Ameliorative effect of Panax quinquefolius on sodium arsenite induced toxicity in Charles Foster rats
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Abstract
An estimated 70 million population are exposed to arsenic poisoning in India in the 2020. The present study is aimed to develop the antidote for arsenic-induced toxicity in Charles Foster rats. A total of n=18 rats (12 weeks old) of an average weight of 160 ± 20 g were used for the study. The study group included three groups, n=6 control (Group I: Untreated ) and n= 12 (group II) treated with sodium arsenite orally at the dose of 8mg/Kg b.w daily for 6 months. The n= 6 animals were dissected and the rest n=6 (Group III) was administered orally with Panax quinquefolius (Ginseng) root ethanolic extract at 300mg/Kg body weight per day for 8 weeks. All the animals were sacrificed after the completion of their respective doses and their blood samples were taken for haematological and biochemical evaluation, while the vital tissues such as liver and kidneys for the histopathological study. The study revealed significant fluctuation (p<0.0001/p<0.001/p<0.05) in the haematological parameters viz. leukocyte count, haemoglobin, red blood cell count, haematocrit percentage, MCV, MCH and MCHC and biochemical parameters such as SGPT, SGOT, ALP, bilirubin, urea, uric acid, creatinine and lipid peroxidation in arsenic-treated groups. There was a significant reduction (p<0.0001/p<0.001/p<0.05) in the levels of haematological and biochemical parameters after the administration of ginseng extract. Similarly, the histopathological study revealed a high magnitude of degeneration in the hepatocytes and nephrocytes after the treatment of arsenic, but after the administration of ginseng extract, there was significant restoration at the cellular level. Thus, the root extract of P. quinquefolius possessed significant ameliorative properties against arsenic-induced toxicity in rats.
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Keywords
Arsenic treatment, Ameliorative effect, Charles Foster rats, Panax quinquefolius, Root extract
References
Abbey, A. P., & Belliveau, R. R. (1978). Enumeration of platelets. American Journal of Clinical Pathology, 69(1), 55–56. https://doi.org/10.1093/ajcp/69.1.55.
Attele, A. S., Zhou, Y. P., Xie, J. T., Wu, J. A., Zhang, L., Dey, L., Pugh, W., Rue, P. A., Polonsky, K. S. & Yuan, C. S. (2002). Antidiabetic effects of Panax ginseng berry extract and the identification of an effective component. Diabetes, 51(6), 1851–1858. https://doi.org/10.2337/diabetes.51.6.1851.
Balci, M., Namuslu, M., Devrim, E. & Durak, I. (2009). Effects of computer monitor-emitted radiation on oxidant/antioxidant balance in cornea and lens from rats. Molecular Vision, 15, 2521–2525.
Baserga, R., Peruzzi, F. & Reiss, K. (2003). The IGF-1 receptor in cancer biology. International Journal of Cancer, 107(6), 873–877. https://doi.org/10.1002/ijc.11487.
Bhattacharya S. (2017). Medicinal plants and natural products in amelioration of arsenic toxicity: a short review. Pharmaceutical Biology, 55(1), 349–354. https://doi.org/10.1080/13880209.2016.1235207.
Berthelot, M.P.E. (1859) Berthelot’s Reaction Mechanism. Report de Chimie Applique, 2884.
Bones, R.W. & Tausky, H.H. (1945). Colorimetric determination of creatinine by the Jaffe reaction. J. Biol. Chem., 158, 581-591.
Cardiff, R. D., Miller, C. H. & Munn, R. J. (2014). Manual hematoxylin and eosin staining of mouse tissue sections. Cold Spring Harbor. Protocols, 2014(6), 655–658. https://doi.org/10.1101/pdb.prot073411.
Carter, D. E., Aposhian, H. V. & Gandolfi, A. J. (2003). The metabolism of inorganic arsenic oxides, gallium arsenide, and arsine: a toxicochemical review. Toxicology and Applied Pharmacology, 193(3), 309–334. https://doi.org/10.1016/j.taap.2003.07.009.
Chen, J., Huang, Q., Li, J., Yao, Y., Sun, W., Zhang, Z., Qi, H., Chen, Z., Liu, J., Zhao, D., Mi, J. & Li, X. (2022). Panax ginseng against myocardial ischemia/reperfusion injury: A review of preclinical evidence and potential mechanisms. Journal of Ethnopharmacology, 300, 115715. Advance online publication. https://doi.org/10.10 16/j.jep.2022.115715.
Chen, S., Wu, J. L., Liang, Y., Tang, Y. G., Song, H. X., Wu, L. L., Xing, Y. F., Yan, N., Li, Y. T., Wang, Z. Y., Xiao, S. J., Lu, X., Chen, S. J. & Lu, M. (2021). Arsenic Trioxide Rescues Structural p53 Mutations through a Cryptic Allosteric Site. Cancer cell, 39(2), 225–239.e8. https://doi.org/10.1016/j.ccell.2020.11.013.
Chen, Y., Parvez, F., Liu, M., Pesola, G. R., Gamble, M. V., Slavkovich, V., Islam, T., Ahmed, A., Hasan, R., Graziano, J. H. & Ahsan, H. (2011). Association between arsenic exposure from drinking water and proteinuria: results from the Health Effects of Arsenic Longitudinal Study. International Journal of Epidemiology, 40(3), 828–835. https://doi.org/10.1093/ije/dyr022.
Christensen, L. P. (2009). Ginsenosides chemistry, biosynthesis, analysis, and potential health effects. Advances in Food and Nutrition Research, 55, 1–99. https://doi.org/10.1016/S1043-4526(08)00401-4.
Cohen, S. M., Arnold, L. L., Eldan, M. Lewis, A. S. & Beck, B. D. (2006). Methylated arsenicals: the implications of metabolism and carcinogenicity studies in rodents to human risk assessment. Crit. Rev. Toxicol., 36, 99–133.
Cong, L. I., Xiao-Hui, L., Hai-Rong, X., Xiao-Xiao, L. I., Yue, L. & Chao-Qi, L. (2020). Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica, 45(19), 4725–4731. https://doi.org/10.19540/j.cnki.cjcmm.20200427.401.
de Oliveira Zanuso, B., de Oliveira Dos Santos, A. R., Miola, V., Guissoni Campos, L. M., Spilla, C. & Barbalho, S. M. (2022). Panax ginseng and aging related disorders: A systematic review. Experimental Gerontology, 161, 111731. https://doi.org/10.1016/j.exger.2022.111731.
