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  • Age-related abnormalities in regulation of the ryanodine receptor in rat fast-twitch muscle. 8653753

    The tibialis anterior (TA) muscles of 6-month-old and 24-month-old male Wistar rats, after being characterized, at the fast motor unit level, for twitch properties, were dissected and processed by a procedure [Margreth A., Damiani E., Tobaldin G. Biochem Biophys Res Commun 1993; 197: 1303-1311] aimed at obtaining a representative total membrane fraction comprising 70-80% of the total muscle content of sarcoplasmic reticulum (SR) and transverse tubule (TT) membranes (about 20 mg protein/g). Skeletal muscle membranes were analyzed for protein composition, and the content and functional properties of specific components of the free and junctional subcompartments of the SR and of junctional TT. Our results, while confirming a twitch prolongation in TA of old rats, do not demonstrate any associated age-related change concerning: (a) the overall number and functional properties of Ca2+ pumps, as characterized by kinetic parameters, Ca(2+)-dependency, and the protein isoform specificity of SR Ca(2+)-ATPase; (b) the number of functional junctional SR Ca(2+)-release channels, on the basis of Bmax values for high-affinity binding of [3H]-ryanodine to skeletal muscle membranes at optimal Ca2+; (c) the overall muscle dihydropyridine receptor/ryanodine receptor (RyR) ratio. We conclude from these findings, and the additional negative evidence for changes in membrane density of specific components of junctional SR, including 60 kDa Ca(2+)-calmodulin protein kinase, that this membrane domain, like the Ca(2+)-pump domain of the SR, are in no way basically altered at early stages of the aging process, as investigated here. Because of that, we allege particular significance to the occurrence of age-related, specific abnormalities in regulation of RyR in rat TA. The main supportive evidence is as follows: (a) an increased sensitivity to Ca2+ of the RyR of old muscle, and, more importantly; (b) an increased sensitivity to caffeine of [3H]ryanodine binding to the RyR at optimal Ca2+ and also optimal for the activity of the Ca(2+)-release channel. The results reported here also demonstrate that there are two classes of caffeine sites in rat TA muscle, as defined by differences in EC50 values at resting (pCa 7) and at high Ca2+ (pCa 4-5), that sites involved in stimulation of [3H]-ryanodine binding to the RyR are distinguished by a higher affinity (caffeine below mM), and that only these sites undergo age-related changes. Thus, although the underlying age-related abnormality of the RyR remains to be elucidated, it appears to satisfy the requirement for being regarded as a specific change, which in itself might argue for its being fundamentally related to the twitch prolongation of the muscle.
    Tipo de documento:
    Referencia
    Referencia del producto:
    MAB427
    Nombre del producto:
    Anti-Dihydropyridine-sensitive Calcium Channel α 1 Subunit Antibody, clone 1a

  • Physiological properties of cholinergic and non-cholinergic magnocellular neurons in acute slices from adult mouse nucleus basalis. 20548784

