scholarly journals Inhibition of IL-6 in the LCWE Mouse Model of Kawasaki Disease Inhibits Acute Phase Reactant Serum Amyloid A but Fails to Attenuate Vasculitis

2021 ◽  
Vol 12 ◽  
Author(s):  
Rebecca A. Porritt ◽  
Carol Chase Huizar ◽  
Edward J. Dick ◽  
Shyamesh Kumar ◽  
Renee Escalona ◽  
...  
Keyword(s):  
Kawasaki Disease ◽  
Mouse Model ◽  
Cardiac Tissue ◽  
Serum Levels ◽  
Acute Phase Reactant ◽  
Mass Spectrometry Analysis ◽  
Disease Development ◽  
Spectrometry Analysis ◽  
Amyloid A ◽  
Anakinra Treatment

ObjectiveKawasaki disease (KD) is the most common cause of acquired pediatric heart disease in the developed world. 10% of KD patients are resistant to front-line therapy, and no interventions exist to address secondary complications such as myocardial fibrosis. We sought to identify proteins and pathways associated with disease and anti-IL-1 treatment in a mouse model of KD.MethodsVasculitis was induced via Lactobacillus casei cell wall extract (LCWE) injection in 5-week-old male mice. Groups of mice were injected with LCWE alone, LCWE and IL-1 receptor antagonist anakinra, or saline for controls. Upper heart tissue was assessed by quantitative mass spectrometry analysis. Expression and activation of STAT3 was assessed by immunohistochemistry, immunofluorescence and Western blot, and IL-6 expression by RNA-seq and ELISA. A STAT3 small molecular inhibitor and anti-IL-6R antibody were used to evaluate the role of STAT3 and IL-6 in disease development.ResultsSTAT3 was highly expressed and phosphorylated in cardiac tissue of LCWE-injected mice, and reduced following anakinra treatment. Il6 and Stat3 gene expression was enhanced in abdominal aorta of LCWE-injected mice and reduced with Anakinra treatment. IL-6 serum levels were enhanced in LCWE-injected mice and normalized by anakinra. However, neither inhibition of STAT3 nor blockade of IL-6 altered disease development.ConclusionProteomic analysis of cardiac tissues demonstrates differential protein expression between KD-like, control and anakinra treated cardiac tissue. STAT3 and IL-6 were highly upregulated with LCWE and normalized by anakinra treatment. However, both STAT3 and IL-6 were dispensable for disease development indicating they may be bystanders of inflammation.

scholarly journals RasGRP1 (CalDAG-GEF-II) Mediates L-DOPA-induced Dyskinesia in a Mouse Model of Parkinson Disease

2019 ◽  
Author(s):  
Mehdi Ishragi ◽  
Uri Nimrod Ramirez Jarquin ◽  
Neelam Shahani ◽  
Supriya Swarnkar ◽  
Nicole Galli ◽  
...  
Keyword(s):  
Mouse Model ◽  
Parkinson Disease ◽  
Molecular Mechanisms ◽  
Mammalian Target Of Rapamycin ◽  
Mass Spectrometry Analysis ◽  
Spectrometry Analysis ◽  
Therapeutic Benefits ◽  
Or Gene ◽  
Pka Pathway

ABSTRACTThe therapeutic benefits of L–3,4–dihydroxyphenylalanine (L-DOPA) in Parkinson disease (PD) patients diminishes with the onset of abnormal involuntary movements (L-DOPA induced dyskinesia), a debilitating motor side effect. L-DOPA induced dyskinesia are due to altered dopaminergic signaling in the striatum, a brain region that controls motor and cognitive functions. However, the molecular mechanisms that promote L-DOPA-induced dyskinesia remain unclear. Here, we have reported that RasGRP1 (also known as CalDAG-GEF-II) physiologically mediated L-DOPA induced dyskinesia in a 6-hydroxy dopamine (6-OHDA) lesioned mouse model of PD. In this study, L-DOPA treatment rapidly upregulated RasGRP1 in the striatum. Our findings showed that RasGRP1 deleted mice (RasGRP1−/−) had drastically diminished L-DOPA-induced dyskinesia, andRasGRP1−/−mice did not interfere with the therapeutic benefits of L-DOPA. In terms of its mechanism, RasGRP1 mediates L-DOPA-induced extracellular regulated kinase (ERK), the mammalian target of rapamycin kinase (mTOR) and the cAMP/PKA pathway and binds directly with Ras-homolog-enriched in the brain (Rheb), which is a potent activator of mTOR, both in vitro and in the intact striatum. High-resolution tandem mass tag mass spectrometry analysis of striatal tissue revealed significant targets, such as phosphodiesterase (Pde1c), Pde2a, catechol-o-methyltransferase (comt), and glutamate decarboxylase 1 and 2 (Gad1 and Gad2), which are downstream regulators of RasGRP1 and are linked to L-DOPA-induced dyskinesia vulnerability. Collectively, the findings of this study demonstrated that RasGRP1 is a major regulator of L-DOPA-induced dyskinesia in the striatum. Drugs or gene-depletion strategies targeting RasGRP1 may offer novel therapeutic opportunities for preventing L-DOPA-induced dyskinesia in PD patients.

