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Liraglutide dictates macrophage phenotype in apolipoprotein E null mice during early atherosclerosis
Robyn Bruen Sean Curley Sarina Kajani Daniel Crean Marcella E. O’Reilly Margaret B. Lucitt Catherine G. Godson Fiona C. McGillicuddy Orina Belton 《Cardiovascular diabetology》2017,16(1):143
Background
Macrophages play a pivotal role in atherosclerotic plaque development. Recent evidence has suggested the glucagon-like peptide-1 receptor (GLP-1R) agonist, liraglutide, can attenuate pro-inflammatory responses in macrophages. We hypothesized that liraglutide could limit atherosclerosis progression in vivo via modulation of the inflammatory response.Methods
Human THP-1 macrophages and bone marrow-derived macrophages, from both wild-type C57BL/6 (WT) and apolipoprotein E null mice (ApoE?/?) were used to investigate the effect of liraglutide on the inflammatory response in vitro. In parallel, ApoE?/? mice were fed a high-fat (60% calories from fat) high-cholesterol (1%) diet for 8 weeks to induce atherosclerotic disease progression with/without daily 300 μg/kg liraglutide administration for the final 6 weeks. Macrophages were analysed for MΦ1 and MΦ2 macrophage markers by Western blotting, RT-qPCR, ELISA and flow cytometry. Atherosclerotic lesions in aortae from ApoE?/? mice were analysed by en face staining and monocyte and macrophage populations from bone marrow derived cells analysed by flow cytometry.Results
Liraglutide decreased atherosclerotic lesion formation in ApoE?/? mice coincident with a reduction in pro-inflammatory and increased anti-inflammatory monocyte/macrophage populations in vivo. Liraglutide decreased IL-1beta in MΦ0 THP-1 macrophages and bone marrow-derived macrophages from WT mice and induced a significant increase in the MΦ2 surface marker mannose receptor in both MΦ0 and MΦ2 macrophages. Significant reduction in total lesion development was found with once daily 300 μg/kg liraglutide treatment in ApoE?/? mice. Interestingly, liraglutide inhibited disease progression at the iliac bifurcation suggesting that it retards the initiation and development of disease. These results corresponded to attenuated MΦ1 markers (CCR7, IL-6 and TNF-alpha), augmented MΦ2 cell markers (Arg-1, IL-10 and CD163) and finally decreased MΦ1-like monocytes and macrophages from bone marrow-derived cells.Conclusions
This data supports a therapeutic role for liraglutide as an atheroprotective agent via modulating macrophage cell fate towards MΦ2 pro-resolving macrophages.3.
Oxidative stress can induce mitochondrial dysfunction, mitochondrial DNA (mtDNA) depletion, and neurodegeneration, although
the underlying mechanisms are poorly understood. The major mitochondrial antioxidant system that protects cells consists of
manganese superoxide dismutase (MnSOD), glutathione peroxidase (GPx) and glutathione (GSH). To investigate the putative adaptive
changes in antioxidant enzyme protein expression and targeting to mitochondria as mtDNA depletion occurs, we progressively
depleted U87 astrocytoma cells of mtDNA by chronic treatment with ethidium bromide (EB, 50 ng/ml). Cellular MnSOD protein
expression was markedly increased in a time-related manner while that of GPx showed time-related decreases. The mtDNA depletion
also altered targeting or subcellular distribution of GPx, suggesting the importance of intact mtDNA in mitochondrial genome-nuclear
genome signaling/communication. Cellular NADP+-ICDH activity also showed marked, time-related increases while their GSH content decreased. Thus, our findings suggest that
interventions to elevate MnSOD, GPx, NADP+-ICDH, and GSH levels may protect brain cells from oxidative stress. 相似文献
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Temperature Sensitivity of Maltose Utilization and Lambda Resistance in Escherichia coli B 总被引:4,自引:3,他引:1
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Escherichia coli B strains that have acquired the malB region from E. coli K-12 are able to utilize maltose and to adsorb phage lambda when grown at 30 C, but when grown at 40 C they do not absorb phage lambda and are devoid of amylomaltase activity. These Mal(ts) Lam(ts) cells can be mutated or transduced to become able to grow on maltose at 40 C, but they still have no detectable amylomaltase activity nor functional lambda receptors at that temperature. This Mal(40) phenotype is governed by a gene located near or at malA. It is suggested that the temperature sensitivity of both characters results from a defect in malT. However, transduction of malA from E. coli B to E. coli K-12 results in a wild-type phenotype, whereas E. coli B cells that have acquired malA from E. coli K-12 donors are still temperature sensitive for both amylomaltase and lambda-receptor production. 相似文献
