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31.
Abstract: Nerve growth factor (NGF) induces persistent p42 and p44 mitogen-activated protein kinase (MAPK) activity in sympathetic neurones in parallel to its survival-promoting activity. To investigate whether these MAPK activities are necessary for NGF-induced survival, we have inhibited NGF-stimulated p42/p44 MAPK activity over extended periods using the compound 2-(2'-amino-3'-methoxyphenyl)-oxanaphthalen-4-one (PD98059). Despite attaining up to 95% inhibition of p42/p44 MAPK activity in cultures treated with NGF and PD98059, neuronal survival is maintained undiminished, although a decrease in the density of the neuritic network is observed. Because p21Ras activity is essential for NGF-induced survival, we conclude that p21Ras-linked activities other than p42 and p44 MAPKs are responsible for mediating NGF-dependent survival of rat sympathetic neurones. 相似文献
32.
Susan N. Edwards Anne E. Buckmaster Aviva M. Tolkovsky 《Journal of neurochemistry》1991,57(6):2140-2143
We have examined whether sympathetic neurones that have lost the potential to be rescued by protein and RNA synthesis inhibitors after a period of nerve growth factor (NGF) deprivation are irreversibly committed to die. We found that 15 h after withdrawal of NGF from 7-day cultures of neonatal rat superior cervical ganglion neurones, 50% of the neurones lost the potential to be rescued by cycloheximide but that NGF rescued most of the neurones. By 22 h after NGF withdrawal, only 10% of the neurones were rescued by inhibition of macromolecular synthesis with cycloheximide, puromycin, or actinomycin D, but as many as 60-80% of the neurones were rescued by NGF. This is after the time at which a DNA "ladder," consistent with cell death by apoptosis, was first detected (18 h). As long as 27 h of NGF withdrawal was required before 50% of the neurones lost the potential to be rescued by NGF. The survival-promoting agent 8-(4-chlorophenylthio)cyclic AMP (CPTcAMP) or depolarization with 50 mM KCl (HK) rescued neurones with kinetics similar to those of NGF, and rescue by all three agents did not require protein synthesis. Thus, NGF, CPTcAMP, and HK can rescue neurones deprived of NGF at much later times than either protein or RNA synthesis inhibitors by acting at the posttranslational level, a finding suggesting that initiation of the cell death programme in sympathetic neurones is not an irreversible step. 相似文献
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34.
Aviva Schiffmiller Damon Anderson Alan Finkelstein 《The Journal of general physiology》2015,146(2):183-192
Anthrax toxin consists of three ∼85-kD proteins: lethal factor (LF), edema factor (EF), and protective antigen (PA). PA63 (the 63-kD, C-terminal portion of PA) forms heptameric channels ((PA63)7) in planar phospholipid bilayer membranes that enable the translocation of LF and EF across the membrane. These mushroom-shaped channels consist of a globular cap domain and a 14-stranded β-barrel stem domain, with six anionic residues lining the interior of the stem to form rings of negative charges. (PA63)7 channels are highly cation selective, and, here, we investigate the effects on both cation selectivity and protein translocation of mutating each of these anionic residues to a serine. We find that although some of these mutations reduce cation selectivity, selectivity alone does not directly predict the rate of protein translocation; local changes in electrostatic forces must be considered as well. 相似文献
35.
We have examined whether the apoptosis-specific protein p45ASP and human Apg5 are identical proteins. Like p45ASP, myc-hApg5 cross-reacted with a c-Jun antibody and approximately 50% of myc-hApg5 was bound to a Triton X-100-insoluble fraction in HeLa cells. However, soluble myc-hApg5 was degraded during apoptosis induced by staurosporine or TNFalpha/cycloheximide whilst expression of soluble p45ASP was stabilised. Furthermore, myc-hApg5 degradation was blocked by the caspase inhibitor Boc-Asp(OMe)FMK whilst p45ASP expression was eliminated. Moreover, myc-hApg5 ( approximately 32 kDa) never assumed the size of p45ASP (45 kDa). It is therefore likely that p45ASP and human Apg5 are distinct proteins although they do share some common characteristics. 相似文献
36.
Khaliulin I Schneider A Houminer E Borman JB Schwalb H 《Free radical biology & medicine》2004,37(7):969-976
This study examined the hypothesis that low-concentration apomorphine improves postischemic hemodynamic and mitochondrial function in the isolated rat heart model by attenuating oxidation of myocardial proteins. Control and apomorphine-treated hearts were subjected to 35 min of perfusion, 25 min of normothermic global ischemia, and 60 min of reperfusion. Apomorphine (2 microM) was introduced into the perfusate for 20 min starting from the onset of reperfusion. Apomorphine significantly (p <.05) improved postischemic hemodynamic function: work index of the heart (product of LVDP and heart rate) was twice as high in apomorphine-treated hearts compared to controls at the end of reperfusion (p <.01). After isolation of cardiac mitochondria, the respiratory control ratio (RCR) was calculated from the oxygen consumption rate of State 3 and State 4 respiration. Apomorphine significantly improved postischemic RCR (87% of preischemic value vs. 39% in control, p <.05). Using an immunoblot technique, carbonyl content of multiple unidentified myocardial proteins (mitochondrial and nonmitochondrial) was observed to be elevated after global ischemia and reperfusion. Apomorphine significantly attenuated the increased protein oxidation at the end of reperfusion. These results support the conclusion that apomorphine is capable of preventing ischemia/reperfusion-induced oxidative stress and thereby attenuating myocardial protein oxidation and preserving mitochondrial respiration function. 相似文献
37.
