HM Medical Clinic

Even if Viagra is not needed, it is possible that the doctor will be able to determine the etiology of erectile dysfunction and prescribe appropriate treatmen viagra australia it doesn't pay to forget about sexual activeness even at the first sings of malfunction.

Ss-pub.org


"Science Stays True Here" Biological and Chemical Research, Volume 2015, 241-257 Science Signpost Publishing Natural Coumarins: QSTR Approaches Regarding Their
Genotoxicity

Estela Guardado Yordi1,2,*, Maria João Matos2, Lourdes Santana2, Eugenio Uriarte2, Orlando Abreu1 and Enrique Molina Pérez2,3 1. Departamento de Ciencia y Tecnología de los Alimentos, Universidad de Camagüey "Ignacio Agramonte Loynaz",
Circunvalación Norte Km 5 ½, 7200, Camagüey, Cuba.
2. Departamento de Química Orgánica, Universidad de Santiago de Compostela, Facultad de Farmacia, Campus Vida, 15782,
Santiago de Compostela, España.
3. Departamento de Química, Universidad de Camagüey "Ignacio Agramonte Loynaz", Circunvalación Norte Km 5 ½, 7200,
Camagüey, Cuba.

Received: May 26, 2015 / Accepted: June 29, 2015 / Published: August 25, 2015
Abstract: Coumarins are a group of phytochemicals with multiple applications in different fields, such as food and medicine. Many
of their benefits are based on the different activities that they display, within which stand antioxidant properties. However, some
conflicting evidences suggest the need to clarify or estimate the safety aspects and genotoxicity of this group of compounds. In this
sense it has been shown in previous studies that some of them have presented pro-oxidant activity in vitro and clastogenic activity in
silico
. Therefore, in this paper chemical structures of coumarins that come from several natural sources were studied. These
coumarins belong to the chemical subclasses: simple coumarins, furocoumarins, dihydrofurocoumarins, pyranocoumarins,
phenylcoumarins and biscoumarins. Thepre-selected database was formed taking into account topological-structural information,
using molecular descriptors from the TOPSMODE approach. A virtual screening, that used a structure-clastogenic activity model and
linear discriminant analysis (LDA) technique, was also performed. Several natural coumarins showed clastogenic activity in silico.
For this family, the QSTR associated the probability of being active to the presence of hydroxy and methoxy groups in the molecules.
It is of positive contribution of the fragment that forms the bay region of the pyranocoumarinic system. These in silico results may
contribute to the safe design of new foods, nutraceuticals or drugs. It may also be important in the prevention of cancer, in which
pathology these substances show pro-oxidant activity.
Keywords: Coumarins, clastogenic activity, pro-oxidant activity, TOPSMODE approach.
Nutrition, which was once intended to meet the nutrient needs, it is today directed to a research toward preventing and treating chronic diseases . Constitutes an alternative seeking nutritional bioactive components other than medicinal purposes, which is a challenge to the biomedical sciences . It is in this context that the concept of functional foods emerged . There are, several bioactive compounds that confer functionality to food Corresponding author: Estela Guardado Yordi, Departamento de Ciencia y Tecnología de los Alimentos, Universidad de
Camagüey "Ignacio Agramonte Loynaz", E-mail: estela.guardado@reduc.edu.cu. Natural Coumarins: QSTR Approaches Regarding Their Genotoxicity
and are part of the daily diet . Therefore numerous studies direct their efforts to identify these components and evaluate their isolated health benefits or as part of dietary regimens. Within this huge range of compounds there are included the phenolic compounds, many of which have been recognized as in vitro antioxidants . This activity has been linked to the possible prevention of diseases such as cardiovascular, cancer, neurodegenerative, etc . However, many of these compounds have been presented pro-oxidant activity and even in vitro, in vivo and in silico clastogenic activity . Examples of this are some phenolic acids present in many food sources of plant origin, which have shown dual behaviour . These considerations demonstrate the importance of continuing research on the safety associated with this family of compounds respects. The pro-oxidant activity causes the formation of reactive oxygen species and inhibition of antioxidants systems . This can generateoxidative damageto cells and tissues and biomolecules such asproteins, DNA and lipids . It is added thefact that it is recognized that the development of many chronic diseases may be due to oxygen reactive species (ROS) , where the antioxidants and pro-oxidants levels balance is not achieved and, the result is a pathological process. The pro-oxidants catalyse, then, oxidative reactions to these biomolecules, which may lead to cellular dysfunction that ends with cell death . Some pro-oxidant compounds presented clastogenic activity. Clastogenic processes are considered the endpoint of oxidative damage to DNA, in conjunction with mutations . Another group of phenolic type compounds are the coumarins (benzo-α-pyrones), which have been less investigated. There are few studies evaluating