Draper, H. H. & Hadley, M. (1992). Malondialdehyde determination as index of lipid peroxidation. Methods in Enzymology, 186, 421–431. https://doi.org/10.1016/0076-6879(90)86135-i.
Duker, A. A., Carranza, E. J. & Hale, M. (2005). Arsenic geochemistry and health. Environment international, 31(5), 631–641. https://doi.org/10.1016/j.envint.2004.10.020.
Faita, F., Cori, L., Bianchi, F. & Andreassi, M. G. (2013). Arsenic-induced genotoxicity and genetic susceptibility to arsenic-related pathologies. International Journal of Environmental Research and Public Health, 10(4), 1527–1546. https://doi.org/10.3390/ijerph10041527.
Fawcett JK & Scott JE. 1960. A rapid and precise method for the determination of urea. J. Chem. Pathol. 13,156.
Fu, W., Sui, D., Yu, X., Gou, D., Zhou, Y. & Xu, H. (2015). Protective effects of ginsenoside Rg2 against H2O2-induced injury and apoptosis in H9c2 cells. International Journal of Clinical and Experimental Medicine, 8(11), 19938–19947.
Fuzzati, N. (2004). Analysis methods of ginsenosides. Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences, 812(1-2), 119–133. https://doi.org/10.1016/j.jchromb.2004.07.039.
Hassan, M (2018) Arsenic in groundwater. CRC Press, Boca Raton.
Helleday, T., Nilsson R. & Jenssen D. (2000); Arsenic [III] and heavy metal ions induce intrachromosomal homologous recombination in the hprt gene V79 Chinese hamster cells. Environ. Mol. Mutagen., 35: 114–122.
Hsueh, Y. M., Chung, C. J., Shiue, H. S.., Chen, J. B., Chiang, S. S., Yang, M. H., Tai, C. W. & Su, C. T. (2009). Urinary arsenic species and CKD in a Taiwanese population: a case-control study. American Journal of Kidney Diseases: the official Journal of the National Kidney Foundation, 54(5), 859–870. https://doi.org/10.1053/j.ajkd.20 09.06.016.
Hu, X., Li, H., Ip, T. K., Cheung, Y. F., Koohi-Moghadam, M., Wang, H., Yang, X., Tritton, D. N., Wang, Y., Wang, Y., Wang, R., Ng, K. M., Naranmandura, H., Tse, E. W., & Sun, H. (2021). Arsenic trioxide targets Hsp60, triggering degradation of p53 and survivin. Chemical Science, 12(32), 10893–10900. https://doi.org/10.1039/d1sc03119h.
Huang K. C. (1999). The Pharmacology of Chinese Herbs. Boca Raton, FL: CRC Press; 1999.
Huang, J., Liu, D., Wang, Y., Liu, L., Li, J., Yuan, J., Jiang, Z., Jiang, Z., Hsiao, W. W., Liu, H., Khan, I., Xie, Y., Wu, J., Xie, Y., Zhang, Y., Fu, Y., Liao, J., Wang, W., Lai, H., Shi, A., … Leung, E. L. (2022). Ginseng polysaccharides alter the gut microbiota and kynurenine/tryptophan ratio, potentiating the antitumour effect of antiprogrammed cell death 1/programmed cell death ligand 1 (anti-PD-1/PD-L1) immunotherapy. Gut, 71(4), 734–745. https://doi.org/10.1136/gutjnl-2020-321031.
Jendrassik, G. F. & Grofs, B, M. (1938). Quantitative colorimetric determination of bilirubin in serum or plasma. Clin. Chem. Acta. (27),79.
Jha, V., Garcia-Garcia, G., Iseki, K., Li, Z., Naicker, S., Plattner, B., Saran, R., Wang, A. Y., & Yang, C. W. (2013). Chronic kidney disease: global dimension and perspectives. Lancet (London, England), 382(9888), 260–272. https://doi.org/10.1016/S0140-6736(13)60687-X.
Jung, N. P. (1996). Studies on the physiological and biochemical effects of Korean ginseng. Korean J Ginseng Sci., 20, 431-471.
Kaushal, S., Ahsan, A. U., Sharma, V. L. & Chopra, M. (2019). Epigallocatechin gallate attenuates arsenic induced genotoxicity via regulation of oxidative stress in balb/C mice. Molecular Biology Reports, 46(5), 5355–5369. https://doi.org/10.1007/s11033-019-04991-5.
Kim, H., Lee, H. J., Kim, D. J., Kim, T. M., Moon, H. S. & Choi, H. (2013). Panax ginseng exerts antiproliferative effects on rat hepatocarcinogenesis. Nutrition Research (New York, N.Y.), 33(9), he753–760. https://doi.org/10.1016/j.nutres.2013.07.005.
Kind, P. R. H. & King, E. J. (1954). Determination of alkaline phosphatase activity in serum. J. Clin. Path., 7, 322.
Kumar, A., Ali, M., Rahman, S. M., Iqubal, A. M., Anand, G., Niraj, P. K., ... & Kumar, R. (2015). Ground water arsenic poisoning in “Tilak Rai Ka Hatta” village of Buxar district, Bihar, India causing severe health hazards and hormonal imbalance. J. Environ. Anal. Toxicol., 5(4), 1-7.
Kumar, A., Rahman, M.S., Iqubal, M.A., Ali, M., Niraj, P.K., Anand, G., Kumar, P., Abhinav, Ghosh, A.K., (2016). Ground Water Arsenic Contamination: A Local Survey in India. International Journal of Preventive Medicine. 7:100. https://doi.org/10.4103/2008-7802.188085.
Kumar, A., Rahman, M.S., Kumar, R., Ali, M., Niraj, P.K., Srivastava, A., Singh, S.K., Ghosh, A.K., (2019a). Arsenic contamination in groundwater causing impaired memory and intelligence in school children of Simri village of Buxar district of Bihar. J. Mental Health Hum Behav. 24:132–138. https://doi.org/10.4103/jmhhb.jmhhb_31_18.
