Phyllanthin identified from Phyllanthus amarus attenuates arsenite-induced liver and kidney damage: Role of NF-kB pathway inhibition.
La filantina identificada en Phyllanthus amarus atenúa el daño hepático y renal inducido por arsenito: papel de la inhibición de la vía NF-Kb.
Keywords:
Antioxidant, Hepatotoxicity, Nephrotoxicity, NF-κb, Oxidative stress, Phyllanthus amarus, Sodium arsenite
Abstract
Sodium arsenite is a common and highly toxic inorganic arse- nic compound that causes liver and kidney damage. Phyllanthus amarus is well known for its protective effects on these organs. This study aimed to identify the active phytoconstituents of the methanolic extract of P. amarus (PAME) and to explore their effects on arsenite-induced liver and kidney toxicity in experi- mental rats. The standardization of P. amarus extract was performed using high- performance liquid chromatography (HPLC). Male Wistar rats developed liver and kidney toxicity after daily oral administration of sodium arsenite (5 mg/ kg) for 4 weeks. The rats were simultaneously given coenzyme Q10 (CoQ10; 10 mg/kg) or PAME (50, 100, and 200 mg/kg). Results showed that HPLC analy- sis detected phyllanthin at a retention time of 25.41 minutes with an area of 71.84%. Arsenite treatment caused a significant (p<0.001) increase in hepatic enzymes (ALT, AST, and ALP), renal markers (BUN, uric acid, and creatinine), and direct and total bilirubin in the serum. It also significantly increased hepatic and renal levels of malondialdehyde, nitric oxide, NF-κB p65, interleukins (ILs), and TNF-α (p<0.001), while decreasing hepatic antioxidant enzymes (GSH and SOD) and overall hepatic antioxidant capacity. Notably, P. amarus extract (200 mg/kg) markedly (p<0.001) mitigated arsenite-induced changes in these serum markers, oxidative stress indicators, NF-kB p65, and inflammatory cytokines. It also improved the structure of liver and kidney tissues, maintained cellular ar- chitecture, and reduced necrosis and inflammation. In conclusion, these results suggest that phyllanthin from P. amarus protects against arsenite-induced liver and kidney damage by inhibiting NF-κB activation, reducing inflammatory cyto- kine release, and decreasing oxidative and nitrosative stress, thereby enhancing overall antioxidant capacity. Therefore, P. amarus extract may be a promising treatment for pesticide-related liver and kidney injuries in rats.
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References
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Santos AR, Filho VC, Yunes RA, Calixto JB. Analysis of the mechanisms underlying the antinociceptive effect of the extracts of plants from the genus Phyllanthus. Gen Pharmacol 1995;26:1499-1506. https://doi.org/10.1016/0306-3623(95)00030-5
Kandhare AD, Ghosh P, Ghule AE, Zambare GN, Bodhankar SL. Protective effect of Phyllanthus amarus by modulation of endogenous biomarkers and DNA damage in acetic acid induced ulcerative colitis: Role of phyllanthin and hypophyllanthin. Apollo Med 2013;10:87-97.
Kandhare AD, Kumar VS, Adil M, Rajmane AR, Ghosh P, Bodhankar SL. Investigation of gastro protective activity of Xanthium strumarium L. by modulation of cellular and biochemical marker. Orient Pharm Exper Med 2012;12:287-299.
Kandhare AD, Raygude KS, Ghosh P, Ghule AE, Bodhankar SL. Neuroprotective effect of naringin by modulation of endogenous biomarkers in streptozotocin induced painful diabetic neuropathy. Fitoterapia 2012;83:650-659. https://doi.org/10.1016/j.fitote.2012.01.010
Gosavi TP, Ghosh P, Kandhare AD, Kumar VS, Adil M, Rajmane AR et al. Therapeutic effect of H. pylori nosode, a homeopathic preparation in healing of chronic H. pylori infected ulcers in laboratory animals. Asian Pac J Trop Dis 2012;2:S603-S611.
