Background Sparganosis caused by Spirometra erinaceieuropaei spargana is a zoonotic parasitic infection that has been reported in many countries, including China, Japan, Thailand and Korea, as well as European countries and the USA. The biological and clinical significance of the parasite have previously been reported. Although the genomic and transcriptomic analysis of S. erinaceieuropaei provided insightful views about the development and pathogenesis of this species, little knowledge has been acquired in terms of post-translational regulation that is essential for parasite growth, development and reproduction. Here, we performed site-specific phosphoproteomic profiling, with an aim to obtain primary information about the global phosphorylation status of spargana. Results A total of 3228 phosphopeptides and 3461 phosphorylation sites were identified in 1758 spargana proteins. The annotated phosphoproteins were involved in a variety of biological pathways, including cellular (28%), metabolic (20%) and single-organism (17%) processes. The functional enrichment of phosphopeptides by Gene Ontology analysis indicated that most spargana phosphoproteins were related to the cytoskeleton cellular compartment, signaling molecular function, and a variety of biological processes, including a molecular function regulator, guanyl-nucleotide exchange factor activity, protein kinase activities, and calcium ion binding. The highly enriched pathways of phosphorylation proteins include the phosphatidylinositol signaling system, phagosome, endocytosis, inositol phosphate metabolism, terpenoid backbone biosynthesis, and peroxisome. Domain analysis identified an EF-hand domain and pleckstrin homology domain among the key domains. Conclusions To our knowledge, this study performed the first global phosphoproteomic analysis of S. erinaceieuropaei. The dataset reported herein provides a valuable resource for future studies on the signaling pathways of this important zoonotic parasite.
Background Persistent activation of endoplasmic reticulum stress and the unfolded protein response (UPR) induces vascular cell apoptosis, contributing to atherogenesis. Aging and hypercholesterolemia are 2 independent proatherogenic factors. How they affect vascular UPR signaling remains unclear. Methods and Results Transcriptome analysis of aortic tissues from high fat diet–fed and aged ApoE −/− mice revealed 50 overlapping genes enriched for endoplasmic reticulum stress‐ and UPR‐related pathways. Aortae from control, Western diet (WD)–fed, and aged ApoE −/− mice were assayed for (1) 3 branches of UPR signaling (pancreatic ER eIF2‐alpha kinase /alpha subunit of the eukaryotic translation initiation factor 1/activating transcription factor 4, inositol‐requiring enzyme 1 alpha/XBP1s, activating transcription factor 6); (2) UPR‐mediated protective adaptation (upregulation of immunoglobulin heavy chain‐binding protein and protein disulfide isomerase); and (3) UPR‐mediated apoptosis (induction of C/EBP homologous transcription factor, p‐JNK, and cleaved caspase‐3). Aortic UPR signaling was differentially regulated in the aged and WD‐fed groups. Consumption of WD activated all 3 UPR branches; in the aged aorta, only the ATF6α arm was activated, but it was 10 times higher than that in the WD group. BiP and protein disulfide isomerase protein levels were significantly decreased only in the aged aorta despite a 5‐fold increase in their mRNA levels. Importantly, the aortae of aged mice exhibited a substantially enhanced proapoptotic UPR compared with that of WD‐fed mice. In lung tissues, UPR activation and the resultant adaptive/apoptotic responses were not significantly different between the 2 groups. Conclusions Using a mouse model of atherosclerosis, this study provides the first in vivo evidence that aging and an atherogenic diet activate differential aortic UPR pathways, leading to distinct vascular responses. Compared with dietary intervention, aging is associated with impaired endoplasmic reticulum protein folding and increased aortic apoptosis.
