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1.
Aims
Dietary flavonoid intake shows a significant inverse association with mortality from coronary heart disease, incidence of myocardial infarction and stroke. Quercetin is one of the most common flavonoids in our diet and has several favorable biological activities. Quercetin glucosides, which are enzymatically trans-glycosylated isoquercitrin, have high water-solubility and bioavailability compared with quercetin. Here, we investigated the effects of quercetin glucosides on collateral development in a murine hindlimb ischemia model.Main methods
We induced hindlimb ischemia in 24- to 32-week-old male C3H/HeJ mice by resecting the right femoral artery. Then, 0.5% carboxymethyl cellulose (control) or quercetin glucosides (100 mg/kg/day) were administered daily by gavage. Blood flow was monitored weekly by laser Doppler imaging.Key findings
Recovery of blood flow to the ischemic leg was significantly enhanced by quercetin glucosides (blood flow ratio at 4 weeks: control, 0.57 ± 0.11; quercetin glucosides, 0.95 ± 0.10, p < 0.05). Furthermore, anti-CD31 immunostaining revealed that quercetin glucosides increased capillary density in the ischemic muscle (control, 200 ± 24/mm2; quercetin glucosides, 364 ± 41/mm2, p < 0.01). Quercetin glucosides did not promote tumor growth. The beneficial effect of quercetin glucosides was abrogated in eNOS-deficient mice.Significance
These results suggest that quercetin glucosides may have therapeutic potential to promote angiogenesis in ischemic tissue. 相似文献2.
Guilherme Henrique Souza Bomfim Luciana Ferreira Verde Roberto Frussa-FilhoAron Jurkiewicz Neide Hyppolito Jurkiewicz 《Life sciences》2014
Aims
Alcohol withdrawal syndrome (AWS) is characterized by a set of physiological modifications triggered by abrupt withdrawal and/or decreasing consumption of ethanol (EtOH), which may manifest 16–48 h after ceasing consumption. The relationship between the effects of AWS and central and peripheral sympathetic neurotransmission is unknown. This study investigates the possible mechanisms on the sympathetic system during periods of AWS.Main methods
Male Wistar rats were treated with EtOH (6–10 g/kg/day/v.o. 5 days). Subsequently, 1 h, 24 h, 48 h and 120 h after administration of the last dose of EtOH, the animals were sacrificed, and their vas deferens (VD) were removed to perform the following evaluations: (a) concentration–effect curves of sympathetic agonist; (b) activity of α2-adrenoreceptor; (c) function of voltage-dependent calcium channels (Cav); and (d) release of endogenous catecholamines measured in real time coupled to HPLC.Key findings
The results showed that the maximum effects of contraction were increased by agonists tested in at 24 h and 48 h EtOH withdrawal. The inhibitory affinity (pIC50) of guanfacine was decreased 24 h EtOH withdrawal. The function of Cav was also decreased as pIC50 values dropped 24 h and 48 h EtOH withdrawal. The release of catecholamines increased 48 h after EtOH withdrawal. It is suggested that AWS triggers hyperactivity in peripheral sympathetic neurotransmission.Significance
The mechanisms underlying hyperactivity are possibly explained by a failure of autoregulation from catecholamines released by α2-adrenoreceptors and/or an increase of Cav function, which may be potential targets to attenuate the symptoms of AWS at the peripheral level. 相似文献3.
