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11.
Tomáš Šimůnek Martin Štěrba Olga Popelová Michaela Adamcová Radomír Hrdina Vladimír Geršl 《Pharmacological reports : PR》2009,61(1):154-171
The risk of cardiotoxicity is the most serious drawback to the clinical usefulness of anthracycline antineoplastic antibiotics, which include doxorubicin (adriamycin), daunorubicin or epirubicin. Nevertheless, these compounds remain among the most widely used anticancer drugs. The molecular pathogenesis of anthracycline cardiotoxicity remains highly controversial, although the oxidative stress-based hypothesis involving intramyocardial production of reactive oxygen species (ROS) has gained the widest acceptance. Anthracyclines may promote the formation of ROS through redox cycling of their aglycones as well as their anthracycline-iron complexes. This proposed mechanism has become particularly popular in light of the high cardioprotective efficacy of dexrazoxane (ICRF-187). The mechanism of action of this drug has been attributed to its hydrolytic transformation into the iron-chelating metabolite ADR-925, which may act by displacing iron from anthracycline-iron complexes or by chelating free or loosely bound cellular iron, thus preventing site-specific iron-catalyzed ROS damage. However, during the last decade, calls for the critical reassessment of this “ROS and iron” hypothesis have emerged. Numerous antioxidants, although efficient in cellular or acute animal experiments, have failed to alleviate anthracycline cardiotoxicity in clinically relevant chronic animal models or clinical trials. In addition, studies with chelators that are stronger and more selective for iron than ADR-925 have also yielded negative or, at best, mixed outcomes. Hence, several lines of evidence suggest that mechanisms other than the traditionally emphasized “ROS and iron” hypothesis are involved in anthracycline-induced cardiotoxicity and that these alternative mechanisms may be better bases for designing approaches to achieve efficient and safe cardioprotection. 相似文献
12.
Holly L Rosenzweig Manabu Minami Nikola S Lessov Sarah C Coste Susan L Stevens David C Henshall Robert Meller Roger P Simon Mary P Stenzel-Poore 《Journal of cerebral blood flow and metabolism》2007,27(10):1663-1674
Lipopolysaccharide (LPS) preconditioning provides neuroprotection against subsequent cerebral ischemic injury. Tumor necrosis factor-alpha (TNFalpha) is protective in LPS-induced preconditioning yet exacerbates neuronal injury in ischemia. Here, we define dual roles of TNFalpha in LPS-induced ischemic tolerance in a murine model of stroke and in primary neuronal cultures in vitro, and show that the cytotoxic effects of TNFalpha are attenuated by LPS preconditioning. We show that LPS preconditioning significantly increases circulating levels of TNFalpha before middle cerebral artery occlusion in mice and show that TNFalpha is required to establish subsequent neuroprotection against ischemia, as mice lacking TNFalpha are not protected from ischemic injury by LPS preconditioning. After stroke, LPS preconditioned mice have a significant reduction in the levels of TNFalpha (approximately threefold) and the proximal TNFalpha signaling molecules, neuronal TNF-receptor 1 (TNFR1), and TNFR-associated death domain (TRADD). Soluble TNFR1 (s-TNFR1) levels were significantly increased after stroke in LPS-preconditioned mice (approximately 2.5-fold), which may neutralize the effect of TNFalpha and reduce TNFalpha-mediated injury in ischemia. Importantly, LPS-preconditioned mice show marked resistance to brain injury caused by intracerebral administration of exogenous TNFalpha after stroke. We establish an in vitro model of LPS preconditioning in primary cortical neuronal cultures and show that LPS preconditioning causes significant protection against injurious TNFalpha in the setting of ischemia. Our studies suggest that TNFalpha is a twin-edged sword in the setting of stroke: TNFalpha upregulation is needed to establish LPS-induced tolerance before ischemia, whereas suppression of TNFalpha signaling during ischemia confers neuroprotection after LPS preconditioning. 相似文献
13.
Ljiljana Ševaljević Sanja Marinković Desanka Bogojević Svetlana Matić Bogdan Bošković 《Archives of toxicology》1989,63(5):406-411
We have studied the effect of soman intoxication on serum acute phase reactants (APR) levels, and the relationship of the APR and corticosterone concentrations and the immunosuppressive activity of the serum. One day after the injection of 1.8 LD50 soman the concentrations of 2-macroglobulin (2-MG) and 1-acid glycoprotein (AGP) in the serum of antidote protected rats increased 4- and 7-fold, respectively, whereas those of hemopexin (Hx), haptoglobin (Hp) and cysteine protease inhibitor (CPI) were two to three times higher than in the controls. A similar magnitude of increase of serum acute phase reactants levels was observed when 0.3 LD50 soman was administered at 24-h intervals over the 5-day period. The relationship of changes in the APR concentration, corticosterone level and immunosuppressive activity of the serum was also comparable to that observed in the acute phase response to tissue injury. 相似文献
14.
