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111.
Fedor F. Severin Inna I. Severina Yury N. Antonenko Tatiana I. Rokitskaya Dmitry A. Cherepanov Elena N. Mokhova Mikhail Yu. Vyssokikh Antonina V. Pustovidko Olga V. Markova Lev S. Yaguzhinsky Galina A. Korshunova Nataliya V. Sumbatyan Maxim V. Skulachev Vladimir P. Skulachev 《Proceedings of the National Academy of Sciences of the United States of America》2010,107(2):663-668
A unique phenomenon of mitochondria-targeted protonophores is described. It consists in a transmembrane H+-conducting fatty acid cycling mediated by penetrating cations such as 10-(6’-plastoquinonyl)decyltriphenylphosphonium (SkQ1) or dodecyltriphenylphosphonium (C12TPP). The phenomenon has been modeled by molecular dynamics and directly proved by experiments on bilayer planar phospholipid membrane, liposomes, isolated mitochondria, and yeast cells. In bilayer planar phospholipid membrane, the concerted action of penetrating cations and fatty acids is found to result in conversion of a pH gradient (ΔpH) to a membrane potential (Δψ) of the Nernstian value (about 60 mV Δψ at ΔpH = 1). A hydrophobic cation with localized charge (cetyltrimethylammonium) failed to substitute for hydrophobic cations with delocalized charge. In isolated mitochondria, SkQ1 and C12TPP, but not cetyltrimethylammonium, potentiated fatty acid-induced (i) uncoupling of respiration and phosphorylation, and (ii) inhibition of H2O2 formation. In intact yeast cells, C12TPP stimulated respiration regardless of the extracellular pH value, whereas a nontargeted protonophorous uncoupler (trifluoromethoxycarbonylcyanide phenylhydrazone) stimulated respiration at pH 5 but not at pH 3. Hydrophobic penetrating cations might be promising to treat obesity, senescence, and some kinds of cancer that require mitochondrial hyperpolarization. 相似文献
112.
Antonina Mikocka‐Walus Harriet C. Beevor Belinda Gabbe Russell L. Gruen Jason Winnett Peter Cameron 《ANZ journal of surgery》2010,80(3):157-161
Background: There has been a shift from operative to conservative management of splenic injuries in the last two decades, but the current practice in Australia is not known. This study aims to determine the profile of splenic injury in major trauma victims and the approach to treatment in Victoria for the last 2 years. Methods: A review of prospectively collected data from the Victorian State Trauma Registry (VSTR) from July 2005 to June 2007 was conducted. Demographic data, details of the event, clinical observations, management and associated outcomes were extracted from the database. The patients were categorized into four groups according to management (conservative, splenectomy, embolization and repair) and were compared accordingly. Multivariate binary logistic regression was performed to identify predictors of treatment (conservative versus splenectomy) on arrival. Results: Of the 318 major trauma patients with splenic injuries, 186 (59%) were treated conservatively, 103 (32%) with splenectomy, 17 (5%) with arterial embolization and 12 (4%) with repair. Of these, 14 (14%) splenectomy cases and 2 (12%) embolization cases did not receive their respective treatments within 24 h. The severity of the spleen injury (as measured by the Abbreviated Injury Scale (AIS)) and age were identified as significant independent predictors of the form of treatment provided. Conclusion: In Victoria, conservative management is the preferred approach in patients with minor (AIS = 2) to moderate (AIS = 3) splenic injuries. The low rates of embolization warrant further research into whether splenectomy is overused. 相似文献
113.