    BACKGROUND: The basal forebrain is a series of nuclei that provides cholinergic input to much of the forebrain. The most posterior of these nuclei, nucleus basalis, provides cholinergic drive to neocortex and is involved in arousal and attention. The physiological properties of neurons in anterior basal forebrain nuclei, including medial septum, the diagonal band of Broca and substantia innominata, have been described previously. In contrast the physiological properties of neurons in nucleus basalis, the most posterior nucleus of the basal forebrain, are unknown. METHODOLOGY/PRINCIPAL FINDINGS: Here we investigate the physiological properties of neurons in adult mouse nucleus basalis. We obtained cell-attached and whole-cell recordings from magnocellular neurons in slices from P42-54 mice and compared cholinergic and non-cholinergic neurons, distinguished retrospectively by anti-choline acetyltransferase immunocytochemistry. The majority (70-80%) of cholinergic and non-cholinergic neurons were silent at rest. Spontaneously active cholinergic and non-cholinergic neurons exhibited irregular spiking at 3 Hz and at 0.3 to 13.4 Hz, respectively. Cholinergic neurons had smaller, broader action potentials than non-cholinergic neurons (amplitudes 64+/-3.4 and 75+/-2 mV; half widths 0.52+/-0.04 and 0.33+/-0.02 ms). Cholinergic neurons displayed a more pronounced slow after-hyperpolarization than non-cholinergic neurons (13.3+/-2.2 and 3.6+/-0.5 mV) and were unable to spike at high frequencies during tonic current injection (maximum frequencies of approximately 20 Hz and >120 Hz). CONCLUSIONS/SIGNIFICANCE: Our results indicate that neurons in nucleus basalis share similar physiological properties with neurons in anterior regions of the basal forebrain. Furthermore, cholinergic and non-cholinergic neurons in nucleus basalis can be distinguished by their responses to injected current. To our knowledge, this is the first description of the physiological properties of cholinergic and non-cholinergic neurons in the posterior aspects of the basal forebrain complex and the first study of basal forebrain neurons from the mouse.
    Tipo de documento:
    Referencia
    Referencia del producto:
    AB144P
    Nombre del producto:
    Anti-Choline Acetyltransferase Antibody

  • Antitumor activity of orally bioavailable farnesyltransferase inhibitor, ABT-100, is mediated by antiproliferative, proapoptotic, and antiangiogenic effects in xenograft ... 15837760

    PURPOSE: To evaluate the preclinical pharmacokinetics, antitumor efficacy, and mechanism of action of a novel orally active farnesyltransferase inhibitor, ABT-100. EXPERIMENTAL DESIGN: In vitro sensitivity of a panel of human cell lines was determined using proliferation and clonogenic assays. In vivo efficacy of ABT-100 was evaluated in xenograft models (flank or orthotopic) by assessing angiogenesis, proliferation, and apoptosis in correlation with pharmacokinetics. Efficacy of the racemate of ABT-100 (A-367074) was also compared with R115777 (tipifarnib). RESULTS: ABT-100 inhibited proliferation of cells in vitro carrying oncogenic H-Ras (EJ-1 bladder; IC(50) 2.2 nmol/L), Ki-Ras (DLD-1 colon, MDA-MB-231 breast, HCT-116 colon, and MiaPaCa-2 pancreatic; IC(50) range, 3.8-9.2 nmol/L), and wild-type Ras (PC-3 and DU-145; IC(50), 70 and 818 nmol/L, respectively) as well as clonogenic potential. ABT-100 shows 70% to 80% oral bioavailability in mice. ABT-100 regressed EJ-1 tumors (2-12.5 mg/kg/d s.c., every day for 21 days) and showed significant efficacy in DLD-1, LX-1, MiaPaCa-2, or PC-3 tumor-bearing mice (6.25-50 mg/kg/d s.c. once daily or twice daily orally). A-367074 showed equivalent efficacy to R115777 given at approximately one-fourth the total dose of R115777 for a shorter duration (EJ-1 and LX-1). Antitumor activity was associated with decreased cell proliferation (Ki-67), increased apoptosis (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling), and decreased angiogenesis. A reduction in tumor angiogenic cytokine levels (vascular endothelial growth factor, basic fibroblast growth factor, and interleukin-8) correlated with a reduction in tumor vascularity (CD31). CONCLUSIONS: Overall, ABT-100 has an acceptable pharmacokinetic profile, is well tolerated, and possesses broad-spectrum antitumor activity against a series of xenograft models similar to farnesyltransferase inhibitors in clinical development; therefore, it is an attractive candidate for clinical evaluation.
    Tipo de documento:
    Referencia
    Referencia del producto:
    S7101
    Nombre del producto:
    ApopTag® Plus Peroxidase In Situ Apoptosis Kit

  • Apoptotic index and apoptosis influencing proteins bcl-2, mcl-1, bax and caspases 3, 6 and 8 in pancreatic carcinoma. 9839167

