Raja Fayad

Selenoprotein deficiency enhances radiation-induced micronuclei formation.

The availability of selenium and the levels of specific selenoproteins might affect cancer risk by influencing the ability of DNA damaging agents to cause genomic instability and mutations. Transgenic mice that express reduced levels of selenoproteins and previously shown to be more susceptible to pathology associated with cancer development were used to study this possibility. These mice were exposed to X-rays and DNA damage assessed in the erythrocytes, where micronuclei formation was higher compared to the same cells obtained from irradiated wild-type controls. To determine whether the selenoprotein glutathione peroxidase-1 (GPx-1) might be involved in this protection, its levels were reduced by siRNA targeting in LNCaP human prostate cells. UV-induced micronuclei frequency was higher in these cells compared to control-transfected cells. These results indicate a role for selenoproteins in protecting DNA from damage and support human data implicating GPx-1 as a possible target of the chemoprotective effect of selenium.

Role of leptin receptor-induced STAT3 signaling in modulation of intestinal and hepatic inflammation in mice

Leptin‐deficient ob/ob mice are resistant to dextran sulfate sodium (DSS)‐induced colitis and Concanavalin A (Con A)‐induced hepatitis. However, the signal transduction pathways involved have not been identified. The present study investigated the effect of leptin‐induced STAT3 signaling in the DSS and Con A models. Mice carrying a leptin receptor (LEPR) gene mutant for Y1138 (s/s mice), with abrogated leptin‐induced STAT3 signaling, were compared with wild‐type (WT) and LEPR‐deficient db/db mice. Administration of DSS to s/s mice resulted in a clinical score and colon shortening of intermediate severity compared with disease induced in WT and db/db mice—the latter group having the lowest disease severity. A comparable degree of inflammatory infiltrate and epithelial damage was observed in the colon of WT and s/s mice, and these parameters were reduced in db/db mice. Levels of IFN‐γ, IL‐6, IL‐10, and TNF‐α were comparable in the colon of s/s and db/db mice, and a similar trend was observed for CXCL2. s/s and WT mice developed severe liver disease in response to Con A, whereas db/db mice were protected. However, Con A‐induced serum IL‐6 and TNF‐α levels in s/s mice mimicked levels observed in db/db rather than WT mice. In conclusion, lack of leptin‐induced STAT3 signaling is associated with reduced cytokine production following DSS and Con A administration, but it appears to sensitize mice to the effects of proinflammatory mediators.

Induction of thymocyte apoptosis by systemic administration of concanavalin A in mice: role of TNF‐α, IFN‐γ and glucocorticoids

Administration of concanavalin A (Con A) is a well‐established model of acute immune‐mediated hepatitis. Here, we demonstrate that intravenous injection of Con A in mice induces profound thymic atrophy. Compared to liver damage, the kinetics of Con A‐induced thymic atrophy is slower and more prolonged; the nadir in thymocyte number is reached 4 days after Con A injection, whereas peak transaminase levels are observed at 12–24 h. Marked alterations in the ratio of CD4+ and CD8+ cells in the thymus and spleen and significantly increased rates of thymocyte and splenocyte apoptosis are observed. Neutralization of the cytokines TNF‐α or IFN‐γ, which protects mice from Con A‐induced hepatitis, prevents thymic atrophy as well as alterations in CD4+ and CD8+ cell numbers and apoptosis rates. However, neither TNF‐α nor IFN‐γ are detectable in thymocyte lysates after Con A injection, whereas both cytokines are present in liver, spleen and serum. Administration of the glucocorticoid receptor antagonist mifepristone does not prevent thymic atrophy, thus ruling out a possible contribution of endogenous glucocorticoids. Con A‐induced thymic atrophy is accompanied by down‐regulation of Bcl‐2 expression in the thymus, which is prevented by neutralization of TNF‐α or IFN‐γ. These data demonstrate that the thymus is a critical target organ of Con A‐induced inflammation; the effects of Con A on the thymus are mediated by extrathymic production of TNF‐α and IFN‐γ, but not by glucocorticoids.

Adiponectin deficiency does not affect development and progression of spontaneous colitis in IL-10 knockout mice