the genetic toxicity of natural and synthetic coumarin derivatives in the literature . Coumarins are a family of phenolic compounds that represent different constituents of the non-energetic part of the human diet . The simplicity and versatility of the coumarin scaffold make it an interesting starting-point for a wide range of applications . Coumarin derivative molecules (or coumarin metabolites) are naturally generated by the metabolism of coumarin in the cell. These derivatives have been described for their numerous therapeutic applications, such as: antitumor and anti-HIV agents and central nervous system stimulants, anti-inflammatory and antibacterial agents, anti-coagulants, among others . Their structural variability and similarity to other phenolic compounds, suggesting the need to identify structural alerts associated with genotoxicity. Some background has been in silico studied and showed clastogenic activity in some of them . This leads to the hypothesis that some natural coumarins might also have clastogenic activity based on in silico studies and reports. For these reasons, the objective of this study is to conduct a virtual screening based on the TOPSMODE approach, considering an external database of natural coumarins present in edible and medicinal plants. 2. Materials and Methods
For this study, three different in silico steps were defined. Figure 1 shows the in silico pathway for the elaboration of the virtual screening.








Natural Coumarins: QSTR Approaches Regarding Their Genotoxicity
Step 1. Development of the Step 2. Use of TOPSMODE Step 3. Virtual Screening structural external database Fig 1. Different steps of a QSTR study taking into account the TOPSMODE approach.
To evaluate the studied coumarinic compounds, it was used an external database (DB1) that is represented in Table 1. Molecules used in the virtual screening (DB1).
Compounds
Esculetin
Ammoresinol
Ostruthin
484-12-8
Novobiocin
Fraxidin
Imperatorin
Psoralen
Bergapten
Methoxsalen
Marmesin
Rutaretin
Natural Coumarins: QSTR Approaches Regarding Their Genotoxicity
Aegelinol
Xanthyletin
Inophyllum A
Inophyllum C
Inophyllum G1
Calanolide A
Pseudocordatolide C
Isodispar B
Mammea AB
Dicoumarol
Fraxetin
1 Chemical Abstracts Service Number; 2 Simplified Molecular Input Line Entry System
TOPS-MODE approach represents a useful platform for the automatic generation of structural alerts . It is based on the calculation of spectral moments of molecular bond matrices appropriately weighted taking into account the hydrophobic, electronic and steric molecular features. Spectral moments are the trace of the kth power of a matrix, i.e., the sum of all the main diagonal entries of such matrices . These matrices represent the molecular skeleton without taking into account hydrogen atoms. Bond weights are placed as diagonal entries of such matrices and represent quantitative contributions to different physic-chemical properties. Use of the TOPSMODE approach: • Weighting of the topological properties of link information: bond distance (SD), standard bond dipole moments (DM), hydrophobicity (H), polar surface area (PS), polarizability (Pol), molar refractivity (MR), van der Waals radii (vdW), and Gasteiger-Marsili charges (Ch). • Generation of molecular descriptors (spectral moments) of each molecular entity using the MODESLAB software and the theoretical statistic model (MTE) developed by : Natural Coumarins: QSTR Approaches Regarding Their Genotoxicity
× 10 [Ω(µ4 )] × 10 [Ω(µ5 )] × 10 [Ω(µ5 )] 3 8263 × 10 [Ω(µ8 )]− Ω(µ )]− 6517 Statisticians: Wilks´- λ= 0.629; F(14.194)=8.148; D2=2.353; p<0.0000 AC indicates clastogenic activity. The Ω is used to indicate that the corresponding variable in brackets was orthogonalized respecting to the rest of the variables included in the model. µn are the spectral moments (molecular descriptors) and their exponents correspond to the bonds' properties mentioned before. The classification model obtained is given below, together with the statistical parameters of the linear discriminate of the squared analysis, where λ is the Wilks' statistics, D2 is the Mahalanobis distance and F is the Fisher ratio. The construction of this model by Estrada et al. (2006) was based in a dataset of 372 organic compounds, including known carcinogens, presented in the groups of drugs, food, agrochemicals, additives, medicinal products, cosmetics and household materials . This model was internally and externally validated . The linear discriminate analysis (LDA), implemented in Statistic software, has been used to generate the classification (active/inactive). A compound with probability of 50± 2.5 % was considered as not classified (NC). The clastogenic model used in the virtual screening was externally validated from the percentage of good classification (expression indicating the correspondence between the theoretical and experimental prediction) to a series of external compounds. The percentage of good classification also indicates the robustness of the model to predictthe clastogenic activity. 6,7-Dihydroxycoumarinor esculetin (6,7-HC, CAS: 305-01-1) was deeply studied because it has been used in in vitro and in vivo clastogenicity studies (Figure 2). Fig. 2.Chemical structure and SMILE code of 6,7-HC.
