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31.
Lee SY Kim JR Hu Y Khan R Kim SJ Bharadwaj KG Davidson MM Choi CS Shin KO Lee YM Park WJ Park IS Jiang XC Goldberg IJ Park TS 《The Journal of biological chemistry》2012,287(22):18429-18439
The role of serine palmitoyltransferase (SPT) and de novo ceramide biosynthesis in cardiac ceramide and sphingomyelin metabolism is unclear. To determine whether the de novo synthetic pathways, rather than ceramide uptake from circulating lipoproteins, is important for heart ceramide levels, we created cardiomyocyte-specific deficiency of Sptlc2, a subunit of SPT. Heart-specific Sptlc2-deficient (hSptlc2 KO) mice had a >35% reduction in ceramide, which was limited to C18:0 and very long chain ceramides. Sphingomyelinase expression, and levels of sphingomyelin and diacylglycerol were unchanged. But surprisingly phospholipids and acyl CoAs contained increased saturated long chain fatty acids. hSptlc2 KO mice had decreased fractional shortening and thinning of the cardiac wall. While the genes regulating glucose and fatty acid metabolism were not changed, expression of cardiac failure markers and the genes involved in the formation of extracellular matrices were up-regulated in hSptlc2 KO hearts. In addition, ER-stress markers were up-regulated leading to increased apoptosis. These results suggest that Sptlc2-mediated de novo ceramide synthesis is an essential source of C18:0 and very long chain, but not of shorter chain, ceramides in the heart. Changes in heart lipids other than ceramide levels lead to cardiac toxicity. 相似文献
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33.
Guntur KV Velasquez D Chadwell L Carroll C Weintraub S Cassill JA Renthal R 《Archives of insect biochemistry and physiology》2004,57(3):101-110
Antennal proteins of the male fire ant (Solenopsis invicta) were analyzed by two-dimensional gel electrophoresis, with the objective of identifying pheromone-binding proteins, which have not previously been found in ant antennae. The major low-molecular weight protein found in the male fire ant antenna was subjected to Edman degradation to determine the N-terminal amino acid sequence. Degenerate PCR primers based on this sequence were used to obtain a cDNA sequence corresponding to the full-length protein sequence. In-gel trypsin digestion followed by MALDI-TOF mass spectrometry and HPLC-ESI/MS/MS demonstrated that the protein gel spot contained only the protein corresponding to the cDNA sequence obtained by PCR. The sequence is similar to apolipophorin-III, an exchangeable lipid-binding protein. Fire ant apolipophorin-III is expressed in the antenna as well as the head, thorax and abdomen. 相似文献
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35.
Irene Zagol-Ikapite Iberia R. Sosa Denise Oram Audra Judd Kalyani Amarnath Venkataraman Amarnath Donald Stec John A. Oates Olivier Boutaud 《Journal of lipid research》2015,56(11):2196-2205
The thromboxane synthase converts prostaglandin H2 to thromboxane A2 and malondialdehyde (MDA) in approximately equimolar amounts. A reactive dicarbonyl, MDA forms covalent adducts of amino groups, including the ε-amine of lysine, but the importance of this reaction in platelets was unknown. Utilizing a novel LC/MS/MS method for analysis of one of the MDA adducts, the dilysyl-MDA cross-link, we demonstrated that dilysyl-MDA cross-links in human platelets are formed following platelet activation via the cyclooxygenase (COX)-1/thromboxane synthase pathway. Salicylamine and analogs of salicylamine were shown to react with MDA preferentially, thereby preventing formation of lysine adducts. Dilysyl-MDA cross-links were measured in two diseases known to be associated with increased platelet activation. Levels of platelet dilysyl-MDA cross-links were increased by 2-fold in metabolic syndrome relative to healthy subjects, and by 1.9-fold in sickle cell disease (SCD). In patients with SCD, the reduction of platelet dilysyl-MDA cross-links following administration of nonsteroidal anti-inflammatory drug provided evidence that MDA modifications of platelet proteins in this disease are derived from the COX pathway. In summary, MDA adducts of platelet proteins that cross-link lysines are formed on platelet activation and are increased in diseases associated with platelet activation. These protein modifications can be prevented by salicylamine-related scavengers. 相似文献
36.
Sapna Pandey Kalyani Dhusia Pramod Katara Satendra Singh 《Journal of biomolecular structure & dynamics》2020,38(14):4259-4272
Abstract Mutation in two genes deglycase gene (DJ-1) and retromer complex component gene (VPS35) are linked with neurodegenerative disorder such as Parkinson's disease, Huntington's disease, and Alzheimer's disease. DJ-1 gene located at 1p36 chromosomal position and involved in PD pathogenesis through many pathways including mitochondrial dysfunction and oxidative injury. VPS35 gene located at 16q13-q21 chromosomal position and the two pathways, the Wnt signaling pathway, and retromer-mediated DMT1 missorting are proposed for basis of VPS35 related PD. The study focuses on identifying most deleterious SNPs through computational analysis. Result obtained from various bioinformatics tools shows that D149A is most deleterious in DJ-1 and A54W, R365H, and V717M are most deleterious in VPS35. To understand the functionality of protein comparative modeling of DJ-1 and VPS35 native and mutants was done by MODELLER. The generated structures are validated by two web servers–ProSa and RAMPAGE. Molecular dynamic simulation (MDS) analysis done for the most validated structures to know the functional and structural nature of native and mutants protein of DJ-1 and VPS35. Native structure of DJ-1 and VPS35 show more flexibility through MDS analysis. DJ-1 D149A mutant structures become more compact which shows the structural perturbation and loss of DJ-1 protein function which in turn are probable cause for PD. A54W, R365H, and V717M mutant protein of VPS35 also shows compactness which cause structure perturbation and absence of retromer function which likely to be linked to PD pathogenesis. This in silico study may provide a new insight for fundamental molecular mechanism involved in Parkinson’s disease. Communicated by Ramaswamy H. Sarma 相似文献
37.
