scholarly journals Protective Bystander Effects Simulated with the State-Vector Model

Dose-Response ◽  
2007 ◽  
Vol 5 (3) ◽  
pp. dose-response.0 ◽  
Author(s):  
Helmut Schöllnberger ◽  
Peter M. Eckl
Keyword(s):  
State Vector ◽  
Hybrid Cell ◽  
The State ◽  
Vector Model ◽  
High Dose ◽  
Data Sets ◽  
Low Doses ◽  
Protective Effects ◽  
Multistage Model

Apoptosis induced in non-hit bystander cells is an important biological mechanism which operates after exposure to low doses of low-LET radiation. This process was implemented into a deterministic multistage model for in vitro neoplastic transformation: the State-Vector Model (SVM). The new model is tested on two data sets that show a reduction of the transformation frequency below the spontaneous level after exposure of the human hybrid cell line CGL1 to low doses of γ-radiation. Stronger protective effects are visible in the data for delayed plating while the data for immediate plating show more of an LNT-like dose-response curve. It is shown that the model can describe both data sets. The calculation of the time-dependent numerical solution of the model also allows to obtain information about the time-dependence of the protective apoptosis-mediated process after low dose exposures. These findings are compared with experimental observations after high dose exposures.

scholarly journals Newly Developed Recombinant Antithrombin Protects the Endothelial Glycocalyx in an Endotoxin-Induced Rat Model of Sepsis

2020 ◽  
Vol 22 (1) ◽  
pp. 176
Author(s):  
Toshiaki Iba ◽  
Jerrold H. Levy ◽  
Koichiro Aihara ◽  
Katsuhiko Kadota ◽  
Hiroshi Tanaka ◽  
...  
Keyword(s):  
Dose Group ◽  
Low Dose ◽  
Leukocyte Adhesion ◽  
Endothelial Glycocalyx ◽  
High Dose Group ◽  
Control Group ◽  
High Dose ◽  
Protective Effects ◽  
Circulating Levels

(1) Background: The endothelial glycocalyx is a primary target during the early phase of sepsis. We previously reported a newly developed recombinant non-fucosylated antithrombin has protective effects in vitro. We further evaluated the effects of this recombinant antithrombin on the glycocalyx damage in an animal model of sepsis. (2) Methods: Following endotoxin injection, in Wistar rats, circulating levels of hyaluronan, syndecan-1 and other biomarkers were evaluated in low-dose or high-dose recombinant antithrombin-treated animals and a control group (n = 7 per group). Leukocyte adhesion and blood flow were evaluated with intravital microscopy. The glycocalyx was also examined using side-stream dark-field imaging. (3) Results: The activation of coagulation was inhibited by recombinant antithrombin, leukocyte adhesion was significantly decreased, and flow was better maintained in the high-dose group (both p < 0.05). Circulating levels of syndecan-1 (p < 0.01, high-dose group) and hyaluronan (p < 0.05, low-dose group; p < 0.01, high-dose group) were significantly reduced by recombinant antithrombin treatment. Increases in lactate and decreases in albumin levels were significantly attenuated in the high-dose group (p < 0.05, respectively). The glycocalyx thickness was reduced over time in control animals, but the derangement was attenuated and microvascular perfusion was better maintained in the high-dose group recombinant antithrombin group (p < 0.05). (4) Conclusions: Recombinant antithrombin maintained vascular integrity and the microcirculation by preserving the glycocalyx in this sepsis model, effects that were more prominent with high-dose therapy.

The protective effects of carvacrol and thymol against paracetamol–induced toxicity on human hepatocellular carcinoma cell lines (HepG2)

2016 ◽  
Vol 35 (12) ◽  
pp. 1252-1263 ◽  
Author(s):  
SS Palabiyik ◽  
E Karakus ◽  
Z Halici ◽  
E Cadirci ◽  
Y Bayir ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Inflammatory Cytokines ◽  
Hepg2 Cells ◽  
Folk Medicine ◽  
Hepatoprotective Activity ◽  
High Dose ◽  
Protective Effects ◽  
And Oxidative Stress ◽  
Pro Inflammatory Cytokines

