Evaluation of prophylactic efficacy of cinnamaldehyde in murine model against Paradendryphiella arenariae mycotoxin tenuazonic acid-induced oxidative stress and organ toxicity

Cinnamaldehyde (Cin) is a natural product obtained from cinnamon and is reported to have a potential anti-fungal, anti-oxidant, anti-inflammatory and anticancer effect. The present study investigated the possible protective role of Cin against tenuazonic acid-induced mycotoxicity in the murine model. Tenuazonic acid (TeA), a toxin produced by Alternaria is a common contaminant in tomato and tomato-based products. Here, Swiss male mice were administered with TeA isolated from Paradendryphiella arenariae (MW504999) (source-tomato) through injection (238 µg/kg BW) and ingestion (475 µg/kg BW) routes for 2 weeks. Thereafter, the prophylaxis groups were treated with Cin (210 mg/kg BW). The experiment was carried out for 8 weeks. The treated groups were compared to the oral and intra-peritoneal experimental groups that received the toxin solely for 8 weeks. Haematological, histopathological and biochemical aspects of the experimental and the control mice were analysed. Sub-chronic intoxication of mice with TeA showed elevated malondialdehyde (MDA), reduced catalase (CAT) and superoxide dismutase (SOD) production; abnormal levels of aspartate transaminase (AST) and alanine transaminase (ALT). Treatment with Cin reversed TeA-induced alterations of antioxidant defense enzyme activities and significantly prevented TeA-induced organ damage. Thus, cinnamaldehyde showed therapeutic effects and toxicity reduction in TeA induced mycotoxicosis.

Toxic Mechanisms of Five Heavy Metals: Mercury, Lead, Chromium, Cadmium, and Arsenic

The industrial activities of the last century have caused massive increases in human exposure to heavy metals. Mercury, lead, chromium, cadmium, and arsenic have been the most common heavy metals that induced human poisonings. Here, we reviewed the mechanistic action of these heavy metals according to the available animal and human studies. Acute or chronic poisonings may occur following exposure through water, air, and food. Bioaccumulation of these heavy metals leads to a diversity of toxic effects on a variety of body tissues and organs. Heavy metals disrupt cellular events including growth, proliferation, differentiation, damage-repairing processes, and apoptosis. Comparison of the mechanisms of action reveals similar pathways for these metals to induce toxicity including ROS generation, weakening of the antioxidant defense, enzyme inactivation, and oxidative stress. On the other hand, some of them have selective binding to specific macromolecules. The interaction of lead with aminolevulinic acid dehydratase and ferrochelatase is within this context. Reactions of other heavy metals with certain proteins were discussed as well. Some toxic metals including chromium, cadmium, and arsenic cause genomic instability. Defects in DNA repair following the induction of oxidative stress and DNA damage by the three metals have been considered as the cause of their carcinogenicity. Even with the current knowledge of hazards of heavy metals, the incidence of poisoning remains considerable and requires preventive and effective treatment. The application of chelation therapy for the management of metal poisoning could be another aspect of heavy metals to be reviewed in the future.

Effect of Marine Bacteria and Ulvan on the Activity of Antioxidant Defense Enzymes and the Bio-Protection of Papaya Fruit against Colletotrichum gloeosporioides

Anthracnose, caused by Colletotrichum gloeosporioides, is one of the most important diseases in papaya fruit. Its control has been achieved with synthetic fungicides, but the application of marine bacteria and the sulphated polysaccharide ulvan (structural description: β[1,4]-D-GlcA-α[1,4]-L-Rha 3 sulfate, β[1,4]-L-IdoA-α[1,4]-L-Rha 3 sulfate, β[1,4]-D-Xyl-α[1,4]-L-Rha 3 sulfate, and β[1,4]-D-Xyl 2-sulfate-α[1,4]-L-Rha 3 sulfate) from Ulva sp. can be an alternative in the use of agrochemicals. Thus, the objective of this study was to assess the effect in vitro and in vivo of two marine bacteria, Stenotrophomonas rhizophila and Bacillus amyloliquefaciens, and ulvan in papaya fruit’s bio-protection against C. gloeosporioides. The capacity of marine bacteria to inhibit mycelial growth and phytopathogen spore germination in vitro through volatile organic compounds (VOCs) and carbohydrate competition was evaluated. Fruit was inoculated with bacteria, ulvan, and C. gloeosporioides and incubated at 25 °C and 90% of relative humidity (RH) for seven days. Disease incidence (%), lesion diameter (mm), and antioxidant defense enzyme activity (such as superoxide dismutase (SOD), catalase (CAT), and peroxidase (POD) were quantified. In vitro, C. gloeosporioides was inhibited by S. rhizophila and B. amyloliquefaciens. In vivo, disease incidence and the lesion diameter of anthracnose on papaya fruit were significantly reduced by marine bacteria and ulvan. Antioxidant defense enzyme activity played an important role in fruit bio-protection against C. gloeosporioides. The application of marine bacteria and ulvan can be an alternative in the sustainable postharvest management of papaya.