Natural Coumarins: QSTR Approaches Regarding Their Genotoxicity
3. Results and Discussion
1. Description of Natural Coumarins that Comprise the Databases
Compounds compiled in DB1 are presented in different families/species of DB2. In previous chemotaxonomic studies have been identified those plant families in which more genera and species with coumarins were reported and/or with greater structural diversity . From this source and others, the database (DB2) of interest for future studies of coumarins, their medicinal or food uses and natural sources was designed (Table 2). Table 2. Some plant families containing natural coumarins (DB2).
Family/specie (vernacular name)
Coumarin
Reference
Imperatorin, Bergapten, Ammimajus (Bishop's flower) Bergapten, imperatorin, Angelica archangelica (Angelica) osthol,umbelliferone bergapten, rutaretin, Apiumgraveolens (Celery) Coriandrumsativum (Coriander) Ferula assafoetida (Asafoetida) bergapten, esculetin, Foeniculumvulgare (Fennel) umbelliferone, psoralen bergapten, imperatorin, Petroselinumcrispum (Parsley) Pimpinellaanisum (Aniseed) umbelliferone, bergapten Arnica montana (Arnica) Matricariarecutita (Chamomille) C. limonum (Lemon Tree) umbelliferone, bergapten Zanthoxilumamericanum (Northern Prickly Ash) Glycyrrizaglabra (Liquorice) Justiciapectoralis (Tilo ) Natural Coumarins: QSTR Approaches Regarding Their Genotoxicity
Passifloraincarnata (Passion Flower) Herniariaglabra (Rupture wort) Salvia officinalis (Garden Sage) C. brasiliense (Guanandi, Ocuje) C. cerasiferum (-) calanolide B Calophylluminophyllum (Borneo mahogany) inophyllum A and P Calophyllumlanigerum var. austrocoriaceum (+)- calanolide A C. teysmannii var. inophylloide (-) calanolide B, C. verticillatum Adapted from unpublished Work ; M: medicinal use; F: food use. Some polyphenolic flavonoid-type substances presenting reported pro-oxidant activity have also proved to have in vitroclastogenic activity . In silicoprevious studies, it seems to be a relationship between the clastogenic activity and pro-oxidant . This suggests the fact that it is possible to estimate the pro-oxidant activity using Equation 1, since currently has not been able to get a QSAR model specifically for pro-oxidant activity. If these postulates are used, the active compounds, behind clastogenic activity, could present pro-oxidant activity, corroborating the relationship that was proposed in our unpublished works. From all the compounds represented in DB1, fraxetin and 4-methyldaphnetin were studied for their pro-oxidant activity. 2. Classification Model and Virtual Screening
The prediction obtained for each of the analysed subclasses, are shown in Tables 3-9. The probability of belonging to the group of active compounds (G_2: 1) or possible genotoxic or inactive compounds (G_1: -1), was expressed in percentage of good probability. 2.1. QSTR of Simple Coumarins, Furocoumarins, Dihydrofurocoumarins
The results obtained for simple coumarins are shown in Table 3. It can be observed that the combination of hydroxy and methoxy groups seems to be related to the probability of being active (iefraxidin). Similar Natural Coumarins: QSTR Approaches Regarding Their Genotoxicity
chemoinformatics results were obtained for simple methoxylated coumarins, being in correspondence with the clastogenic activity exhibited in vitro [20]. Another group that appears to influence the activity is the amide group esterified with a glucoside, as in the case of novobiocin. Table 3. Predictions made using TOPSMODE classification model to simple coumarins compounds.
