Oxidative Stress Management in Pre-Cancer: History
View Latest Version
Please note this is an old version of this entry, which may differ significantly from the current revision.
Subjects: Oncology
Contributor:
Daisuke Uchida
,
Akinobu Takaki
,
Atsushi Oyama
,
Takuya Adachi
,
Nozomu Wada
,
Hideki Onishi
,
Hiroyuki Okada

Chronic viral hepatitis B and C and non-alcoholic fatty liver disease (NAFLD) have been widely acknowledged to be the leading causes of liver cirrhosis and hepatocellular carcinoma. As anti-viral treatment progresses, the impact of NAFLD is increasing. NAFLD can coexist with chronic viral hepatitis and exacerbate its progression. Oxidative stress has been recognized as a chronic liver disease progression-related and cancer-initiating stress response. However, there are still many unresolved issues concerning oxidative stress, such as the correlation between the natural history of the disease and promising treatment protocols. Recent findings indicate that oxidative stress is also an anti-cancer response that is necessary to kill cancer cells. Oxidative stress might therefore be a cancer-initiating response that should be down regulated in the pre-cancerous stage in patients with risk factors for cancer, while it is an anti-cancer cell response that should not be down regulated in the post-cancerous stage, especially in patients using anti-cancer agents. Antioxidant nutrients should be administered carefully according to the patients’ disease status.

  • oxidative stress
  • chronic hepatitis
  • hepatocellular carcinoma
  • antioxidant

1. Introduction

Given that oxidative stress is involved in chronic viral hepatitis and NAFLD cross-sectional pathology, the management strategy can be commonly applied. Nutritional support or supplementation is used to eliminate ROS or activate antioxidant pathways, such as the Nrf2 pathway[1]. In the case of the simultaneous activation of Nrf2 and NFkB, Nrf2 acts antagonistically against NFkB[2]. In a chemically induced liver fibrosis model, antioxidant pomegranate juice, which contained anthocyanins and hydrolysable tannins, reduced hepatic fibrosis via Nrf2 activation and NFkB inactivation[3]. Adjusting for the balance of inflammatory or oxidative stress responses and the antioxidant response in the presence of disease according to the patient’s oxidative stress condition is necessary; however, at present, this approach is not widely applied. The difficulty in defining the oxidative stress status is one reason for this. This background probably explains why the results of clinical studies of antioxidants to regulate carcinogenesis are often unsuccessful.

Trace elements are involved in oxidative stress-related conditions. Some of them, such as iron and zinc, are able to be measured as standard clinical markers and monitored. Iron has been shown to be toxic as an oxidative stress inducer in chronic liver disease, as mentioned in Section 2.4, and its level can be reduced by phlebotomy or iron chelator administration in chronic hepatitis and NASH[4]. Zinc plays a role in the reduction of inflammatory cytokines and oxidative stress via the synthesis of antioxidant enzymes and catalyzing enzymes, or by influencing transcriptional factors[5]. One of the inflammation related transcription factors NF-κB is reduced via its negative regulator zinc finger protein (A20) or PPAR-αα. An antioxidant enzyme Cu,Zn- SOD (SOD1) contains zinc as a co-factor. Zinc has been shown to be deficient in cases of chronic liver disease, especially cirrhosis, possibly because of the impaired absorption from the intestine and increased excretion in the urine[6]. Zinc is necessary for the function of Paneth cells, which prevent pathogenic microbial invasion in the intestine, a risk for subsequent hepatic inflammation via α-defensin production[7]. However, the presence of excess dietary zinc increases oxidative stress with an increased intestinal permeability that should be avoided[8]. An appropriate and effective supplementation strategy is therefore necessary, even for trace elements.

Selenium is one of the essential elements required for the normal development of human and animal organisms. Selenium activates GPx, which is a representative antioxidant enzyme. The Gpx-1 enzyme activity and mRNA levels decrease dramatically in a selenium deficient diet, whereas other selenoproteins are less sensitive[9]. Feeding a selenium deficient diet with glutathione deficiency resulted in oxidative stress, during which the protein malondialdehyde levels increase in the liver and an individual thus becomes sensitive to drug induced liver injury, thereby indicating the necessity of selenium for antioxidant system activation[10]. Given that the blood selenium level was observed to decrease in liver cirrhosis patients, supplementation may be one approach to improve the antioxidant function in such cases[11].