scholarly journals Per- and polyfluoroalkyl substances (PFASs) in Swedish household dust and exposure of pet cats

2021 ◽  
Author(s):  
Jana M. Weiss ◽  
Bernt Jones ◽  
Jacco Koekkoek ◽  
Anders Bignert ◽  
Marja H. Lamoree
Keyword(s):  
Thyroid Hormone ◽  
Solid Phase ◽  
Serum Levels ◽  
Mass Spectrometry Analysis ◽  
Household Dust ◽  
Serum Samples ◽  
Spectrometry Analysis ◽  
Exposure Pathway ◽  
Wide Range ◽  
Polyfluoroalkyl Substances

AbstractPer- and polyfluoroalkyl substances (PFASs) are used in a wide range of products and have been found ubiquitously in our indoor environment, and there is evidence that exposure to PFAS can lead to adverse endocrine effects, such as thyroid hormone disruption. Pet cats have a high dust intake due to their grooming behavior and have been shown to be a suitable sentinel species for assessment of toddler’s exposure. Here we used paired household dust (n=46) and cat serum (n=27) samples to establish whether dust is a relevant exposure pathway to PFASs. An analytical method for PFAS analysis was optimized using a low volume of cat serum samples, combining solid-phase extraction and online sample cleanup. Dust was extracted with methanol by sonication and cleaned up by addition of active carbon. In total, 27 PFASs were analyzed by liquid chromatography/mass spectrometry analysis. The correlation between PFAS levels in dust and serum, serum lipids and thyroid hormone levels, and PFAS levels in dust between different rooms were statistically evaluated. PFOS and PFDA could be quantified in all cat serum samples (median 2300 pg/mL and 430 pg/mL, respectively), followed by PFOA (median 1100 pg/mL), quantified in 96% of the samples. The levels of 6:2 and 8:2 diPAPs were determined in 65% and 92% of the serum samples, respectively, and were an order of magnitude lower (1.4–160 pg/mL). Household dust on the other hand was dominated by 6:2 and 8:2 diPAPs, with a median of 65 ng/g dust and 49 ng/g dust, respectively. PFOS (median 13 ng/g dust) and PFOA (median 9 ng/g dust) were quantified in 93% of the dust samples. Only eight PFASs were detected (>LOD) in at least 50% of the samples of both matrices and could be paired. Significant correlations between cat serum and dust were found for PFOA (rS=0.32, p<0.049) and PFUnDA (rS=0.55, p<0.001). Significant positive correlations were found between serum total thyroxine (rS=0.11, p<0.05) and PFNA and between serum cholesterol and PFHpA (rS=0.46, p<0.01), PFUnDA (rS=0.40, p<0.05), PFDoDA (rS=0.44, p<0.01), and sum PFAS (rS=0.48, p<0.01). In conclusion, this study confirmed that dust is a relevant exposure pathway for the ingestion of some PFASs for cats, and the serum levels of PFASs could be of relevance for the cat’s health.

scholarly journals Prognostic accuracy of MALDI-TOF mass spectrometric analysis of plasma in COVID-19

2021 ◽  
Vol 4 (8) ◽  
pp. e202000946
Author(s):  
Lucas Cardoso Lazari ◽  
Fabio De Rose Ghilardi ◽  
Livia Rosa-Fernandes ◽  
Diego M Assis ◽  
José Carlos Nicolau ◽  
...  
Keyword(s):  
Viral Infections ◽  
Low Risk ◽  
Mass Spectrometry Analysis ◽  
Spectrometric Analysis ◽  
Ionization Mass ◽  
Health Crisis ◽  
Spectrometry Analysis ◽  
Amyloid A ◽  
Maldi Tof ◽  
Prognostic Accuracy

SARS-CoV-2 infection poses a global health crisis. In parallel with the ongoing world effort to identify therapeutic solutions, there is a critical need for improvement in the prognosis of COVID-19. Here, we report plasma proteome fingerprinting that predict high (hospitalized) and low-risk (outpatients) cases of COVID-19 identified by a platform that combines machine learning with matrix-assisted laser desorption ionization mass spectrometry analysis. Sample preparation, MS, and data analysis parameters were optimized to achieve an overall accuracy of 92%, sensitivity of 93%, and specificity of 92% in dataset without feature selection. We identified two distinct regions in the MALDI-TOF profile belonging to the same proteoforms. A combination of SDS–PAGE and quantitative bottom-up proteomic analysis allowed the identification of intact and truncated forms of serum amyloid A-1 and A-2 proteins, both already described as biomarkers for viral infections in the acute phase. Unbiased discrimination of high- and low-risk COVID-19 patients using a technology that is currently in clinical use may have a prompt application in the noninvasive prognosis of COVID-19. Further validation will consolidate its clinical utility.

scholarly journals Relationship Between the Gastrointestinal Side Effects of an Anti-Hypertensive Medication and Changes in the Serum Lipid Metabolome

