The platelet-derived chemokine CXCL4 exerts protective role in non-alcoholic steatohepatitis (NASH) in vivo

SummaryThe platelet aggregating activity of extracts of different layers of the arterial wall was compared to that of Achilles tendon. Arterial media and tendon extracts, adjusted to equivalent protein content as an index of concentration, aggregated platelets to the same extent but an arterial intima extract did not aggregate platelets. Platelet aggregation induced by collagen could be inhibited by mixing with intima extract, but only to a maximum of about 80%. Pre-mixing adenosine diphosphate (ADP) with intima extracts diminished the platelet aggregation activity of the ADP. Depending on the relationship between ADP and intima extract concentrations aggregating activity could either be completely inhibited or inhibition abolished. Incubation of ADP with intima extract and subsequent separation of degradation products by paper chromatography, demonstrated a time-dependent breakdown of ADP with AMP, adenosine, inosine and hypoxanthine as metabolic products; ADP removal was complete. Collagen, thrombin and adrenaline aggregate platelets mainly by endogenous ADP of the release reaction. Results of experiments comparing inhibition of aggregation caused by premixing aggregating agent with intima extract, before exposure to platelets, and the sequential addition of first the intima extract and then aggregating agent to platelets, suggest that the inhibitory effect of intima extract results from ADP breakdown. It is suggested that this ADP degradation by intima extract may play a protective role in vivo by limiting the size of platelet aggregates forming at the site of minimal “wear and tear” vascular trauma.

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MyD88-Dependent Glucose Restriction and Itaconate Production Control Brucella Infection

Infection and Immunity ◽

10.1128/iai.00156-21 ◽

2021 ◽

Author(s):

Carolyn A. Lacey ◽

Bárbara Ponzilacqua-Silva ◽

Catherine A. Chambers ◽

Alexis S. Dadelahi ◽

Jerod A. Skyberg

Keyword(s):

Glucose Transporter ◽

Production Control ◽

Brucella Melitensis ◽

Underlying Mechanism ◽

Protective Role ◽

Ifn Γ ◽

Glucose Restriction ◽

Myd88 Signaling

Brucellosis is one of the most common global zoonoses and is caused by facultative intracellular bacteria of the genus Brucella . Numerous studies have found that MyD88 signaling contributes to protection against Brucella , however the underlying mechanism has not been entirely defined. Here we show that MyD88 signaling in hematopoietic cells contributes both to inflammation and to control of Brucella melitensis infection in vivo . While the protective role of MyD88 in Brucella infection has often been attributed to promotion of IFN-γ production, we found that MyD88 signaling restricts host colonization by B. melitensis even in the absence of IFN-γ. In vitro , we show that MyD88 promotes macrophage glycolysis in response to B. melitensis . Interestingly, a B. melitensis mutant lacking the glucose transporter, GluP, was more highly attenuated in MyD88 -/- than in WT mice, suggesting MyD88 deficiency results in an increased availability of glucose in vivo which Brucella can exploit via GluP. Metabolite profiling of macrophages identified several metabolites regulated by MyD88 in response to B. melitensis , including itaconate. Subsequently, we found that itaconate has antibacterial effects against Brucella and also regulates the production of pro-inflammatory cytokines in B. melitensis -infected macrophages. Mice lacking the ability to produce itaconate were also more susceptible to B. melitensis in vivo . Collectively, our findings indicate that MyD88-dependent changes in host metabolism contribute to control of Brucella infection.

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Cardiotoxicity and myocardial infarction-associated DNA damage induced by thiamethoxam in vitro and in vivo: Protective role ofTrigonella foenum-graecumseed-derived polysaccharide

Environmental Toxicology ◽

10.1002/tox.22682 ◽

2018 ◽

Vol 34 (3) ◽

pp. 271-282 ◽

Cited By ~ 6

Author(s):

Amal Feki ◽

Hajer Ben Saad ◽

Intidhar Bkhairia ◽

Naourez Ktari ◽

Manel Naifar ◽

...

