperitoneally 3 min before reperfusion. After 30 min of ischemia and 180 min of reperfusion, the myocardial infarct size was determined using nitroblue tetrazolium staining. Myocardial myeloperoxidase activity was determined through biochemical assay. HE staining was used for histopathological evaluation. Myocardial SSAO activity was assayed with high performance liquid chromatography analysis. Additionally, the endothelial expression of P-selectin was evaluated using immunohistochemistry after 30 min of ischemia and 20 min of reperfusion.Key findingsMyocardial SSAO activity was increased in myocardial I/R injury. Administration of SCZ, HYD, or LJP 1207 reduced the myocardial infarct size and decreased leukocyte infiltration and endothelial P-selectin expression in myocardial I/R injury in vivo.SignificanceThese data suggest that myocardial I/R injury up-regulates myocardial SSAO activity, and the inhibition of SSAO prior to reperfusion is able to attenuate acute myocardial I/R injury. 相似文献
14.
AimsWe recently reported that acute exposure to nicotine vasodilates the renal vasculature of male rats via facilitation of endothelial nitric oxide synthase (eNOS). In this study, we investigated whether this effect of nicotine is sexually dimorphic and the role of estrogen in modulating the nicotine effect.Main methodsNicotine-evoked vasodilation was evaluated in phenylephrine-preconstricted perfused kidneys obtained from male, proestrus female, ovariectomized (OVX) and estrogen-replaced OVX (OVXE2) rats.Key findingsNicotine infusion (5 × 10? 5, 1 × 10? 4, and 5 × 10? 4 M) produced greater concentration-dependent reductions in the renal perfusion pressure (RPP) in an isolated kidney from proestrus females than from males. Inhibition of NOS by NG-nitro-l-arginine abolished the nicotine-evoked reduction in RPP and abolished the gender difference in the nicotine effect. Nicotine vasodilation was also attenuated in kidneys isolated from OVX and diestrus rats, models characterized by reduced estrogen levels. Further, estrogen or l-arginine supplementation in OVX rats largely restored the renal vasodilatory response to nicotine. Estrogen receptor blockade by tamoxifen abrogated the enhanced nicotine-evoked vasodilation elicited by E2 in OVX rats. The nitrite/nitrate levels and protein expressions of eNOS and α7 nicotinic cholinergic receptor (α7 nAChRs) were significantly higher in renal tissues of OVXE2 compared with OVX rats, suggesting a facilitatory effect for E2 on α7 nAChRs/eNOS signaling.SignificanceEstrogen-dependent facilitation of NOS signaling mediates the enhanced vasodilator capacity of nicotine in the renal vasculature of female rats. Preliminary evidence also suggests a potential role for α7 nAChRs in this estrogen-dependent phenomenon. 相似文献
15.
AimsThis study was to determine the effects of zinc plus arachidonic acid (ZA) treatment on the insulin action in the specific ZA target organs using hyperinsulinemic euglycemic clamp method.Main methods18 Sprague–Dawley rats weighing ~ 130 g were divided into 3 groups of 6 rats and treated them with 1) normal rat chow, 2) high fructose (60.0%) diet only, or 3) the same fructose diet plus drinking water containing 10 mg zinc plus 50 mg arachidonic acid (AA)/L. In a separate study, male Wistar rats weighing ~ 250 g were fed normal rat chow (n = 4) or high fat (66.5%) diet with drinking water containing zero (n = 9) or 10 mg AA plus 20 mg zinc /L (n = 9). After 4 week treatment, insulin action was assessed using the hyperinsulinemic eguglycemic clamp technique.Key findingsHigh fructose feeding impaired suppression of hepatic glucose output by insulin compared to controls during the clamp procedure (4.39 vs. 2.35 mg/kg/min; p < 0.05). However, ZA treatment in high fructose-fed rats showed a significant improvement of hepatic insulin sensitivity compared to non-treatment controls (4.39 vs. 2.18 mg/kg/min; p < 0.05). Glucose infusion rates in Wistar rats maintained on a high fat diet (HFD) were significantly lower compared to control rats (22.8 ± 1.3 vs. 31.9 ± 1.4 mg/kg/min; p < 0.05). ZA treatment significantly improved (~ 43%) peripheral tissue insulin sensitivity in HFD fed animals (26.7 ± 1.3 [n = 9] vs. 22.8 ± 1.3 mg/kg/min; p < 0.05).SignificanceThese data demonstrate that ZA treatment is effective in improving glucose utilization in hyperglycemic rats receiving either a high-fructose or a high-fat diet. 相似文献
16.