Simple coumarins
4-Methyldaphnetin The scaffold without substituents (coumarin) was predicted as not clastogenic in previous studies . While in the present data, mammea AB presenting two (saturated and unsaturated) aliphatic radicals and a carbonyl group, is also an inactive molecule. It could be argued that as these types of radicals appear more often, increases the probability of being inactive, as in the case of ostruthin (94.2%). The presence of a group esterified with aromatic or aliphatic unsaturated chain, seems to be a structural feature for an inactive molecule, as in the case of esculetin. Furocoumarins (ie psoralen) are inactive compounds (Table 4), but are activated when methoxy radical (ie bergapten, methoxsalen) are introduced. The analysis of this subclass corroborated the information noted above, that the molecule is inactivated when esterified with unsaturated aliphatic groups (ie imperatorin). Natural Coumarins: QSTR Approaches Regarding Their Genotoxicity
Table 4. Predictions made using TOPS-MODE classification model to furocoumarins.
Prob. (%)
Table 5 shows the results obtained for the dihydrofurocoumarins. The two molecules considered in the study are inactive, considering the tert-butyl radical. The presence of the hydroxy radical in the rutaretin decreases the probability of toxicity. Table 5. Predictions made using TOPSMODE classification model to dihydrofurocoumarins.
2.2. QSTR of pyranocoumarins
Table 6 shows the results of linear pyranocoumarins, which are predicted as inactive by the model (equation 1). Table 6. Predictions made using TOPSMODE classification model to pyranocoumarins (linear type).
(linear type)
Prob. (%)
Natural Coumarins: QSTR Approaches Regarding Their Genotoxicity
In Table 7 it is shown the classification and probability of angular pyranocoumarins. Table 7. Predictions made using TOPSMODE classification model to angular pyranocoumarins.
(angular type)
OCH(CH3)CH(CH3)CH(OH) G_2:1 68.6 -OCH(CH3)CH(CH3)CO)- OCH(CH3)CH(CH3)CH(OH) G_2:1 76.9 Dihydrocalanolide A Pseudocordatolide C -OCH(CH3)CH(CH3)CH(OH)- It can be observed that all the molecules are active and have the presence of a bay region in the pyranocoumarinic system (Figure 3b). Contributions fragments comprising this region were calculated according to equation 1, from the local spectral moments calculated using fragment contributions MODESLAB software module. Its basis isthat the spectral moments of the adjacency matrix of edges inwhich the TOPSMODE approach can be expressed as linearcombinations of the various structural fragments of the molecular graph.The bay region fragment has a positive contribution (0.892) to the activity (Figure 3). Similar bay region was designated as a structural alert of azafenantrene (Figure 3a) or polycyclic aromatic hydrocarbons , but with the difference in the presence of oxygen in the region. The contributions of the fragments that comprise it, are positive (Figure 3b) . Saeki et al. (2003) observed that the BhQ is a potent ligand for the aryl hydrocarbon receptor (AhR) . Meanwhile the AhR is a transcription factor that mediates ligand-activated cellular responses through dioxin and PAHs, causing the expression of gene disruption and toxicity . Natural Coumarins: QSTR Approaches Regarding Their Genotoxicity
It can then be argued for the analogy of the contributions in the bay region, that the fused ring system of active pyranocoumarins is a bioisoster of the azafenantrene or polycyclic aromatic hydrocarbons (PAHs). These bioisosteres could also be a transcription factor that mediates cellular responses causing toxicity. These assumptions should be considered in future work. Within the structural features that are present in the compounds as inophyllum, it can be observed the permutation of a hydroxy group with a carbonyl one, in the C12 position. A slight decrease in toxicity (inophyllum C, 68.1%) compared to inophyllum A (68.6%), which could be explained by the presence of the carbonyl group (electron acceptor), is evident. Fig.3.The bay region bond contributions.(a) Benzo[h]quinoline (BhQ), from Estrada et al.(2006); (b)
Pyranocoumarins (angular type). In the case of calanolides, an unsaturation between carbons C7:C8 is observed, for the case of calanolide A, while in the same position for the (+)-dihydrocalanolide A that position is saturated. This indicates that the toxicity seems to decrease with the saturation. 2.2.1. Inophyllum A, Inophyllum C and Inophyllum G1 Structures
The structures of inophyllum A, inophyllum C and inophyllum G1 are shown in Figure 4. Fig. 4. Ring C fragment structures of inophyllum and pyranocoumarinic system.