Aims
Acute ethanol intoxication (AEI) attenuates the arginine vasopressin (AVP) response to hemorrhage leading to impaired hemodynamic counter-regulation and accentuated hemodynamic stability. Previously we identified that the ethanol-induced impairment of circulating AVP concentrations in response to hemorrhage was the result of augmented central nitric oxide (NO) inhibition. The aim of the current study was to examine the mechanisms underlying ethanol-induced up-regulation of paraventricular nucleus (PVN) NO concentration. Angiotensin (ANG) (1-7) is an important mediator of NO production through activation of the Mas receptor. We hypothesized that Mas receptor inhibition would decrease central NO concentration and thus restore the rise in circulating AVP levels during hemorrhagic shock in AEI rats.Main methods
Conscious male Sprague–Dawley rats (300–325 g) received a 15 h intra-gastric infusion of ethanol (2.5 g/kg + 300 mg/kg/h) or dextrose prior to a fixed-pressure (~ 40 mm Hg) 60 min hemorrhage. The Mas receptor antagonist A-779 was injected through an intracerebroventricular (ICV) cannula 15 min prior to hemorrhage.Key findings
PVN NOS activity and NO were significantly higher in AEI compared to DEX-treated controls at the completion of hemorrhage. ICV A-779 administration decreased NOS activity and NO concentration, partially restoring the rise in circulating AVP level at completion of hemorrhage in AEI rats.Significance
These results suggest that Mas receptor activation contributes to the NO-mediated inhibitory tone of AVP release in the ethanol-intoxicated hemorrhaged host. 相似文献4.
Bingrong Dang Yuping Yang Erdong Zhang Wenjian Li Xiangquan Mi Yue Meng Siqi Yan Zhuanzi Wang Wei Wei Chunlin Shao Rui Xing Changjun Lin 《Life sciences》2014
Aims
Microgravity and radiation, common in space, are the main factors influencing astronauts' health in space flight, but their combined effects on immune cells are extremely limited. Therefore, the effect of simulated microgravity on heavy ion radiation-induced apoptosis, and reactive oxygen species (ROS)-sensitive apoptosis signaling were investigated in human B lymphoblast HMy2.CIR cells.Main methods
Simulated microgravity was achieved using a Rotating Wall Vessel Bioreactor at 37 °C for 30 min. Heavy carbon-ion irradiation was carried out at 300 MeV/u, with a linear energy transfer (LET) value of 30 keV/μm and a dose rate of 1 Gy/min. Cell survival was evaluated using the Trypan blue exclusion assay. Apoptosis was indicated by Annexin V/propidium iodide staining. ROS production was assessed by cytometry with a fluorescent probe dichlorofluorescein. Malondialdehyde was detected using a kit. Extracellular signal-regulated kinase (ERK), mitogen-activated protein kinase phosphatase-1 (MKP-1) and caspase-3 activation were measured by immunoblotting.Key findings
Simulated microgravity decreased heavy ion radiation-induced cell survival and increased apoptosis in HMy2.CIR cells. It also amplified heavy ion radiation-elicited intracellular ROS generation, which induced ROS-sensitive ERK/MKP-1/caspase-3 activation in HMy2.CIR cells. The above phenomena could be reversed by the antioxidants N-acetyl cysteine (NAC) and quercetin.Significance
These results illustrated that simulated microgravity increased heavy ion radiation-induced cell apoptosis, mediated by a ROS-sensitive signal pathway in human B lymphoblasts. Further, the antioxidants NAC and quercetin, especially NAC, might be good candidate drugs for protecting astronauts' and space travelers' health and safety. 相似文献5.
Aims
Activation of retinal microglial cells (RMCs) is known to contribute to retinal ganglion cell (RGC) death after optic nerve injury. The purpose of this study was to investigate the effects of intravenous injection of α-crystallin on RGC survival and RMC activation in a rat model of optic nerve crush.Main methods
RGCs were retrogradely labeled with fluorogold. Rats were intravenously injected with normal saline or α-crystallin (0.05 g/kg, 0.5 g/kg, and 5 g/kg) at 2, 4, 6, 8, 10, and 12 days after the optic nerve crush. Activated RMCs were characterized using immunofluorescence labeling with CD11b, and TNF-α and iNOS expression was detected using immunoblot analyses. We analyzed the morphology and numbers of RGC and RMC 2 and 4 weeks after injury using fluorescence and confocal microscopy.Key findings
The number of RGCs decreased after optic nerve injury, accompanied by significantly increased numbers of activated RMCs. Intravenous injection of α-crystallin decreased the number of RMCs, and enhanced the number of RGCs compared to saline injection. α-Crystallin administration inhibited TNF-α and iNOS protein expression induced by optic nerve injury.Significance
Our results suggest that α-crystallin promotes RGC survival and inhibits RMC activation. Intravenous injection of α-crystallin could be a possible strategy for the treatment of optic nerve injury. 相似文献6.