2. Dietary Intervention for Oxidative Stress

The potential dietary antioxidant intake has been assessed in several studies. Even an increase in the food frequency questionnaire-defined dietary total antioxidant capacity was shown to be correlated with a lower liver histological assessment of NASH-related hepatocellular ballooning[12]. The intake of orange juice, a source of flavonoids and vitamin C, for eight weeks, resulted in a reduction of total cholesterol, LDL-cholesterol, C reactive protein, and oxidative stress related markers, in a randomized study of 43 chronic hepatitis C patients [13]. Dietary vitamin C intake was shown to be inversely correlated with the presence of NAFLD, similarly to vitamin E, suggesting the favorable effect of both vitamins[14]. The positive effect of the intake of vitamin C on NAFLD prevention was shown to be dominant in middle-aged, non-obese males[15].

An iron-reduced diet, often coupled with phlebotomy, has been shown to be effective against chronic hepatitis C and NASH, resulting in a reduction of the risk of hepatocarcinogenesis[16]. Zinc supplementation has been evaluated in more than 1300 studies, although not many have shown statistically significant favorable results[17].

A small number of studies showed the preferable effects of zinc supplementation, suggesting the important role for antioxidant response. The transaminase level in chronic hepatitis C patients decreased[18], and the serum levels of type IV collagen and tissue inhibitors of matrix-metalloproteinase-1 (TIMP-1) levels in chronic hepatitis patients also decreased[19]. In cirrhosis patients, zinc supplementation may help to improve protein catabolism[20]. As zinc is often involved in standard laboratory examinations, to measure, evaluate, and adequate supplementation are thus all necessary steps. Large scale studies defining the best approach in chronic liver diseases are thus called for in the future.

Selenium supplementation has been shown to be effective in some patients with chronic thyroiditis, due to its immune targeting effect[21]. During chemotherapy for cancer patients, selenium supplementation has been shown to be associated with an improvement in fatigue, as well as in the liver and renal function[22]. However, in primary biliary cirrhosis, the supplementation of selenium did not show any antioxidant activities, while the renal excretion was increased, suggesting that a cirrhotic liver could not take advantage of selenium adequately[23]. Although selenium administration helps in the recovery of hepatic steatosis via PPAR-α activation in some diabetic mouse models[24], selenium supplementation to humans has been cautioned to increase the risk of type 2 diabetes[25]. It therefore remains difficult to draw any definite conclusions about selenium supplementation as an antioxidant.

3. Clinical Trials for Oxidative Stress

Many clinical trials have been undertaken to investigate whether antioxidants prevent cancer or death; however, the results are confusing. In the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC), alpha-tocopherol reduced the incidence of prostate cancer, whereas beta-carotene increased the incidence of lung cancer and total mortality[26]. The Selenium and Vitamin E Cancer Prevention Trial (SELECT), a randomized control trial (RCT) that aimed to show the potential for vitamin E to reduce the risk of prostate cancer, showed a 17% increase in the incidence of prostate cancer[27]. Another study showed that beta-carotene supplementation was associated with an increased risk of lung cancer[28]. An epidemiologic study showed that dietary vitamin E intake and vitamin E supplement use was associated with a reduced risk of liver cancer, although vitamin C and multivitamin intake increased the risk of liver cancer[29]. To define the real effect of antioxidant supplementation, studies should be planned according to the oxidative stress-related conditions before the start of intervention.

Antioxidant therapy, such as the administration of vitamin E, has been shown to be effective in improving inflammation and histological activity in NASH and is recommended in several guidelines for NAFLD. However, the long-term effect of these therapies, including the beneficial effects on the risk of hepatocarcinogenesis, is unclear[30][31]. There are also other antioxidant agents that have been shown to have favorable effects on NASH and NASH-related hepatocarcinogenesis.

