Mitigation of Acute Hepatotoxicity Induced by Cadmium Through Morin: Modulation of Oxidative and Pro-apoptotic Endoplasmic Reticulum Stress and Inflammatory Responses in Rats.
Cadmium
Endoplasmic reticulum stress
Hepatotoxicity
Inflammation
Morin
Rat
Journal
Biological trace element research
ISSN: 1559-0720
Titre abrégé: Biol Trace Elem Res
Pays: United States
ID NLM: 7911509
Informations de publication
Date de publication:
19 Jan 2024
19 Jan 2024
Historique:
received:
21
10
2023
accepted:
06
01
2024
medline:
19
1
2024
pubmed:
19
1
2024
entrez:
18
1
2024
Statut:
aheadofprint
Résumé
Cadmium (Cd) is a toxic heavy metal with significant environmental health hazards. It enters the body through various routes with tissue accumulation. The relatively longer half-life with slow body clearance significantly results in hepatotoxicity during its liver detoxification. Therefore, researchers are exploring the potential use of herbal-derived phytocomponents to mitigate their toxicity. Here, we investigated, for the first time, the possible ameliorative effect of the phytochemical Morin (3,5,7,29,49-pentahydroxyflavone) against acute Cd-induced hepatotoxicity while resolving its underlying cellular mechanisms in a rat animal model. The study involved 50 adult male Sprague-Dawley rats weighing 200-250 g. The animals were divided into five equal groups: control, Cd, Morin100 + Cd, Morin200 + Cd, and Morin200. The 2nd, 3rd, and 4th groups were intraperitoneally treated with Cd (6.5 mg/kg), while the 3rd, 4th, and 5th groups were orally treated with Morin (100 and 200 mg/kg) for 5 consecutive days. On the 6th day, hepatic function (serum ALT, AST, ALP, LDH enzyme activities, and total bilirubin level) testing, transcriptome analysis, and immunohistochemistry were performed to elucidate the ameliorative effect of Morin on hepatotoxicity. In addition to restoring liver function and tissue injury, Morin alleviated Cd-induced hepatic oxidative/endoplasmic reticulum stress in a dose-dependent manner, as revealed by upregulating the expression of antioxidants (SOD, GSH, Gpx, CAT, and Nrf2) and decreasing the expression of ER stress markers. The expression of the proinflammatory mediators (TNF-α, IL-1-β, and IL-6) was also downregulated while improving the anti-inflammatory (IL-10 and IL-4) expression levels. Morin further slowed the apoptotic cascades by deregulating the expression of pro-apoptotic Bax and Caspase 12 markers concomitant with an increase in anti-apoptotic Blc2 mRNA expression. Furthermore, Morin restored Cd-induced tissue damage and markedly suppressed the cytoplasmic expression of JNK and p-PERK immunostained proteins. This study demonstrated the dose-dependent antioxidant hepatoprotective effect of Morin against acute hepatic Cd intoxication. This effect is likely linked with the modulation of upstream p-GRP78/PERK/ATF6 pro-apoptotic oxidative/ER stress and the downstream JNK/BAX/caspase 12 apoptotic signaling pathways.
Identifiants
pubmed: 38238535
doi: 10.1007/s12011-024-04064-0
pii: 10.1007/s12011-024-04064-0
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Ataturk University Scientific Research Projects Coordination Unit
ID : TCD-2020-8726
Organisme : Ataturk University Scientific Research Projects Coordination Unit
ID : TCD-2020-8726
Organisme : Ataturk University Scientific Research Projects Coordination Unit
ID : TCD-2020-8726
Organisme : Ataturk University Scientific Research Projects Coordination Unit
ID : TCD-2020-8726
Organisme : Ataturk University Scientific Research Projects Coordination Unit
ID : TCD-2020-8726
Organisme : Ataturk University Scientific Research Projects Coordination Unit
ID : TCD-2020-8726
Organisme : Ataturk University Scientific Research Projects Coordination Unit
ID : TCD-2020-8726
Organisme : Ataturk University Scientific Research Projects Coordination Unit
ID : TCD-2020-8726
Informations de copyright
© 2024. The Author(s).