Acetaminophen (APAP) overdose could induce liver damage and lead to acute liver failure. The treatment of APAP overdoses could be improved by new therapeutic strategies. Thymus spp., which has many beneficial effects and has been used in folk medicine, is one such potential strategy. In the present study, the hepatoprotective activity of the main constituents of Thymus spp., carvacrol and thymol, were evaluated in light of APAP-induced hepatotoxicity. We hoped to understand the hepatoprotective mechanism of these agents on the antioxidant system and pro-inflammatory cytokines in vitro. Dose-dependent effects of thymol and carvacrol (25, 50, and 100 µM) were tested on cultured HepG2 cells. N-Acetylcysteine (NAC) was tested as positive control. We showed that APAP inhibited HepG2 cell growth by inducing inflammation and oxidative stress. Incubating APAP-exposed HepG2 cells with carvacrol and thymol for 24 h ameliorated this inflammation and oxidative stress. We also evaluated alanine transaminase and lactate dehydrogenase levels of HepG2 cells. We found that thymol and carvacrol protected against APAP-induced toxicity in HepG2 cells by increasing antioxidant activity and reducing pro-inflammatory cytokines, such as tumor necrosis factor α and interleukin 1β. Taking together high-dose thymol and carvacrol treatment has an effect close to NAC treatment in APAP toxicity, but thymol has better treatment effect than carvacrol.

Rhizophora Mucronata Lam. (Mangrove) Bark Extract Prevents Ethanol-induced Liver Injury, Oxidative Stress and Apoptosis in Swiss Albino Mice

2021 ◽  
Author(s):  
Chitra Jairaman ◽  
Sabine Matou-Nasri ◽  
Zeyad I Alehaideb ◽  
Syed Ali Mohamed Yacoob ◽  
Anuradha Venkataraman ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Liver Injury ◽  
Histopathological Examination ◽  
Bark Extract ◽  
High Dose ◽  
Protective Effects ◽  
Rhizophora Mucronata ◽  
Ethanol Intoxication ◽  
Hepatoprotective Effects

Abstract The bark extract of Rhizophora mucronata (BERM) was recently reported for its prominent in vitro protective effects against liver cell line toxicity caused by various toxicants, including ethanol. Here, we aimed to verify the in vivo hepatoprotective effects of BERM against ethanol intoxication. An oral administration of different concentrations (100, 200, and 400 mg/kg) of BERM prior to high-dose ethanol via intraperitoneal injection was performed in mice. On the 7th day, liver and kidney sections were dissected out for histopathological examination. The ethanol intoxication caused large areas of liver necrosis while the kidneys were not affected. Pre-BERM administration decreased ethanol-induced liver injury, as compared to the mice treated with ethanol alone. In addition, the pre-BERM administration resulted in a decrement in the level of ethanol-induced oxidative stress, revealed by a concomitant increase of GSH and a decrease of MDA hepatic levels. The BERM extract also reversed the ethanol-induced liver injury and hepatotoxicity, characterized by the low detection of TNF-α gene expression level and fragmented DNA, respectively. Altogether, BERM extract exerts antioxidative activities and present promising hepatoprotective effects against ethanol intoxication. The identification of the related bioactive compounds will be of interest for future use at physiological concentrations in ethanol-intoxicated individuals.

scholarly journals Trimetazidine attenuates dexamethasone-induced muscle atrophy via inhibiting NLRP3/GSDMD pathway-mediated pyroptosis

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Li Wang ◽  
Xin-Feng Jiao ◽  
Cheng Wu ◽  
Xiao-Qing Li ◽  
Hui-Xian Sun ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Muscle Performance ◽  
Skeletal Muscle Atrophy ◽  
C2c12 Myotubes ◽  
High Dose ◽  
Protective Effects ◽  
Akt Inhibitor ◽  
Caspase 1

AbstractSkeletal muscle atrophy is one of the major side effects of high dose or sustained usage of glucocorticoids. Pyroptosis is a novel form of pro-inflammatory programmed cell death that may contribute to skeletal muscle injury. Trimetazidine, a well-known anti-anginal agent, can improve skeletal muscle performance both in humans and mice. We here showed that dexamethasone-induced atrophy, as evidenced by the increase of muscle atrophy F-box (Atrogin-1) and muscle ring finger 1 (MuRF1) expression, and the decrease of myotube diameter in C2C12 myotubes. Dexamethasone also induced pyroptosis, indicated by upregulated pyroptosis-related protein NLR family pyrin domain containing 3 (NLRP3), Caspase-1, and gasdermin-D (GSDMD). Knockdown of NLRP3 or GSDMD attenuated dexamethasone-induced myotube pyroptosis and atrophy. Trimetazidine treatment ameliorated dexamethasone-induced muscle pyroptosis and atrophy both in vivo and in vitro. Activation of NLRP3 using LPS and ATP not only increased the cleavage and activation of Caspase-1 and GSDMD, but also increased the expression levels of atrophy markers MuRF1 and Atrogin-1 in trimetazidine-treated C2C12 myotubes. Mechanically, dexamethasone inhibited the phosphorylation of PI3K/AKT/FoxO3a, which could be attenuated by trimetazidine. Conversely, co-treatment with a PI3K/AKT inhibitor, picropodophyllin, remarkably increased the expression of NLRP3 and reversed the protective effects of trimetazidine against dexamethasone-induced C2C12 myotube pyroptosis and atrophy. Taken together, our study suggests that NLRP3/GSDMD-mediated pyroptosis might be a novel mechanism for dexamethasone-induced skeletal muscle atrophy. Trimetazidine might be developed as a potential therapeutic agent for the treatment of dexamethasone-induced muscle atrophy.