Johnathan Cooper-Knock J Robin Highley Judith Hartley Antonio Milano Stephen Sawcer Alistair Compston Antonina Frolov Gavin Charlesworth Nicholas Wood Oliver Bandmann Christopher J McDermott Janine Kirby Paul Ince Pamela Shaw 《Lancet》2013
BackgroundCrossover between neurodegenerative diseases is described but poorly understood. Hexanucleotide repeat expansions of C9ORF72 are a major cause of motorneuron disease (MND)/frontotemporal dementia but we and others have observed clinical heterogeneity within C9ORF72-positive probands and their families, including a high incidence of parkinsonism. We aimed to determine whether C9ORF72 expansions are an upstream cause of clinically and pathologically distinct neurodegenerative diseases. This would have significant implications for neurodegeneration research.MethodsIn cohorts of patients with clinical parkinsonism (n=518), multiple sclerosis (MS) (n=215), and MND (n=563) we screened DNA for the C9ORF72 expansion, reviewed clinical histories, and undertook pathological evaluation of brain tissue where available.FindingsWe identified the C9ORF72 expansion in one patient with clinical parkinsonism (0·2%), 23 patients with MND (13·7%), and none of the patients with MS. The C9ORF72 positive parkinsonian patient had a family history of MND and displayed pathology consistent with MND with C9ORF72 expansion in addition to α-synucleinopathy. Two further patients with MND were identified with α-synucleinopathy: one with the C9ORF72 expansion, the other without. Of five MND patients who initially presented with MS, four (80%) were positive for the C9ORF72 expansion. C9ORF72-MND is more rapidly progressive in the presence of preceding MS. Pathological examination of MND patients with C9ORF72 expansions revealed p62 positive, TDP-43 negative neuronal cytoplasmic inclusions in frontal cortex, hippocampus, and substantia nigra, which were relatively absent in MND patients without C9ORF72 expansions.InterpretationC9ORF72 expansions are not a major cause of either classic Parkinson's disease with α-synucleinopathy or MS. MS appears to increase the penetrance of the C9ORF72 expansion and exaggerate the severity. We suggest that p62 positive, TDP-43 negative neuronal cytoplasmic inclusions within the substantia nigra account for the association between C9ORF72 expansions and parkinsonism. Moreover we suggest that the distribution of these inclusions determines the clinical heterogeneity of C9ORF72 disease.FundingUK Medical Research Council. 相似文献
114.
Bondì ML Craparo EF Giammona G Cervello M Azzolina A Diana P Martorana A Cirrincione G 《Drug delivery》2007,14(2):61-67
This article describes the development of nanostructured lipid carriers (NLC) as colloidal carriers for two antitumor compounds that possess a remarkable antineoplastic activity. But their limited stability and low solubility in water could give a very low parenteral bioavailability. Results revealed an enhancement of the cytotoxicity effect of drug-loaded NLC on human prostate cancer (PC-3) and human hepatocellular carcinoma (HuH-6, HuH-7) cell lines with respect to that of both free drugs. Results of characterization studies strongly support the potential application of these drugs-loaded NLC as prolonged delivery systems for lipophilic drugs by several administration routes, in particular for intravenous administration. 相似文献
115.
Ahmetov II Mozhayskaya IA Flavell DM Astratenkova IV Komkova AI Lyubaeva EV Tarakin PP Shenkman BS Vdovina AB Netreba AI Popov DV Vinogradova OL Montgomery HE Rogozkin VA 《European journal of applied physiology》2006,97(1):103-108
Peroxisome proliferator-activated receptor α (PPARα) regulates genes responsible for skeletal and heart muscle fatty acid oxidation. Previous studies have shown that the PPARα intron 7 G/C polymorphism was associated with left ventricular growth in response to exercise. We speculated that GG homozygotes should be more prevalent within a group of endurance-oriented athletes, have normal fatty acid metabolism, and increased percentages of slow-twitch fibers. We have tested this hypothesis in the study of a mixed cohort of 786 Russian athletes in 13 different sporting disciplines prospectively stratified by performance (endurance-oriented athletes, power-oriented athletes and athletes with mixed endurance/power activity). PPARα intron 7 genotype and allele frequencies were compared to 1,242 controls. We found an increasing linear trend of C allele with increasing anaerobic component of physical performance (P=0.029). GG genotype frequencies in endurance-oriented and power-oriented athletes were 80.3 and 50.6%, respectively, and were significantly (P<0.0001) different compared to controls (70.0%). To examine the association between PPARα gene variant and fiber type composition, muscle biopsies from m. vastus lateralis were obtained and analyzed in 40 young men. GG homozygotes (n=25) had significantly (P=0.003) higher percentages of slow-twitch fibers (55.5±2.0 vs 38.5±2.3%) than CC homozygotes (n=4). In conclusion, PPARα intron 7 G/C polymorphism was associated with physical performance in Russian athletes, and this may be explained, in part, by the association between PPARα genotype and muscle fiber type composition. 相似文献
116.