Kumar, S., Singh, R., Venkatesh, A.S., Udayabhanu, G., Sahoo, P.R., (2019b). Medical Geological assessment of fluoride contaminated groundwater in parts of Indo-Gangetic Alluvial plains. Scientific reports, 9(1), 16243. https://doi.org/10.1038/s41598-019-52812-3
Kumar, A., Ali, M., Kumar, R., Rahman, M.S., Srivastava, A., Chayal, N.K., Sagar, V., Kumari, R., Parween, S., Kumar, R., Niraj, P.K., Anand, G., Singh, S.K. & Ghosh, A.K., (2020a). High arsenic concentration in blood samples of people of village Gyaspur Mahaji, Patna, Bihar drinking arsenic contaminated water. Springer Nature J. Expos Health. 12:131–140. https://doi.org/10.1007/s12403-018-00294-5.
Kumar, V., Akhouri, V., Singh, S. K., & Kumar, A. (2020b). Phytoremedial effect of Tinospora cordifolia against arsenic induced toxicity in Charles Foster rats. Biometals, 33(6), 379–396. https://doi.org/10.1007/s10534-020-00256-y.
Kumar, A., Ali, M., Kumar, R., Kumar, M., Sagar, P., Pandey, R.K., Akhouri, V., Kumar, V., Anand, G., Niraj, P.K., Rani, R., Kumar, S., Kumar, D., Bishwapriya, A. & Ghosh, A.K., (2021a). Arsenic exposure in Indo Gangetic plains of Bihar causing increased cancer risk. Scientific Reports. 11(1):2376. https://doi.org/10.1038/s41598-021-81579-9.
Kumar, A. & Ghosh, A.K., (2021b). Assessment of arsenic contamination in groundwater and affected population of Bihar. N. Kumar (ed.), Arsenic Toxicity: Challenges and Solutions. [ISBN 978-981-33-6067-9; ISBN 978-981-33-6068-6 (eBook)] https://doi.org/10.1007/978-981-33-6068-6_7.
Kumar, A., Kumar, R., Rahman, M.S., Ali, M., Kumar, R., Nupur, N., Gaurav, A., Raj, V., Anand, G., Niraj, P. K., Kumar, N., Srivastava, A., Biswapriya, A., Chand, G.B., Kumar, D., Rashmi, T., Kumar, S., Sakamoto, M., Ghosh, A.K., (2021c). Assessment of arsenic exposure in the population of Sabalpur village of Saran District of Bihar with mitigation approach. Environmental Science and Pollution Research International, 10.1007/s11356-021-13521-5. Advance online publication. https://doi.org/10.1007/s11356-021-13521-5.
Kumar, A., Rahman, M.S., Ali, M., Kumar, R., Niraj, P.K., Akhouri, V., Singh, S.K., Kumar, D., Rashmi, T., Bishwapriya, A., Chand G.B., Sakamoto, M., Ghosh, A.K., (2021d). Assessment of arsenic exposure and its mitigation intervention in severely exposed population of Buxar district of Bihar, India. Toxicol. Environ. Health Sci. https://doi.org/10.1007/s13530-021-00086-6.
Kumar, A., Kumar, V., Akhouri, V., Kumar R., Ali., M, Rashmi T., Chand G.B., Singh S.K., Ghosh A.K. (2022): Protective efficacy of Coriandrum sativum seeds against arsenic induced toxicity in Swiss albino mice. Toxicol. Res. (2022). https://doi.org/10.1007/s43188-022-00123-7
Kwiatkowski D. J. (2003). Rhebbing up mTOR: new insights on TSC1 and TSC2, and the pathogenesis of tuberous sclerosis. Cancer Biology & Therapy, 2(5), 471–476. https://doi.org/10.4161/cbt.2.5.446.
Lewis SM. (1982). Visual hemocytometry. In: van Assendelft OW, England JM, eds. Advances in Hematological Methods: the Blood Count. Boca Raton, Florida: CRC Press; 40–7.
Liu, J. & Waalkes, M. P. (2008). Liver is a target of arsenic carcinogenesis. Toxicological Sciences , 5(1), 24–32. https://doi.org/10.1093/toxsci/kfn120.
Liu, Z., Li, Y., Li, X., Ruan, C. C., Wang, L. J. & Sun, G. Z. (2012). The effects of dynamic changes of malonyl ginsenosides on evaluation and quality control of Panax ginseng C.A. Meyer. Journal of Pharmaceutical and Biomedical Analysis, 64-65, 56–63. https://doi.org/10.1016/j.jpba.2012.02.005.
Loh S. N. (2021). Arsenic and an Old Place: Rescuing p53 Mutants in Cancer. Cancer cell, 39(2), 140–142. https://doi.org/10.1016/j.ccell.2021.01.012
Ma, Z. N., Li, Y. Z., Li, W., Yan, X. T., Yang, G., Zhang, J., Zhao, L. C. & Yang, L. M. (2017). Nephroprotective effects of saponins from leaves of Panax quinquefolius against cisplatin-induced acute kidney injury. International Journal of Molecular Sciences, 18(7), 1407. https://doi.org/10.3390/ijms18071407.
Mallikarjuna, G. U., Dhanalakshmi, S., Raisuddin, S., & Rao, A. R. (2003). Chemomodulatory influence of Ferula asafoetida on mammary epithelial differentiation, hepatic drug metabolizing enzymes, antioxidant profiles and N-methyl-N-nitrosourea-induced mammary carcinogenesis in rats. Breast Cancer Research and Treatment, 81(1), 1–10. https://doi.org/10.1023/a:1025448620558.
Miller, W.H., Schipper, H.M., Lee, J.S., Waxman, S. (2002). Mechanisms of action of arsenic trioxide. Cancer Res., 62: 3893-3903.
Porfire, A. S., Leucuţa, S. E., Kiss, B., Loghin, F. & Pârvu, A. E. (2014). Investigation into the role of Cu/Zn-SOD delivery system on its antioxidant and antiinflammatory activity in rat model of peritonitis. Pharmacological Reports, 6(4), 670–676. https://doi.org/10.1016/j.pharep.2 014.03.011.
Reitman’s S. & Frankel’s S. (1957). A colorimetric method for determination of serum glutamate oxalacetic and glutamic pyruvate transaminases. Amer. J. Clin. Path., 28(1): 56-63.