Natural Coumarins: QSTR Approaches Regarding Their Genotoxicity
As observed in Table 7, inophyllum G1 showed a lower toxicity probability value (51.6%). If its structure is compared to the rest of inophyllum compounds (Figure 4), it can be observed a structural difference (isomeric ratio) in the C ring of the pyranocoumarinic system. This characteristic could be the explanation for the decrease in the genotoxicity in silico. 2.3. QSTR of Phenylcoumarins and Biscoumarins
Table 8 shows the same regularity: carbonyl groups esterified with saturated aliphatic groups, and the presence of aromatic groups, inactivate the molecule (ie isodispar B). Meanwhile the biscoumarin studied (Table 9) was also predicted to be inactive (ie dicoumarol). Table 8. Predictions made using TOPSMODE classification model to phenylcoumarins.
Prob. (%)
Table 9. Predictions made using TOPSMODE classification model to biscoumarins.
Biscoumarin
3. Overview of QSTR Regarding Natural Coumarins from the DB1 and Virtual Screening Validation
From a scan for regularities between chemical subclasses, it can be observed that when the scaffold has minimal substitutions, these molecules are inactive, eiumbelliferone, psoralen and xanthyletin. The presence of an Natural Coumarins: QSTR Approaches Regarding Their Genotoxicity
electron-withdrawing group (carbonyl) and esterified oxygen, and saturated and unsaturated aliphatic and aromatic groups, are associated with inactivity of molecules (ieammoresinol, ostruthin, osthole and mammea AB). Methoxy and hydroxy radicals seems to cause increased toxicity. This is related with the probability of clastogenicity, such in the cases of fraxidin, bergapten and methoxsalen. Similar results were obtained for other families of phenolic compounds in previous studies . The bay region present in pyranocoumarins (angular type) is also associated with genotoxicity. There are few studies evaluating the genetic toxicity (clastogenic activity) of natural coumarin (described in the DB1) in the literature. However, genotoxic experimental studies performed with the 6,7-HC, showed in vivo antigenotoxic effects and that there were not clastogenic/aneugenic effects in bone marrow cells of mice (micronucleus test) . The prediction proved to be similar to the experimental results obtained by Maistroet al. (2015), and it is also corroborated by preliminar genetic toxicity studied in vitro: Salmonella/microsome, comet and micronucleus assays. These results showed that this natural coumarin did not present mutagenic, genotoxic or clastogenic/aneugenic activities. In the present study, this compound was classified as inactive, with a probability of 56 %. The correspondence between prediction and experimental data allow to state that for this series of external data. Therefore, the model reached 100 % of goodclassification.6,7-HC, due to the presence of two hydroxyl groups on its benzene ring, seems to affect the formation and scavenging of ROS and influence free radical-mediated oxidative damage, being considered one of the most effective antioxidant in the family of coumarins . Because of that, this compounds has a great potential to be used as an antioxidant, protecting against DNA damage, cancer and aging. In addition, Payaet al. indicated that fraxetin and 4-methyldaphnetin showed in vitro pro-oxidant activity . The model did not explain these experimental results based on the hypothesis (relative clastogenicity-pro-oxidation) for the studied database, since these two molecules were considered inactive, although with very low percentage of probability (Table 3). The most abundant compounds in the plant families of BD1 are inactive compounds (ie umbelliferone, imperatorin and esculetin, which are present in various species with food use). Of the most active compounds, the most abundant in natural sources is bergapten, which can be found in Angelica archangelica, Apiumgraveolens, Foeniculumvulgare, Petroselinumcrispum, Pimpinellaanisum and C. limonum (Table 2). The structural features associated with in silico clastogenic activity that have been determined, can be considered in the formation of toxicological structural alerts associated with genotoxicity. This becomes important because the DNA damage, chromosome aberrations and consequently disorder in metabolic functioning, contributed to the initiation of the carcinogenetic process, through generation of ROS . Another view of the phenomenon has been postulated in which is now recognized that the pro-oxidant action of bioactive natural phenols has a unique preference rather than their antioxidant action, since it can play an Natural Coumarins: QSTR Approaches Regarding Their Genotoxicity