Keyword(s):

Myocardial Infarction ◽

Dna Damage ◽

Protective Role

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TNFR1 and TNFR2 Signaling Interplay in Cardiac Myocytes

Journal of Biological Chemistry ◽

10.1074/jbc.m704003200 ◽

2007 ◽

Vol 282 (49) ◽

pp. 35564-35573 ◽

Cited By ~ 51

Author(s):

Nicole Defer ◽

Anie Azroyan ◽

Françoise Pecker ◽

Catherine Pavoine

Keyword(s):

Cardiac Myocytes ◽

Protective Role ◽

Limiting Factor ◽

Receptor Subtypes ◽

Ros Production ◽

Altered Cell ◽

Factor Α ◽

Positive Effect ◽

Fractional Shortening

Tumor necrosis factor α (TNFα) plays a major role in chronic heart failure, signaling through two different receptor subtypes, TNFR1 and TNFR2. Our aim was to further delineate the functional role and signaling pathways related to TNFR1 and TNFR2 in cardiac myocytes. In cardiac myocytes isolated from control rats, TNFα induced ROS production, exerted a dual positive and negative action on [Ca2+] transient and cell fractional shortening, and altered cell survival. Neutralizing anti-TNFR2 antibodies exacerbated TNFα responses on ROS production and cell death, arguing for a major protective role of the TNFR2 pathway. Treatment with either neutralizing anti-TNFR1 antibodies or the glutathione precursor, N-acetylcysteine (NAC), favored the emergence of TNFR2 signaling that mediated a positive effect of TNFα on [Ca2+] transient and cell fractional shortening. The positive effect of TNFα relied on TNFR2-dependent activation of the cPLA2 activity, independently of serine 505 phosphorylation of the enzyme. Together with cPLA2 redistribution and AA release, TNFα induced a time-dependent phosphorylation of ERK, MSK1, PKCζ, CaMKII, and phospholamban on the threonine 17 residue. Taken together, our results characterized a TNFR2-dependent signaling and illustrated the close interplay between TNFR1 and TNFR2 pathways in cardiac myocytes. Although apparently predominant, TNFR1-dependent responses were under the yoke of TNFR2, acting as a critical limiting factor. In vivo NAC treatment proved to be a unique tool to selectively neutralize TNFR1-mediated effects of TNFα while releasing TNFR2 pathways.

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Protective role of methanol extracts of Gentiana asclepiadea L. and G. cruciata L. against genotoxic damage induced by ethyl methanesulfonate

Genetika ◽

10.2298/gensr1302329m ◽

2013 ◽

Vol 45 (2) ◽

pp. 329-340 ◽

Cited By ~ 2

Author(s):

Sanja Matic ◽

Snezana Stanic ◽

Slavica Solujic ◽

Nevena Stankovic ◽

Milan Mladenovic ◽

...

Keyword(s):

Aerial Part ◽

Protective Role ◽

Negative Control ◽

Ethyl Methanesulfonate ◽

Recessive Lethal ◽

Methanol Extracts ◽

Strong Mutagen ◽

Gentiana Cruciata

The methanol extracts from the underground and aerial part of the two species of Gentiana genus, Gentiana asclepiadea L. and Gentiana cruciata L. from Serbia, were investigated for their antigenotoxic activity against wellestablished mutagenic agent ethyl methanesulfonate (EMS) using the in vivo sexlinked recessive lethal (SLRL) test on Drosophila melanogaster. For this purpose, three days old Canton S males were treated with the potent mutagen EMS in concentration of 0.75 ppm, alone and combined with methanol extracts obtained from underground or aerial part of G. asclepiadea and G. cruciata in concentration of 5%, separately. Although EMS in concentration of 0.75 ppm increased the mutation frequency in all three broods, post-treatments with methanol extracts obtained from the underground and aerial part of G. asclepiadea and G. cruciata in concentration of 5%, respectively, drastically reduced the frequency of sex-linked recessive lethal mutations induced by EMS. Compared to the sucrose, as a negative control, methanol extract obtained from underground part of G. cruciata showed the most potent antigenotoxic activity. Extracts from the underground and aerial part of the two species of Gentiana genus, G. asclepiadea L. and G. cruciata L. from Serbia used in our experiments showed a clear antimutagenic effect, reducing the frequency of mutations induced by a strong mutagen such as EMS.

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In Vivo Antioxidant And Kidney Protective Potential Of Atorvastatin In Rat Cadmium-Induced Toxicity

10.21203/rs.3.rs-589839/v1 ◽

2021 ◽

Author(s):

Esmaeil Karami ◽

Zahra Goodarzi ◽

Ali Ghanbari ◽

Ahmad Reza Bandegi ◽

Sedighe Yosefi ◽

...