Aims
The anterior pretectal nucleus (APtN) and electroacupuncture (EA) activate descending mechanisms to modulate nociceptive inputs in the spinal dorsal horn. This study examines qualitatively whether mechanisms in the APtN participate in the EA-induced analgesia in rats.Main methods
The tail-flick test was utilized to examine the changes produced by non-selective antagonists of serotonergic (methysergide, 37 pg), muscarinic (atropine, 10 ng) and opioid (naloxone, 10 ng) receptors; selective antagonists against μ (CTOP, 6.4 μg), δ (ICI174,864, 6.9 μg) or κ (nor-BNI, 7.3 μg); 5HT1 (methiothepin, 0.47 μg), 5HT2 (ketanserin, 5.4 μg), or 5HT3 (MDL 72222, 15.7 μg); and GABAA (bicuculline, 150 ng) receptors injected into the dorsal (d) or ventral (v) APtN on the antinociception induced by a 20-min EA applied at 2- or 100-Hz frequency to the Zusanli and Sanyinjiao acupoints.Key findings
The 2-Hz EA-induced analgesia was blocked by naloxone, CTOP or atropine, was less intense after bicuculline, was shorter after methysergide or methiothepin in dAPtN, and was less intense after methysergide, methiothepin and bicuculline in vAPtN. The 100-Hz EA-induced analgesia was less intense after methysergide, methiothepin and CTOP in vAPtN, and remained unchanged after injection of the antagonists into the dAPtN.Significance
The 2-Hz EA-induced analgesia utilizes cholinergic muscarinic, μ-opioid, GABAA and 5-HT1 mechanisms in the dAPtN and μ-opioid and 5-HT1 mechanisms in the vAPtN, while 100-Hz EA-induced analgesia utilizes μ-opioid and 5-HT1 mechanisms in the vAPtN but does not utilize them in the dAPtN. 相似文献7.
Catalina Carrasco-Pozo Edgar Pastene Carola Vergara Moises Zapata Cristian Sandoval Martin Gotteland 《Biochimica et Biophysica Acta (BBA)/General Subjects》2012
Background
The effect of indomethacin (INDO) on Ca2 + mobilization, cytotoxicity, apoptosis and caspase activation and the potential protective effect of quercetin (QUE), resveratrol (RES) and rutin (RUT) were determined in Caco-2 cells.Methods
Caco-2 cells were incubated with INDO in the presence or absence of QUE, RES or RUT. The concentrations of Ca2 + in the cytosol (Fluo-3 AM) and mitochondria (Rhod-2 AM) were determined as well as the cytotoxicity (MTT reduction and LDH leakage), apoptosis (TUNEL) and caspase-3 and 9 activities.Results
INDO promoted Ca2 + efflux from the endoplasmic reticulum (ER), resulting in an early, but transient, increment of cytosolic Ca2 + at 3.5 min, followed by a subsequent increment of intra-mitochondrial Ca2 + at 24 min. INDO also induced cytotoxicity, apoptosis, and increased caspase activities and cytochrome c release. All these alterations were prevented by the inhibitors of the IP3R and RyR receptors, 2-Aminoethoxydiphenyl borate (2-APB) and dantrolene. QUE was the most efficient polyphenol in preventing Ca2 + mobilization induced by INDO and all of its consequences including cytotoxicity and apoptosis.Conclusions
In Caco-2 cells, INDO stimulates ER Ca2 + mobilization, probably through the activation of IP3R and RyR receptors, and the subsequent entry of Ca2 + into the mitochondria. Polyphenols protected the cells against the Ca2 + mobilization induced by INDO and its consequences on cytotoxicity and apoptosis.General significance
These results confirm the possibility of using polyphenols and particularly QUE for the protection of the gastroduodenal mucosa in subjects consuming NSAIDs. 相似文献8.