Gosavi TP, Kandhare AD, Ghosh P, Bodhankar SL. Anticonvulsant activity of Argentum metallicum, a homeopathic preparation. Der Pharmacia Lettre 2012; 4:626-637.
Momen-Beitollahi J, Mansourian A, Momen-Heravi F, Amanlou M, Obradov S, Sahebjamee M. Assessment of salivary and serum antioxidant status in patients with recurrent aphthous stomatitis. Med Oral Patol Oral Cir Bucal 2010;15:e557-561. https://doi.org/10.4317/medoral.15.e557
Kandhare AD, Bodhankar SL, Mohan V, Thakurdesai PA. Effect of glycosides based standardized fenugreek seed extract in bleomycin-induced pulmonary fibrosis in rats: Decisive role of Bax, Nrf2, NF-kappaB, Muc5ac, TNF-alpha and IL -1beta. Chem Biol Interact 2015;237:151-165. https://doi.org/10.1016/j.cbi.2015.06.019
Honmore V, Kandhare A, Zanwar AA, Rojatkar S, Bodhankar S, Natu A. Artemisia pallens alleviates acetaminophen induced toxicity via modulation of endogenous bio-markers. Pharm Biol 2015;53:571-581. https://doi.org/10.3109/13880209.2014. 934382
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Wen J, Li A, Wang Z, Guo X, Zhang G, Litzow MR et al. Hepatotoxicity induced by arsenic trioxide: clinical features, mechanisms, preventive and potential therapeutic strategies. Front Pharmacol 2025;16:1536388. https://doi.org/10.3389/fphar.2025.1536388
Sharma AK, Kaur J, Kaur T, Singh B, Yadav HN, Pathak D et al. Ameliorative role of bosentan, an endothelin receptor antagonist, against sodium arsenite-induced renal dysfunction in rats. Environ Sci Pollut Res Int 2021;28:7180-7190. https://doi.org/10.1007/s11356-020-11035-0
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Ogunmoyole T, Awodooju M, Idowu S, Daramola O. Phyllanthus amarus extract restored deranged biochemical parameters in rat model of hepatotoxicity and nephron-toxicity. Heliyon 2020;6:e05670. https://doi.org/10.1016/j.heliyon.2020.e05670
Adil M, Kandhare AD, Visnagri A, Bodhankar SL. Naringin ameliorates sodium arsenite-induced renal and hepatic toxicity in rats: decisive role of KIM-1, Caspase-3, TGF-beta, and TNF-alpha. Ren Fail 2015;37:1396-1407. https://doi.org/10.3109/0886022X.2015.1074462
Afolabi AO, Akhigbe TM, Odetayo AF, Anyogu DC, Hamed MA, Akhigbe RE. Restoration of Hepatic and Intestinal Integrity by Phyllanthus amarus Is Dependent on Bax/Caspase 3 Modulation in Intestinal Ischemia-/Reperfusion-Induced Injury. Molecules 2022;27:5073. https://doi.org/10.3390/molecules27165073
Kandhare AD, Liu Z, Mukherjee AA, Bodhankar SL. Therapeutic Potential of Morin in Ovalbumin-induced Allergic Asthma Via Modulation of SUMF2/IL -13 and BLT2/ NF-kB Signaling Pathway. Curr Mol Pharmacol 2019;12:122-138. https://doi.org/1 0.2174/1874467212666190102105052
Sarkate AP, Murumkar PR, Lokwani DK, Kandhare AD, Bodhankar SL, Shinde DB et al. Design of selective TACE inhibitors using molecular docking studies: Synthesis and preliminary evaluation of anti-inflammatory and TACE inhibitory activity. SAR QSAR Environ Res 2015;26:905-923. https://doi.org/10.1080/1062936X. 2015.1095240
Zhou Z, Kandhare AD, Kandhare AA, Bodhankar SL. Hesperidin ameliorates bleomycin-induced experimental pulmonary fibrosis via inhibition of TGF-β1/ Smad3/AMPK and IκBα/NF-κB pathways. EXCLI Journal 2019;18:723-745.