Keyword(s):

Oxidative Stress ◽

Biochemical Parameters ◽

Cadmium Chloride ◽

Rat Kidney ◽

Intraperitoneal Administration ◽

Kidney Injury ◽

Protective Role ◽

Histological Changes ◽

Male Wistar Rats

Abstract Purpose: Environmental and occupational exposure to cadmium chloride is known to cause nephrotoxicity linked with oxidative stress in humans and animals. This study used Atorvastatin to examine its effect on cadmium chloride-induced nephrotoxicity in rat model using biochemical and histological methodologies.Methods: Experiments were performed on 56 adult male Wistar rats (200 ±20 g), randomly assigned to eight groups. Atorvastatin was administered by oral for 15 days at 20 mg/kg/day, started 7 days before cadmium chloride intraperitoneal administration (1, 2, and 3 mg/kg) for eight days. On day 16, blood samples were collected, and kidneys were excised to evaluate the biochemical and histopathological changes.Cadmium chloride significantly increased malondialdehyde (MDA), serum creatinine (Cr), blood urea nitrogen (BUN), and decreased superoxide dismutase (SOD), glutathione (GSH), and glutathione peroxidase (GPx) levels. Results: Administration of Atorvastatin (20 mg/kg) significantly improved lipid peroxidation, glutathione and activities of antioxidant enzymes and significantly decreased BUN and Creatinine. Atorvastatin clearly improved the histological changes, demonstrating its protective role against Cadmium chloride-induced kidney injury.Conclusion: Treatment with Atorvastatin significantly improves all biochemical parameters and suggests a protecting role against cadmium chloride-induced oxidative stress and histological changes in rat kidney.

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Protective Role of Coenzyme Q10 in Acute Sepsis-Induced Liver Injury in BALB/c Mice

BioMed Research International ◽

10.1155/2020/7598375 ◽

2020 ◽

Vol 2020 ◽

pp. 1-9

Author(s):

Qian-wei Li ◽

Qin Yang ◽

Hong-Yang Liu ◽

Yu-ling Wu ◽

Yu-Hua Hao ◽

...

Keyword(s):

Liver Injury ◽

Coenzyme Q10 ◽

Cecal Ligation ◽

Protective Role ◽

Hepatic Tissue ◽

Control Group ◽

Cecal Ligation And Puncture ◽

Sequestosome 1

Sepsis increases the risk of the liver injury development. According to the research works, coenzyme Q10 exhibits hepatoprotective properties in vivo as well as in vitro. Current work aimed at investigating the protective impacts of coenzyme Q10 against liver injury in septic BALB/c mice. The male BALB/c mice were randomly segregated into 4 groups: the control group, the coenzyme Q10 treatment group, the puncture and cecal ligation group, and the coenzyme Q10+cecal ligation and puncture group. Cecal ligation and puncture was conducted after gavagaging the mice with coenzyme Q10 during two weeks. Following 48 h postcecal ligation and puncture, we estimated hepatic biochemical parameters and histopathological changes in hepatic tissue. We evaluated the expression of factors associated with autophagy, pyroptosis, and inflammation. Findings indicated that coenzyme Q10 decreased the plasma levels in alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase in the cecal ligation and puncture group. Coenzyme Q10 significantly inhibited the elevation of sequestosome-1, interleukin-1β, oligomerization domain-like receptor 3 and nucleotide-binding, interleukin-6, and tumor necrosis factor-α expression levels; coenzyme Q10 also increased beclin 1 levels. Coenzyme Q10 might be a significant agent in the treatment of liver injury induced by sepsis.

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Phenotypic Traits and Immunomodulatory Properties of Leuconostoc carnosum Isolated From Meat Products

Frontiers in Microbiology ◽

10.3389/fmicb.2021.730827 ◽

2021 ◽

Vol 12 ◽

Author(s):

Stefano Raimondi ◽

Gloria Spampinato ◽

Francesco Candeliere ◽

Alberto Amaretti ◽

Paola Brun ◽

...

Keyword(s):