Effect of Caffeic Acid on Ischemia-Reperfusion-Induced Acute Renal Failure in Rats

Background: Cyclooxygenase (COX)-lipooxygenase (LOX) pathway plays a key role in the pathogenesis of renal ischemia/reperfusion (IR). Objective: This study was aimed to evaluate the role of dietary phenol caffeic acid (CA), alone and in combination with selective COX-2 inhibitor celecoxib (CEL) in IR-induced acute renal failure (ARF) in rats. Materials and Methods: Renal IR was induced by bilateral occlusion of renal pedicels for 90 min followed by reperfusion for 24 h. Rats were randomized into 4 groups: Sham, IR, CA + IR, and CA + CEL + IR, with 7 day treatment before IR. Serum creatinine (SCr), blood urea nitrogen (BUN), antioxidant enzymes, tumor necrosis factor alpha (TNF-α), and histopathological changes were evaluated in the kidney after IR. Results: Renal IR caused significant derangement in renal function and histology. In the IR group, an increase in lipid peroxidation and decreased antioxidant defense enzyme activity were observed. Pretreatment with CA and CA + CEL showed a significant decrease in the BUN, SCr, TNF-α, oxidative stress markers and corrected the histological changes in the kidney. Conclusion: This study demonstrated the renoprotective potential of CA and combination of CA + CEL in IR-induced ARF in rats. The plausible mechanisms for the efficacy of CA could be attributed to its ability to modulate the ­COX-LOX system in renal IR.

PPAR-γImpairment Alters Peroxisome Functionality in Primary Astrocyte Cell Cultures

Peroxisomes provide glial cells with protective functions against the harmful effects of H2O2on neurons and peroxisome impairment results in nervous lesions. Agonists of theγ-subtype of the Peroxisome-Proliferator-Activated-Receptors (PPAR) have been proposed as neuroprotective agents in neurodegenerative disorders. Nevertheless, the role of PPAR-γalterations in pathophysiological mechanisms and the relevance of peroxisome functions in the PPAR-γeffects are not yet clear. In a primary cell culture of rat astrocytes, the irreversible PPAR-γantagonist GW9662 concentration-dependently decreased the activity of catalase, the most important antioxidant defense enzyme in peroxisomes. Catalase functionality recovered in a few days and the PPAR-γagonist rosiglitazone promoted reversal of enzymatic damage. The reversible antagonist G3335 reduced both the activity and expression of catalase in a rosiglitazone-prevented manner. G3335 reduced also the glutathione reductase expression, indicating that enzyme involved in glutathione regeneration was compromised. Neither the PPAR-αtarget gene Acyl-Coenzyme-A-oxidase-1 nor the mitochondrial detoxifying enzyme NADH:ubiquinone-oxidoreductase (NDFUS3) was altered by PPAR-γinhibition. In conclusion, PPAR-γinhibition induced impairment of catalase in astrocytes. A general decrease of the antioxidant defenses of the cell suggests that a PPAR-γhypofunction could participate in neurodegenerative mechanisms through peroxisomal damage. This series of experiments could be a useful model for studying compounds able to restore peroxisome functionality.

The Flavin-Containing Monooxygenase 3 Gene and Essential Hypertension: The Joint Effect of Polymorphism E158K and Cigarette Smoking on Disease Susceptibility

Gene encoding flavin-containing monooxygenase 3 (FMO3), a microsomal antioxidant defense enzyme, has been suggested to contribute to essential hypertension (EH). The present study was designed to investigate whether common functional polymorphism E158K (rs2266782) of theFMO3gene is associated with EH susceptibility in a Russian population. A total of 2 995 unrelated subjects from Kursk (1 362 EH patients and 843 healthy controls) and Belgorod (357 EH patients and 422 population controls) regions of Central Russia were recruited for this study. DNA samples from all study participants were genotyped for theFMO3gene polymorphism through PCR followed by RFLP analysis. We found that the polymorphism E158K is associated with increased risk of essential hypertension in both discovery population from Kursk region (OR 1.36 95% CI 1.09–1.69,P=0.01) and replication population from Belgorod region (OR 1.54 95% CI 1.07–1.89,P=0.02) after adjustment for gender and age using logistic regression analysis. Further analysis showed that the increased hypertension risk in carriers of genotype 158KK gene occurred in cigarette smokers, whereas nonsmoker carriers of this genotype did not show the disease risk. This is the first study reporting the association of theFMO3gene polymorphism and the risk of essential hypertension.