scholarly journals Hormetic effect of amyloid-beta peptide in hippocampal synaptic plasticity and memory

2021 ◽  
Vol 11 (40) ◽  
pp. 156-156
Author(s):  
Daniela Puzzo ◽  
Agostino Palmeri
Keyword(s):  
Synaptic Plasticity ◽  
Amyloid Beta ◽  
Hippocampal Slices ◽  
Reference Memory ◽  
High Dose ◽  
Low Doses ◽  
Hormetic Effect ◽  
Physiologic Function ◽  
High Doses

Background: The term hormesis refers to a biphasic dose-response phenomenon characterized by low-dose stimulation and high-dose inhibition represented by a J-shaped or U-shaped curve, depending on the parameter measured (Calabrese and Baldwin, Hum Exp Toxicol, 2002). Indeed, several, if not all, physiological molecules (i.e. glutamate, glucocorticoids, nitric oxide) are likely to present a hormetic effect, exhibiting opposite effects at high or low concentrations. In the last few years, we have focused on amyloid-beta (A), a peptide widely known because it is produced in high amounts during Alzheimer’s disease (AD). A is considered a toxic fragment causing synaptic dysfunction and memory impairment (Selkoe, Science, 2002). However, the peptide is normally produced in the healthy brain and growing evidences indicate that it might have a physiologic function. Aim: Based on previous results showing that picomolar concentrations of A42 enhance synaptic plasticity and memory (Puzzo et al, J Neurosci, 2008) and that endogenous A is necessary for synaptic plasticity and memory (Puzzo et al, Ann Neurol, 2011), the aim of our study was to demonstrate the hormetic role of A in synaptic plasticity and memory. Methods: We used 3-month old wild type mice to analyze how synaptic plasticity, measured on hippocampal slices in vitro, and spatial reference memory were modified by treatment with different doses of A (from 2 pM to 20 μM). Results: We demonstrated that A has a hormetic effect (Puzzo et al, Neurobiol Aging, 2012) with low-doses (200 pM) stimulating synaptic plasticity and memory and high-doses (≥ 200 nM) inhibiting these processes. Conclusions: Our results suggest that, paradoxically, very low doses of A might serve to enhance memory at appropriate concentrations and conditions. These findings raise several issues when designing effective and safe approaches to AD therapy.

scholarly journals Protective Effects of D-Penicillamine on Catecholamine-Induced Myocardial Injury

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Michal Říha ◽  
Pavlína Hašková ◽  
Jan Martin ◽  
Tomáš Filipský ◽  
Kateřina Váňová ◽  
...  
Keyword(s):  
Iron Reduction ◽  
Myocardial Injury ◽  
Troponin T ◽  
High Dose ◽  
Plasma Vitamin ◽  
Specific Marker ◽  
Dependent Manner ◽  
Protective Effects ◽  
Copper Release

Iron and copper release participates in the myocardial injury under ischemic conditions and hence protection might be achieved by iron chelators. Data on copper chelation are, however, sparse. The effect of the clinically used copper chelator D-penicillamine in the catecholamine model of acute myocardial injury was tested in cardiomyoblast cell line H9c2 and in Wistar Han rats. D-Penicillamine had a protective effect against catecholamine-induced injury bothin vitroandin vivo. It protected H9c2 cells against the catecholamine-induced viability loss in a dose-dependent manner. In animals, both intravenous D-penicillamine doses of 11 (low) and 44 mg/kg (high) decreased the mortality caused by s.c. isoprenaline (100 mg/kg) from 36% to 14% and 22%, respectively. However, whereas the low D-penicillamine dose decreased the release of cardiac troponin T (specific marker of myocardial injury), the high dose resulted in an increase. Interestingly, the high dose led to a marked elevation in plasma vitamin C. This might be related to potentiation of oxidative stress, as suggested by additionalin vitroexperiments with D-penicillamine (iron reduction and the Fenton reaction). In conclusion, D-penicillamine has protective potential against catecholamine-induced cardiotoxicity; however the optimal dose selection seems to be crucial for further application.