Meat Products ◽

Gastrointestinal Transit ◽

Antibiotic Resistance Genes ◽

Protective Role ◽

Phenotypic Traits ◽

Natural Habitats ◽

Genes Encoding ◽

Immunomodulatory Properties ◽

Leuconostoc Carnosum

Twelve strains of Leuconostoc carnosum from meat products were investigated in terms of biochemical, physiological, and functional properties. The spectrum of sugars fermented by L. carnosum strains was limited to few mono- and disaccharides, consistently with the natural habitats of the species, including meat and fermented vegetables. The strains were able to grow from 4 to 37°C with an optimum of approximately 32.5°C. The ability to grow at temperatures compatible with refrigeration and in presence of up to 60 g/L NaCl explains the high loads of L. carnosum frequently described in many meat-based products. Six strains produced exopolysaccharides, causing a ropy phenotype of colonies, according to the potential involvement on L. carnosum in the appearance of slime in packed meat products. On the other side, the study provides evidence of a potential protective role of L. carnosum WC0321 and L. carnosum WC0323 against Listeria monocytogenes, consistently with the presence in these strains of the genes encoding leucocin B. Some meat-based products intended to be consumed without cooking may harbor up to 108 CFU/g of L. carnosum; therefore, we investigated the potential impact of this load on health. No strains survived the treatment with simulated gastric juice. Three selected strains were challenged for the capability to colonize a mouse model and their immunomodulatory properties were investigated. The strains did not colonize the intestine of mice during 10 days of daily dietary administration. Intriguingly, despite the loss of viability during the gastrointestinal transit, the strains exhibited different immunomodulatory effect on the maturation of dendritic cells in vivo, the extent of which correlated to the production of exopolysaccharides. The ability to stimulate the mucosal associated immune system in such probiotic-like manner, the general absence of antibiotic resistance genes, and the lack of the biosynthetic pathways for biogenic amines should reassure on the safety of this species, with potential for exploitation of selected starters.

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In Vitro and in Vivo Characterisation of P. Aeruginosa Oxidoreductase Enzymes in Pathogenesis and Therapy

10.26686/wgtn.17003215 ◽

2021 ◽

Author(s):

◽

Laura Kay Green

Keyword(s):

Bacterial Pathogen ◽

Protective Role ◽

Infection Model ◽

Virulence Determinants ◽

Genetic Redundancy ◽

Quinone Oxidoreductase ◽

Native Form ◽

Enzyme Prodrug Therapy

<p>Pseudomonas aeruginosa, an increasingly multi-drug resistant human pathogen, is now one of the top three causes of opportunistic infection and there is much interest in identifying novel therapeutic targets for treatment. As a bacterial pathogen, P. aeruginosa encounters innate immune system defences and must continue to adapt to its defence strategies to accommodate the ever-changing environment. Though P. aeruginosa virulence determinants have been heavily characterised over the last several decades, most recent work acknowledges the complex interaction between the human host and the pathogen as an on-going dialogue of virulence factors adapting to the continuum that is the immune response. A major challenge that P. aeruginosa must overcome are reactive oxygen species (ROS) that are released at all stages of infection. Based on previous work which demonstrated a role for soluble nitro- and quinone oxidoreductase (NQOR) enzymes in protecting a related bacterium (Pseudomonas putida) from oxidative stress, we hypothesized that P. aeruginosa would similarly utilize NQORs to withstand ROS. This thesis seeks to understand the role of ROS-protecting enzymes in pathogenesis as well as their potential applications in a therapeutic context. Several NQORs of P. aeruginosa were identified to possess biochemical characteristics consistent with the enzymatic capacity to indirectly reduce reactive species like H₂O₂. However, when individual genes encoding NQORs were deleted from P. aeruginosa, no apparent H₂O₂ sensitivity was seen. In contrast, when candidate genes were over-expressed, certain NQOR enzymes conferred the ability to tolerate H₂O₂ challenge at low concentrations; indicating that these NQORs may play a protective role whose effects are masked in vitro by genetic redundancy as well as a highly active endogenous catalase. By developing a novel in vivo cell culture infection model, the survival of P. aeruginosa post exposure to immunocompetent murine macrophages was also assessed. This not only demonstrated that several putative NQORs were activated in the presence of macrophages but also that an in vivo modelling system is likely to be more appropriate for discovering virulence determinants. In a different aspect of this study it was investigated whether the reductive capacity of the P. aeruginosa-derived NQORs might hold potential for gene-directed enzyme-prodrug therapy (GDEPT). Prodrugs, such as 5-(aziridin-1-yl)-2,4-dinitrobenzamide (CB1954) or the nitro-chloromethyl benzindoline SN 26438, are nontoxic in their native form, but become highly toxic upon reduction of their nitro functional groups. The P. aeruginosa NQORs, were tested to identify enzymes capable of efficient activation of CB1954 or SN 26438. Although none of these enzymes exhibited greater activity with CB1954 than the “best in class” Eschericha coli enzymes NfsA or NfsB, the P. aeruginosa NfsB orthologue (PA5190) demonstrated greater than 20-fold improved activity over NfsB from Escherichia coli in its ability to sensitise human cells to SN 26438. This finding offers promise for development of PA5190 and SN 26438 as a novel enzyme-prodrug paradigm for GDEPT.</p>

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