Risks of Environmental Genotoxicants

Humans have throughout their development been exposed to various environmental genotoxicants through food, air, water, and soil. Environmental exposure to genotoxic compounds may induce damage to human health and thereby increase risks of human cancers and other diseases. Environmental genotoxic chemicals have the ability to induce mutations. Such mutations can give rise to cancer in somatic cells. However, when germ cells are affected, the damage can also have an effect on the next and successive generations. Because of the potential health hazard represented by exposure to genotoxic chemicals, it is important that all chemicals for which there is possible human exposure be screened for genotoxic activity. If genotoxic hazard is detected, then the risks of exposure can be assessed and the use of the chemical controlled and when appropriate eliminated from the market and the environment. In this chapter, a general overview of the genotoxicity and the genotoxicity of some environmental genotoxicants are discussed. This is followed by a description of the genotoxic properties of some environmental genotoxicants such as bisphenols and mycotoxins, which are prominent environmental contaminates, and is believed to be genotoxic agents that contribute to the high incidence of carcinogenicity among populations

Evaluation of Chromosomal Instability in Diabetic Rats Treated with Naringin

We used the bone marrow DNA strand breaks, micronucleus formations, spermatocyte chromosomal aberrations, and sperm characteristic assays to investigate the chromosomal instability in somatic and germinal cells of diabetic rats treated with multiple doses of naringin. The obtained results revealed that naringin was neither cytotoxic nor genotoxic for the rats at all tested doses. Moreover, naringin significantly reduced the diabetes-induced chromosomal instability in somatic and germinal cells in a dose-dependent manner. In addition, diabetes induced marked biochemical alterations characteristic of oxidative stress including enhanced lipid peroxidation, accumulation of oxidized glutathione, reduction in reduced glutathione, and accumulation of intracellular reactive oxygen species. Treatment with naringin ameliorated these biochemical markers dose-dependently. In conclusion, naringin confers an appealing protective effect against diabetes-induced chromosomal instability towards rat somatic and germinal cells which might be explained partially via diminishing the de novo free radical generation induced by hyperglycemia. Thus, naringin might be a good candidate to reduce genotoxic risk associated with hyperglycemia and may provide decreases in the development of secondary malignancy and abnormal reproductive outcomes risks, which seems especially important for diabetic patients

Deleterious Effects of Reactive Metabolites

A number of drugs have been withdrawn from the market or severely restricted in their use because of unexpected toxicities that become apparent only after the launch of new drug entities. Circumstantial evidence suggests that, in most cases, reactive metabolites are responsible for these unexpected toxicities. In this review, a general overview of the types of reactive metabolites and the consequences of their formation are presented. The current approaches to evaluate bioactivation potential of new compounds with particular emphasis on the advantages and limitation of these procedures will be discussed. Reasonable reasons for the excellent safety record of certain drugs susceptible to bioactivation will also be explored and should provide valuable guidance in the use of reactive-metabolite assessments when nominating drug candidates for development. This will, in turn, help us to design and bring safer drugs to the market

Genetic Algorithm Based Control System Design of a Self-Excited Induction Generator

This paper presents an application of the genetic algorithm (GA) for optimizing controller gains of the Self-Excited Induction Generator (SEIG) driven by the Wind Energy Conversion Scheme (WECS). The proposed genetic algorithm is introduced to adapt the integral gains of the conventional controllers of the active and reactive control loop of the system under study, where GA calculates the optimum value for the gains of the variables based on the best dynamic performance and a domain search of the integral gains. The proposed genetic algorithm is used to regulate the terminal voltage or reactive power control, by adjusting the self excitation, and to control the mechanical input power or active power control by adapting the blade angle of WECS, in order to adjust the stator frequency. The GA is used for optimizing these gains, for an active and reactive power loop, by solving the related optimization problem. The simulation results show a better dynamic performance using the GA than using the conventional PI controller for active and reactive control