We present the design, synthesis, anti-HIV-1 and mode of action of neomycin and neamine conjugated at specific sites to arginine 6- and 9-mers D- and L-arginine peptides (APACs). The d-APACs inhibit the infectivity of X4 HIV-1 strains by one or two orders of magnitude more potently than their respective L-APACs. D-arginine conjugates exhibit significantly higher affinity towards CXC chemokine receptor type 4 (CXCR4) than their L-arginine analogs, as determined by their inhibition of monoclonal anti-CXCR4 mAb 12G5 binding to cells and of stromal cell-derived factor 1alpha (SDF-1alpha)/CXCL12 induced cell migration. These results indicate that APACs inhibit X4 HIV-1 cell entry by interacting with CXCR4 residues common to glycoprotein 120 and monoclonal anti-CXCR4 mAb 12G5 binding. D-APACs readily concentrate in the nucleus, whereas the l-APACs do not. 9-mer-D-arginine analogues are more efficient inhibitors than the 6-mer-D-arginine conjugates and the neomycin-D-polymers are better inhibitors than their respective neamine conjugates. This and further structure-function studies of APACs may provide new target(s) and lead compound(s) of more potent HIV-1 cell entry inhibitors. 相似文献
38.
Must A Bandini LG Tybor DJ Phillips SM Naumova EN Dietz WH 《Obesity (Silver Spring, Md.)》2007,15(7):1774-1781
Objective: The impact of activity and inactivity on relative weight and fatness change are best evaluated longitudinally. We examined the longitudinal relationship of physical activity, inactivity, and screen time with relative weight status and percentage body fat (%BF) and explored how it differed by parental overweight status. Research Methods and Procedures: Non‐obese pre‐menarcheal girls (173), 8 to 12 years old, were followed until 4 years post‐menarche. %BF, BMI z‐score, and time spent sleeping, sitting, standing, walking, and in vigorous activity were assessed annually. We developed a physical activity index to reflect time and intensity of activity. Inactivity was defined as the sum of time spent sleeping, sitting, and standing. Screen time was defined as time spent viewing television, videotapes, or playing video games. Parental overweight was defined as at least one parent with BMI > 25. Results: In separate linear mixed effects models, activity, inactivity, and screen time were unrelated to BMI z‐score longitudinally, with and without accounting for parental overweight. After controlling for parental overweight, activity was inversely related (p < 0.001), and inactivity was directly related (p < 0.035) to increased %BF longitudinally. Screen time was unrelated to %BF change. With stratification for parental overweight, effects of activity and inactivity on %BF were observed only among girls with at least one overweight parent. Discussion: In this cohort of initially non‐overweight girls, activity and inactivity were related to accrual of BF over adolescence, particularly among children with at least one overweight parent. These results suggest that girls with a family history of overweight represent a target population of high priority for interventions around physical activity and inactivity. 相似文献
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40.
Kaufmann R Straussberg R Mandel H Fattal-Valevski A Ben-Zeev B Naamati A Shaag A Zenvirt S Konen O Mimouni-Bloch A Dobyns WB Edvardson S Pines O Elpeleg O 《American journal of human genetics》2010,87(5):667-670
Primary microcephaly of postnatal onset is a feature of many neurological disorders, mostly associated with mental retardation, seizures, and spasticity, and it typically carries a grave prognosis. Five infants from four unrelated families of Caucasus Jewish origin presented soon after birth with spasticity, epilepsy, and profound psychomotor retardation. Head circumference percentiles declined, and brain MRI disclosed marked cereberal and cerebellar atrophy with severe myelination defect. A search for a common homozygous region revealed a 2.28 Mb genomic segment on chromosome 11 that encompassed 16 protein-coding genes. A missense mutation in one of them, MED17, segregated with the disease state in the families and was carried by four of 79 anonymous Caucasus Jews. A corresponding mutation in the homologous S.cerevisiae gene SRB4 inactivated the protein, according to complementation assays. Screening of MED17 in additional patients with similar clinical and radiologic findings revealed four more patients, all homozygous for the p.L371P mutation and all originating from Caucasus Jewish families. We conclude that the p. L371P mutation in MED17 is a founder mutation in the Caucasus Jewish community and that homozygosity for this mutation is associated with infantile cerebral and cerebellar atrophy with poor myelination. 相似文献