Antidiabetic agents are recommended for NAFLD patients complicated with diabetes. Most of the antidiabetic agents, but not insulin or insulin producers, have been shown to be effective for NAFLD. Metformin and pioglitazone have been accepted as representative antioxidant agents[32]. Metformin has also been shown to activate AMPK by inhibiting mitochondrial complex I and inducing AMPK-independent lysosomal changes, resulting in many favorable effects in carcinogenesis and the post-carcinogenesis control of cancers[33]. Metformin-related AMPK pathway activation is involved in many cell types, including T cells, B cells, hepatocytes, and even liver fibrosis-inducing hepatic stellate cells (HSCs). As an antioxidant agent, metformin activates the Nrf2 signaling pathway, resulting in the production of heme oxygenase-1 (HO-1; an antioxidant enzyme), in human endothelial cells and thereby increasing the antioxidant function of these cells. However, in several cancer cell lines, including HCC, metformin suppressed the Nrf2 expression in an AMPK-independent manner[34]. Research on the effect of metformin on normal and cancerous cells is still ongoing. At present, this agent is recognized as suitable for pre-cancer administration, to prevent hepatocarcinogenesis and post-cancer administration, to prevent HCC recurrence.

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that play key roles in cellular metabolic homeostasis and inflammation. Pioglitazone is a diabetes agent that activates PPAR-g. It has been shown to improve insulin resistance, and several studies reported a favorable effect on NASH. One six-month randomized study of pioglitazone plus hypocaloric diet showed a plasma aminotransferase decrease, insulin sensitivity improvement, hepatic fat content decrease, and a histopathological reduction in liver necro-inflammation[35]. However, an additional analysis of select patients in the same cohort revealed that pioglitazone induced whole-body weight gain, and the increased weight was due to an increase in adipose tissue mass and not water retention [36].

Other antioxidants have been shown to be effective in several small series of studies. The administration of L-carnitine (a mitochondrial long-chain fatty acid uptake-related molecule) was reported to be associated with the histological improvement of NASH in a mouse model[37] and an RCT[38] . Flavonoids (heterogeneous polyphenols) have been shown to exert an antioxidant function, protecting the liver in a CCl4-induced liver injury model[39]. A mixture of flavonolignans and minor polyphenolic compounds derived from the milk thistle plant (Silybum marianum) named silymarin has been shown to have antioxidant power [40]. The main component of silymarin, silybin, has been shown to restore nicotinamide adenine dinucleotide (NAD+) levels, decreasing the glucose uptake and lipid peroxidation and resulting in the improvement of NAFLD[41][42]. Silymarin was shown to be effective for improving NASH-related fibrosis in a randomized, double-blind, placebo-controlled study, although the number of patients was relatively small (49 for silymarin and 50 for placebo)[43] .

Many studies using antioxidant agents have shown promising results for NAFLD, suggesting that these agents may be viable candidate compounds in addition to standard vitamin E.

