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121.
Raetz CR Garrett TA Reynolds CM Shaw WA Moore JD Smith DC Ribeiro AA Murphy RC Ulevitch RJ Fearns C Reichart D Glass CK Benner C Subramaniam S Harkewicz R Bowers-Gentry RC Buczynski MW Cooper JA Deems RA Dennis EA 《Journal of lipid research》2006,47(5):1097-1111
The LIPID MAPS Consortium (www.lipidmaps.org) is developing comprehensive procedures for identifying all lipids of the macrophage, following activation by endotoxin. The goal is to quantify temporal and spatial changes in lipids that occur with cellular metabolism and to develop bioinformatic approaches that establish dynamic lipid networks. To achieve these aims, an endotoxin of the highest possible analytical specification is crucial. We now report a large-scale preparation of 3-deoxy-D-manno-octulosonic acid (Kdo)(2)-Lipid A, a nearly homogeneous Re lipopolysaccharide (LPS) sub-structure with endotoxin activity equal to LPS. Kdo(2)-Lipid A was extracted from 2 kg cell paste of a heptose-deficient Escherichia coli mutant. It was purified by chromatography on silica, DEAE-cellulose, and C18 reverse-phase resin. Structure and purity were evaluated by electrospray ionization/mass spectrometry, liquid chromatography/mass spectrometry and (1)H-NMR. Its bioactivity was compared with LPS in RAW 264.7 cells and bone marrow macrophages from wild-type and toll-like receptor 4 (TLR-4)-deficient mice. Cytokine and eicosanoid production, in conjunction with gene expression profiling, were employed as readouts. Kdo(2)-Lipid A is comparable to LPS by these criteria. Its activity is reduced by >10(3) in cells from TLR-4-deficient mice. The purity of Kdo(2)-Lipid A should facilitate structural analysis of complexes with receptors like TLR-4/MD2. 相似文献
122.
Amino acid starvation induced autophagic cell death in PC-12 cells: Evidence for activation of caspase-3 but not calpain-1 总被引:2,自引:0,他引:2
Sadasivan S Waghray A Larner SF Dunn WA Hayes RL Wang KK 《Apoptosis : an international journal on programmed cell death》2006,11(9):1573-1582
While the apoptotic and necrotic cell death pathways have been well studied, there lacks a comprehensive understanding of
the molecular events involving autophagic cell death. We examined the potential roles of the apoptosis-linked caspase-3 and
the necrosis/apoptosis-linked calpain-1 after autophagy induction under prolonged amino acid (AA) starvation conditions in
PC-12 cells. Autophagy induction was observed as early as three hours following amino acid withdrawal. Cell death, measured
by lactate dehydrogenase (LDH) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays occurred within
24 h following starvation and was accompanied by an upregulation in caspase-3 activity but not calpain-1. The cell death that
occurred following AA starvation was significantly alleviated by treatment with the autophagy inhibitor 3-methyl adenine but
not with the broad spectrum caspase inhibitors. Thus, this study demonstrates that 3-methyladenine-sensitive autophagic cell
death due to AA starvation in PC-12 cells is mechanistically and biochemically similar to, yet distinct from, classic caspase
dependent apoptosis.
Shankar Sadasivan and Anu Waghray have contributed equally to this work. 相似文献
123.
124.
Hüll M Müksch B Akundi RS Waschbisch A Hoozemans JJ Veerhuis R Fiebich BL 《Neurochemistry international》2006,48(8):663-672
Prostaglandins (PGs) are generated by the enzymatic activity of cyclooxygenase-1 and -2 (COX-1/2) and modulate several functions in the CNS such as the generation of fever, the sleep/wake cycle, and the perception of pain. Moreover, the induction of COX-2 and the generation of PGs has been linked to neuroinflammatory aspects of Alzheimer's disease (AD). Non-steroidal anti-inflammatory drugs (NSAIDs) that block COX enzymatic activity have been shown to reduce the incidence of AD in various epidemiological studies. While several reports investigated the expression of COX-2 in neurons and microglia, expression of COX-2 in astroglial cells has not been investigated in detail. Here we show that amyloid β peptide 25–35 (Aβ25–35) induces COX-2 mRNA and protein synthesis and a subsequent release of prostaglandin E2 (PGE2) in primary midbrain astrocytes. We further demonstrate that protein kinase C (PKC) is involved in Aβ25–35-induced COX-2/PGE2 synthesis. PKC-inhibitors prevent Aβ25–35-induced COX-2 and PGE2 synthesis. Furthermore Aβ25–35 rapidly induces the phosphorylation and enzymatic activation of PKC in primary rat midbrain glial cells and in primary human astrocytes from post mortem tissue. Our data suggest that the PKC isoforms and/or β are most probably involved in Aβ25–35-induced expression of COX-2 in midbrain astrocytes. The potential role of astroglial cells in the phagocytosis of amyloid and the involvement of PGs in this process suggests that a modulation of PGs synthesis may be a putative target in the prevention of amyloid deposition. 相似文献
125.