Roy, J. S., Chatterjee, D., Das, N., & Giri, A. K. (2018). Substantial Evidence Indicate That Inorganic Arsenic Is a Genotoxic Carcinogen: a Review. Toxicological Research, 34(4), 311–324. https://doi.org/10.5487/TR.2018.34.4.311
Sengupta, S., Toh, S. A., Sellers, L. A., Skepper, J. N., Koolwijk, P., Leung, H. W., Yeung, H. W., Wong, R. N., Sasisekharan, R. & Fan, T. P. (2004). Modulating angiogenesis: the yin and the yang in ginseng. Circulation, 110(10), 1219–1225. https://doi.org/10.1161/01.CIR.000 0140676.88412.CF.
Shaji, E., Santosh, M., Sarath, K. V., Prakash, P., Deepchand, V. & Divya, B. V. (2021). Arsenic contamination of groundwater: A global synopsis with focus on the Indian Peninsula. Geoscience Frontiers, 12(3), 101079.
Sherr, C. J., & Roberts, J. M. (1995). Inhibitors of mammalian G1 cyclin-dependent kinases. Genes & Development, 9(10), 1149–1163. https://doi.org/10.1101/gad.9.10.1149.
Sng, K. S., Li, G., Zhou, L. Y., Song, Y. J., Chen, X. Q., Wang, Y. J., Yao, M. & Cui, X. J. (2022). Ginseng extract and ginsenosides improve neurological function and promote antioxidant effects in rats with spinal cord injury: A meta-analysis and systematic review. Journal of Ginseng Research, 46(1), 11–22. https://doi.org/10.1016/j.jgr.2021.05.009.
Stýblo, M., Drobná, Z., Jaspers, I., Lin, S., & Thomas, D. J. (2002). The role of biomethylation in toxicity and carcinogenicity of arsenic: a research update. Environmental Health Perspectives, 110 (Suppl 5), 767–771. https://doi.org/10.1289/ehp.110-1241242.
Tao, Y., Qiu, T., Yao, X., Jiang, L., Wang, N., Jia, X., Wei, S., Wang, Z., Pei, P., Zhang, J., Zhu, Y., Yang, G., Liu, X., Liu, S. & Sun, X. (2020). Autophagic- CTSB-inflamma some axis modulates hepatic stellate cells activation in arsenic-induced liver fibrosis. Chemosphere, 242, 124959. https://doi.org/10.1016/j.chemosphere.20 19.124959.
Toro,G. and Ackermann, P.G., (1975) practical clinical chem. P:154.
Tsikas D. (2020). Urinary Dimethylamine (DMA) and Its Precursor Asymmetric Dimethylarginine (ADMA) in Clinical Medicine, in the Context of Nitric Oxide (NO) and Beyond. Journal of Clinical Medicine, 9(6), 1843. https://doi.org/10.3390/jcm9061843.
Wang, X. J., Xie, Q., Liu, Y., Jiang, S., Li, W., Li, B., Wang, W., & Liu, C. X. (2020). Panax japonicus and chikusetsusaponins: A review of diverse biological activities and pharmacology mechanism. Chinese Herbal Medicines, 13(1), 64–77. https://doi.org/10.1016/j.chmed.20 20.12.003.
Wang, Y., Liu, T. E., Pan, W., Chi, H., Chen, J., Yu, Z. & Chen, C. (2016). Small molecule compounds alleviate anisomycin-induced oxidative stress injury in SH-SY5Y cells via downregulation of p66shc and Aβ1-42 expression. Experimental and Therapeutic Medicine, 11(2), 593–600. https://doi.org/10.3892/etm.2015.2921.
Wanibuchi, H., Yamamoto, S., Chen, H., Yoshida, K., Endo, G., Hori, T., & Fukushima, S. (1996). Promoting effects of dimethylarsinic acid on N-butyl-N-(4-hydroxybutyl)nitrosamine-induced urinary bladder carcinogenesis in rats. Carcinogenesis, 17(11), 2435–2439. https://doi.org/10.1093/carcin/17.11.2435.
Washida, D., & Kitanaka, S. (2003). Determination of polyacetylenes and ginsenosides in Panax species using high performance liquid chromatography. Chemical & Pharmaceutical Bulletin, 51(11), 1314–1317. https://doi.org/10.1248/cpb.51.1314.
Wintrobe MM. (1975) 'Clinical Hematology' 7th Edition. Philadelphia: Lea and Febiger;114-115.
Wu, W., Jiao, C., Li, H., Ma, Y., Jiao, L., & Liu, S. (2018). LC-MS based metabolic and metabonomic studies of Panax ginseng. Phytochemical analysis : PCA, 29(4), 331–340. https://doi.org/10.1002/pca.2752.
Xu, X. Y., Hu, J. N., Liu, Z., Zhang, R., He, Y. F., Hou, W., Wang, Z. Q., Yang, G. & Li, W. (2017). Saponins (Ginsenosides) from the leaves of Panax quinquefolius ameliorated acetaminophen-induced hepatotoxicity in mice. Journal of Agricultural and Food Chemistry, 65(18), 3684–3692. https://doi.org/10.1021/acs.jafc.7b00610
Yamamoto, S., Konishi, Y., Matsuda, T., Murai, T., Shibata, M. A., Matsui-Yuasa, I., Otani, S., Kuroda, K., Endo, G. & Fukushima, S. (1995). Cancer induction by an organic arsenic compound, dimethylarsinic acid (cacodylic acid), in F344/DuCrj rats after pretreatment with five carcinogens. Cancer Research, 55(6), 1271–1276.
Yamanaka K, Kato, K., Mizoi, M., An, Y., Takabayashi, F., Nakano, M., Hoshino, M., & Okada S. (2004); The role of active arsenic species produced by metabolic reduction of dimethylarsinic acid in genotoxicity and tumorigenesis. Toxicol. Appl. Pharmacol., 198: 385–393.
Yang, Z., Deng, J., Liu, M., He, C., Feng, X., Liu, S. & Wei, S. (2022). A review for discovering bioactive minor saponins and biotransformative metabolites in Panax quinquefolius L. Frontiers in Pharmacology, 13, 972813. https://doi.org/10.3389/fphar.2022.972813.
Zhang, Q., Li, X., Gao, X., Cao, C., Hu, Y. & Guo, H. (2022). Total saponins from stems and leaves of Panax quinquefolius L. ameliorate podophyllotoxin-induced myelosuppression and gastrointestinal toxicity. Biomedical Chromatography: BMC, 36(2), e5266. https://doi.org/10.1002/bmc.5266.