Natural Cholesterol Busters

Hypercholesterolemia, a risk factor for cardiovascular and cerebrovascular diseases, is a silent health problem. It occurs due to buildup of large amount of cholesterol in blood vessels resulting in narrowed blood vessels or blockage of the flow of blood and causes cellular dysfunction. The predisposing factors for hypercholesterolemia are carbohydrates‐enriched diet, unhealthy fats, and red meat. Moreover, family history, obesity, hypokinetic lifestyle, aging, and oxidative stress are associated with hypercholesterolemia. Therapeutic interventions of hypercholesterolemia involve cessation of bad habits, regular exercise, consumption of cholesterol buster diets, and cholesterol‐lowering drugs. However, cholesterol‐lowering drugs have low efficacy, and some patients cannot tolerate the adverse effects of hypocholesterolemic drugs. In light of this, there has been great interest to address natural cholesterol busters as first choice as cholesterol‐lowering option. Healthy diet, regular exercise and natural cholesterol‐lowering agents are documented to decrease blood cholesterol level. Natural cholesterol busters include dietary fibers, plant sterols, healthy fats, smart proteins, antinutrients, antioxidants, and L‐arginine. These busters not only decrease cholesterol oxidation and absorption but also increase cholesterol catabolism and elimination. Most of these busters are found in cereals, oatmeal, fruits, vegetables, legumes, and fermented foods. The natural cholesterol busters are recommended strategies for treatment of hypercholesterolemia alone or in combination with cholesterol‐lowering drugs

Evaluation of chromosomal instability in diabetic rats treated with naringin

We used the bone marrow DNA strand breaks, micronucleus formations, spermatocyte chromosomal aberrations, and sperm characteristic assays to investigate the chromosomal instability in somatic and germinal cells of diabetic rats treated with multiple doses of naringin. The obtained results revealed that naringin was neither cytotoxic nor genotoxic for the rats at all tested doses. Moreover, naringin significantly reduced the diabetes-induced chromosomal instability in somatic and germinal cells in a dose-dependent manner. In addition, diabetes induced marked biochemical alterations characteristic of oxidative stress including enhanced lipid peroxidation, accumulation of oxidized glutathione, reduction in reduced glutathione, and accumulation of intracellular reactive oxygen species. Treatment with naringin ameliorated these biochemical markers dose-dependently. In conclusion, naringin confers an appealing protective effect against diabetes-induced chromosomal instability towards rat somatic and germinal cells which might be explained partially via diminishing the de novo free radical generation induced by hyperglycemia. Thus, naringin might be a good candidate to reduce genotoxic risk associated with hyperglycemia and may provide decreases in the development of secondary malignancy and abnormal reproductive outcomes risks, which seems especially important for diabetic patients

Influence of pravastatin chitosan nanoparticles on erythrocytes cholesterol and redox homeostasis: An in vitro study

AbstractThe objective of this study was to develop and characterize chitosan nanoparticles (CSNPs) to increase efficacy of pravastatin (PR) on erythrocytes redox status. CSNPs and PR loaded CSNPs (PRCSNPs) were prepared by ionic gelation method. The particle size, zeta potential, scanning electron microscopy (SEM), differential scanning calorimetry (DSC), Fourier-transform infrared (FTIR) and X-ray diffraction (XRD) were used to investigate physicochemical characters of the prepared nanoparticles. The present results revealed that CSNPs and PRCSNPs have nanosize about 90nm with spherical shape, positive zeta potential and prolonged PR release. Moreover, DSC and FTIR indicated no chemical interactions between PR and CS. In vitro studies revealed that, erythrocyte uptake of PR from PRCSNPs was higher than free PR solution. Incubation of erythrocytes in high cholesterol plasma, hypercholesterolemia (HC), increases membrane cholesterol, erythrocyte hemolysis, oxidized glutathione (GSH), protein carbonyl (PCC), and malondialdeyhe (MDA). However, HC significantly decreases PR uptake by erythrocytes, superoxide dismutase (SOD), glutathione peroxidase (GPx) catalase (CAT) activities, reduced GSH and nitrite levels compared to control. By contrast, treatment of HC with PR plus CS as free drug or nanostructure formula keeps the measured parameters at values near that of control. The effect of CSNPs and PRCSNPs on redox status of erythrocytes was more prominent than free drugs. In conclusion, PRCSNPs are promising drug carrier to deliver PR into erythrocytes, moreover, PRCSNPs possess promising characteristics with high biological safety for treatment of HC induced disruption of redox homeostasis

Regulation of TNF-α and NF-κB activation through the JAK/STAT signaling pathway downstream of histamine 4 receptor in a rat model of LPS-induced joint inflammation.