Saeid Haghighi Poodeh Leena Alhonen Tuire Salonurmi Markku J. Savolainen 《Biochemical and biophysical research communications》2014
Introduction
Polyamines play a fundamental role during embryogenesis by regulating cell growth and proliferation and by interacting with RNA, DNA and protein. The polyamine pools are regulated by metabolism and uptake from exogenous sources. The use of certain inhibitors of polyamine synthesis causes similar defects to those seen in alcohol exposure e.g. retarded embryo growth and endothelial cell sprouting.Methods
CD-1 mice received two intraperitoneal injections of 3 g/kg ethanol at 4 h intervals 8.75 days post coitum (dpc). The fetal head, trunk, yolk sac and placenta were collected at 9.5 and 12.5 dpc and polyamine concentrations were determined.Results
No measurable quantity of polyamines could be detected in the embryo head at 9.5 dpc, 12 h after ethanol exposure. Putrescine was not detectable in the trunk of the embryo at that time, whereas polyamines in yolk sac and placenta were at control level. Polyamine deficiency was associated with slow cell growth, reduction in endothelial cell sprouting, an altered pattern of blood vessel network formation and consequently retarded migration of neural crest cells and growth restriction.Discussion
Our results indicate that the polyamine pools in embryonic and extraembryonic tissues are developmentally regulated. Alcohol administration, at the critical stage, perturbs polyamine levels with various patterns, depending on the tissue and its developmental stage. The total absence of polyamines in the embryo head at 9.5 dpc may explain why this stage is so vulnerable to the development of neural tube defect, and growth restriction, the findings previously observed in fetal alcohol syndrome. 相似文献9.
Nigel Irwin Pamela FrizelleFinbarr P.M. O'Harte Peter R. Flatt 《Biochimica et Biophysica Acta (BBA)/General Subjects》2013
Background
Cholecystokinin (CCK) is a gastrointestinal hormone that has been proposed as a potential therapeutic option for obesity–diabetes. As such, (pGlu-Gln)-CCK-8 is an N-terminally modified CCK-8 analogue with improved biological effectiveness over the native peptide.Methods
The current study has examined the in vitro stability, biological activity and in vivo therapeutic applicability of a novel second generation mini-PEGylated form of (pGlu-Gln)-CCK-8, (pGlu-Gln)-CCK-8[mPEG].Results
(pGlu-Gln)-CCK-8[mPEG] was completely resistant to enzymatic degradation and in addition displayed similar insulinotropic (p < 0.05 to p < 0.001) and satiating effects (p < 0.01 to p < 0.001) as (pGlu-Gln)-CCK-8. This confirmed the capability of (pGlu-Gln)-CCK-8[mPEG] to bind to and activate the CCK receptor. Sub-chronic twice daily injection of (pGlu-Gln)-CCK-8[mPEG] in high fat fed mice for 35 days significantly decreased body weight gain (p < 0.05), food intake (p < 0.01 to p < 0.001) and triacylglycerol deposition in liver (p < 0.001) and muscle (p < 0.001). Furthermore, (pGlu-Gln)-CCK-8[mPEG] markedly improved intraperitoneal glucose tolerance (p < 0.05) and insulin sensitivity (p < 0.001). Despite this therapeutic profile, once daily injection of (pGlu-Gln)-CCK-8[mPEG] in high fat fed mice for 33 days, at the same dose, was not associated with alterations in food intake and body weight. In addition, metabolic responses to exogenous glucose and insulin injection were similar to saline treated controls.Conclusion
These studies emphasise the therapeutic potential of (pGlu-Gln)-CCK-8[mPEG] and similar molecules.General significance
A more detailed analysis of the dose and administration schedule employed for (pGlu-Gln)-CCK-8[mPEG] could provide a novel and effective compound to treat obesity–diabetes. 相似文献10.