The goal of this study was to investigate the role of the adipokine adiponectin (APN) in development of spontaneous colitis in IL-10 knockout (KO) mice. To this aim, we generated double IL-10 APN KO mice and compared their disease development to that of single IL-10 KO mice. Both IL-10 KO and double IL-10 APN KO mice spontaneously developed colitis of comparable severity. No significant differences in inflammatory infiltrate or crypt elongation were observed in colonic tissue obtained from IL-10 KO and double IL-10 APN KO mice at either 12 or 20 wk of age. A comparable increase in circulating levels of serum amyloid A and IFN-gamma was observed in IL-10 KO and double IL-10 APN KO mice as disease progressed. In vitro stimulation of lymphocytes from mesenteric lymph nodes with anti-CD3 and anti-CD28 induced a significantly higher production of IL-17 and TNF-alpha in IL-10 KO and double IL-10 APN KO mice compared with their healthy littermates. No significant differences in cytokine production from lymphocytes or colonic mRNA expression of cytokines were observed between IL-10 KO and double IL-10 APN KO mice. Both IL-10 KO and double IL-10 APN KO mice had a similar decrease in body weight and bone mass compared with their respective healthy littermates. Finally, APN deficiency did not lead to development of insulin resistance, either in APN KO or double IL-10 APN KO mice. In conclusion, lack of APN does not play a significant role in the pathogenesis of spontaneous colonic inflammation in the IL-10 KO model.

Ginger Protects the Liver against the Toxic Effects of Xenobiotic Compounds: Preclinical Observations

According to the World Health Organization, chronic liver disease is a major ailment and causes significant morbidity and mortality in both western and developing countries. However, till date no ideal hepatoprotective agents are available in the modern system of medicine to effective prevent and cure liver ailments. This has necessitated the need to depend on complementary and alternative systems of medicine for liver ailments and diseases. Zingiber officinale Roscoe commonly known as ginger is arguably one of the most commonly used spice, and is an integral part of our diet. In addition to its dietary use, ginger is also reported to possess myriad health benefits, and has been used in the various traditional and folk systems of medicine to treat various ailments and illnesses. Preclinical studies carried out in the past decade have shown that ginger possesses hepatoprotective effects, and to protect against diverse xenobiotic compounds like alcohol, acetaminophen, fungicides, tetracycline, heavy metals and organophosphorus compounds. Mechanistic studies have shown that the protective actions are mediated through free radical scavenging, antioxidant, cytoprotective, and to modulate the levels of the detoxifying enzymes. This review for the first time summarizes the results related to the beneficial properties of ginger in ameliorating the toxic effects of hepatotoxins, and also emphasizes the aspects that warrant future research to establish its activity and utility as a broad spectrum hepatoprotective agent.

Effect of adiponectin deficiency on intestinal damage and hematopoietic responses of mice exposed to gamma radiation.

Adiponectin (APN) is an adipose tissue-derived cytokine that regulates insulin sensitivity and inflammation. It is also involved in modulation of cell proliferation by binding to various growth factors. Based on its known effects in modulating cell proliferation and oxidative stress, APN may potentially be involved in regulating tissue damage and repair following irradiation. Adiponectin KO mice and their WT littermates were exposed to a single whole-body dose of 3 or 6Gy gamma radiation. Radiation-induced alterations were studied in jejunum, blood, bone marrow and thymus at days 1 and 5 post-irradiation and compared with sham-irradiated groups. In WT mice, irradiation did not significantly alter serum APN levels while inducing a significant decrease in serum leptin. Irradiation caused a significant reduction in thymocyte cellularity, with concomitant decrease in CD4(+), CD8(+) and CD4(+)CD8(+) T cell populations, with no significant differences between WT and APN KO mice. Irradiation resulted in a significantly higher increase in the frequency of micronucleated reticulocytes in the blood of APN KO compared with WT mice, whereas frequency of micronucleated normochromatic erythrocytes in the bone marrow at day 5 was significantly higher in WT compared with APN KO mice. Finally, irradiation induced similar alterations in villus height and crypt cell proliferation in the jejunum of WT and APN KO mice. Jejunum explants from sham-irradiated APN KO mice produced higher levels of IL-6 compared with tissue from WT animals, but the difference was no longer apparent following irradiation. Our data indicate that APN deficiency does not play a significant role in modulating radiation-induced gastrointestinal injury in mice, while it may participate in regulation of damage to the hematopoietic system.

Polyphenols in the Prevention of Acute Pancreatitis

The prevalence of acute pancreatitis, a disease with variable severity, is increasing, posing new challenges for health care providers. To complicate the condition, currently available therapies are limited to supportive measures and to treating complications. Pharmacological agents like antisecretory agents, protease inhibitors, antioxidants, immunomodulators, non-steroidal anti-inflammatory medications, and prophylactic antibiotics have been used with variable degrees of success. However, regular intake of these agents is unsafe as they can possess long-term damage, and this has necessitated the need for non-toxic agents that are both effective and safe. Almost 25 centuries ago, Hippocrates, the father of medicine, proclaimed “Let food be thy medicine and medicine be thy food.” Exploring the association between diet and health continues even today. Preclinical studies carried out in the recent past have shown that the polyphenols of dietary sources like curcumin, resveratrol, quercetin, genistein, ellagic acid, cinnamtannin B-1 and green tea polyphenols protect against chemical-induced acute pancreatitis in laboratory animals. The present review collates the protective effects of these agents and the mechanism of action responsible for the effect.