Zheng, L. Y., Umans, J. G., Tellez-Plaza, M., Yeh, F., Francesconi, K. A., Goessler, W., Silbergeld, E. K., Guallar, E., Howard, B. V., Weaver, V. M. & Navas-Acien, A. (2013). Urine arsenic and prevalent albuminuria: evidence from a population-based study. American Journal of Kidney Diseases, 61(3), 385–394. https://doi.org/10.1053/j.ajkd.2012.09.011.
Zheng, L., Kuo, C. C., Fadrowski, J., Agnew, J., Weaver, V. M. & Navas-Acien, A. (2014). Arsenic and Chronic Kidney Disease: A systematic review. Current Environmental Health Reports, 1(3), 192–207. https://doi.org/10.1007/s40572-014-0024-x.
Attele, A. S., Zhou, Y. P., Xie, J. T., Wu, J. A., Zhang, L., Dey, L., Pugh, W., Rue, P. A., Polonsky, K. S. & Yuan, C. S. (2002). Antidiabetic effects of Panax ginseng berry extract and the identification of an effective component. Diabetes, 51(6), 1851–1858. https://doi.org/10.2337/diabetes.51.6.1851.
Balci, M., Namuslu, M., Devrim, E. & Durak, I. (2009). Effects of computer monitor-emitted radiation on oxidant/antioxidant balance in cornea and lens from rats. Molecular Vision, 15, 2521–2525.
Baserga, R., Peruzzi, F. & Reiss, K. (2003). The IGF-1 receptor in cancer biology. International Journal of Cancer, 107(6), 873–877. https://doi.org/10.1002/ijc.11487.
Bhattacharya S. (2017). Medicinal plants and natural products in amelioration of arsenic toxicity: a short review. Pharmaceutical Biology, 55(1), 349–354. https://doi.org/10.1080/13880209.2016.1235207.
Berthelot, M.P.E. (1859) Berthelot’s Reaction Mechanism. Report de Chimie Applique, 2884.
Bones, R.W. & Tausky, H.H. (1945). Colorimetric determination of creatinine by the Jaffe reaction. J. Biol. Chem., 158, 581-591.
Cardiff, R. D., Miller, C. H. & Munn, R. J. (2014). Manual hematoxylin and eosin staining of mouse tissue sections. Cold Spring Harbor. Protocols, 2014(6), 655–658. https://doi.org/10.1101/pdb.prot073411.
Carter, D. E., Aposhian, H. V. & Gandolfi, A. J. (2003). The metabolism of inorganic arsenic oxides, gallium arsenide, and arsine: a toxicochemical review. Toxicology and Applied Pharmacology, 193(3), 309–334. https://doi.org/10.1016/j.taap.2003.07.009.
Chen, J., Huang, Q., Li, J., Yao, Y., Sun, W., Zhang, Z., Qi, H., Chen, Z., Liu, J., Zhao, D., Mi, J. & Li, X. (2022). Panax ginseng against myocardial ischemia/reperfusion injury: A review of preclinical evidence and potential mechanisms. Journal of Ethnopharmacology, 300, 115715. Advance online publication. https://doi.org/10.10 16/j.jep.2022.115715.
Chen, S., Wu, J. L., Liang, Y., Tang, Y. G., Song, H. X., Wu, L. L., Xing, Y. F., Yan, N., Li, Y. T., Wang, Z. Y., Xiao, S. J., Lu, X., Chen, S. J. & Lu, M. (2021). Arsenic Trioxide Rescues Structural p53 Mutations through a Cryptic Allosteric Site. Cancer cell, 39(2), 225–239.e8. https://doi.org/10.1016/j.ccell.2020.11.013.
Chen, Y., Parvez, F., Liu, M., Pesola, G. R., Gamble, M. V., Slavkovich, V., Islam, T., Ahmed, A., Hasan, R., Graziano, J. H. & Ahsan, H. (2011). Association between arsenic exposure from drinking water and proteinuria: results from the Health Effects of Arsenic Longitudinal Study. International Journal of Epidemiology, 40(3), 828–835. https://doi.org/10.1093/ije/dyr022.
Christensen, L. P. (2009). Ginsenosides chemistry, biosynthesis, analysis, and potential health effects. Advances in Food and Nutrition Research, 55, 1–99. https://doi.org/10.1016/S1043-4526(08)00401-4.
Cohen, S. M., Arnold, L. L., Eldan, M. Lewis, A. S. & Beck, B. D. (2006). Methylated arsenicals: the implications of metabolism and carcinogenicity studies in rodents to human risk assessment. Crit. Rev. Toxicol., 36, 99–133.
Cong, L. I., Xiao-Hui, L., Hai-Rong, X., Xiao-Xiao, L. I., Yue, L. & Chao-Qi, L. (2020). Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica, 45(19), 4725–4731. https://doi.org/10.19540/j.cnki.cjcmm.20200427.401.
de Oliveira Zanuso, B., de Oliveira Dos Santos, A. R., Miola, V., Guissoni Campos, L. M., Spilla, C. & Barbalho, S. M. (2022). Panax ginseng and aging related disorders: A systematic review. Experimental Gerontology, 161, 111731. https://doi.org/10.1016/j.exger.2022.111731.
Draper, H. H. & Hadley, M. (1992). Malondialdehyde determination as index of lipid peroxidation. Methods in Enzymology, 186, 421–431. https://doi.org/10.1016/0076-6879(90)86135-i.
Duker, A. A., Carranza, E. J. & Hale, M. (2005). Arsenic geochemistry and health. Environment international, 31(5), 631–641. https://doi.org/10.1016/j.envint.2004.10.020.
Faita, F., Cori, L., Bianchi, F. & Andreassi, M. G. (2013). Arsenic-induced genotoxicity and genetic susceptibility to arsenic-related pathologies. International Journal of Environmental Research and Public Health, 10(4), 1527–1546. https://doi.org/10.3390/ijerph10041527.
Fawcett JK & Scott JE. 1960. A rapid and precise method for the determination of urea. J. Chem. Pathol. 13,156.