Background
α-Synucein is a small (14 kDa), abundant, intrinsically disordered presynaptic protein, whose aggregation is believed to be a critical step in Parkinson's disease (PD). Oxidative stress is reported to be a risk factor for dopamine cell degeneration in PD. Flavonoids are suggested to be important antioxidant against oxidative stress. Flavonoids were reported to inhibit fibrillization and disaggregate the preformed fibrils of α-synucein, but the molecular mechanism was still not clear.Methods
Quercetin, a well-recognized flavonoid antioxidant, was tested for its inhibition of α-synucein aggregation by thioflavin T assay, light scattering measurement, size-exclusion high performance liquid chromatography, atomic force microscopy, etc.Results
The pre-incubated quercetin exhibited a noticeably stronger inhibition behavior to the fibril formation than that of the freshly prepared. The inhibition is significant in the presence of ortho- and para-benzenediol isomers and inconsiderable in the presence of meta-isomer. The oxidized quercetin species (i.e., chalcantrione, benzyfuranone, quercetinchinone, and other derivatives) cause stronger inhibition than quercetin does because of the elevated polarity and hydrophilicity. Presence of quercetin disaggregates α-synucein fibrils, rather than oligomers and amorphous aggregations.Conclusions
Instead of the antioxidant activity, the 1:1 covalent binding of quercetin with α-synucein, and the increased hydophilicity of the covalently modified α-synucein oligomers or monomers, account for the inhibition of α-synucein fibrillation.General significance
Clarification of the molecular mechanism of the inhibition and disaggregation may help to screen safer and more effective flavonoid therapeutic in combating PD. 相似文献11.
Aims
Previous animal studies have examined the potential for cytostatic drugs to induce learning and memory deficits in laboratory animals but, to date, there is no pre-clinical evidence that taxanes have the potential to cause cognitive impairment. Therefore our aim was to explore the short- and long-term cognitive effects of different dosing schedules of the taxane docetaxel (DTX) on laboratory rodents.Main methods
Healthy male hooded Wistar rats were treated with DTX (6 mg/kg, 10 mg/kg) or physiological saline (control), once a week for 3 weeks (Experiment 1) or once only (10 mg/kg; Experiment 2). Cognitive function was assessed using the novel object recognition (NOR) task and spatial water maze (WM) task 1 to 3 weeks after treatment and again 4 months after treatment.Key findings
Shortly after DTX treatment, rats perform poorly on NOR regardless of treatment regimen. Treatment with a single injection of 10 mg/kg DTX does not appear to induce sustained deficits in object recognition or peripheral neuropathy.Significance
Overall these findings show that treatment with the taxane DTX in the absence of cancer and other anti-cancer treatments causes cognitive impairment in healthy rodents. 相似文献12.