scholarly journals Effects of bovine lactoferrin on the immature porcine intestine

2013 ◽  
Vol 111 (2) ◽  
pp. 321-331 ◽  
Author(s):  
Duc Ninh Nguyen ◽  
Yanqi Li ◽  
Per T. Sangild ◽  
Stine B. Bering ◽  
Dereck E. W. Chatterton
Keyword(s):  
Cell Proliferation ◽  
Enteral Nutrition ◽  
Hypoxia Inducible Factor ◽  
Milk Proteins ◽  
Bovine Lactoferrin ◽  
Low Doses ◽  
Protective Effects ◽  
Positive Effects ◽  
Extracellular Signal

Bioactive milk proteins may be important in protecting preterm infants from developing inflammation and necrotising enterocolitis (NEC). A preterm pig model was used to investigate the protective effects of enteral bovine lactoferrin (bLF) against NEC development and inflammation. Caesarean-delivered preterm pigs were fed parenteral and minimal enteral nutrition for the first 2 d followed by 2 d of total enteral nutrition before euthanasia. Pigs were stratified into two groups and fed with either a control formula (CON,n15) or a 10 g/l of bLF-enriched formula (LF,n13). NEC incidence, gut functions and inflammatory cytokines were analysed. NEC incidence and nutrient absorption were similar between the two groups. In pigs that developed NEC, disease outcome was more severe in the colon accompanied by increased intestinal permeability in LF pigs. In contrary, the LF pigs had a lowered IL-1β level in the proximal small intestine. Dose-dependent effects of bLF on cell proliferation, intracellular signalling and cytokine secretion were tested in porcine intestinal epithelial cells (PsIc1)in vitro.Low doses (0·1–1 g/l) increased cell proliferation via extracellular signal-regulated kinase (ERK), limited IL-8 secretion and prevented NF-κB and hypoxia-inducible factor-1α (HIF-1α) activation, suggesting anti-inflammatory effects. In contrast, at a higher dose (10 g/l), bLF exerted adverse effects by reducing cell proliferation, stimulating IL-8 release, inhibiting ERK activation and up-regulating NF-κB and HIF-1α activation. Overall, at a dose of 10 g/l, bLF exacerbated disease severity in pigs that developed NEC, while thein vitrostudies indicated the positive effects of bLF at low doses (0·1–1 g/l). Supplementation of infant formulas with bLF should therefore be optimised carefully.

scholarly journals In vitrofolate supplementation alleviates oxidative stress, mitochondria-associated death signalling and apoptosis induced by 7-ketocholesterol

2004 ◽  
Vol 92 (6) ◽  
pp. 887-894 ◽  
Author(s):  
R.-F. S. Huang ◽  
H.-C. Yaong ◽  
S.-C. Chen ◽  
Y.-F. Lu
Keyword(s):  
Oxidative Stress ◽  
Nuclear Dna ◽  
High Dose ◽  
Protective Effects ◽  
Folate Supplementation ◽  
Mitochondria Membrane Potential ◽  
Induced Apoptosis ◽  
Apoptotic Damage

Folate has recently been proposed as a new antioxidant. Folate supplementation may have a protective effect in counteracting oxidant-induced apoptotic damage. The present studies were undertaken to examine whether there is a direct link between folate levels, antioxidant capability and reduced apoptotic damage. Using anin vitrocellular model of 7-ketocholesterol (KC)-induced apoptosis, U937 cells were pre-cultured with a folate-deficient medium supplemented with various levels of folate (2–1500μmol/l) before treatment with 7-KC. Apoptotic markers, mitochondria-associated death signals and levels of reactive oxygen species were assayed. After treatment with 7-KC for 30h, low and high levels of folate supplementation significantly (P<0.05) reduced nuclear DNA loss. Only high levels of folate supplementation (>1000μmol/l) were effective in counteracting 7-KC-promoted apoptotic membrane phosphatidylserine exposure and DNA laddering. The attenuation of 7-KC-induced apoptotic damage by high-dose folate supplementation coincided with a partial normalization of mitochondria membrane potential dissipation, a suppression of cytochromecrelease and an inhibition of procaspase 3 activation. The prevention of mitochondrial dysfunctions and apoptotic processes was associated with antioxidant actions of high-dose folate by a marked scavenging of intracellular superoxide. Collectively, our present results demonstrate thatin vitrofolate supplementation exerts differentially protective effects against 7-KC-induced damage. High-dose supplementation alleviates oxidative stress, mitochondria-associated death signalling and apoptosis induced by 7-KC. However, thein vivorelevance is not clear and requires further study.

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