This entry is adapted from the peer-reviewed paper 10.3390/nu12061576

References

  1. Peternelj, T.T.; Coombes, J.S. Antioxidant supplementation during exercise training: Beneficial or detrimental? Sports Med. 2011, 41, 1043–1069.
  2. Bellezza, I.; Mierla, A.L.; Minelli, A. Nrf2 and NF-kappaB and Their Concerted Modulation in Cancer Pathogenesis and Progression. Cancers 2010, 2, 483–497.
  3. Husain, H.; Latief, U.; Ahmad, R. Pomegranate action in curbing the incidence of liver injury triggered by Diethylnitrosamine by declining oxidative stress via Nrf2 and NFkappaB regulation. Sci. Rep. 2018, 8, 8606.
  4. Czaja, A.J. Review article: Iron disturbances in chronic liver diseases other than haemochromatosis-pathogenic, prognostic, and therapeutic implications. Aliment. Pharm. Ther. 2019, 49, 681–701.
  5. Olechnowicz, J.; Tinkov, A.; Skalny, A.; Suliburska, J. Zinc status is associated with inflammation, oxidative stress, lipid, and glucose metabolism. J. Physiol. Sci. 2018, 68, 19–31.
  6. Stamoulis, I.; Kouraklis, G.; Theocharis, S. Zinc and the liver: An active interaction. Dig. Dis. Sci. 2007, 52, 1595–1612.
  7. Zhong, W.; Wei, X.; Hao, L.; Lin, T.D.; Yue, R.; Sun, X.; Guo, W.; Dong, H.; Li, T.; Ahmadi, A.R.; et al. Paneth Cell Dysfunction Mediates Alcohol-related Steatohepatitis Through Promoting Bacterial Translocation in Mice: Role of Zinc Deficiency. Hepatology 2020, 71, 1575–1591.
  8. Podany, A.; Rauchut, J.; Wu, T.; Kawasawa, Y.I.; Wright, J.; Lamendella, R.; Soybel, D.I.; Kelleher, S.L. Excess Dietary Zinc Intake in Neonatal Mice Causes Oxidative Stress and Alters Intestinal Host-Microbe Interactions. Mol. Nutr. Food Res. 2019, 63, e1800947.
  9. Sunde, R.A.; Raines, A.M.; Barnes, K.M.; Evenson, J.K. Selenium status highly regulates selenoprotein mRNA levels for only a subset of the selenoproteins in the selenoproteome. Biosci. Rep. 2009, 29, 329–338.
  10. Goda, K.; Muta, K.; Yasui, Y.; Oshida, S.; Kitatani, K.; Takekoshi, S. Selenium and Glutathione-Depleted Rats as a Sensitive Animal Model to Predict Drug-Induced Liver Injury in Humans. Int. J. Mol. Sci. 2019, 20, 3141.
  11. Loguercio, C.; De Girolamo, V.; Federico, A.; Feng, S.L.; Crafa, E.; Cataldi, V.; Gialanella, G.; Moro, R.; Del Vecchio Blanco, C. Relationship of blood trace elements to liver damage, nutritional status, and oxidative stress in chronic nonalcoholic liver disease. Biol. Trace Elem. Res. 2001, 81, 245–254.
  12. De Oliveira, D.G.; de Faria Ghetti, F.; Moreira, A.P.B.; Hermsdorff, H.H.M.; de Oliveira, J.M.; de Castro Ferreira, L. Association between dietary total antioxidant capacity and hepatocellular ballooning in nonalcoholic steatohepatitis: A cross-sectional study. Eur. J. Nutr. 2019, 58, 2263–2270.
  13. Goncalves, D.; Lima, C.; Ferreira, P.; Costa, P.; Costa, A.; Figueiredo, W.; Cesar, T. Orange juice as dietary source of antioxidants for patients with hepatitis C under antiviral therapy. Food Nutr. Res. 2017, 61, 1296675.
  14. Ivancovsky-Wajcman, D.; Fliss-Isakov, N.; Salomone, F.; Webb, M.; Shibolet, O.; Kariv, R.; Zelber-Sagi, S. Dietary vitamin E and C intake is inversely associated with the severity of nonalcoholic fatty liver disease. Dig. Liver Dis. 2019, 51, 1698–1705.
  15. Wei, J.; Lei, G.H.; Fu, L.; Zeng, C.; Yang, T.; Peng, S.F. Association between Dietary Vitamin C Intake and Non-Alcoholic Fatty Liver Disease: A Cross-Sectional Study among Middle-Aged and Older Adults. PLoS ONE 2016, 11, e0147985.