Liana Dantas da Costa e Silva Laise Carla Lima Verde Rodrigues Viviane Ramos dos Santos Mariangela da Costa Allgayer Alexandre de Barros Falcão Ferraz Helena Campos Rolla Patrícia Pereira Jaqueline Nascimento Picada 《Life sciences》2014
Aim
Lobeline is a natural alkaloid derived from Lobelia inflata that has been investigated as a clinical candidate for the treatment of alcoholism. In a pre-clinical trial, lobeline decreased the preference for and consumption of ethanol, due to the modulation of the nicotinic acetylcholine receptor. However, the interaction between lobeline and ethanol is poorly known and thus there are safety concerns.The present study was conducted to evaluate the mutagenic and genotoxic effects of lobeline and assess its modulation of ethanol-induced toxicological effects.Main methods
CF-1 male mice were divided into five groups. Groups received an intraperitoneal injection of saline solution, lobeline (5 or 10 mg/kg), ethanol (2.5 g/kg), or lobeline plus ethanol, once a day for three consecutive days. Genotoxicity was evaluated in peripheral blood using the alkaline comet assay. The mutagenicity was evaluated using both Salmonella/microsome assay in TA1535, TA97a, TA98, TA100, and TA102 Salmonella typhimurium strains and the micronucleus test in bone marrow. Possible liver and kidney injuries were evaluated using biochemical analysis.Key findings
Lobeline did not show genotoxic or mutagenic effects and did not increase the ethanol-induced genotoxic effects in blood. Lobeline also protected blood cells against oxidative damage induced by hydrogen peroxide. Biochemical parameters were not altered, indicating no liver or kidney injuries or alterations in lipid and carbohydrate metabolisms.Significance
These findings suggest that lobeline does not induce gene or chromosomal mutations, and that this lack of genetic toxicity is maintained in the presence of ethanol, providing further evidence of the safety of this drug to treat alcohol dependence. 相似文献13.
Niko S. Radulović Ivan Jovanović Ivan R. Ilić Pavle J. Randjelović Nikola M. Stojanović Ana B. Miltojević 《Life sciences》2013
Aims
Two natural alkaloids, methyl (M) and isopropyl (I) N-methylanthranilates, with recently demonstrated significant pharmacological activities, were assayed for their possible overall effect on intact gastric mucosa and their protective properties towards the onset of gastric lesions induced by diclofenac (a non-steroidal anti-inflammatory drug, NSAID) or ethanol.Main methods
The influence of I and M on gastric mucosa integrity was assessed by oral administration in doses of 200 mg/kg. The gastroprotective action of I and M in doses of 50, 100 and 200 mg/kg was analyzed in the diclofenac and ethanol-induced gastric lesion models in rats. After the treatment, the stomachs of the animals were analyzed (captured by a digital camera). Ulcer scoring, morphometric and histopathological analyses of the stomachs were done.Key findings
The oral application of these compounds on their own, even in quite high doses (200 mg/kg) did not induce gastric lesions. Both alkaloids exerted a very strong antiulcer activity, even in low doses (50 mg/kg), by decreasing the number of lesions caused by the application of either diclofenac or ethanol, eliminating them completely or reducing them to a form of mucosal hyperemia.Significance
Their possible mechanism of action was discussed and due to their many positive properties including anxiolytic, antidepressant, antinociceptive, anti-inflammatory and gastroprotective activities, as well as a cheap and simple synthetic route for their preparation, methyl and isopropyl N-methylanthranilates, both alike, might represent a cost effective alternative sought for in the treatment of peptic ulcers and/or new safer NSAIDs for pain management. 相似文献14.
Adriana G. Guimarães Luciana Scotti Marcus Tullius Scotti Francisco J.B. Mendonça Júnior Nayara S.R. Melo Rafael S. Alves Waldecy De Lucca Júnior Daniel P. Bezerra Daniel P. Gelain Lucindo J. Quintans Júnior 《Life sciences》2014
Aims
The present study evaluated the carvacrol (CARV) effect on hyperalgesia and nociception induced by sarcoma 180 (S180) in mice.Main methods
Carvacrol treatment (12.5–50 mg/kg s.c.) once daily for 15 days was started 24 h after injection of the sarcoma cells in the hind paw (s.c.). Mice were evaluated for mechanical sensitivity (von Frey), spontaneous and palpation-induced nociception, limb use and tumor growth on alternate days. CARV effects on the central nervous system were evaluated through immunofluorescence for Fos protein. Molecular docking studies also were performed to evaluate intermolecular interactions of the carvacrol and muscimol, as ligands of interleukin-10 and GABAA receptors.Key findings
CARV was able to significantly reduce mechanical hyperalgesia and spontaneous and palpation-induced nociception, improve use paw, decrease the number of positively marked neurons in lumbar spinal cord and activate periaqueductal gray, nucleus raphe magnus and locus coeruleus. CARV also caused significant decreased tumor growth. Docking studies showed favorable interaction overlay of the CARV with IL-10 and GABAA.Significance
Together, these results demonstrated that CARV may be an interesting option for the development of new analgesic drugs for the management of cancer pain. 相似文献15.