Fu, W., Sui, D., Yu, X., Gou, D., Zhou, Y. & Xu, H. (2015). Protective effects of ginsenoside Rg2 against H2O2-induced injury and apoptosis in H9c2 cells. International Journal of Clinical and Experimental Medicine, 8(11), 19938–19947.
Fuzzati, N. (2004). Analysis methods of ginsenosides. Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences, 812(1-2), 119–133. https://doi.org/10.1016/j.jchromb.2004.07.039.
Hassan, M (2018) Arsenic in groundwater. CRC Press, Boca Raton.
Helleday, T., Nilsson R. & Jenssen D. (2000); Arsenic [III] and heavy metal ions induce intrachromosomal homologous recombination in the hprt gene V79 Chinese hamster cells. Environ. Mol. Mutagen., 35: 114–122.
Hsueh, Y. M., Chung, C. J., Shiue, H. S.., Chen, J. B., Chiang, S. S., Yang, M. H., Tai, C. W. & Su, C. T. (2009). Urinary arsenic species and CKD in a Taiwanese population: a case-control study. American Journal of Kidney Diseases: the official Journal of the National Kidney Foundation, 54(5), 859–870. https://doi.org/10.1053/j.ajkd.20 09.06.016.
Hu, X., Li, H., Ip, T. K., Cheung, Y. F., Koohi-Moghadam, M., Wang, H., Yang, X., Tritton, D. N., Wang, Y., Wang, Y., Wang, R., Ng, K. M., Naranmandura, H., Tse, E. W., & Sun, H. (2021). Arsenic trioxide targets Hsp60, triggering degradation of p53 and survivin. Chemical Science, 12(32), 10893–10900. https://doi.org/10.1039/d1sc03119h.
Huang K. C. (1999). The Pharmacology of Chinese Herbs. Boca Raton, FL: CRC Press; 1999.
Huang, J., Liu, D., Wang, Y., Liu, L., Li, J., Yuan, J., Jiang, Z., Jiang, Z., Hsiao, W. W., Liu, H., Khan, I., Xie, Y., Wu, J., Xie, Y., Zhang, Y., Fu, Y., Liao, J., Wang, W., Lai, H., Shi, A., … Leung, E. L. (2022). Ginseng polysaccharides alter the gut microbiota and kynurenine/tryptophan ratio, potentiating the antitumour effect of antiprogrammed cell death 1/programmed cell death ligand 1 (anti-PD-1/PD-L1) immunotherapy. Gut, 71(4), 734–745. https://doi.org/10.1136/gutjnl-2020-321031.
Jendrassik, G. F. & Grofs, B, M. (1938). Quantitative colorimetric determination of bilirubin in serum or plasma. Clin. Chem. Acta. (27),79.
Jha, V., Garcia-Garcia, G., Iseki, K., Li, Z., Naicker, S., Plattner, B., Saran, R., Wang, A. Y., & Yang, C. W. (2013). Chronic kidney disease: global dimension and perspectives. Lancet (London, England), 382(9888), 260–272. https://doi.org/10.1016/S0140-6736(13)60687-X.
Jung, N. P. (1996). Studies on the physiological and biochemical effects of Korean ginseng. Korean J Ginseng Sci., 20, 431-471.
Kaushal, S., Ahsan, A. U., Sharma, V. L. & Chopra, M. (2019). Epigallocatechin gallate attenuates arsenic induced genotoxicity via regulation of oxidative stress in balb/C mice. Molecular Biology Reports, 46(5), 5355–5369. https://doi.org/10.1007/s11033-019-04991-5.
Kim, H., Lee, H. J., Kim, D. J., Kim, T. M., Moon, H. S. & Choi, H. (2013). Panax ginseng exerts antiproliferative effects on rat hepatocarcinogenesis. Nutrition Research (New York, N.Y.), 33(9), he753–760. https://doi.org/10.1016/j.nutres.2013.07.005.
Kind, P. R. H. & King, E. J. (1954). Determination of alkaline phosphatase activity in serum. J. Clin. Path., 7, 322.
Kumar, A., Ali, M., Rahman, S. M., Iqubal, A. M., Anand, G., Niraj, P. K., ... & Kumar, R. (2015). Ground water arsenic poisoning in “Tilak Rai Ka Hatta” village of Buxar district, Bihar, India causing severe health hazards and hormonal imbalance. J. Environ. Anal. Toxicol., 5(4), 1-7.
Kumar, A., Rahman, M.S., Iqubal, M.A., Ali, M., Niraj, P.K., Anand, G., Kumar, P., Abhinav, Ghosh, A.K., (2016). Ground Water Arsenic Contamination: A Local Survey in India. International Journal of Preventive Medicine. 7:100. https://doi.org/10.4103/2008-7802.188085.
Kumar, A., Rahman, M.S., Kumar, R., Ali, M., Niraj, P.K., Srivastava, A., Singh, S.K., Ghosh, A.K., (2019a). Arsenic contamination in groundwater causing impaired memory and intelligence in school children of Simri village of Buxar district of Bihar. J. Mental Health Hum Behav. 24:132–138. https://doi.org/10.4103/jmhhb.jmhhb_31_18.
Kumar, S., Singh, R., Venkatesh, A.S., Udayabhanu, G., Sahoo, P.R., (2019b). Medical Geological assessment of fluoride contaminated groundwater in parts of Indo-Gangetic Alluvial plains. Scientific reports, 9(1), 16243. https://doi.org/10.1038/s41598-019-52812-3
Kumar, A., Ali, M., Kumar, R., Rahman, M.S., Srivastava, A., Chayal, N.K., Sagar, V., Kumari, R., Parween, S., Kumar, R., Niraj, P.K., Anand, G., Singh, S.K. & Ghosh, A.K., (2020a). High arsenic concentration in blood samples of people of village Gyaspur Mahaji, Patna, Bihar drinking arsenic contaminated water. Springer Nature J. Expos Health. 12:131–140. https://doi.org/10.1007/s12403-018-00294-5.
Kumar, V., Akhouri, V., Singh, S. K., & Kumar, A. (2020b). Phytoremedial effect of Tinospora cordifolia against arsenic induced toxicity in Charles Foster rats. Biometals, 33(6), 379–396. https://doi.org/10.1007/s10534-020-00256-y.
