Ashu Bhan Tiku

Chemopreventive and Therapeutic Potential of “Naringenin,” a Flavanone Present in Citrus Fruits

Cancer is one of the major causes of deaths in developed countries and is emerging as a major public health burden in developing countries too. Changes in cancer prevalence patterns have been noticed due to rapid urbanization and changing lifestyles. One of the major concerns is an influence of dietary habits on cancer rates. Approaches to prevent cancer are many and chemoprevention or dietary cancer prevention is one of them. Therefore, nutritional practices are looked at as effective types of dietary cancer prevention strategies. Attention has been given to identifying plant-derived dietary agents, which could be developed as a promising chemotherapeutic with minimal toxic side effects. Naringenin, a phytochemical mainly present in citrus fruits and tomatoes, is a frequent component of the human diet and has gained increasing interest because of its positive health effects not only in cancer prevention but also in noncancer diseases. In the last few years, significant progress has been made in studying the biological effects of naringenin at cellular and molecular levels. This review examines the cancer chemopreventive/therapeutic effects of naringenin in an organ-specific format, evaluating its limitations, and its considerable potential for development as a cancer chemopreventive/therapeutic agent.

Radio-modulatory effects of Green Tea Catechin EGCG on pBR322 plasmid DNA and murine splenocytes against gamma-radiation induced damage

Green tea is rich in polyphenols, like catechins, which are thought to contribute to the health benefits of tea. The aim of this study was to evaluate the radioprotective effect of EGCG (epigallocatechin-3-gallate), a green tea catechin on γ-radiation induced cell damage. Under acellular condition of radiation exposure, pBR322 plasmid DNA was protected by EGCG in a concentration dependent manner. Treatment of murine splenocytes with EGCG 2h prior to radiation (3Gy), protected the cellular DNA against radiation-induced strand breaks. EGCG also inhibited γ-radiation induced cell death in splenocytes. EGCG pretreatment to the cells decreased the radiation induced lipid peroxidation and membrane damage. The levels of phase II enzymes, glutathione and lactate dehydrogenase were restored with EGCG treatment prior to radiation. Our results show that pretreatment with EGCG offers protection to pBR322 DNA under acellular condition and normal splenocytes under cellular condition, against γ-radiation induced damage and is better radioprotector in comparison to quercetin and vitamin C.

Adaptive response and split-dose effect of radiation on the survival of mice

Although the importance of radiation-induced adaptive response has been recognized in human health, risk assessment and clinical application, the phenomenon has not been understood well in terms of survival of animals. To examine this aspect Swiss albino mice were irradiated with different doses (2–10 Gy) at 0015 Gy/s dose rate and observed on a regular basis for 30 days. Since almost 50% lethality was seen with 8 Gy, it was selected as the challenging dose for further studies. Irradiation of mice with conditioning doses (0.25 or 0.5 Gy) and subsequent exposure to 8 Gy caused significant increase in the survival of mice compared to irradiated control. The splitting of challenging dose did not influence the efficiency of conditioning doses (0.25 Gy and 0.5 Gy) to induce an adaptive response. However conditioning doses given in fractions (0.25 Gy + 0.25 Gy) or (0.5 Gy + 0.5 Gy) were able to modulate the response of challenging dose of 8 Gy. These results clearly showed the occurrence of adaptive response in terms of survival of animals. The conditioning dose given in small fractions seemed to be more effective. The findings have been discussed from a mechanistic point of view. The possible biological implications, potential medical benefits, uncertainties and controversies related to adaptive response have also been addressed

Protective effect of the cruciferous vegetable mustard leaf (Brassica campestris) against in vivo chromosomal damage and oxidative stress induced by γ‐radiation and genotoxic chemicals