O.O. Ojo D.K. SrinivasanB.O. Owolabi J.M. ConlonP.R. Flatt Y.H.A. Abdel-Wahab 《Biochimica et Biophysica Acta (BBA)/General Subjects》2015
Background
Magainin-AM2, a previously described amphibian host-defense peptide, stimulates insulin- and glucagon-like peptide-1-release in vitro. This study investigated anti-diabetic effects of the peptide in mice with diet-induced obesity and glucose intolerance.Methods
Male National Institute of Health Swiss mice were maintained on a high-fat diet for 12-weeks prior to the daily treatment with magainin-AM2. Various indices of glucose tolerance were monitored together with insulin secretory responsiveness of islets at conclusion of study.Results
Following twice daily treatment with magainin-AM2 for 15 days, no significant difference in body weight and food intake was observed compared with saline-treated high fat control animals. However, non-fasting blood glucose was significantly (P < 0.05) decreased while plasma insulin concentrations were significantly (P < 0.05) increased. Oral and intraperitoneal glucose tolerance and insulin secretion following glucose administration via both routes were significantly (P < 0.05) enhanced. The peptide significantly (P < 0.001) improved insulin sensitivity as well as the beta cell responses of islets isolated from treated mice to a range of insulin secretagogues. Oxygen consumption, CO2 production, respiratory exchange ratio and energy expenditure were not significantly altered by sub-chronic administration of magainin-AM2 but a significant (P < 0.05) reduction in fat deposition was observed.Conclusion
These results indicate that magainin-AM2 improves glucose tolerance, insulin sensitivity and islet beta cells secretory responsiveness in mice with obesity-diabetes.General significance
The activity of magainin-AM2 suggests the possibility of exploiting this peptide for treatment of type 2 diabetes. 相似文献16.
Élodie Breton Christian Goetz Jacqueline Kintz Nathalie Accart Gaëlle Aubertin Bernard Grellier Philippe Erbs Ronald Rooke André Constantinesco Philippe Choquet 《Comptes rendus biologies》2010,333(3):220-225
Purpose
The aim of this study was to monitor in vivo with low field MRI growth of a murine orthotopic glioma model following a suicide gene therapy.Methods
The gene therapy consisted in the stereotactic injection in the mice brain of a modified vaccinia virus Ankara (MVA) vector encoding for a suicide gene (FCU1) that transforms a non toxic prodrug 5-fluorocytosine (5-FC) to its highly cytotoxic derivatives 5-fluorouracil (5-FU) and 5’-fluorouridine-5’monophosphate (5’-FUMP). Using a warmed-up imaging cell, sequential 3D T1 and T2 0.1T MRI brain examinations were performed on 16 Swiss female nu/nu mice bearing orthotopic human glioblastoma (U87-MG cells). The 6-week in vivo MRI follow-up consisted in a weekly measurement of the intracerebral tumor volume leading to a total of 65 examinations. Mice were divided in four groups: sham group (n = 4), sham group treated with 5-FC only (n = 4), sham group with injection of MVA-FCU1 vector only (n = 4), therapy group administered with MVA-FCU1 vector and 5-FC (n = 4). Measurements of tumor volumes were obtained after manual segmentation of T1- and T2-weighted images.Results
Intra-observer and inter-observer tumor volume measurements show no significant differences. No differences were found between T1 and T2 volume tumor doubling times between the three sham groups. A significant statistical difference (p < 0.05) in T1 and T2 volume tumor doubling times between the three sham groups and the animals treated with the intratumoral injection of MVA-FCU1 vector in combination with 2 weeks per os 5-FC administration was demonstrated.Conclusion
Preclinical low field MRI was able to monitor efficacy of suicide gene therapy in delaying the tumor growth in an in vivo mouse model of orthotopic glioblastoma. 相似文献17.