Min-Kyoo Shin Edwin Vázquez-Rosa Yeojung Koh Matasha Dhar Kalyani Chaubey Coral J. Cintrón-Pérez Sarah Barker Emiko Miller Kathryn Franke Maria F. Noterman Divya Seth Rachael S. Allen Cara T. Motz Sriganesh Ramachandra Rao Lara A. Skelton Machelle T. Pardue Steven J. Fliesler Chao Wang Andrew A. Pieper 《Cell》2021,184(10):2715-2732.e23
38.
Lipid aldehydes generated by lipid peroxidation induce cell damage and inflammation. Recent evidence indicates that γ-ketoaldehydes (isolevuglandins, IsoLGs) form inflammatory mediators by modifying the ethanolamine headgroup of phosphatidylethanolamines (PEs). To determine if other species of aldehyde-modified PEs (al-PEs) with inflammatory bioactivity were generated by lipid peroxidation, we oxidized liposomes containing arachidonic acid and characterized the resulting products. We detected PE modified by IsoLGs, malondialdehyde (MDA), and 4-hydroxynonenal (HNE), as well as a novel series of N-acyl-PEs and N-carboxyacyl-PEs in these oxidized liposomes. These al-PEs were also detected in high-density lipoproteins exposed to myeloperoxidase. When we tested the ability of al-PEs to induce THP-1 monocyte adhesion to cultured endothelial cells, we found that PEs modified by MDA, HNE, and 4-oxononenal induced adhesion with potencies similar to those of PEs modified by IsoLGs (~2μM). A commercially available medium-chain N-carboxyacyl-PE (C11:0CAPE) also stimulated adhesion, whereas C4:0CAPE and N-acyl-PEs did not. PEs modified by acrolein or by glucose were only partial agonists for adhesion. These studies indicate that lipid peroxidation generates a large family of al-PEs, many of which have the potential to drive inflammation. 相似文献
39.
Chen Q Bryant VC Lopez H Kelly DL Luo X Natarajan A 《Bioorganic & medicinal chemistry letters》2011,21(7):1929-1932
The quinoxaline core is considered a privileged scaffold as it is found in a variety of biologically relevant molecules. Here we report the synthesis of a quinoxalin-6-amine library, screening against a panel of cancer cell lines and a structure-activity relationship (SAR). This resulted in the identification of a bisfuranylquinoxalineurea analog (7c) that has low micromolar potency against the panel of cancer cell lines. We also show that cells treated with quinoxalineurea 7c results in caspase 3/7 activation, PARP cleavage and Mcl-1 dependent apoptosis. 相似文献
40.
Shimano M Ouchi N Nakamura K Oshima Y Higuchi A Pimentel DR Panse KD Lara-Pezzi E Lee SJ Sam F Walsh K 《The Journal of biological chemistry》2011,286(11):9840-9848
Transforming growth factor-β family cytokines have diverse actions in the maintenance of cardiac homeostasis. Follistatin-like 3 (Fstl3) is an extracellular regulator of certain TGF-β family members, including activin A. The aim of this study was to examine the role of Fstl3 in cardiac hypertrophy. Cardiac myocyte-specific Fstl3 knock-out (KO) mice and control mice were subjected to pressure overload induced by transverse aortic constriction (TAC). Cardiac hypertrophy was assessed by echocardiography and histological and biochemical methods. KO mice showed reduced cardiac hypertrophy, pulmonary congestion, concentric LV wall thickness, LV dilatation, and LV systolic dysfunction after TAC compared with control mice. KO mice displayed attenuated increases in cardiomyocyte cell surface area and interstitial fibrosis following pressure overload. Although activin A was similarly up-regulated in KO and control mice after TAC, a significant increase in Smad2 phosphorylation only occurred in KO mice. Knockdown of Fstl3 in cultured cardiomyocytes inhibited PE-induced cardiac hypertrophy. Conversely, adenovirus-mediated Fstl3 overexpression blocked the inhibitory action of activin A on hypertrophy and Smad2 activation. Transduction with Smad7, a negative regulator of Smad2 signaling, blocked the antihypertrophic actions of activin A stimulation or Fstl3 ablation. These findings identify Fstl3 as a stress-induced regulator of hypertrophy that controls myocyte size via regulation of Smad signaling. 相似文献