We evaluated the possible protective effect of the popular Indian cruciferous vegetable mustard leaf (Brassica campestris) against chromosomal damage and oxidative stress induced by γ‐radiation, cyclophosphamide (CPH) and urethane (URE), in mice. In vivo bone marrow micronucleus test was performed to assess chromosomal damage, and oxidative stress was monitored by estimating the changes in lipid peroxidation and the status of glutathione (GSH) as well as redox cycle antioxidants. Pretreatment with 50–250 mg/kg body wt of mustard leaf extract (MLE) for seven days significantly reduced the frequencies of micronuclei induced by γ‐radiation, CPH and URE. The protective effect against chromosomal damage was associated with modulation of lipid peroxidation as well as an increase in GSH and the GSH‐dependent enzyme glutathione S‐transferase (GST). Mass spectral analysis showed the presence of glucosinolates in MLE used for the pretreatment of mice. These findings indicate that intake of the green leafy cruciferous vegetable mustard leaf can lead to protection against in vivo genotoxicity and oxidative stress. Environ. Mol. Mutagen., 2008.

Biochemical and Molecular Mechanisms of Radioprotective Effects of Naringenin, a Phytochemical from Citrus Fruits

The present study was aimed to evaluate the radioprotective effects of naringenin in vivo using Swiss albino mice as a model system. Oral administration of 50 mg/kg body weight of naringenin for 7 days prior to radiation exposure protected mice against radiation-induced DNA, chromosomal and membrane damage. Naringenin pretreatment also increased the antioxidant status of irradiated mice. Multiple factors operating at cellular and molecular levels led to increased endogenous spleen colonies and survival of mice. Although naringenin induces apoptosis in cancer cells we found that it can protect against radiation-induced apoptosis in normal cells by modulating the expression of p53, Bax, and Bcl-2. The results from the present study indicate that naringenin inhibits the NF-kB pathway and down regulates radiation-induced apoptotic proteins resulting in radioprotection at the cellular, tissue and organism levels.

Immunomodulatory potential of acemannan (polysaccharide from Aloe vera) against radiation induced mortality in Swiss albino mice

Plant polysaccharides have been reported to stimulate growth, differentiation and proliferation of hematopoietic progenitor and stem cells to protect against the deleterious effects of radiations. This study evaluated the radioprotective potential of acemannan, a major polysaccharide component of aloe vera gel. Treatment of mice with 50 mg/kg body weight of acemannan by oral gavage for 7 days was able to protect against the radiation-induced mortality. Seven-day pretreatment or post-treatment of mice with acemannan resulted in the increase in median survival by 60 and 20%, respectively. The decrease in mortality can be attributed to the induction of hematopoiesis (peripheral lymphocytes counts, spleen cellularity, spleen index) and the upregulation of cytokines like TNF-α and IL-1 by acemannan in irradiated mice. Data indicate that acemannan has the ability to protect mice against radiation-induced mortality by immunomodulation and can be developed as a radiation damage mitigation agent.

Emodin, an anthraquinone derivative, protects against gamma radiation-induced toxicity by inhibiting DNA damage and oxidative stress

Abstract Purpose: In the present study, we explored the modulatory effect of emodin (1,3,8-trihydroxy-6-methylanthraquinone, C15H10O5) against gamma radiation-induced DNA damage and oxidative stress in acellular and cellular systems, respectively. Materials and methods: For cellular systems, concanavalin A (ConA)-stimulated murine splenocytes were used. Cytotoxic effect of emodin (0–400 μM), radiation (3–12 Gy) and emodin + radiation was measured by MTT [3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide] assay. Gamma radiation (3–12 Gy)-induced production of reactive oxygen species (ROS), an increase in nitric oxide (NO) level and its inhibition by emodin were estimated by DCFDA (2ʹ,7ʹ-dichlorofluorescein diacetate) and Griess regent, respectively. Analysis of radiation-induced apoptosis was performed using flow cytometery and acridine orange/ethidium bromide staining. DNA damage was evaluated in acellular system using pBR322 plasmid relaxation assay. Results: Emodin was able to effectively scavenge radiation- induced free radicals (ROS and NO) in murine splenocytes. Radiation-induced apoptosis and cell death was also inhibited by emodin pre-treatment. It could significantly prevent radiation-induced DNA damage. Conclusions: Protection against gamma radiation-induced cell death and DNA damage by emodin could be attributed to its free radical scavenging activity. The present study is the first report of the radioprotective role of emodin in mammalian cells.