    AIMS: To study the expression of bcl-2, bax and mcl-1 and caspases 3, 6 and 8 and apoptosis in pancreatic carcinoma. METHODS AND RESULTS: Eighty-seven pancreatic carcinomas were studied immunohistochemically with antibodies to bcl-2, mcl-1, bax and caspases 3, 6 and 8. Apoptosis was detected by the TUNEL method. bcl-2 and mcl-1 positivity was observed in 13% and 86% of the cases, while bax was observed in all of them. The bax immunoreactivity was weak in 30% of the tumours. Caspase 3, 6 and 8 immunoreactivity was observed in 80%, 80% and 74% of the cases, respectively. The staining was mainly cytoplasmic and diffuse, but sometimes also fragmented granular (mainly caspase 6) or membrane-associated (mainly caspase 8) staining was seen. The mean apoptotic index in pancreatic carcinomas was 0.69%. The apoptotic index in bcl-2 positive cases was lower (0.35%) than in cases showing no immunoreactivity (0.64%) (P = 0.013). The apoptotic index was higher in tumours with strong bax immunoreactivity (0.70%) than in the other cases (0.34%) (P = 0.002). There was no significant association between the apoptotic index and the expression of mcl-1 or caspases 3, 6 and 8. CONCLUSIONS: Both bcl-2 and bax influence the extent of apoptosis in pancreatic carcinoma. The strong expression of caspases 3, 6 and 8 in pancreatic carcinoma is evidence of the activation of the apoptotic machinery in malignant cells in pancreatic carcinoma and shows that the genes of these proteins are often upregulated in them.
    Tipo de documento:
    Referencia
    Referencia del producto:
    MAB4603
    Nombre del producto:
    Anti-Caspase 3 Antibody, large subunit & proform, clone 3CSP03

  • A lipoprotein receptor cluster IV mutant preferentially binds amyloid-β and regulates its clearance from the mouse brain. 23580652

    Soluble low density lipoprotein receptor-related protein-1 (sLRP1) binds ~70% of amyloid β-peptide (Aβ) in human plasma. In Alzheimer disease (AD) and individuals with mild cognitive impairment converting to AD, plasma sLRP1 levels are reduced and sLRP1 is oxidized, which results in diminished Aβ peripheral binding and higher levels of free Aβ in plasma. Experimental studies have shown that free circulating Aβ re-enters the brain and that sLRP1 and/or its recombinant wild type cluster IV (WT-LRPIV) prevent Aβ from entering the brain. Treatment of Alzheimer APPsw(+/0) mice with WT-LRPIV has been shown to reduce brain Aβ pathology. In addition to Aβ, LRPIV binds multiple ligands. To enhance LRPIV binding for Aβ relative to other LRP1 ligands, we generated a library of LRPIV-derived fragments and full-length LRPIV variants with glycine replacing aspartic acid residues 3394, 3556, and 3674 in the calcium binding sites. Compared with WT-LRPIV, a lead LRPIV-D3674G mutant had 1.6- and 2.7-fold higher binding affinity for Aβ40 and Aβ42 in vitro, respectively, and a lower binding affinity for other LRP1 ligands (e.g. apolipoprotein E2, E3, and E4 (1.3-1.8-fold), tissue plasminogen activator (2.7-fold), matrix metalloproteinase-9 (4.1-fold), and Factor Xa (3.8-fold)). LRPIV-D3674G cleared mouse endogenous brain Aβ40 and Aβ42 25-27% better than WT-LRPIV. A 3-month subcutaneous treatment of APPsw(+/0) mice with LRPIV-D3674G (40 μg/kg/day) reduced Aβ40 and Αβ42 levels in the hippocampus, cortex, and cerebrospinal fluid by 60-80% and improved cerebral blood flow responses and hippocampal function at 9 months of age. Thus, LRPIV-D3674G is an efficient new Aβ clearance therapy.
    Tipo de documento:
    Referencia
    Referencia del producto:
    MAB348
    Nombre del producto:
    Anti-APP A4 Antibody, a.a. 66-81 of APP {NT}, clone 22C11
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