  16. Kato, J.; Miyanishi, K.; Kobune, M.; Nakamura, T.; Takada, K.; Takimoto, R.; Kawano, Y.; Takahashi, S.; Takahashi, M.; Sato, Y.; et al. Long-term phlebotomy with low-iron diet therapy lowers risk of development of hepatocellular carcinoma from chronic hepatitis C. J. Gastroenterol. 2007, 42, 830–836. [Google Scholar] [CrossRef]
  17. Diglio, D.C.; Fernandes, S.A.; Stein, J.; Azeredo-da-Silva, A.; de Mattos, A.A.; Tovo, C.V. Role of zinc supplementation in the management of chronic liver diseases: A systematic review and meta-analysis. Ann. Hepatol. 2020, 19, 190–196.
  18. Murakami, Y.; Koyabu, T.; Kawashima, A.; Kakibuchi, N.; Kawakami, T.; Takaguchi, K.; Kita, K.; Okita, M. Zinc supplementation prevents the increase of transaminase in chronic hepatitis C patients during combination therapy with pegylated interferon alpha-2b and ribavirin. J. Nutr. Sci. Vitaminol. 2007, 53, 213–218.
  19. Takahashi, M.; Saito, H.; Higashimoto, M.; Hibi, T. Possible inhibitory effect of oral zinc supplementation on hepatic fibrosis through downregulation of TIMP-1: A pilot study. Hepatol. Res. 2007, 37, 405–409.
  20. Kodama, H.; Tanaka, M.; Naito, Y.; Katayama, K.; Moriyama, M. Japan’s Practical Guidelines for Zinc Deficiency with a Particular Focus on Taste Disorders, Inflammatory Bowel Disease, and Liver Cirrhosis. Int. J. Mol. Sci. 2020, 21, 2941.
  21. Winther, K.H.; Papini, E.; Attanasio, R.; Negro, R.; Hegedus, L. A 2018 European Thyroid Association Survey on the Use of Selenium Supplementation in Hashimoto’s Thyroiditis. Eur. Thyroid. J. 2020, 9, 99–105.
  22. Vieira, M.L.; Fonseca, F.L.; Costa, L.G.; Beltrame, R.L.; Chaves, C.M.; Cartum, J.; Alves, S.I.; Azzalis, L.A.; Junqueira, V.B.; Pereria, E.C.; et al. Supplementation with selenium can influence nausea, fatigue, physical, renal, and liver function of children and adolescents with cancer. J. Med. Food 2015, 18, 109–117.
  23. Valimaki, M.; Alfthan, G.; Vuoristo, M.; Ylikahri, R. Effects of selenium supplementation on blood and urine selenium levels and liver function in patients with primary biliary cirrhosis. Clin. Chim. Acta 1991, 196, 7–15.
  24. Shi, Y.; Zou, Y.; Shen, Z.; Xiong, Y.; Zhang, W.; Liu, C.; Chen, S. Trace Elements, PPARs, and Metabolic Syndrome. Int. J. Mol. Sci. 2020, 21, 2612.
  25. Vinceti, M.; Filippini, T.; Rothman, K.J. Selenium exposure and the risk of type 2 diabetes: A systematic review and meta-analysis. Eur. J. Epidemiol. 2018, 33, 789–810.
  26. Taylor, P.R.; Li, B.; Dawsey, S.M.; Li, J.Y.; Yang, C.S.; Guo, W.; Blot, W.J. Prevention of esophageal cancer: The nutrition intervention trials in Linxian, China. Linxian Nutrition Intervention Trials Study Group. Cancer Res. 1994, 54, 2029s–2031s.
  27. Klein, E.A.; Thompson, I.M., Jr.; Tangen, C.M.; Crowley, J.J.; Lucia, M.S.; Goodman, P.J.; Minasian, L.M.; Ford, L.G.; Parnes, H.L.; Gaziano, J.M.; et al. Vitamin E and the risk of prostate cancer: The Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 2011, 306, 1549–1556.
  28. Omenn, G.S.; Goodman, G.E.; Thornquist, M.D.; Balmes, J.; Cullen, M.R.; Glass, A.; Keogh, J.P.; Meyskens, F.L., Jr.; Valanis, B.; Williams, J.H., Jr.; et al. Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial. J. Natl. Cancer Inst. 1996, 88, 1550–1559.
  29. Guobin He; Michael Karin; NF-κB and STAT3 – key players in liver inflammation and cancer. Cell Research 2010, 21, 159-168, 10.1038/cr.2010.183.
  30. Al-Busafi, S.A.; Bhat, M.; Wong, P.; Ghali, P.; Deschenes, M. Antioxidant therapy in nonalcoholic steatohepatitis. Hepat. Res. Treat. 2012, 2012, 947575.
  31. Sanyal, A.J.; Chalasani, N.; Kowdley, K.V.; McCullough, A.; Diehl, A.M.; Bass, N.M.; Neuschwander-Tetri, B.A.; Lavine, J.E.; Tonascia, J.; Unalp, A.; et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N. Engl. J. Med. 2010, 362, 1675–1685.