Antioxidant Defense Enzyme Genes and Asthma Susceptibility: Gender-Specific Effects and Heterogeneity in Gene-Gene Interactions between Pathogenetic Variants of the Disease

Oxidative stress resulting from an increased amount of reactive oxygen species and an imbalance between oxidants and antioxidants plays an important role in the pathogenesis of asthma. The present study tested the hypothesis that genetic susceptibility to allergic and nonallergic variants of asthma is determined by complex interactions between genes encoding antioxidant defense enzymes (ADE). We carried out a comprehensive analysis of the associations between adult asthma and 46 single nucleotide polymorphisms of 34 ADE genes and 12 other candidate genes of asthma in Russian population using set association analysis and multifactor dimensionality reduction approaches. We found for the first time epistatic interactions between ADE genes underlying asthma susceptibility and the genetic heterogeneity between allergic and nonallergic variants of the disease. We identifiedGSR(glutathione reductase) andPON2(paraoxonase 2) as novel candidate genes for asthma susceptibility. We observed gender-specific effects of ADE genes on the risk of asthma. The results of the study demonstrate complexity and diversity of interactions between genes involved in oxidative stress underlying susceptibility to allergic and nonallergic asthma.

A redox signature score identifies diffuse large B-cell lymphoma patients with a poor prognosis

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease in which approximately 40% of the patients respond well to current chemotherapy, but the prognosis for the other 60% is poor. The Leukemia/Lymphoma Molecular Profiling Project (LLMPP) used microarray technology to define a molecular profile for each of 240 patients with DLBCL and develop a molecular outcome predictor score that accurately predicted patient survival. Data from our laboratory and others suggest that alterations in antioxidant defense enzyme levels and redox environment can be oncogenic and affect the response to glucocorticoid treatment, one of the components of combination chemotherapy regimens for lymphoma. The goal of the current study was to reanalyze the LLMPP microarray data to determine whether the levels of antioxidant defense enzymes and redox proteins were correlated with prognosis in DLBCL. We found that patients with DLBCL with the worst prognosis, according to the outcome predictor score, had decreased expression of catalase, glutathione peroxidase, manganese superoxide dismutase, and VDUP1, a protein that inhibits thioredoxin activity. The data suggest that the patients with the worst prognosis combine a decrease in antioxidant defense enzyme expression with an increase in thioredoxin system function (the redox signature score).

Role of Bach-1 in Regulation of Heme Oxygenase-1 in Human Liver Cells

Heme oxygenase-1 is an antioxidant defense enzyme that converts heme to biliverdin, iron, and carbon monoxide. Bach-1 is a bZip protein that forms heterodimers with small Maf proteins and was reported recently to down-regulate theHO-1gene in mice. Using small interfering RNAs targeted to human Bach-1 mRNA, we investigated whether modulation of human hepatic Bach-1 expression by small interfering (si)RNA technology influences heme oxygenase-1 gene expression. We found that Bach-1 siRNAs transfected into Huh-7 cells significantly reduced Bach-1 mRNA and protein levels ∼80%, compared with non siRNA-treated cells. In contrast, transfection with the same amounts of nonspecific control duplexes or LaminB2-duplex did not reduce Bach-1 mRNA or protein levels, confirming the specificity of Bach-1 siRNA. Expression of the heme oxygenase-1 gene in Bach-1 siRNA-transfected cells was up-regulated 7-fold, compared with cells without Bach-1 siRNA. The effect of increasing concentrations of heme to up-regulate levels of heme oxygenase-1 was more pronounced when Bach-1 siRNA was present. Taken together, these results indicated that Bach-1 has a specific and selective ability to repress expression of human hepatic heme oxygenase-1. Silencing of Bach-1 by siRNAs is a useful method for up-regulatingHO-1gene expression. Exogenous heme produces additional up-regulation, beyond that produced by Bach-1 siRNAs, suggesting that heme does not act solely through its effects on Bach-1.