Fátima Husein Abdalla Andréia Machado Cardoso Luciane Belmonte Pereira Roberta Schmatz Jamile Fabbrin Gonçalves Naiara Stefanello Amanda Maino Fiorenza Jessié Martins Gutierres Jonas Daci da Silva Serres Daniela Zanini Victor Camera Pimentel Juliano Marchi Vieira Maria Rosa Chitolina Schetinger Vera Maria Morsch Cinthia Melazzo Mazzanti 《Molecular and cellular biochemistry》2013,372(1-2):1-8
This study investigated the effect of quercetin on nucleoside triphosphate diphosphohydrolase (NTPDase), 5′-nucleotidase, adenosine deaminase (ADA), and acetylcholinesterase (AChE) activities in synaptosomes from cerebral cortex of adult rats exposed to cadmium (Cd). Rats were exposed to Cd (2.5 mg/Kg) and quercetin (5, 25 or 50 mg/Kg) by gavage for 45 days. Rats were randomly divided into eight groups (n = 8–10): saline/ethanol, saline/Querc 5 mg/kg, saline/Querc 25 mg/kg, saline/Querc 50 mg/kg, Cd/ethanol, Cd/Querc 5 mg/kg, Cd/Querc 25 mg/kg, and Cd/Querc 50 mg/kg. Results demonstrated that AChE activity increased in the Cd/ethanol group when compared to saline/ethanol group. Treatment with quercetin prevented the increase in AChE activity when compared to Cd/ethanol group. Quercetin treatment prevented the cadmium-induced increase in NTPDase, 5-nucleotidase, and ADA activities in Cd/ethanol group when compared to saline/ethanol group. Our data showed that quercetin have a protector effect against Cd intoxication. This way, is a promising candidate among the flavonoids to be investigated as a therapeutic agent to attenuate neurological disorders associated with Cd intoxication. 相似文献
18.
19.
Aims
Bombesin receptors (BB receptors) and bombesin related peptides are expressed in the lower urinary tract of rodents. Here we investigated whether in vivo activation of BB receptors can contract the urinary bladder and facilitate micturition in sham rats and in a diabetic rat model of voiding dysfunction.Material and methods
In vivo cystometry experiments were performed in adult female Sprague–Dawley rats under urethane anesthesia. Diabetes was induced by streptozotocin (STZ; 65 mg/kg, i.p.) injection. Experiments were performed 9 and 20 weeks post STZ-treatment. Drugs included neuromedin B (NMB; BB1 receptor preferring agonist), and gastrin-releasing peptide (GRP; BB2 receptor preferring agonist).Key findings
NMB and GRP (0.01–100 μg/kg in sham rats; 0.1–300 μg/kg in STZ-treated rats, i.v.) increased micturition frequency, bladder contraction amplitude and area under the curve dose dependently in both sham and STZ-treated rats. In addition, NMB (3, 10 μg/kg i.v.) triggered voiding in > 80% of STZ-treated rats when the bladder was filled to a sub-threshold voiding volume. NMB and GRP increased mean arterial pressure and heart rate at the highest doses, 100 and 300 μg/kg.Significance
Activation of bombesin receptors facilitated neurogenic bladder contractions in vivo. Single applications of agonists enhanced or triggered voiding in sham rats as well as in the STZ-treated rat model of diabetic voiding dysfunction. These results suggest that BB receptors may be targeted for drug development for conditions associated with poor detrusor contraction such as an underactive bladder condition. 相似文献20.
Jacklyn N. Hellwege Nicholette D. Palmer Julie T. Ziegler Carl D. Langefeld Carlos Lorenzo Jill M. Norris Toshinari Takamura Donald W. Bowden 《Gene》2014