Nutrients ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 205 ◽  
Author(s):  
Yoomin Ahn ◽  
Myung Hee Nam ◽  
Eungbin Kim
Keyword(s):  
Serum Levels ◽  
Ultra Performance Liquid Chromatography ◽  
Mass Spectrometry Analysis ◽  
Control Group ◽  
Double Bonds ◽  
Spectrometry Analysis ◽  
Beneficial Effects ◽  
Large Numbers ◽  
Gastrointestinal Side Effects ◽  
Group Serum

An earlier study using a rat model system indicated that the active ingredients contained in the anti-hypertensive medication amlodipine (AMD) appeared to induce various bowel problems, including constipation and inflammation. A probiotic blend was found to alleviate intestinal complications caused by the medicine. To gain more extensive insight into the beneficial effects of the probiotic blend, we investigated the changes in metabolite levels using a non-targeted metabolic approach with ultra-performance liquid chromatography-quadrupole/time-of-fligh (UPLC-q/TOF) mass spectrometry. Analysis of lipid metabolites revealed that rats that received AMD had a different metabolome profile compared with control rats and rats that received AMD plus the probiotic blend. In the AMD-administered group, serum levels of phosphatidylcholines, lysophosphatidylcholines, sphingomyelins, triglycerides with large numbers of double bonds, cholesterols, sterol derivatives, and cholesterol esters (all p < 0.05) were increased compared with those of the control group and the group that received AMD plus the probiotic blend. The AMD-administered group also exhibited significantly decreased levels of triglycerides with small numbers of double bonds (all p < 0.05). These results support our hypothesis that AMD-induced compositional changes in the gut microbiota are a causal factor in inflammation.

scholarly journals Proteolytic Potential of the MSC Exosome Proteome: Implications for an Exosome-Mediated Delivery of Therapeutic Proteasome

2012 ◽  
Vol 2012 ◽  
pp. 1-14 ◽  
Author(s):  
Ruenn Chai Lai ◽  
Soon Sim Tan ◽  
Bao Ju Teh ◽  
Siu Kwan Sze ◽  
Fatih Arslan ◽  
...  
Keyword(s):  
Mouse Model ◽  
Therapeutic Efficacy ◽  
Ischemia Reperfusion ◽  
Membrane Vesicle ◽  
Mass Spectrometry Analysis ◽  
20S Proteasome ◽  
Paracrine Factors ◽  
Spectrometry Analysis ◽  
H9c2 Cardiomyocytes ◽  
Myocardial Ischemia Reperfusion

Mesenchymal stem cells (MSCs) are used in many of the current stem cell-based clinical trials and their therapeutic efficacy has increasingly been attributed to secretion of paracrine factors. We have previously demonstrated that a therapeutic constituent of this secretion is exosome, a secreted bilipid membrane vesicle of ~50–100 nm with a complex cargo that is readily internalized by H9C2 cardiomyocytes. It reduces infarct size in a mouse model of myocardial ischemia/reperfusion (MI/R) injury. We postulate that this therapeutic efficacy is derived from the synergy of a select permutation of individual exosome components. To identify protein candidates in this permutation, the proteome was profiled and here we identified 20S proteasome as a protein candidate. Mass spectrometry analysis detected all seven α and seven β chains of the 20S proteasome, and also the three beta subunits of “immunoproteasome” with a very high confidence level. We demonstrated that a functional proteasome copurified with MSC exosomes with a density of 1.10–1.18 g/mL, and its presence correlated with a modest but significant reduction in oligomerized protein in a mouse model of myocardial infarction. Circulating proteasomes in human blood also copurified with exosomes. Therefore, 20S proteasome is a candidate exosome protein that could synergize with other constituents to ameliorate tissue damage.

Spectrophotometry Measurement of Polynuclear Aromatic Hydrocarbons in Hamilton Harbour Sediments

1991 ◽  
Vol 26 (1) ◽  
pp. 1-16 ◽  
Author(s):  
T.P. Murphy ◽  
H. Brouwer ◽  
M.E. Fox ◽  
E. Nagy
Keyword(s):  
Aromatic Hydrocarbons ◽  
Total Concentration ◽  
Coal Tar ◽  
Sediment Cores ◽  
Polynuclear Aromatic Hydrocarbons ◽  
Mass Spectrometry Analysis ◽  
Gas Chromatography Mass Spectrometry ◽  
Near Surface ◽  
Spectrometry Analysis ◽  
Hamilton Harbour

Abstract Eighty-one sediment cores were collected to determine the extent of coal tar contamination in a toxic area of Hamilton Harbour. Over 800 samples were analyzed by a UV spectrophotometric technique that was standardized with gas chromatography/mass spectrometry analysis. The coal tar distribution was variable. The highest concentrations were near the Stelco outfalls and the Hamilton-Wentworth combined sewer outfalls. The total concentration of the 16 polynuclear aromatic hydrocarbons (PAHs) in 48,300 m3 of near-surface sediments exceeded 200 µg/g.

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