Kumar, A., Ali, M., Kumar, R., Kumar, M., Sagar, P., Pandey, R.K., Akhouri, V., Kumar, V., Anand, G., Niraj, P.K., Rani, R., Kumar, S., Kumar, D., Bishwapriya, A. & Ghosh, A.K., (2021a). Arsenic exposure in Indo Gangetic plains of Bihar causing increased cancer risk. Scientific Reports. 11(1):2376. https://doi.org/10.1038/s41598-021-81579-9.
Kumar, A. & Ghosh, A.K., (2021b). Assessment of arsenic contamination in groundwater and affected population of Bihar. N. Kumar (ed.), Arsenic Toxicity: Challenges and Solutions. [ISBN 978-981-33-6067-9; ISBN 978-981-33-6068-6 (eBook)] https://doi.org/10.1007/978-981-33-6068-6_7.
Kumar, A., Kumar, R., Rahman, M.S., Ali, M., Kumar, R., Nupur, N., Gaurav, A., Raj, V., Anand, G., Niraj, P. K., Kumar, N., Srivastava, A., Biswapriya, A., Chand, G.B., Kumar, D., Rashmi, T., Kumar, S., Sakamoto, M., Ghosh, A.K., (2021c). Assessment of arsenic exposure in the population of Sabalpur village of Saran District of Bihar with mitigation approach. Environmental Science and Pollution Research International, 10.1007/s11356-021-13521-5. Advance online publication. https://doi.org/10.1007/s11356-021-13521-5.
Kumar, A., Rahman, M.S., Ali, M., Kumar, R., Niraj, P.K., Akhouri, V., Singh, S.K., Kumar, D., Rashmi, T., Bishwapriya, A., Chand G.B., Sakamoto, M., Ghosh, A.K., (2021d). Assessment of arsenic exposure and its mitigation intervention in severely exposed population of Buxar district of Bihar, India. Toxicol. Environ. Health Sci. https://doi.org/10.1007/s13530-021-00086-6.
Kumar, A., Kumar, V., Akhouri, V., Kumar R., Ali., M, Rashmi T., Chand G.B., Singh S.K., Ghosh A.K. (2022): Protective efficacy of Coriandrum sativum seeds against arsenic induced toxicity in Swiss albino mice. Toxicol. Res. (2022). https://doi.org/10.1007/s43188-022-00123-7
Kwiatkowski D. J. (2003). Rhebbing up mTOR: new insights on TSC1 and TSC2, and the pathogenesis of tuberous sclerosis. Cancer Biology & Therapy, 2(5), 471–476. https://doi.org/10.4161/cbt.2.5.446.
Lewis SM. (1982). Visual hemocytometry. In: van Assendelft OW, England JM, eds. Advances in Hematological Methods: the Blood Count. Boca Raton, Florida: CRC Press; 40–7.
Liu, J. & Waalkes, M. P. (2008). Liver is a target of arsenic carcinogenesis. Toxicological Sciences , 5(1), 24–32. https://doi.org/10.1093/toxsci/kfn120.
Liu, Z., Li, Y., Li, X., Ruan, C. C., Wang, L. J. & Sun, G. Z. (2012). The effects of dynamic changes of malonyl ginsenosides on evaluation and quality control of Panax ginseng C.A. Meyer. Journal of Pharmaceutical and Biomedical Analysis, 64-65, 56–63. https://doi.org/10.1016/j.jpba.2012.02.005.
Loh S. N. (2021). Arsenic and an Old Place: Rescuing p53 Mutants in Cancer. Cancer cell, 39(2), 140–142. https://doi.org/10.1016/j.ccell.2021.01.012
Ma, Z. N., Li, Y. Z., Li, W., Yan, X. T., Yang, G., Zhang, J., Zhao, L. C. & Yang, L. M. (2017). Nephroprotective effects of saponins from leaves of Panax quinquefolius against cisplatin-induced acute kidney injury. International Journal of Molecular Sciences, 18(7), 1407. https://doi.org/10.3390/ijms18071407.
Mallikarjuna, G. U., Dhanalakshmi, S., Raisuddin, S., & Rao, A. R. (2003). Chemomodulatory influence of Ferula asafoetida on mammary epithelial differentiation, hepatic drug metabolizing enzymes, antioxidant profiles and N-methyl-N-nitrosourea-induced mammary carcinogenesis in rats. Breast Cancer Research and Treatment, 81(1), 1–10. https://doi.org/10.1023/a:1025448620558.
Miller, W.H., Schipper, H.M., Lee, J.S., Waxman, S. (2002). Mechanisms of action of arsenic trioxide. Cancer Res., 62: 3893-3903.
Porfire, A. S., Leucuţa, S. E., Kiss, B., Loghin, F. & Pârvu, A. E. (2014). Investigation into the role of Cu/Zn-SOD delivery system on its antioxidant and antiinflammatory activity in rat model of peritonitis. Pharmacological Reports, 6(4), 670–676. https://doi.org/10.1016/j.pharep.2 014.03.011.
Reitman’s S. & Frankel’s S. (1957). A colorimetric method for determination of serum glutamate oxalacetic and glutamic pyruvate transaminases. Amer. J. Clin. Path., 28(1): 56-63.
Roy, J. S., Chatterjee, D., Das, N., & Giri, A. K. (2018). Substantial Evidence Indicate That Inorganic Arsenic Is a Genotoxic Carcinogen: a Review. Toxicological Research, 34(4), 311–324. https://doi.org/10.5487/TR.2018.34.4.311
Sengupta, S., Toh, S. A., Sellers, L. A., Skepper, J. N., Koolwijk, P., Leung, H. W., Yeung, H. W., Wong, R. N., Sasisekharan, R. & Fan, T. P. (2004). Modulating angiogenesis: the yin and the yang in ginseng. Circulation, 110(10), 1219–1225. https://doi.org/10.1161/01.CIR.000 0140676.88412.CF.
Shaji, E., Santosh, M., Sarath, K. V., Prakash, P., Deepchand, V. & Divya, B. V. (2021). Arsenic contamination of groundwater: A global synopsis with focus on the Indian Peninsula. Geoscience Frontiers, 12(3), 101079.
Sherr, C. J., & Roberts, J. M. (1995). Inhibitors of mammalian G1 cyclin-dependent kinases. Genes & Development, 9(10), 1149–1163. https://doi.org/10.1101/gad.9.10.1149.