Radiomodification of glyoxalase I in the liver and spleen of mice: Adaptive response and split-dose effect

Glyoxalase system, particularly glyoxalase I (Gly I) plays an important role in regulation of cell division and is considered to be a metabolic indicator of cell proliferation. The glyoxalase system is likely to have a close link with cellular radiosensitivity. Therefore, we have examined the effect of adaptive and split-dose of γ-rays on the activity of Gly I in the liver and spleen of mice. For the adaptive response studies, mice pre-treated with a conditioning dose of 0.5 Gy were given a challenging dose of 4 Gy at varying time intervals. In the split-dose studies, a dose of 4 Gy was delivered into two equal fractions and spaced at different time intervals. The results show that pre-exposure to a conditioning dose or the fractionation of total dose decreased the specific activity of Gly I in the liver and spleen of mice. The decreased activity of Gly I was suggestive of protective action induced by the conditioning dose and fractionation of dose. The similar pattern of radiation response of Gly I probably supported the possibility of involvement of a common pathway in the radiation-induced adaptive and split-dose effect. From these observations a close link between the Gly I and the adaptive-response as well as the split-dose effect is speculated. Since, the glyoxalase system is vital for a variety of biological functions including cell division and repair, the present findings may have relevance in understanding the dose-fractionation as well as the biological defence induced by low doses of radiations.

Emodin inhibits splenocyte proliferation and inflammation by modulating cytokine responses in a mouse model system

Abstract Emodin, an anthraquinone derivative, was investigated for potential anti-inflammatory and anti-proliferative effects in vitro. The potential to induce these outcomes was assessed using concanavalin A (ConA)-stimulated mouse splenocytes. Dose–response studies showed that emodin at 100 µM was not cytotoxic to naive cells, and that the same dose caused proliferation to be significantly reduced in ConA-stimulated cells. In addition, emodin significantly reduced ConA-induced nitric oxide (NO) production and the formation/release of TH1 (IL-2, IFNγ, TNFα) and TH17 (IL-6 and IL-17) cell cytokines, but induced those of TH2 (IL-4) and Treg (IL-10) cells. From the results, it is concluded that earlier-reported immunomodulatory effects imparted by emodin may have been attributable, in part, to anti-proliferative effects on lymphocytes, as well as a shift within the TH1/TH2 and TH17/Treg balance (towards TH2 and Treg). These findings, while providing evidence of mechanisms of emodin immunomodulation, are also potentially important for sparking studies that ultimately may result in the potential use of this agent in preventive and/or corrective strategies against autoimmune and other inflammatory diseases.

Significance and nature of bystander responses induced by various agents

Bystander effects in a biological system are the responses shown by non-targeted neighbouring cells/tissues/organisms. These responses are triggered by factors released from targeted cells when exposed to a stress inducing agent. The biological response to stress inducing agents is complex, owing to the diversity of mechanisms and pathways activated in directly targeted and bystander cells. These responses are highly variable and can be either beneficial or hazardous depending on the cell lines tested, dose of agent used, experimental end points and time course selected. Recently non-targeted cells have even been reported to rescue the directly exposed cells by releasing protective signals that might be induced by non-targeted bystander responses. The nature of bystander signal/s is not yet clear. However, there are evidences suggesting involvement of ROS, RNS, protein factors and even DNA molecules leading to the activation of a number of signaling pathways. These can act independently or in a cascade, to induce events leading to changes in gene expression patterns that could elicit detrimental or beneficial effects. Many review articles on radiation induced bystander responses have been published. However, to the best of our knowledge, a comprehensive review on bystander responses induced by other genotoxic chemicals and stress inducing agents has not been published so far. Therefore, the aim of the present review is to give an overview of the literature on different aspects of bystander responses: agents that induce these responses, factors that can modulate bystander responses and the mechanisms involved.