Exploring the recognition of quadruplex DNA by an engineered Cys2-His2 zinc finger protein 总被引:3,自引:0,他引:3
Ladame S Schouten JA Roldan J Redman JE Neidle S Balasubramanian S 《Biochemistry》2006,45(5):1393-1399
We have recently described an engineered zinc finger protein (Gq1) that binds with high specificity to the intramolecular G-quadruplex formed by the human telomeric sequence 5'-(GGTTAG)(5)-3', and that inhibits the activity of the enzyme telomerase in vitro. Here we report site-directed mutagenesis, biophysical, and molecular modeling studies that provide new insights into quadruplex recognition by the zinc finger scaffold. We show that any one finger of Gq1 can be replaced with the corresponding finger of Zif268, without significant loss of quadruplex affinity or quadruplex versus duplex discrimination. Replacement of two fingers, with one being finger 2, of Gq1 by Zif268 results in significant impairment of quadruplex recognition and loss of discrimination. Molecular modeling suggests that the zinc fingers of Gq1 can bind to the human parallel-stranded quadruplex structure in a stable arrangement, whereas Zif268-quadruplex models show significantly weaker binding energy. Modeling also suggests that an important role of the key protein finger residues in the Gq1-quadruplex complex is to maintain Gq1 in an optimum conformation for quadruplex recognition. 相似文献
126.
Jagadeesh S Padma T Parimala H Chandramouli KH D'Souza CJ Thimmaiah KN 《Biochemical and biophysical research communications》2006,342(3):690-701
Phenoxazine derivatives were examined for their ability to inhibit the calmodulin-mediated activation of phosphodiesterase, which is based on the hydrolysis of cAMP to AMP by phosphodiesterase in the presence or absence of inhibitor, followed by quantitative analysis by HPLC method. Anticalmodulin activity of phenoxazines with respect to substitution at C-2 position follows the order: 2-trifluoromethyl>2-chloro>unsubstituted phenoxazines. The interaction of phenoxazines with calmodulin using fluorescence spectroscopy has been performed. Binding study showed that calmodulin has two types of binding sites for phenoxazines. One is high affinity binding site (Kd value 0.07-0.46 microM) and the other, a low affinity binding site (Kd value 0.7-34.5 microM). The change in secondary structure of calmodulin upon binding to phenoxazines was studied by circular dichroism (CD) method, which showed that the percentage of helicity decreased with an extensive change in tertiary structure of calmodulin. Kinetic analysis of the phenoxazine-calmodulin interaction showed that phenoxazines competitively inhibited the activation of phosphodiesterase without affecting Vmax. Thus, these studies showed a good correlation between the ability of phenoxazines to block the activation of phosphodiesterase and their ability to bind to the activator. 相似文献
127.
doi: 10.1111/j.1741‐2358.2011.00610.x The effect of osteoporosis on residual ridge resorption and masticatory performance in denture wearers Aim: To compare masticatory performance, masticatory efficiency and residual ridge resorption (RRR) in osteoporotic and non‐osteoporotic edentulous subjects after rehabilitation with complete dentures. Method: Thirty subjects fulfilling the inclusion criteria were enrolled from the patients visiting the Department of Prosthodontics for complete denture fabrication. Two groups consisting of control subjects (group I; N = 15) and osteoporotic subjects (group II; N = 15) were formed. Complete dentures satisfying certain criteria were fabricated for both groups. Masticatory performance and efficiency were measured 6 months after denture insertion. Areal measurements were taken on lateral cephalograms before and 6 months after denture fabrication. The data were then computed to analyse differences between groups I and II using SPSS statistical software version 15.0. Results: Six months after denture fabrication, the masticatory performance and efficiency were significantly higher (p < 0.001) for group I, with a significant decrease in maxillary and mandibular sagittal area seen in both groups. The rate of bone loss was more in group II compared with group I. Conclusion: Greater masticatory function was demonstrated by the non‐osteoporotic group, and the rate of RRR was more in the osteoporotic group compared with the normal group. In this pilot study, osteoporosis leads to greater RRR, decreased masticatory performance and efficiency in edentulous subjects 6 months after denture insertion. Screening for osteoporosis is suggested as a routine procedure for all edentulous subjects undergoing rehabilitation. Recall check‐ups for osteoporotic patients should be more frequent, and these patients may require more frequent denture remakes. 相似文献
128.