Sng, K. S., Li, G., Zhou, L. Y., Song, Y. J., Chen, X. Q., Wang, Y. J., Yao, M. & Cui, X. J. (2022). Ginseng extract and ginsenosides improve neurological function and promote antioxidant effects in rats with spinal cord injury: A meta-analysis and systematic review. Journal of Ginseng Research, 46(1), 11–22. https://doi.org/10.1016/j.jgr.2021.05.009.
Stýblo, M., Drobná, Z., Jaspers, I., Lin, S., & Thomas, D. J. (2002). The role of biomethylation in toxicity and carcinogenicity of arsenic: a research update. Environmental Health Perspectives, 110 (Suppl 5), 767–771. https://doi.org/10.1289/ehp.110-1241242.
Tao, Y., Qiu, T., Yao, X., Jiang, L., Wang, N., Jia, X., Wei, S., Wang, Z., Pei, P., Zhang, J., Zhu, Y., Yang, G., Liu, X., Liu, S. & Sun, X. (2020). Autophagic- CTSB-inflamma some axis modulates hepatic stellate cells activation in arsenic-induced liver fibrosis. Chemosphere, 242, 124959. https://doi.org/10.1016/j.chemosphere.20 19.124959.
Toro,G. and Ackermann, P.G., (1975) practical clinical chem. P:154.
Tsikas D. (2020). Urinary Dimethylamine (DMA) and Its Precursor Asymmetric Dimethylarginine (ADMA) in Clinical Medicine, in the Context of Nitric Oxide (NO) and Beyond. Journal of Clinical Medicine, 9(6), 1843. https://doi.org/10.3390/jcm9061843.
Wang, X. J., Xie, Q., Liu, Y., Jiang, S., Li, W., Li, B., Wang, W., & Liu, C. X. (2020). Panax japonicus and chikusetsusaponins: A review of diverse biological activities and pharmacology mechanism. Chinese Herbal Medicines, 13(1), 64–77. https://doi.org/10.1016/j.chmed.20 20.12.003.
Wang, Y., Liu, T. E., Pan, W., Chi, H., Chen, J., Yu, Z. & Chen, C. (2016). Small molecule compounds alleviate anisomycin-induced oxidative stress injury in SH-SY5Y cells via downregulation of p66shc and Aβ1-42 expression. Experimental and Therapeutic Medicine, 11(2), 593–600. https://doi.org/10.3892/etm.2015.2921.
Wanibuchi, H., Yamamoto, S., Chen, H., Yoshida, K., Endo, G., Hori, T., & Fukushima, S. (1996). Promoting effects of dimethylarsinic acid on N-butyl-N-(4-hydroxybutyl)nitrosamine-induced urinary bladder carcinogenesis in rats. Carcinogenesis, 17(11), 2435–2439. https://doi.org/10.1093/carcin/17.11.2435.
Washida, D., & Kitanaka, S. (2003). Determination of polyacetylenes and ginsenosides in Panax species using high performance liquid chromatography. Chemical & Pharmaceutical Bulletin, 51(11), 1314–1317. https://doi.org/10.1248/cpb.51.1314.
Wintrobe MM. (1975) 'Clinical Hematology' 7th Edition. Philadelphia: Lea and Febiger;114-115.
Wu, W., Jiao, C., Li, H., Ma, Y., Jiao, L., & Liu, S. (2018). LC-MS based metabolic and metabonomic studies of Panax ginseng. Phytochemical analysis : PCA, 29(4), 331–340. https://doi.org/10.1002/pca.2752.
Xu, X. Y., Hu, J. N., Liu, Z., Zhang, R., He, Y. F., Hou, W., Wang, Z. Q., Yang, G. & Li, W. (2017). Saponins (Ginsenosides) from the leaves of Panax quinquefolius ameliorated acetaminophen-induced hepatotoxicity in mice. Journal of Agricultural and Food Chemistry, 65(18), 3684–3692. https://doi.org/10.1021/acs.jafc.7b00610
Yamamoto, S., Konishi, Y., Matsuda, T., Murai, T., Shibata, M. A., Matsui-Yuasa, I., Otani, S., Kuroda, K., Endo, G. & Fukushima, S. (1995). Cancer induction by an organic arsenic compound, dimethylarsinic acid (cacodylic acid), in F344/DuCrj rats after pretreatment with five carcinogens. Cancer Research, 55(6), 1271–1276.
Yamanaka K, Kato, K., Mizoi, M., An, Y., Takabayashi, F., Nakano, M., Hoshino, M., & Okada S. (2004); The role of active arsenic species produced by metabolic reduction of dimethylarsinic acid in genotoxicity and tumorigenesis. Toxicol. Appl. Pharmacol., 198: 385–393.
Yang, Z., Deng, J., Liu, M., He, C., Feng, X., Liu, S. & Wei, S. (2022). A review for discovering bioactive minor saponins and biotransformative metabolites in Panax quinquefolius L. Frontiers in Pharmacology, 13, 972813. https://doi.org/10.3389/fphar.2022.972813.
Zhang, Q., Li, X., Gao, X., Cao, C., Hu, Y. & Guo, H. (2022). Total saponins from stems and leaves of Panax quinquefolius L. ameliorate podophyllotoxin-induced myelosuppression and gastrointestinal toxicity. Biomedical Chromatography: BMC, 36(2), e5266. https://doi.org/10.1002/bmc.5266.
Zheng, L. Y., Umans, J. G., Tellez-Plaza, M., Yeh, F., Francesconi, K. A., Goessler, W., Silbergeld, E. K., Guallar, E., Howard, B. V., Weaver, V. M. & Navas-Acien, A. (2013). Urine arsenic and prevalent albuminuria: evidence from a population-based study. American Journal of Kidney Diseases, 61(3), 385–394. https://doi.org/10.1053/j.ajkd.2012.09.011.
Zheng, L., Kuo, C. C., Fadrowski, J., Agnew, J., Weaver, V. M. & Navas-Acien, A. (2014). Arsenic and Chronic Kidney Disease: A systematic review. Current Environmental Health Reports, 1(3), 192–207. https://doi.org/10.1007/s40572-014-0024-x.
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Ameliorative effect of Panax quinquefolius on sodium arsenite induced toxicity in Charles Foster rats. (2022). Journal of Applied and Natural Science, 14(4), 1532-1541. https://doi.org/10.31018/jans.v14i4.3957