Kiemer AK, Hartung T, Huber C, Vollmar AM. Phyllanthus amarus has anti-inflammatory potential by inhibition of iNOS, COX- 2, and cytokines via the NF-kappaB pathway. J Hepatol 2003;38:289-297. https://doi.org/10.1016/s0168-8278(02)00417-8
Jagtap S, Khare P, Mangal P, Kondepudi KK, Bishnoi M, Bhutani KK. Protective effects of phyllanthin, a lignan from Phyllanthus amarus, against progression of high fat diet induced metabolic disturbances in mice. RSC Advances 2016;6:58343-58353. https://doi.org/10.1039/c6ra10774e
Thyagarajan SP, Subramanian S, Thirunalasundari T, Venkateswaran PS, Blumberg BS. Effect of Phyllanthus amarus on chronic carriers of hepatitis B virus. Lancet 1988;2:764-766. https://doi.org/10.1016/s0140-6736(88)92416-6
Xin-Hua W, Chang-Qing L, Xing-Bo G, Lin-Chun F. A comparative study of Phyllanthus amarus compound and interferon in the treatment of chronic viral hepatitis B. Southeast Asian J Trop Med Public Health 2001;32:140-142.
Wang M, Cheng H, Li Y, Meng L, Zhao G, Mai K. Herbs of the genus Phyllanthus in the treatment of chronic hepatitis B: observations with three preparations from different geographic sites. J Lab Clin Med 1995;126:350-352.
Moshi MJ, Lutale JJ, Rimoy GH, Abbas ZG, Josiah RM, Swai AB. The effect of Phyllanthus amarus aqueous extract on blood glucose in non-insulin dependent diabetic patients. Phytother Res 2001;15:577-580. https://doi.org/10.1002/ptr.780
Abu Hassan MR, Hj Md Said R, Zainuddin Z, Omar H, Md Ali SM, Aris SA et al. Effects of one-year supplementation with Phyllanthus niruri on fibrosis score and metabolic markers in patients with non-alcoholic fatty liver disease: A randomized, double-blind, placebo-controlled trial. Heliyon 2023;9:e16652. https://doi.org/10.1016/j.heliyon.2023.e16652.
World Health Organization. Arsenic. World Health Organization; 2012. Podgorski J, Berg M. Global threat of arsenic in groundwater. Science 2020;368:845-850. https://doi.org/10.1126/science.aba1510
Alkully T, El-Refaei MF, Abdallah EAA. Protective Effects of Ellagic Acid Against Arsenic-Induced Hepatotoxicity in Male Wistar Rats: Impact of Heme Oxygenase-1 Upregulation. Food Sci Nutr 2025;13:e70344. https://doi.org/10.1002/fsn3.70344
Opeyemi Olaoluwa L, Joseph-Peace A, Okikijesu O, Emeka Gabriel E, Precious O, Tella A et al. Protective effects of Butylated Hydroxytoluene (BHT) against sodium Arsenite (NaAsO2) - Induced hepatotoxicity in Wistar Rats. International Journal of Science and Research Archive 2024;12:067-102. https://doi.org/10.30574/ijsra.2024.12.2.1130
Gong X, Ivanov VN, Davidson MM, Hei TK. Tetramethylpyrazine (TMP) protects against sodium arsenite-induced nephron-toxicity by suppressing ROS production, mitochondrial dysfunction, pro-inflammatory signaling pathways and programed cell death. Arch Toxicol 2015;89:1057- 1070. https://doi.org/10.1007/s00204-014-1302-y
Mwaeni VK, Nyariki JN, Jillani N, Omwenga G, Ngugi M, Isaac AO. Coenzyme Q(10) protected against arsenite and enhanced the capacity of 2,3-dimercaptosuccinic acid to ameliorate arsenite-induced toxicity in mice. BMC Pharmacol Toxicol 2021;22:19. https://doi.org/10.1186/s40360-021-00484-z