  32. Biondo, L.A.; Teixeira, A.A.S.; de Oliveira Santos Ferreira, K.C.; Neto, J.C.R. Pharmacological strategies for insulin sensitivity: Thiazolidinediones and metformin. Curr. Pharm. Des. 2020, 10.2174/1381612826666200122124116.
  33. Rena, G.; Hardie, D.G.; Pearson, E.R. The mechanisms of action of metformin. Diabetologia 2017, 60, 1577–1585.
  34. Minh Truong Do; Hyung Gyun Kim; Tilak Khanal; Jae Ho Choi; Dong Hee Kim; Tae Cheon Jeong; Hye Gwang Jeong; Metformin inhibits heme oxygenase-1 expression in cancer cells through inactivation of Raf-ERK-Nrf2 signaling and AMPK-independent pathways. Toxicology and Applied Pharmacology 2013, 271, 229-238, 10.1016/j.taap.2013.05.010.
  35. Renata Belfort; Stephen A. Harrison; Kenneth Brown; Celia Darland; Joan Finch; Jean Hardies; Bogdan Balas; Amalia Gastaldelli; Fermin Tio; Joseph Pulcini; et al. A Placebo-Controlled Trial of Pioglitazone in Subjects with Nonalcoholic Steatohepatitis. New England Journal of Medicine 2006, 355, 2297-2307, 10.1056/nejmoa060326.
  36. Bogdan Balas; Renata Belfort; Stephen A. Harrison; Celia Darland; Joan Finch; Steven Schenker; Amalia Gastaldelli; Kenneth Cusi; Pioglitazone treatment increases whole body fat but not total body water in patients with non-alcoholic steatohepatitis. Journal of Hepatology 2007, 47, 565-570, 10.1016/j.jhep.2007.04.013.
  37. Hisashi Ishikawa; Akinobu Takaki; Ryuichiro Tsuzaki; Tetsuya Yasunaka; Kazuko Koike; Yasuyuki Shimomura; Hiroyuki Seki; Hiroshi Matsushita; Yasuhiro Miyake; Fusao Ikeda; et al. L-Carnitine Prevents Progression of Non-Alcoholic Steatohepatitis in a Mouse Model with Upregulation of Mitochondrial Pathway. PLoS ONE 2014, 9, e100627, 10.1371/journal.pone.0100627.
  38. Mariano Malaguarnera; Maria Pia Gargante; Cristina Russo; Tijana Antic; Marco Vacante; Michele Malaguarnera; Teresio Avitabile; Giovanni Li Volti; Fabio Galvano; L-Carnitine Supplementation to Diet: A New Tool in Treatment of Nonalcoholic Steatohepatitis—A Randomized and Controlled Clinical Trial. American Journal of Gastroenterology 2010, 105, 1338-1345, 10.1038/ajg.2009.719.
  39. Yu Liu; Pei‑Hao Wen; Xin‑Xue Zhang; Yang Dai; Qiang He; Breviscapine ameliorates CCl4‑induced liver injury in mice through inhibiting inflammatory apoptotic response and ROS generation. International Journal of Molecular Medicine 2018, 42, 755-768, 10.3892/ijmm.2018.3651.
  40. Carmela Loguercio; Silybin and the liver: From basic research to clinical practice. World Journal of Gastroenterology 2011, 17, 2288-2301, 10.3748/wjg.v17.i18.2288.
  41. Salomone, F.; Barbagallo, I.; Godos, J.; Lembo, V.; Currenti, W.; Cina, D.; Avola, R.; D’Orazio, N.; Morisco, F.; Galvano, F.; et al. Silibinin Restores NAD(+) Levels and Induces the SIRT1/AMPK Pathway in Non-Alcoholic Fatty Liver. Nutrients 2017, 9, 1086.
  42. Lama, S.; Vanacore, D.; Diano, N.; Nicolucci, C.; Errico, S.; Dallio, M.; Federico, A.; Loguercio, C.; Stiuso, P. Ameliorative effect of Silybin on bisphenol A induced oxidative stress, cell proliferation and steroid hormones oxidation in HepG2 cell cultures. Sci. Rep. 2019, 9, 3228.
  43. Chan Wah Kheong; Nik Raihan Nik Mustapha; Sanjiv Mahadeva; A Randomized Trial of Silymarin for the Treatment of Nonalcoholic Steatohepatitis. Clinical Gastroenterology and Hepatology 2017, 15, 1940-1949.e8, 10.1016/j.cgh.2017.04.016.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
This entry is offline, you can click here to edit this entry!
ScholarVision Creations
Feedback