important role in cancer prevention . It was recently reported that dietary polyphenols could mobilize endogenous copper in humans, leading to oxidative DNA damage, which could be responsible for inducing anti-cancer properties . 4. Conclusion
Coumarins represent a diverse class of phytochemicals that are ubiquitous in the human diet and display several medicinal properties. Apiaceae family is a prominent food source of coumarins: carrots, celery, parsley, coriander, cumin, fennel and aniseed are present in the culinary practice around the world and in food industry. Rutaceae also proved to contain a great number of coumarins with nutritional and economic interest, standing out the citrus and some other like bael fruits. Besides, fruits and vegetables, olive oil, and beverages like coffee, wine, and black and green tea, are also important dietary sources of coumarins. Various natural coumarins showed clastogenic activity in silico. However, experimental studies are required to corroborate the information described in this chemoinformatic study. Generally, for this family, the QSTR associated the probability of being active to the presence of hydroxy and methoxy groups in the molecules. It is of particular significance the large number of active molecules from the subclass of pyranocoumarins (angular type), which has been linked to the positive contribution of the fragment that forms the bay region of the pyranocoumarinic system. These in silico results may contribute to the design of novel foods and drugs, contributing to its security. The genotoxicity of these compounds is of interest in the initiation of carcinogenic processes that occur through the generation of ROS. It may also be important in the prevention of cancer when these substances display pro-oxidant activity. The authors thank the partial financial support of University of Santiago de Compostela, University of Camagüey Ignacio Agramonte Loynazand Galician Plan of research, innovation and growth 2011-2015 (Plan I2C, ED481B 2014/086-0). References
[1]. Slavin, J.L., The challenges of nutrition policymaking. Nutrition Journal, 2015. 14(1): p. 151-157. [2]. Cunliffe, E. and T. Vincent, Experience-sensitive epigenetic mechanisms, developmental plasticity, and the biological embedding of chronic disease risk. Wiley Interdisciplinary Reviews: Systems Biology and Medicine, 2015. 7(2): p. 53-71. [3]. Siró, I., et al., Functional food. Product development, marketing and consumer acceptance—A review. Appetite, 2008. 51(3): p. 456–467. [4]. Chengguo, L. and N. Zhongguo, Functional dairy products ingredients and its standard. Tang, Wenqian, 2014. Natural Coumarins: QSTR Approaches Regarding Their Genotoxicity
[5]. Valko, M., et al., Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol, 2007. 39(1): p. 44-84 [6]. Bouayed, J., Polyphenols: a potential new strategy for the prevention and treatment of anxiety and depression. Curr Nutr Food Sci, 2010. 6: p. 13-18. [7]. Ratnam, D., et al., Role of antioxidants in prophylaxis and therapy: A pharmaceutical perspective. Journal of Controlled Release, 2006. 113(3): p. 189-207. [8]. Pandey, K. and S. Rizvi, Plant polyphenols as dietary antioxidants in human health and disease. Oxid Med Cell Longev, 2009. 2(5): p. 270-278. [9]. Uttara, B., et al., Oxidative stress and neurodegenerative diseases: a review of upstream and downstream antioxidant therapeutic options. Curr. Neuropharmacol, 2009. 7(1): p. 65-74. [10]. Reuter, S., et al., Oxidative stress, inflammation, and cancer: How are they linked? . Free Radical Biol. Med, 2010. 49(11): p. 1603-1616. [11]. Azam, S., et al., Prooxidant property of green tea polyphenols epicatechin and epigallocatechin-3-gallate: implications for anticancer properties. Toxicol In Vitro, 2004. 18(5): p. 555-561. [12]. Decker, E.A., Phenolics: prooxidants or antioxidants? Nutr Rev, 1997. 