Plant based medicines have gained popularity worldwide due to their almost negligible side effects. In India, the three traditional medicinal systems, namely homeopathy, Ayurveda and Siddha rely heavily on plants for medicinal formulations. To prevent the indiscriminate collection of these valuable medicinal plants and for their proper authentication and conservation, it is imperative to go for sustained efforts towards proper germplasm cataloguing and devising conservation strategies. For this purpose, molecular markers have a significant role, as they provide information ranging from diversity at nucleotide level (single nucleotide polymorphisms) to gene and allele frequencies (genotype information), the extent and distribution of genetic diversity, and population structure. Over the past twenty years, the molecular marker field has completely transformed the meaning of conservation genetics which has emerged from a theory-based field of population biology to a full-fledged pragmatic discipline. In this review, we have explored the transition and transformation of molecular marker technologies throughout these years. 相似文献
129.
Role of autophagy in angiogenesis in aortic endothelial cells 总被引:1,自引:0,他引:1
Du J Teng RJ Guan T Eis A Kaul S Konduri GG Shi Y 《American journal of physiology. Cell physiology》2012,302(2):C383-C391
Angiogenesis plays critical roles in the recovery phase of ischemic heart disease and peripheral vascular disease. An increase in autophagy is protective under hypoxic and chronic ischemic conditions. In the present study we determined the role of autophagy in angiogenesis. 3-Methyladenine (3-MA) and small interfering RNA (siRNA) against ATG5 were used to inhibit autophagy induced by nutrient deprivation of cultured bovine aortic endothelial cells (BAECs). Assays of BAECs tube formation and cell migration revealed that inhibition of autophagy by 3-MA or siRNA against ATG5 reduced angiogenesis. In contrast, induction of autophagy by overexpression of ATG5 increased BAECs tube formation and migration. Additionally, inhibiting autophagy impaired vascular endothelial growth factor (VEGF)-induced angiogenesis. However, inhibition of autophagy did not alter the expression of pro-angiogenesis factors such as VEGF, platelet-derived growth factor, or integrin αV. Furthermore, autophagy increased reactive oxygen species (ROS) formation and activated AKT phosphorylation. Inhibition of autophagy significantly decreased the production of ROS and activation of AKT but not of extracellular regulated kinase, whereas overexpression of ATG5 increased cellular ROS production and AKT activation in BAECs. Inhibition of AKT activation or ROS production significantly decreased the tube formation induced by ATG5 overexpression. Here we report a novel observation that autophagy plays an important role in angiogenesis in BAECs. Induction of autophagy promotes angiogenesis while inhibition of autophagy suppresses angiogenesis, including VEGF-induced angiogenesis. ROS production and AKT activation might be important mechanisms for mediating angiogenesis induced by autophagy. Our findings indicate that targeting autophagy may provide an important new tool for treating cardiovascular disease. 相似文献
130.
Hristov KL Chen M Soder RP Parajuli SP Cheng Q Kellett WF Petkov GV 《American journal of physiology. Cell physiology》2012,302(2):C360-C372
Voltage-gated K(+) (K(V)) channels are implicated in detrusor smooth muscle (DSM) function. However, little is known about the functional role of the heterotetrameric K(V) channels in DSM. In this report, we provide molecular, electrophysiological, and functional evidence for the presence of K(V)2.1 and electrically silent K(V) channel subunits in guinea pig DSM. Stromatoxin-1 (ScTx1), a selective inhibitor of the homotetrameric K(V)2.1, K(V)2.2, and K(V)4.2 as well as the heterotetrameric K(V)2.1/6.3 and K(V)2.1/9.3 channels, was used to examine the role of these K(V) channels in DSM function. RT-PCR indicated mRNA expression of K(V)2.1, K(V)6.2-6.3, K(V)8.2, and K(V)9.1-9.3 subunits in isolated DSM cells. K(V)2.1 protein expression was confirmed by Western blot and immunocytochemistry. Perforated whole cell patch-clamp experiments revealed that ScTx1 (100 nM) inhibited the amplitude of the K(V) current in freshly isolated DSM cells. ScTx1 (100 nM) did not significantly change the steady-state activation and inactivation curves for K(V) current. However, ScTx1 (100 nM) decreased the activation time-constant of the K(V) current at positive voltages. Although our patch-clamp data could not exclude the presence of the homotetrameric K(V)2.1 channels, the biophysical characteristics of the ScTx1-sensitive current were consistent with the presence of heterotetrameric K(V)2.1/silent K(V) channels. Current-clamp recordings showed that ScTx1 (100 nM) did not change the DSM cell resting membrane potential. ScTx1 (100 nM) increased the spontaneous phasic contraction amplitude, muscle force, and muscle tone as well as the amplitude of the electrical field stimulation-induced contractions of isolated DSM strips. Collectively, our data revealed that K(V)2.1-containing channels are important physiological regulators of guinea pig DSM excitability and contractility. 相似文献