J Wang T Kobayashi N Floc'h CW Kinkade A Aytes D Dankort C Lefebvre A Mitrofanova RD Cardiff M McMahon A Califano MM Shen C Abate-Shen 《Cancer research》2012,72(18):4765-4776
Both the PI3K → Akt → mTOR and mitogen-activated protein kinase (MAPK) signaling pathways are often deregulated in prostate tumors with poor prognosis. Here we describe a new genetically engineered mouse model of prostate cancer in which PI3K-Akt-mTOR signaling is activated by inducible disruption of PTEN, and extracellular signal-regulated kinase 1/2 (ERK1/2) MAPK signaling is activated by inducible expression of a BRAF(V600E) oncogene. These tissue-specific compound mutant mice develop lethal prostate tumors that are inherently resistant to castration. These tumors bypass cellular senescence and disseminate to lymph nodes, bone marrow, and lungs where they form overt metastases in approximately 30% of the cases. Activation of PI3K → Akt → mTOR and MAPK signaling pathways in these prostate tumors cooperate to upregulate c-Myc. Accordingly, therapeutic treatments with rapamycin and PD0325901 to target these pathways, respectively, attenuate c-Myc levels and reduce tumor and metastatic burden. Together, our findings suggest a generalized therapeutic approach to target c-Myc activation in prostate cancer by combinatorial targeting of the PI3K → Akt → mTOR and ERK1/2 MAPK signaling pathways. Cancer Res; 72(18); 4765-76. ?2012 AACR. 相似文献
117.
N Floc'h CW Kinkade T Kobayashi A Aytes C Lefebvre A Mitrofanova RD Cardiff A Califano MM Shen C Abate-Shen 《Cancer research》2012,72(17):4483-4493
Although the prognosis for clinically localized prostate cancer is now favorable, there are still no curative treatments for castration-resistant prostate cancer (CRPC) and, therefore, it remains fatal. In this study, we investigate a new therapeutic approach for treatment of CRPC, which involves dual targeting of a major signaling pathway that is frequently deregulated in the disease. We found that dual targeting of the Akt and mTOR signaling pathways with their respective inhibitors, MK-2206 and ridaforolimus (MK-8669), is highly effective for inhibiting CRPC in preclinical studies in vivo using a refined genetically engineered mouse model of the disease. The efficacy of the combination treatment contrasts with their limited efficacy as single agents, since delivery of MK-2206 or MK-8669 individually had a modest impact in vivo on the overall tumor phenotype. In human prostate cancer cell lines, although not in the mouse model, the synergistic actions of MK-2206 and ridaforolimus (MK-8669) are due in part to limiting the mTORC2 feedback activation of Akt. Moreover, the effects of these drugs are mediated by inhibition of cellular proliferation via the retinoblastoma (Rb) pathway. Our findings suggest that dual targeting of the Akt and mTOR signaling pathways using MK-2206 and ridaforolimus (MK-8669) may be effective for treatment of CRPC, particularly for patients with deregulated Rb pathway activity. Cancer Res; 72(17); 4483-93. ?2012 AACR. 相似文献
118.
In a previous work of ours dehydroxymethyl-epoxyquinomicin (DHMEQ), an inhibitor of NF-κB, was shown to induce apoptosis through Reactive Oxygen Species (ROS) production in hepatoma cells. The present study demonstrated that DHMEQ cooperates with Celecoxib (CLX) to decrease NF-κB DNA binding and to inhibit cell growth and proliferation more effectively than treatment with these single agents alone in the hepatoma cell lines HA22T/VGH and Huh-6. ROS production induced by the DHMEQ-CLX combination in turn generated the expression of genes involved in endoplasmic reticulum (ER) stress and silencing TRB3 mRNA significantly decreased DHMEQ-CLX-induced cell growth inhibition. Moreover, the DHMEQ-CLX combination was associated with induction of PARP cleavage and down-regulation of the anti-apoptotic proteins Bcl-2, Mcl-1 and survivin, as well as activated Akt. CD95 and CD95 ligand expression increased synergistically in the combination treatment, which was reversed in the presence of NAC. Knockdown of CD95 mRNA expression significantly decreased DHMEQ-CLX-induced cell growth inhibition in both cell lines. These data suggest that the DHMEQ-CLX combination kills hepatoma cells via ROS production, ER stress response and the activation of intrinsic and extrinsic apoptotic pathways. 相似文献
119.