55: p. 396-398. [13]. Watjen, W., et al., Low concentrations of flavonoids are protective in rat H4IIE cells whereas high concentrations cause DNA damage and apoptosis. J Nutr., 2005. 135: p. 525-531. [14]. Lambert, S. and Yang., Possible controversy over dietary polyphenols: benefits vs risks. Chemical Research in Toxicology, 2007. 20(4): p. 583-585 [15]. Gutteridge and B. Halliwell, Antioxidats: molecules, medicines, and myths. Biochemical and Biophysical Research Communications 2010. 393: p. 561-564. [16]. Gaspar, J., et al., Pro-oxidant Activities of Flavonols: A Structure Activity Study, in Natural Antioxidants and Food Quality in Atherosclerosis and Cancer Prevention. 1996, Cambridge: Royal Society of Chemistry: UK. [17]. Stich. H, et al., The action of transition metals on the genotoxicity of simple phenols, phenolic acids and cinnamic acids. 1981, Vancouver. Canada: University of British Columbia. [18]. Serra, J., E. Thompson, and P. Jurs, Development of binary classification of structural chromosome aberrations for a diverse set of organic compounds from molecular structure. Chem Res Toxicol, 2003. 16: p. 153-163. [19]. Maistro, E.L., et al., In vitro genotoxicity assessment of caffeic, cinnamic and ferulic acids. Genetics and Molecular Research., 2011. 10(2): p. 1130-1140. [20]. Yordi, E.G., et al. Influence of thermodynamic parameters on the genotoxicity of bioactive phenolic compounds present in food. in 17th Int Electron Conf Synth Org Chem. 2013. University of Santiago de Compostela: Sciforum Electronic Conferences Series.: University of Santiago de Compostela: Sciforum Electronic Conferences Series. [21]. Aruoma, O.I., Methodological considerations for characterizing potential antioxidant actions of bioactive components in plant foods. Mutation Research, 2003. 523-524: p. 9-20. [22]. Jaeschke, H., et al., Mechanisms of hepatotoxicity. Toxicol Sci 2002. 65(2): p. 166-176. Natural Coumarins: QSTR Approaches Regarding Their Genotoxicity
[23]. James, L., P. Mayeux, and J. Hinson, Acetaminophen-induced hepatotoxicity. Drug Metab Dispos 2003. 31(12): p. [24]. Aruoma, O.I., Free radicals, antioxidant and international nutrition. Asia Pacific J Clin Nutr, 1999. 8(1): p. 53-63. [25]. Halliwell, B. and M. Whiteman, Measuring reactive species and oxidative damage in vivo and in cell culture: how should you do it and what do the results mean? Br J Pharmacol., 2004. 142: p. 231-255. [26]. Mayne, S., Antioxidant nutrients and chronic disease: use of biomarkers of exposure and oxidative stress status in epidemiologic research.J Nutr., 2003. 133: p. 933S-940S. [27]. Espín, J. and F. Tomás-Barberán, Constituyentes bioactivos no-nutricionales de alimentos de origen vegetal y su aplicación en alimentos funcionales, in Alimentos funcionales. 2005, Fundación Española para la Ciencia y la Tecnología [FECYT]: Madrid. p. 101-153. [28]. Siân, B.A. and D.G. Lindsay, European Research on the Functional Effects of Dietary Antioxidants. Molecular Aspects of Medicine, 2002 [29]. Marques, E.S., D.B. Salles, and E.L. Maistro, Assessment of the genotoxic/clastogenic potential of coumarin derivative 6,7-dihydroxycoumarin (aesculetin) in multiple mice organs. Toxicology Reports, 2015. [30]. Matos, M.J., et al., Coumarins: an important class of phytochemicals, in Phytochemical, R. Venket, Editor. 2015, Intech: Croatia, in press. [31]. Matos, M.J., et al., Focusing on new monoamine oxidase inhibitors: differently substituted coumarins as an interesting scaffold. Current Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) 2012. 12(20): p. 2210-2239. [32]. Qian, L., et al., Research progress on coumarin and its derivatives. Guangzhou Huagong 2013. 41(1): p. 41-43. [33]. Zheng, L., T. Zhao, and L. Sun, Research progress of the pharmacological action and pharmacokinetics of coumarins. Shizhen Guoyi Guoyao, 2013. 24(3): p. 714-717. [34]. Borges, F., et al., Simple coumarins and analogues in medicinal chemistry: occurrence, synthesis and biological activity. Curr. Med. Chem, 2005. 12: p. 887-916. [35]. Estrada, E. and E. Molina, Novel local (fragment-based) topological molecular descriptors for QSPR/QSAR and molecular design. Journal of Molecular Graphics and Modelling, 2001. 