Ma G, Yan X, Wang C, Ran X, Liang Z, Chen X et al. Mechanism of arsenic-induced liver injury in rats revealed by metabolomics and ionomics based approach. Ecotoxicol Environ Saf 2025;293:118038. https://doi.org/10.1016/j.ecoenv.2025.118038
Turk E, Kandemir FM, Yildirim S, Caglayan C, Kucukler S, Kuzu M. Protective Effect of Hesperidin on Sodium Arsenite-Induced Nephrotoxicity and Hepatotoxicity in Rats. Biol Trace Elem Res 2019;189:95-108. https://doi.org/10.1007/s12011-018-1443-6
Bose Mazumdar Ghosh A, Banerjee A, Chattopadhyay S. An insight into the potent medicinal plant Phyllanthus amarus Schum. and Thonn. Nucleus (Calcutta) 2022;65:437-472. https://doi.org/10.1007/s13237-022-00409-z
Krithika R, Verma RJ, Shrivastav PS, Suguna L. Phyllanthin of Standardized Phyllanthus amarus Extract Attenuates Liver Oxidative Stress in Mice and Exerts Cyto-protective Activity on Human Hepatoma Cell Line. J Clin Exp Hepatol 2011;1:57- 67. https://doi.org/10.1016/S0973-6883(11)60123-0
Faremi TY, Suru SM, Fafunso MA, Obioha UE. Hepatoprotective potentials of Phyl- lanthusamarus against ethanol-induced oxidative stress in rats. Food Chem Toxicol 2008;46:2658-2664. https://doi.org/10.1016/j.fct.2008.04.022
Olorunnisola OS, Fadahunsi OS, Adegbola PI, Ajilore BS, Ajayi FA, Olaniyan LWB. Phyllanthus amarus attenuated derange- ment in renal-cardiac function, redox status, lipid profile and reduced TNF-alpha, interleukins-2, 6 and 8 in high salt diet fed rats. Heliyon 2021;7:e08106. https://doi.org/10.1016/j.heliyon.2021.e08106
Karuna R, Bharathi VG, Reddy SS, Ramesh B, Saralakumari D. Protective effects of Phyllanthus amarus aqueous extract against renal oxidative stress in Streptozotocin-induced diabetic rats. Indian J Pharmacol 2011;43:414-418. https://doi.org/10.4103/0253-7613.83112
Santos AR, Filho VC, Yunes RA, Calixto JB. Analysis of the mechanisms underlying the antinociceptive effect of the extracts of plants from the genus Phyllanthus. Gen Pharmacol 1995;26:1499-1506. https://doi.org/10.1016/0306-3623(95)00030-5
Kandhare AD, Ghosh P, Ghule AE, Zambare GN, Bodhankar SL. Protective effect of Phyllanthus amarus by modulation of endogenous biomarkers and DNA damage in acetic acid induced ulcerative colitis: Role of phyllanthin and hypophyllanthin. Apollo Med 2013;10:87-97.
Kandhare AD, Kumar VS, Adil M, Rajmane AR, Ghosh P, Bodhankar SL. Investigation of gastro protective activity of Xanthium strumarium L. by modulation of cellular and biochemical marker. Orient Pharm Exper Med 2012;12:287-299.
Kandhare AD, Raygude KS, Ghosh P, Ghule AE, Bodhankar SL. Neuroprotective effect of naringin by modulation of endogenous biomarkers in streptozotocin induced painful diabetic neuropathy. Fitoterapia 2012;83:650-659. https://doi.org/10.1016/j.fitote.2012.01.010
Gosavi TP, Ghosh P, Kandhare AD, Kumar VS, Adil M, Rajmane AR et al. Therapeutic effect of H. pylori nosode, a homeopathic preparation in healing of chronic H. pylori infected ulcers in laboratory animals. Asian Pac J Trop Dis 2012;2:S603-S611.