15.
J. Škopková I. Albrecht J. H. Cort 《Pflügers Archiv : European journal of physiology》1973,343(2):123-132
Summary Rats anaesthetised with Inactin, body temp. maintained at 37°C, were infused with mannitol-saline until both urine flow rate and conductivity reached a balanced state. In separate experiments under analogous conditions cardiac output was measured by dye dilution and organ flow rates by86Rb distribution. Doses of oxytocin of 3 ng or less, injected at or just below the carotid bifurcation, caused a highly significant natriuresis with increased tubular rejection, but no measureable haemodynamic changes. The same oxytocin dose given into the internal or external carotid artery above the bifurcation caused neither haemodynamic changes nor natriuresis. Injection of vasopressin, angiotensin and -MSH at the sensitive site did not result in natriuresis in the same dosage range. Section of the sinus nerve significantly decreased the natriuretic response to oxytocin. It is suggested that the carotid body contains a specific oxytocin receptor capable of eliciting natriuresis in the rat. 相似文献
16.
Summary. Two vaccinia virus (VV) strains, WR and Praha, were selected for a study undertaken to determine whether the virus-encoded
interferon-γ receptor (IFN-γR) plays any role in virus virulence. Both of the viruses expressed the B8R gene coding for IFN-γR
in infected cell cultures. The nucleotide sequence of the Praha virus B8R gene was determined, and, when compared with the
published sequence of the WR virus, it only displayed one silent nucleotide substitution. Mutants of the WR and Praha viruses
with deleted B8R gene were constructed. In rabbits, skin lesions produced by the WR B8R-deleted mutants were smaller and tended
to disappear earlier than those caused by wild-type WR virus. Similar results were obtained with both independently prepared
WR B8R-deleted mutants. These data strongly suggested that the product of B8R gene did play a role in virus virulence. A similar
comparison of the wild-type Praha virus and its mutant could not be done because of the very low virulence of the parental
virus for rabbits.
Received March 13, 2000 Accepted August 16, 2000 相似文献
17.
Kreimir Paveli Reno Hraan Sanja Kapitanovia Nikola Karapanda Zoran Vrane Mladen Belicza Boo Krulin Tomislav abrijan 《The Journal of pathology》1995,177(4):395-400
Proto-oncogenes, growth factors/receptors, and tumour suppressor genes were analysed in malignant metastatic insulinomas. Normal pancreas showed only a moderate immunoreaction for c-myc proto-oncogene and a strong reaction for insulin. Benign insulinomas were slightly or moderately positive for transforming growth factor a (TGFα), weakly positive for epidermal growth factor receptor (EGF-R), and strongly positive for c-myc and insulin. In malignant insulinomas, besides a strong immunoreaction for c-myc and TGFα, activation of c-K-ras and overexpression of p53 protein were found. Insulin reaction was moderate or strong. Three out of six malignant insulinomas displayed a c-K-ras point mutation at codon 12. All mutations were guanine to cytosine transversion, resulting in amino acid substitution, glycine to arginine. Mutations were present in metastatic insulinomas only. Patients with mutated c-K-ras oncogene had overexpression of p53 protein as well as c-myc and TGFα overexpression. Our results support the view that malignant progression is a consequence of more than one genetic lesion and suggest that activation of myc, TGFα, and ras genesα plays a role in a multistep process of tumour progression, perhaps serving as an initiating event. 相似文献
18.