Wu L Al-Hejazi A Filion L Ben R Halpenny M Yang L Giulivi A Allan DS 《Cytotherapy》2012,14(2):205-214
Background aimsDelayed neutrophil recovery following autologous hematopoietic stem cell transplantation (aHSCT) increases transplant-related morbidity. Apoptosis induced by cryopreservation and thawing of hematopoietic progenitor cells collected by apheresis (HPC-A) was investigated in this nested case-control study as a factor associated with delayed neutrophil recovery following aHSCT.MethodsAmong patients with lymphoma who underwent aHSCT between 2000 and 2007 (n = 326), 13 cases of primary delayed neutrophil recovery and 22 age- and sex-matched controls were identified. Apoptosis and viability were measured using multiparameter flow cytometry, and colony-forming capacity was determined using semi-solid methylcellulose assays.ResultsHPC-A grafts from cases and controls had similar percentages of viable mononuclear cells (MNC) and CD34+progenitor cells, as determined by standard 7AAD dye exclusion methods measured before and after cryopreservation. Patients with delayed neutrophil recovery received increased numbers of apoptotic MNC (P = 0.02) but similar numbers of apoptotic CD34+ cells per kilogram measured after thawing. Apoptosis was more pronounced in MNC compared with CD34+ cells after thawing, and apoptosis was negligible in freshly collected HPC-A products. Patients with delayed neutrophil recovery had fewer total colony-forming unites (CFU) and CFU-granulocyte–macrophages (GM) per 105 viable post-thaw MNC compared with controls (P < 0.05).ConclusionsIncreased numbers of apoptotic MNC in thawed HPC-A products are associated with delayed neutrophil recovery after aHSCT. Studies that address factors contributing to increased apoptosis are needed, and measuring apoptosis in thawed HPC-A may have a role in the assessment of graft adequacy. 相似文献
17.
AimsThe therapeutic effect of pinocembrin, together with the therapeutic time window, in the transient global cerebral ischemia/reperfusion (I/R) rats was investigated.Main methodsAdult male Sprague–Dawley rats were subjected to global cerebral ischemia for 20 min by four-vessel occlusion. Pinocembrin (1 and 5 mg/kg) was administrated intravenously 30 min before ischemia and 30 min, 2 h, 6 h after reperfusion, respectively. Neurological scores, brain edema and histological examination by Nissl staining were employed to assess the neuronal injury after ischemia and the neuroprotection by pinocembrin. The activities of superoxide dismutase (SOD), myeloperoxidase (MPO) and the content of malondialdehyde (MDA) in brain tissue were tested by colorimetric assays. Alterations of neurotransmitters were determined by a high performance liquid chromatography–electrochemical method.Key findingsPinocembrin significantly ameliorated neurological deficits and brain edema, and alleviated the degree of hippocampal neuronal loss at 24 h after global cerebral I/R with a broad therapeutic time window. It was found that treatment with pinocembrin reduced the compensatory increase of SOD activity and decreased the MDA level and MPO activity in a dose-dependent manner. The metabolic balance between excitatory and inhibitory amino acids was modulated by pinocembrin treatment.SignificanceThese findings suggest that pinocembrin provides neuroprotection against global cerebral ischemic injury with a wide therapeutic time window, which may be attributed to its antioxidative, antiinflammatory and antiexcitotoxic effects. 相似文献
18.
AimsThis study aimed to investigate the effects of cytidine-5′-diphosphocholine (CDP-choline), an endogenous lipid precursor, on the reactivity of the mouse gastric fundus and to determine the mechanism(s) mediating its effects.Main methodsPossible contractile effect of CDP-choline (10? 5–10? 2 M) was investigated in the absence and presence of a muscarinic receptor antagonist, atropine (3 × 10? 6 M), an acetylcholine esterase inhibitor, physostigmine (10? 6 M), a Na+ channel blocker, tetrodotoxin (TTX, 3 × 10? 6 M), a Rho-kinase inhibitor, Y-27632 (10? 5 M), a purinoceptor antagonist, suramin (2 × 10? 4 M), a nitric oxide synthase inhibitor, NG-nitro-L-arginine (L-NA, 3 × 10? 4 M), a Ca2+ channel blocker, nifedipine (10? 6 M), an α7 nicotinic receptor antagonist, methyllycaconitine citrate (MLA, 10? 6 M) and a G protein (Gi/o) inhibitor, pertussis toxin (PTX, 2 μg/ml). The metabolites of CDP-choline, namely choline (10? 4–10? 2 M), cytidine 5′-triphosphate (CTP, 10? 5–10? 2 M), cytidine (10? 5–10? 2 M) and cytidine monophosphate (CMP, 10? 3–10? 2 M) were also tested. Besides, phosphorylation of MYPT1, which indicates Rho-kinase activity, was also detected.Key findingsCDP-choline produced contractions in a concentration-dependent manner. The contractions were not affected by atropine, physostigmine, TTX, PTX, MLA or L-NA. However, Y-27632, suramin or nifedipine partly reduced these contractions. CDP-choline increased phosphorylation of MYPT1. Among CDP-choline metabolites, cytidine had no contractile effects. However, choline induced considerable contractions, which were sensitive to atropine. CMP and CTP had also contractile activity, comparable to that of CDP-choline.SignificanceThese results suggest that CDP-choline produced contraction through, at least in part, purinoceptors and Rho/Rho-kinase signalling in the mouse gastric fundus. 相似文献
19.