Background: Binge drinking has become the most common and deadly pattern of excessive alcohol use in the United States, especially among younger adults. It is closely related to the increased risk of cardiovascular disease. Oxidative stress as a result of ethanol metabolism is the primary pathogenic factor for alcohol-induced end organ injury, but the role of protein S-glutathionylation—a reversible oxidative modification of protein cysteine thiol groups that mediates cellular actions by oxidants—in binge drinking-associated cardiovascular disease has not been explored. The present study defines the effect of alcohol binge drinking on the formation of protein S-glutathionylation in a mouse model of atherosclerosis.Methods and Results: To mimic the weekend binge drinking pattern in humans, ApoE deficient (ApoE−/−) mice on the Lieber-DeCarli liquid diet received ethanol or isocaloric maltose (as a control) gavages (5 g/kg/day, 2 consecutive days/week) for 6 weeks. The primary alcohol-targeted organs (liver, brain), and cardiovascular system (heart, aorta, lung) of these two groups of the mice were determined by measuring the protein S-glutathionylation levels and its regulatory enzymes including [Glutaredoxin1(Grx1), glutathione reductase (GR), glutathione-S-transferase Pi (GST-π)], as well as by assessing aortic endothelial function and liver lipid levels. Our results showed that binge drinking selectively stimulated protein S-glutathionylation in aorta, liver, and brain, which coincided with altered glutathionylation regulatory enzyme expression that is downregulated Grx1 and upregulated GST-π in aorta, massive upregulation of GST-π in liver, and no changes in Grx1 and GST-π in brain. Functionally, binge drinking induced aortic endothelial cell function, as reflected by increased aortic permeability and reduced flow-mediated vasodilation.Conclusions: This study is the first to provide in vivo evidence for differential effects of binge drinking on formation of protein S-glutathionylation and its enzymatic regulation system in major alcohol-target organs and cardiovascular system. The selective induction of protein S-glutathionylation in aorta and liver is associated with aortic endothelial dysfunction and fatty liver, which may be a potential redox mechanism for the increased risk of vascular disease in human binge-drinkers.
It has been known adipocytes increase p53 expression and activity in obesity, however, only canonical p53 functions (i.e. senescence and apoptosis) are attributed to inflammation-associated metabolic phenotypes. Whether or not p53 is directly involved in mature adipocyte metabolic regulation remains unclear. Here we show p53 protein expression can be up-regulated in adipocytes by nutrient starvation without activating cell senescence, apoptosis, or a death-related p53 canonical pathway. Inducing the loss of p53 in mature adipocytes significantly reprograms energy metabolism and this effect is primarily mediated through a AMP-activated protein kinase (AMPK) pathway and a novel downstream transcriptional target, lysosomal acid lipase (LAL). The pathophysiological relevance is further demonstrated in a conditional and adipocyte-specific p53 knockout mouse model. Overall, these data support a non-canonical p53 function in the regulation of adipocyte energy homeostasis and indicate that the dysregulation of this pathway may be involved in developing metabolic dysfunction in obesity.
BACKGROUND: Thoracic aortic aneurysms (TAAs) are abnormal aortic dilatations and a major cardiovascular complication of Marfan syndrome. We previously demonstrated a critical role for vascular smooth muscle (VSM) SirT1 (sirtuin-1), a lysine deacetylase, against maladaptive aortic remodeling associated with chronic oxidative stress and aberrant activation of MMPs (matrix metalloproteinases). METHODS: In this study, we investigated whether redox dysregulation of SirT1 contributed to the pathogenesis of TAA using fibrillin-1 hypomorphic mice (Fbn1 mgR/mgR ), an established model of Marfan syndrome prone to aortic dissection/rupture. RESULTS: Oxidative stress markers 3-nitrotyrosine and 4-hydroxynonenal were significantly elevated in aortas of patients with Marfan syndrome. Moreover, reversible oxidative posttranslational modifications (rOPTM) of protein cysteines, particularly S-glutathionylation, were dramatically increased in aortas of Fbn1 mgR/mgR mice, before induction of severe oxidative stress markers. Fbn1 mgR/mgR aortas and VSM cells exhibited an increase in rOPTM of SirT1, coinciding with the upregulation of acetylated proteins, an index of decreased SirT1 activity, and increased MMP2/9 activity. Mechanistically, we demonstrated that TGFβ (transforming growth factor beta) that was increased in Fbn1 mgR/mgR aortas stimulated rOPTM of SirT1, decreasing its deacetylase activity in VSM cells. VSM cell–specific SirT1-deficient Fbn1 mgR/mgR (SMKO-Fbn1 mgR/mgR ) mice caused a dramatic increase in aortic MMP2 expression and worsened TAA progression, leading to aortic rupture in 50% of SMKO-Fbn1 mgR/mgR mice, compared with 25% of Fbn1 mgR/mgR mice. rOPTM of SirT1, rOPTM-mediated inhibition of SirT1 activity, and increased MMP2/9 activity were all exacerbated by the deletion of Glrx (glutaredoxin-1), a specific deglutathionylation enzyme, while being corrected by overexpression of Glrx or of an oxidation-resistant SirT1 mutant in VSM cells. CONCLUSIONS: Our novel findings strongly suggest a causal role of S-glutathionylation of SirT1 in the pathogenesis of TAA. Prevention or reversal of SirT1 rOPTM may be a novel therapeutic strategy to prevent TAA or TAA dissection/ruptures in individuals with Marfan syndrome, for which, thus far, no targeted therapy has been developed.
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