Gosavi TP, Kandhare AD, Ghosh P, Bodhankar SL. Anticonvulsant activity of Argentum metallicum, a homeopathic preparation. Der Pharmacia Lettre 2012; 4:626-637.
Momen-Beitollahi J, Mansourian A, Momen-Heravi F, Amanlou M, Obradov S, Sahebjamee M. Assessment of salivary and serum antioxidant status in patients with recurrent aphthous stomatitis. Med Oral Patol Oral Cir Bucal 2010;15:e557-561. https://doi.org/10.4317/medoral.15.e557
Kandhare AD, Bodhankar SL, Mohan V, Thakurdesai PA. Effect of glycosides based standardized fenugreek seed extract in bleomycin-induced pulmonary fibrosis in rats: Decisive role of Bax, Nrf2, NF-kappaB, Muc5ac, TNF-alpha and IL -1beta. Chem Biol Interact 2015;237:151-165. https://doi.org/10.1016/j.cbi.2015.06.019
Honmore V, Kandhare A, Zanwar AA, Rojatkar S, Bodhankar S, Natu A. Artemisia pallens alleviates acetaminophen induced toxicity via modulation of endogenous bio-markers. Pharm Biol 2015;53:571-581. https://doi.org/10.3109/13880209.2014. 934382
Concessao PL, Prakash J. Arsenic-induced nephrotoxicity: Mechanisms, biomarkers, and preventive strategies for global health. Kidney 2025;13:15.
Wen J, Li A, Wang Z, Guo X, Zhang G, Litzow MR et al. Hepatotoxicity induced by arsenic trioxide: clinical features, mechanisms, preventive and potential therapeutic strategies. Front Pharmacol 2025;16:1536388. https://doi.org/10.3389/fphar.2025.1536388
Sharma AK, Kaur J, Kaur T, Singh B, Yadav HN, Pathak D et al. Ameliorative role of bosentan, an endothelin receptor antagonist, against sodium arsenite-induced renal dysfunction in rats. Environ Sci Pollut Res Int 2021;28:7180-7190. https://doi.org/10.1007/s11356-020-11035-0
Zhang W, Miao AJ, Wang NX, Li C, Sha J, Jia J et al. Arsenic bioaccumulation and biotransformation in aquatic organisms. Environ Int 2022;163:107221. https://doi.org/10.1016/j.envint.2022.107221
Khodayar MJ, Shirani M, Shariati S, Khorsandi L, Mohtadi S. Antioxidant and anti-inflammatory potential of vanillic acid improves nephrotoxicity induced by sodium arsenite in mice. Int J Environ Health Res 2024;ahead-of-print:1-11. https://doi.org/10.1080/09603123.2024.2439452
Ogunmoyole T, Awodooju M, Idowu S, Daramola O. Phyllanthus amarus extract restored deranged biochemical parameters in rat model of hepatotoxicity and nephron-toxicity. Heliyon 2020;6:e05670. https://doi.org/10.1016/j.heliyon.2020.e05670
Adil M, Kandhare AD, Visnagri A, Bodhankar SL. Naringin ameliorates sodium arsenite-induced renal and hepatic toxicity in rats: decisive role of KIM-1, Caspase-3, TGF-beta, and TNF-alpha. Ren Fail 2015;37:1396-1407. https://doi.org/10.3109/0886022X.2015.1074462
Afolabi AO, Akhigbe TM, Odetayo AF, Anyogu DC, Hamed MA, Akhigbe RE. Restoration of Hepatic and Intestinal Integrity by Phyllanthus amarus Is Dependent on Bax/Caspase 3 Modulation in Intestinal Ischemia-/Reperfusion-Induced Injury. Molecules 2022;27:5073. https://doi.org/10.3390/molecules27165073