Histamine 4 receptor (H4R) is a novel target for the pharmacological modulation of histamine-mediated immune signals during inflammatory diseases. The purpose of this study was to assess the effects of the H4R agonist 4-methylhistamine dihydrochloride (4-MeH) and antagonist JNJ7777120 (JNJ) in the inflamed rat knee. Animals were fasted for 18h before a single dose of 4-MeH or JNJ (30mg/kg) was administered intraperitoneally (i.p.), both followed by intra-articular (i.a.) injection of LPS 2h later. Blood and synovial fluid were collected after a short incubation period and TNF-α, NF-κB, and IkB-α levels were measured via flow cytometry. Additionally, we assessed the effects of H4R engagement on the expression of IL-1β, TNF-α, and NF-κB mRNAs and the protein levels of TNF-α, NF-κB, JAK-1, and STAT-3 in the inflamed knee tissue. These results revealed increased TNF-α and NF-κB expression and decreased IkB-α levels in both the LPS alone and 4-MeH treated groups in whole blood and synovial fluid. Further, IL-1β, TNF-α, and NF-κB mRNA levels were significantly increased and western blot analysis confirmed increased expression of TNF-α, NF-κB, JAK-1, and STAT-3 in both LPS and 4-MeH treatment groups. Furthermore, these increases were completely inhibited in the inflamed knee tissue of the JNJ-treated group. Thus, the inhibition of inflammatory mediators and signaling pathways by the H4R antagonist JNJ suggests the anti-arthritic importance of this molecule

Thymoquinone suppression of the human hepatocellular carcinoma cell growth involves inhibition of IL-8 expression, elevated levels of TRAIL receptors, oxidative stress and apoptosis

Hepatocellular carcinoma (HCC) is the fourth most common solid tumor worldwide. The chemokine interleukin-8 (IL-8) is overexpressed in HCC and is a potential target for therapy. Although the transcription factor NF-κB regulates IL-8 expression, and while thymoquinone (TQ; the most bioactive constituent of black seed oil) inhibits NF-κB activity, the precise mechanisms by which TQ regulates IL-8 and cancer cell growth remain to be clarified. Here, we report that TQ inhibited growth of HCC cells in a dose- and time-dependent manner, caused G2M cell cycle arrest, and stimulated apoptosis. Apoptosis was substantiated by activation of caspase-3 and -9, as well as cleavage of poly(ADP-ribose)polymerase. TQ treatments inhibited expression of NF-κB and suppressed IL-8 and its receptors. TQ treatments caused increased levels of reactive oxygen species (ROS) and mRNAs of oxidative stress-related genes, NQO1 and HO-1. Pretreatment of HepG2 cells with N-acetylcysteine, a scavenger of ROS, prevented TQ-induced cell death. TQ treatment stimulated mRNA expression of pro-apoptotic Bcl-xS and TRAIL death receptors, and inhibited expression of the anti-apoptotic gene Bcl-2. TQ enhanced TRAIL-induced death of HepG2 cells, in part by up-regulating TRAIL death receptors, inhibiting NF-κB and IL-8 and stimulating apoptosis. Altogether, these findings provide insights into the pleiotropic molecular mechanisms of TQ-dependent suppression of HCC cell growth and underscore potential of this compound as anti-HCC drug

Naringin attenuates the development of carrageenan-induced acute lung inflammation through inhibition of NF-κb, STAT3 and pro-inflammatory mediators and enhancement of IκBα and anti-inflammatory cytokines

Naringin has been reported to possess diverse pharmacological properties, including anti-arthritic and anti-inflammatory activities. The aim of the present study was to determine the potential anti-inflammatory effect of naringin in a mouse model of carrageenan-induced pleurisy. A single dose of naringin (40 and 80 mg/kg) was administered per oral (p.o.) 1 h before carrageenan (Cg) administration. Pro- and anti-inflammatory cytokines were analysed in pleural fluid. We also assessed the effects of naringin on the expression levels of iNOS, inducible cyclooxygenase isoform (COX-2), ICAM-1, MIP-2, PGE2, STAT3, TGF-β1, nuclear factor kappa B (NF-κB) and inhibitor of kappa B (IκBα) in lung tissue. The histological examinations revealed anti-inflammatory effect of naringin while Cg group deteriorated. Naringin downregulated Th1 and upregulated Th2 cytokines. Western blot analyses revealed increased protein expression of NF-κB, STAT3 and COX-2 and decreased IκBα in response to Cg treatment, which were reversed by the treatment with naringin. In the Cg group, mRNA expression levels of pro-inflammatory mediators upregulated and anti-inflammatory mediators downregulated. Naringin reversed these actions