20: p. 54-64. [36]. Estrada, E. and E. Molina, Automatic extraction of structural alerts for predicting chromosome aberrations of organic compounds. J Mol Graphics and Model, 2006. 25 p. 275-288. [37]. Yordi, E.G., et al. QSAR study of the potential clastogenic activity of phenolic acids. in 16th International Electronic Conference on Synthetic Organic Chemistry. 2012 Universidad de Santiago de Compostela Universidad de Santiago de Compostela [38]. Ribeiro, C.V. and M.A. Kaplan, Tendências evolutivas de famílias produtoras de cumarinas em angiospermae.Quim. Nova, 2002. 25(4): p. 533-538. [39]. Rizk, E.T. and S.M.M. Hassan, Molluscicidal activity of furanocoumarins isolated from Ammi majus against Biomphalaria alexandrina snails. Egyptian Journal of Pharmaceutical Sciences, 2000. 40(1): p. 61-71. Natural Coumarins: QSTR Approaches Regarding Their Genotoxicity
[40]. Newall, C.A., L.A. Anderson, and J.D. Phillipson, Herbal medicines. A guide for health-care professionals. 1996, London: The Pharmaceutical Press. [41]. Peris, J.B., G. Stübing, and B. Vanaclocha, Fitoterapia aplicada, ed. r. edicion. 1995, Valencia MICOF. [42]. Rodríguez, J.E., O.D. López, and J.M. Gil, Método para la cuantificación de cumarina en extracto seco a partir de extractos de Justicia pectoralis Jacq. Rev Cubana Plant Med 2008 13(3). [43]. Gasparotto, A., et al., Estudo fitoquímico e avaliação da atividade moluscicida do Calophyllum brasiliense Camb (Clusiaceae).Quím. Nova, 2005. 28 (4). [44]. Lemmens, R.H.M.J. and N. Bunyapraphastara, Plant resourses of South-East Asia, in Medicinal and poisonous plant, R.H.M.J. Lemmens and N. Bunyapraphastara, Editors. 2003, Backhuys: Leiden (Holanda). [45]. Yordi, E.G., et al., Structural Alerts for Predicting Clastogenic Activity of Pro-oxidant Flavonoid Compounds: Quantitative Structure—Activity Relationship Study J Biomol Screen, 2011. 17 (2): p. 85-93. [46]. Yordi, E.G., et al., Structural alerts for predicting clastogenic activity of pro-oxidant flavonoid compounds: quantitative structure-activity relationship study. J Biomol Screen, 2012. 17 (2): p. 216-224. [47]. Saeki, K., et al., Activation of the human Ah receptor by aza-polycyclic aromatic hydrocarbons and their halogenated derivatives. BiolPharm Bull. , 2003. 26: p. 448-452. [48]. Safe, S., Molecular biology of the Ah receptor and its role in carcinogenesis. Toxicol Lett., 2001. 120 p. 1-7. [49]. Payá, M., B. Halliwell, and J.R.S. Hoult, Interactions of a series of coumarins with reactive oxygen species: Scavenging of superoxide, hypochlorous acid and hydroxyl radicals. Biochemical Pharmacology, 1992. 44(2): p. 205-214. [50]. Hoult, J.R.S. and M. Payá, Pharmacological and biochemical actions of simple coumarins: Natural products with therapeutic potential. General Pharmacology: The Vascular System, 1996. 27(4): p. 713-722. [51]. Bhattacharyya, S., et al., Immunopharmacology and Inflammation A synthetic coumarin (4-Methyl-7 hydroxy coumarin) has anti-cancer potentials against DMBA-induced skin cancer in mice. European Journal of Pharmacology 2009. 614 p. 128-136. [52]. Lambert, J. and R. Elias, The antioxidant and pro-oxidant activities of green tea polyphenols: A role in cancer prevention. Archives of Biochemistry and Biophysics., 2010. 501(1): p. 65-72. [53]. Azmi, A., S. Bhat, and S. Hadi, Resveratrol-Cu(II) induced DNA breakage in human peripheral lymphocytes: implications for anticancer properties. FEBS Lett, 2005. 579: p. 3131-3135.

Source: http://www.ss-pub.org/wp-content/uploads/2015/08/BCR2015052601.pdf

rjelal.com

Research Journal of English Language and Literature (RJELAL) A Peer Reviewed (Refereed) International Journal http://www.rjelal.com RESEARCH ARTICLE FICTIONALISNG THE BIOGRAPHY: A CASE STUDY OF C.K JANU VIA CULTURAL TRANSLATION ANJU ANTONY Ph.D., Scholar, Kannur University

eexo.gr

JOURNAL OF CLINICAL ONCOLOGY Phase III Randomized Trial of FOLFIRI VersusFOLFOX4 in the Treatment of Advanced ColorectalCancer: A Multicenter Study of the Gruppo OncologicoDell'Italia MeridionaleGiuseppe Colucci, Vittorio Gebbia, Giancarlo Paoletti, Francesco Giuliani, Michele Caruso,Nicola Gebbia, Giacomo Cartenı , Biagio Agostara, Giuseppe Pezzella, Luigi Manzione, Nicola Borsellino,Andrea Misino, Sante Romito, Ernesto Durini, Stefano Cordio, Marisa Di Seri, Massimo Lopez,and Evaristo Maiello