Kandhare AD, Liu Z, Mukherjee AA, Bodhankar SL. Therapeutic Potential of Morin in Ovalbumin-induced Allergic Asthma Via Modulation of SUMF2/IL -13 and BLT2/ NF-kB Signaling Pathway. Curr Mol Pharmacol 2019;12:122-138. https://doi.org/1 0.2174/1874467212666190102105052
Sarkate AP, Murumkar PR, Lokwani DK, Kandhare AD, Bodhankar SL, Shinde DB et al. Design of selective TACE inhibitors using molecular docking studies: Synthesis and preliminary evaluation of anti-inflammatory and TACE inhibitory activity. SAR QSAR Environ Res 2015;26:905-923. https://doi.org/10.1080/1062936X. 2015.1095240
Zhou Z, Kandhare AD, Kandhare AA, Bodhankar SL. Hesperidin ameliorates bleomycin-induced experimental pulmonary fibrosis via inhibition of TGF-β1/ Smad3/AMPK and IκBα/NF-κB pathways. EXCLI Journal 2019;18:723-745.
Kiemer AK, Hartung T, Huber C, Vollmar AM. Phyllanthus amarus has anti-inflammatory potential by inhibition of iNOS, COX- 2, and cytokines via the NF-kappaB pathway. J Hepatol 2003;38:289-297. https://doi.org/10.1016/s0168-8278(02)00417-8
Jagtap S, Khare P, Mangal P, Kondepudi KK, Bishnoi M, Bhutani KK. Protective effects of phyllanthin, a lignan from Phyllanthus amarus, against progression of high fat diet induced metabolic disturbances in mice. RSC Advances 2016;6:58343-58353. https://doi.org/10.1039/c6ra10774e
Thyagarajan SP, Subramanian S, Thirunalasundari T, Venkateswaran PS, Blumberg BS. Effect of Phyllanthus amarus on chronic carriers of hepatitis B virus. Lancet 1988;2:764-766. https://doi.org/10.1016/s0140-6736(88)92416-6
Xin-Hua W, Chang-Qing L, Xing-Bo G, Lin-Chun F. A comparative study of Phyllanthus amarus compound and interferon in the treatment of chronic viral hepatitis B. Southeast Asian J Trop Med Public Health 2001;32:140-142.
Wang M, Cheng H, Li Y, Meng L, Zhao G, Mai K. Herbs of the genus Phyllanthus in the treatment of chronic hepatitis B: observations with three preparations from different geographic sites. J Lab Clin Med 1995;126:350-352.
Moshi MJ, Lutale JJ, Rimoy GH, Abbas ZG, Josiah RM, Swai AB. The effect of Phyllanthus amarus aqueous extract on blood glucose in non-insulin dependent diabetic patients. Phytother Res 2001;15:577-580. https://doi.org/10.1002/ptr.780
Abu Hassan MR, Hj Md Said R, Zainuddin Z, Omar H, Md Ali SM, Aris SA et al. Effects of one-year supplementation with Phyllanthus niruri on fibrosis score and metabolic markers in patients with non-alcoholic fatty liver disease: A randomized, double-blind, placebo-controlled trial. Heliyon 2023;9:e16652. https://doi.org/10.1016/j.heliyon.2023.e16652.
Published
2026-03-04
How to Cite
Xu, J., Sadar, S., Kamble , H., & Zhang, Y. (2026). Phyllanthin identified from Phyllanthus amarus attenuates arsenite-induced liver and kidney damage: Role of NF-kB pathway inhibition.: La filantina identificada en Phyllanthus amarus atenúa el daño hepático y renal inducido por arsenito: papel de la inhibición de la vía NF-Kb. Investigación Clínica, 67(1), 92-107. https://doi.org/10.54817/IC.v67n1a07
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