Richa EM Kunnavakkam R Godley LA Kline J Odenike O Larson RA Nguyen V Stock W Wickrema A Van Besien K Artz AS 《Cytotherapy》2012,14(6):707-715
Background aimsThe rising use of allogeneic transplantation in older recipients necessitates considering older related donors. The effect of related donor age for peripheral blood stem cell allografts (PBSC) on graft maintenance and outcomes, independent of CD34+cell dose, has not been well-characterized.MethodsHLA-related donors (98% siblings) underwent a uniform filgrastim-based mobilization regimen aiming to collect and infuse 5 × 106 CD34+ cells/recipient kg. Donor and recipient age were modeled in multiple ways to account for the correlation, and outcomes reported by decade of donor age.ResultsThe median donor and recipient ages were 52 years and 54 years, respectively. The mean CD34+ cell dose infused was 5.6 × 106 CD34+/kg and 75% of patients received a narrow range between 4.4 and 6.6 × 106 CD34+ cells/kg. Neither better PBSC mobilization nor higher CD34+ content of allografts was significantly associated with engraftment or transplant outcomes. After adjusting for recipient age and other prognostic factors, older donor age by decade conferred a lower risk of non-relapse mortality (NRM) [hazard ratio (HR) = 0.64, 95% confidence interval (CI) 0.45–0.91, P = 0.013] and borderline improvement in overall survival (OS) (HR = 0.76, 95% CI 0.58–0.99, P = 0.045) without altering progression-free survival (PFS) (HR = 0.85, 95% CI 0.66–1.07, P = 0.18).ConclusionsOlder donor age does not worsen outcome after matched related donor PBSC transplantation in patients receiving a narrow range CD34+ cells. The relatively small sample size mandates that the finding of similar to improved outcomes for older related donor age must be confirmed in larger studies. 相似文献
20.
AimsTo investigate the role of src-kinase in ischemic preconditioning induced reversal of ischemia and reperfusion induced cerebral injury in mice.Main methodsBilateral carotid artery occlusion of 17 min followed by reperfusion for 24 h was employed to produce ischemia and reperfusion induced cerebral injury in mice. Cerebral infarct size was measured using triphenyltetrazolium chloride staining using both by volume and by weight methods differently. Memory was evaluated using elevated plus maze test. Rota rod test was employed to assess motor incoordination.Key findingsBilateral carotid artery occlusion followed by reperfusion produced cerebral infarction and impaired memory and motor co-ordination. Three preceding episodes of bilateral carotid artery occlusion for 1 min and reperfusion of 1 min (ischemic preconditioning) prevented markedly ischemia–reperfusion-induced cerebral injury measured in terms of infarct size (38.5 ± 1.3% and 38.5 ± 2.9% mean infarct of control animals was reduced to 24.3 ± 1.2% and 23.5 ± 1.8% of the preconditioning groups respectively), loss of memory (72.2 ± 3.6 mean transfer latency time of control animals was reduced to 25.6 ± 5.2 of the preconditioning group respectively) and motor coordination (78.3 ± 17.6 s mean falling down latency time of control animals was increased to a mean value of 180.9 ± 6.5 s of the preconditioning groups respectively). SU6656 (2 mg/kg, ip) and PP1 (0.1 mg/kg, ip), highly selective src-kinase inhibitors, attenuated this neuroprotective effect of ischemic preconditioning.SignificanceTherefore, neuroprotective effect of ischemic preconditioning may be due to src-kinase linked mechanism. 相似文献