Improved survival of ischemic cutaneous and musculocutaneous flaps after vascular endothelial growth factor gene transfer using adeno-associated virus vectors
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Zacchigna S Papa G Antonini A Novati F Moimas S Carrer A Arsic N Zentilin L Visintini V Pascone M Giacca M 《The American journal of pathology》2005,167(4):981-991
A major challenge in reconstructive surgery is flap ischemia, which might benefit from induction of therapeutic angiogenesis. Here we demonstrate the effect of an adeno-associated virus (AAV) vector delivering vascular endothelial growth factor (VEGF)165 in two widely recognized in vivo flap models. For the epigastric flap model, animals were injected subcutaneously with 1.5 x 10(11) particles of AAV-VEGF at day 0, 7, or 14 before flap dissection. In the transverse rectus abdominis musculocutaneous flap model, AAV-VEGF was injected intramuscularly. The delivery of AAV-VEGF significantly improved flap survival in both models, reducing necrosis in all treatment groups compared to controls. The most notable results were obtained by administering the vector 14 days before flap dissection. In the transverse rectus abdominis musculocutaneous flap model, AAV-VEGF reduced the necrotic area by >50% at 1 week after surgery, with a highly significant improvement in the healing process throughout the following 2 weeks. The therapeutic effect of AAV-VEGF on flap survival was confirmed by histological evidence of neoangiogenesis in the formation of large numbers of CD31-positive capillaries and alpha-smooth muscle actin-positive arteriolae, particularly evident at the border between viable and necrotic tissue. These results underscore the efficacy of VEGF-induced neovascularization for the prevention of tissue ischemia and the improvement of flap survival in reconstructive surgery. 相似文献
19.
L. Janský P. Šrámek J. Šavlíková B. Uličný H. Janáková K. Horký 《European journal of applied physiology》1996,74(1-2):148-152
The purpose of this study was to determine whether or not repeated short-term cold water immersions can induce a change in the activity of the sympathetic nervous system and, consequently, in cardiovascular functions in healthy young athletes. Changes in some plasma hormone concentrations were also followed. A single cold water immersion (head-out, at 14°C, for 1 h) increased sympathetic nervous system activity, as evidenced by a four-fold increase (P < 0.05) in plasma noradrenaline concentration. Plasma adrenaline and dopamine concentrations were not increased significantly. Plasma renin-angiotensin activity was reduced by half (P < 0.05) during immersion but plasma aldosterone concentration was unchanged. Stimulation of the sympathetic nervous system during immersion did not induce significant changes in heart rate, but induced peripheral vasoconstriction (as judged from a decrease in skin temperature) and a small increase (by 10%) in systolic and diastolic blood pressures. No clear change in reactivity of the sympathetic nervous system was observed due to repeated cold water immersions (three times a week, for 6 weeks). Neither the plasma renin-angiotensin activity, aldosterone concentration nor cardiovascular parameters were significantly influenced by repeated cold water immersions. A lowered diastolic pressure and an increase in peripheral vasoconstriction were observed after cold acclimation, however. Evidently, the repeated cold stimuli were not sufficient to induce significant adaptational changes in sympathetic activity and hormone production. 相似文献
20.
Šimurda Jiří Šimurdova Milena Braveny Pavel Šumbera Josef 《Pflügers Archiv : European journal of physiology》1976,362(3):209-218
1. | The relationship of the contractile response of cat papillary muscles and of the slow inward current, recorded under voltage clamp conditions (single sucrose gap), has been studied. The preparations were driven at a rate of 30 per min at 31° C. Both variables were recorded during a train of 7 identical clamp depolarizations (for 1 s from resting potential to –15 to +40 mV). The contractility increased severalfold and reached the steady state within 5–6 consecutive depolarizations. |
2. | The voltage-dependence of slow inward current was confirmed: maximum was found at depolarizations near 0 mV. On repetition of clamp pulses the slow current gradually diminished in amplitude and was more slowly activated and inactivated. The shift of the current-voltage curve indicated a decrease of the reversal potential. |
3. | Under non-steady state conditions the amplitude of the slow current was found to correlate closely with the magnitude of the contractile response at any given level of depolarization. The relation was linear with negative slope. The largest contractile response was not found at voltages which elicited maximum slow current. |
4. | The progressive decrease of the slow current during repetition of voltage clamp depolarizations is not significantly affected by inadequate time for recovery of slowly changing conductances, since it occurs also at stimulation frequency 15 per min and the slow current remains virtually unaltered after 20 s period of quiescence. |
5. | The course of total ionic current during phase 1 and 2 of action potential was reconstructed from a family of current curves obtained as a response to clamp depolarizations to various voltages, respecting the contractility-dependence of the current. The resulting course was correlated with the first derivative of action potential. A general conformity was ascertained. |
6. | The correlation of slow inward current with action potential configuration indicates that the rate of its activation determines the depth of the notch separating spike and plateau, its magnitude determines the voltage of the plateau phase and its rate of inactivation affects repolarization. |
7. | It is concluded that the described simultaneous changes of mechanical and electrical phenomena might be due to increased [Ca]i, which is responsible for more intense activation of the contractile proteins on the one hand, and decreased driving force of the slow inward current, carried by Ca ions, on the other. |