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Peroxisome proliferator-activated receptors (PPARs) play roles in neural cells by regulating energy balance, cell proliferation and anti-oxidant responses although the molecular mechanisms underlying such roles are unclear. Chronic exposure to excess manganese (Mn) leads to neurotoxicity, although Mn-induced neurotoxic mechanisms have not been fully elucidated. We hypothesized Mn neurotoxicity differentially alters the expression of PPARs. We investigated the effects of manganese chloride treatment (0.01–4 mM) on protein expression of PPAR isoforms (α, β, and γ) in human astrocytoma (U87) and neuroblastoma (SK-N-SH) cells. The two cell types expressed the 3 PPAR isoforms differentially: their expression of the PPARs was altered by Mn-treatment. Furthermore, nuclear and cytosolic fractions derived from the 2 cell types, with and without Mn-treatment, exhibited marked differences in the protein content of PPARs. Our results constitute the first demonstration that the PPAR signaling pathway may assume pathophysiological importance in Mn neurotoxicity. 相似文献
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Alireza Poursafar Youbert Ghosta Alexandra S. Orina Philipp B. Gannibal Mohammad Javan-Nikkhah Daniel P. Lawrence 《Mycological Progress》2018,17(3):343-356
During the spring and summer of 2014 and 2015, wheat and barley fields in the Iranian provinces of Golestan and Alborz showed a high incidence of symptoms of black (sooty) head mold of wheat and barley. The isolation results revealed that Alternaria was associated with these symptoms. One hundred and forty isolates were collected and morphologically characterized based on the development of conidial chains with primary, secondary, and tertiary branching patterns, consistent with the three-dimensional sporulation complexity of members of Alternaria in sections Infectoriae and Pseudoalternaria. Subsequently, 16 Alternaria isolates exhibiting high morphological diversity were characterized based on extensive morphological and molecular comparisons. Phylogenetic analyses of three loci [ITS, glyceraldehyde 3-phosphate dehydrogenase (gpd), and plasma membrane ATPase (ATPase)] revealed that 15 isolates belonged to section Infectoriae but could not be assigned to phylogenetic species and one isolate represents a new species, Alternaria kordkuyana sp. nov., in section Pseudoalternaria. Morphological assessments revealed a high degree of variation among section Infectoriae isolates and that A. kordkuyana has significant morphological differences as compared to the three other species currently described in section Pseudoalternaria. 相似文献
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Douglas Ngatuni Peninah Wairagu Ngalla Jillani Alfred Orina Isaac James Nyabuga Nyariki 《Saudi Journal of Biological Sciences》2022,29(6):103278
Glyphosate-based herbicides (GBH) are widely used worldwide. Their negative impact on human health is a matter of debate by regulatory bodies and the public. The present study sought to determine the impact of a GBH on the vital organs; and the potential protective effects of vitamin B12 (cyanocobalamin) supplementation. Sixty white Swiss mice were randomly assigned to five treatment groups, each containing twelve mice. Group one represented the normal control; Group two mice were treated with 375 mg/kg of GBH for 56 days; Group three mice received 10 mg/kg of cyanocobalamin for 56 days; Group four mice were administered with 375 mg/kg of GBH and 10 mg/kg cyanocobalamin for 56 days and Group five received 10 mg/kg cyanocobalamin first for 7 days, then continued thereafter co-administered together with 375 mg/kg of GBH for 56 days). Oral administration of GBH induced severe anemia in mice, which was attenuated by cyanocobalamin. Moreover, GBH resulted in a very significant alteration of platelets, WBCs, and its sub-types. Once again, cyanocobalamin stabilized the levels of platelets and WBCs in the presence of GBH. GBH-induced elevation of triglycerides and HDL was nullified by the administration of cyanocobalamin. Further studies showed evidence for GBH-induced inflammation represented by an imbalance in serum levels of the TNF-α: IL-10 and IFN-γ ratios. The GBH severely depleted GSH levels in the liver. A GBH-induced rise in GSH in the kidney, lungs and brain was noted; and is an indicator of antioxidant capacity enhancement in response to a GBH-induced oxidant challenge. Moreover, cyanocobalamin supplementation abrogated GBH-induced oxidative stress as depicted by stabilized GSH levels in the liver, kidney, lungs, and brain. In the presence of cyanocobalamin, the GBH-induced liver injury depicted by elevation of AST, ALT, and bilirubin, was attenuated. From the results, we conclude that the capacity of cyanocobalamin to assuage GBH-induced inflammatory responses, hepatotoxicity, and hematological alteration as well as oxidative stress may be attributable to its antioxidant and anti-inflammatory properties. The current findings provide a solid foundation for further scrutiny of this phenomenon, with vital implications in GBH exposure and the role of potent antioxidant supplementation in the management of GBH-induced toxicity. 相似文献
8.