Brighina F Palermo A Aloisio A Francolini M Giglia G Fierro B 《Clinical neuropharmacology》2006,29(6):338-342
OBJECTIVE: To evaluate the efficacy of levetiracetam as prophylactic treatment for migraine with aura with high frequency of attacks. BACKGROUND: Migraine with aura with high frequency of attacks could represent a very demanding therapeutic problem. Efficacy of the antiepileptic drug, lamotrigine, has been reported in this form of migraine. Levetiracetam is a new antiepileptic drug with an excellent tolerability profile. Mechanisms of action of this drug remain largely unknown, but recently, it has been shown to exert inhibitory effects on neuronal-type calcium channels. METHODS: We performed a small open-label trial treating 16 patients affected by migraine with aura with high frequency of attacks. After a 1-month run-in period, patients were treated with levetiracetam at a dosage of 1000 mg/d for 6 months. RESULTS: The number of attacks per month was significantly reduced during the first month (compared with run-in; P < 0.001), and it was reduced further during the second (second month vs first month; P < 0.001) and the third months (third month vs second month; P < 0.001) of the treatment. This improvement persisted unchanged for the remaining 3 months of treatment. In 7 (44%) of the 16 patients, the attacks were completely abolished after 3 months of treatment. Severity of headache and duration of headache and aura were also significantly reduced at the third and sixth months of treatment (P < 0.001). Levetiracetam was well tolerated (6 patients complained of slight dizziness, nervousness, and somnolence). CONCLUSIONS: Levetiracetam seems to be a safe and effective treatment for migraine with aura. Controlled trials are needed to confirm the observed results. 相似文献
120.
Bonassi S Znaor A Ceppi M Lando C Chang WP Holland N Kirsch-Volders M Zeiger E Ban S Barale R Bigatti MP Bolognesi C Cebulska-Wasilewska A Fabianova E Fucic A Hagmar L Joksic G Martelli A Migliore L Mirkova E Scarfi MR Zijno A Norppa H Fenech M 《Carcinogenesis》2007,28(3):625-631
The frequency of micronuclei (MN) in peripheral blood lymphocytes (PBL) is extensively used as a biomarker of chromosomal damage and genome stability in human populations. Much theoretical evidence has been accumulated supporting the causal role of MN induction in cancer development, although prospective cohort studies are needed to validate MN as a cancer risk biomarker. A total of 6718 subjects from of 10 countries, screened in 20 laboratories for MN frequency between 1980 and 2002 in ad hoc studies or routine cytogenetic surveillance, were selected from the database of the HUman MicroNucleus (HUMN) international collaborative project and followed up for cancer incidence or mortality. To standardize for the inter-laboratory variability subjects were classified according to the percentiles of MN distribution within each laboratory as low, medium or high frequency. A significant increase of all cancers incidence was found for subjects in the groups with medium (RR=1.84; 95% CI: 1.28-2.66) and high MN frequency (RR=1.53; 1.04-2.25). The same groups also showed a decreased cancer-free survival, i.e. P=0.001 and P=0.025, respectively. This association was present in all national cohorts and for all major cancer sites, especially urogenital (RR=2.80; 1.17-6.73) and gastro-intestinal cancers (RR=1.74; 1.01-4.71). The results from the present study provide preliminary evidence that MN frequency in PBL is a predictive biomarker of cancer risk within a population of healthy subjects. The current wide-spread use of the MN assay provides a valuable opportunity to apply this assay in the planning and validation of cancer surveillance and prevention programs. 相似文献