Ajay Singh Maradumane L. Mohan Alfred Orina Isaac Xiu Luo Jiri Petrak Daniel Vyoral Neena Singh 《PloS one》2009,4(2)
Converging evidence leaves little doubt that a change in the conformation of prion protein (PrPC) from a mainly α-helical to a β-sheet rich PrP-scrapie (PrPSc) form is the main event responsible for prion disease associated neurotoxicity. However, neither the mechanism of toxicity by PrPSc, nor the normal function of PrPC is entirely clear. Recent reports suggest that imbalance of iron homeostasis is a common feature of prion infected cells and mouse models, implicating redox-iron in prion disease pathogenesis. In this report, we provide evidence that PrPC mediates cellular iron uptake and transport, and mutant PrP forms alter cellular iron levels differentially. Using human neuroblastoma cells as models, we demonstrate that over-expression of PrPC increases intra-cellular iron relative to non-transfected controls as indicated by an increase in total cellular iron, the cellular labile iron pool (LIP), and iron content of ferritin. As a result, the levels of iron uptake proteins transferrin (Tf) and transferrin receptor (TfR) are decreased, and expression of iron storage protein ferritin is increased. The positive effect of PrPC on ferritin iron content is enhanced by stimulating PrPC endocytosis, and reversed by cross-linking PrPC on the plasma membrane. Expression of mutant PrP forms lacking the octapeptide-repeats, the membrane anchor, or carrying the pathogenic mutation PrP102L decreases ferritin iron content significantly relative to PrPC expressing cells, but the effect on cellular LIP and levels of Tf, TfR, and ferritin is complex, varying with the mutation. Neither PrPC nor the mutant PrP forms influence the rate or amount of iron released into the medium, suggesting a functional role for PrPC in cellular iron uptake and transport to ferritin, and dysfunction of PrPC as a significant contributing factor of brain iron imbalance in prion disorders. 相似文献
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Olga P. Gavrilova Aleksandra S. Orina Elizaveta D. Kessenikh Lyudmila K. Gustyleva Elena I. Savelieva Nadezhda N. Gogina Tatiana Yu. Gagkaeva 《化学与生物多样性》2020,17(8)
The biological characterization of Microdochium majus, M. nivale, and M. seminicola strains with wide geographical origins showed the diversity of their pathogenic properties and metabolite compounds, allowing them to exist in their habitats. Significant differences in the ability of Microdochium fungi to cause lesions on wheat and oat leaves were found. The intensity of symptoms depended on the species and substrate origin of the strains. On average M. seminicola strains were able to cause less leaf necrosis than M. majus and M. nivale. The volatile organic compound (VOC) profile of Microdochium fungi included 29 putative fungal metabolites. The spectrum of the identified VOCs in M. seminicola strains was much richer than that in M. majus and M. nivale strains. In addition, the strains of M. seminicola emitted at least six sesquiterpenes. Mycotoxin analysis by HPLC/MS/MS revealed that the analyzed Microdochium strains did not produce any toxic metabolites typically produced by filamentous fungi. 相似文献
10.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of arthritis and pain. However, their long-term use is limited by gastrointestinal (GI) side effects such as gastric ulcers. NSAIDs act by inhibiting an enzyme called cyclooxygenase. Cyclooxygenase (COX) catalyses the generation of prostaglandins from arachidonic acid. Two isoforms of the enzyme exist--COX-1 and COX-2--both of which are targets for NSAIDs. Although they are associated with GI toxicity, NSAIDs have important antithrombotic and anti-inflammatory effects. The GI injury has been attributed to COX-1 inhibition and the anti-inflammatory effects to COX-2 inhibition. As COX-2 is traditionally viewed as an inducible enzyme, selective inhibition of COX-2 by 'coxibs' (selective COX-2 inhibitors) has been employed to achieve anti-inflammatory and analgesic effects without GI side effects. However, recently there have been suggestions that chronic administration of coxibs might increase the risk of cardiovascular events, such as atherosclerosis, compared with traditional NSAIDs. In vascular disease, there is increased expression of both COX-1 and COX-2, resulting in enhanced prostaglandin generation. The specific role of COX-1 and COX-2 in vascular regulation is still unknown but such knowledge is essential for the effective use of coxibs. Although more evidence is pointing to selective COX-1 inhibition as a therapeutic measure in inflammatory atherosclerosis, there are some studies that suggest that inhibition of COX-2 might have a potential benefit on atherosclerosis. 相似文献