Références
Pandey G, Madhuri S (2014) Heavy metals causing toxicity in animals and fishes. Int j Animal Vet Fishery Allied Sci 2(2):17–23
Sankhla MS, Kumari M, Nandan M, Kumar R, Agrawal P (2016) Heavy metals contamination in water and their hazardous effect on human health-a review. Int J Curr Microbiol App Sci 5(10):759–766
doi: 10.20546/ijcmas.2016.510.082
Jaishankar M, Tseten T, Anbalagan N, Mathew BB, Beeregowda KN (2014) Toxicity, mechanism and health effects of some heavy metals. Interdiscip Toxicol 7(2):60–72
pubmed: 26109881
pmcid: 4427717
doi: 10.2478/intox-2014-0009
Shixuan L, Fan Y, Mingwen H, Jing C, Guiping C, Aiming H, Xiong L, Danghua F, Chenghong X, Zhiwei X, Yunhui W, Huabin C (2023) Selenium alleviates cadmium-induced mitophagy through FUNDC1-mediated mitochondrial quality control pathway in the lungs of sheep. Environ Pollut 319:120954
doi: 10.1016/j.envpol.2022.120954
Aja PM, Izekwe FI, Famurewa AC, Ekpono EU, Nwite FE, Igwenyi IO, Awoke JN, Ani OG, Aloke C, Obasi NA, Udeh KU, Ale BA (2020) Hesperidin protects against cadmium-induced pancreatitis by modulating insulin secretion, redox imbalance and iNOS/NF-ŒB signaling in rats. Life Sci 259:118268
pubmed: 32800830
doi: 10.1016/j.lfs.2020.118268
Zhang W, Zhi J, Cui Y, Zhang F, Habyarimana A, Cambier C, Gustin P (2014) Potentiated interaction between ineffective doses of budesonide and formoterol to control the inhaled cadmium-induced up-regulation of metalloproteinases and acute pulmonary inflammation in rats. PLoS ONE 9(10):109136
doi: 10.1371/journal.pone.0109136
Sarwar N, Malhi SS, Zia MH, Naeem A, Bibi S, Farid G (2010) Role of mineral nutrition in minimizing cadmium accumulation by plants. J Sci Food Agric 90(6):925–937
pubmed: 20355131
doi: 10.1002/jsfa.3916
Alonso ML, Montaña FP, Miranda M, Castillo C, Hernandez J, Benedito JL (2003) Cadmium and lead accumulation in cattle in NW Spain. Vet Hum Toxicol 45(3):128–130
Prankel SH, Nixon RM, Phillips CJC (2005) Implications for the human food chain of models of cadmium accumulation in sheep. Environ Res 97(3):348–358
pubmed: 15589244
doi: 10.1016/j.envres.2004.07.003
Rahimi E (2013) Lead and cadmium concentrations in goat, cow, sheep, and buffalo milks from different regions of Iran. Food Chem 136(2):389–391
pubmed: 23122075
doi: 10.1016/j.foodchem.2012.09.016
Andjelkovic M, Buha Djordjevic A, Antonijevic E, Antonijevic B, Stanic M, Kotur-Stevuljevic J, Bulat Z (2019) Toxic effect of acute cadmium and lead exposure in rat blood, liver, and kidney. IJERPH 16(2):274
pubmed: 30669347
pmcid: 6351928
doi: 10.3390/ijerph16020274
Josthna P, Geetharathan T, Sujatha P, Deepika G (2012) Accumulation of lead and cadmium in the organs and tissues of albino rat. IJPLS 3:12
Zhang T, Yang F, Dai X, Liao H, Wang H, Peng C, Liu Z, Li Z, Shan J, Cao H (2023) Role of Caveolin-1 on the molybdenum and cadmium exposure induces pulmonary ferroptosis and fibrosis in the sheep. Environ Pollut 1(334):122207
doi: 10.1016/j.envpol.2023.122207
Ansari MA, Raish M, Ahmad A, Alkharfy KM, Ahmad SF, Attia SM, Bakheet SA (2017) Sinapic acid ameliorate cadmium-induced nephrotoxicity: in vivo possible involvement of oxidative stress, apoptosis, and inflammation via NF-κB downregulation. Environ Toxicol Pharmacol 51:100–107
pubmed: 28233699
doi: 10.1016/j.etap.2017.02.014
Refaie MM, El-Hussieny M, Zenhom NM (2018) Protective role of nebivolol in cadmium-induced hepatotoxicity via downregulation of oxidative stress, apoptosis and inflammatory pathways. Environ Toxicol Pharmacol 58:212–219
pubmed: 29408764
doi: 10.1016/j.etap.2018.01.011
Zhang C, Ge J, Lv M, Zhang Q, Talukder M, Li JL (2020) Selenium prevent cadmium-induced hepatotoxicity through modulation of endoplasmic reticulum-resident selenoproteins and attenuation of endoplasmic reticulum stress. Environ Pollut 260:113873
pubmed: 32369892
doi: 10.1016/j.envpol.2019.113873
Gali S, Sharma S, Kundu A, Lee E, Han JH, Shin JK, Choi JS, Kyung SY, Kim JS, Kim HS. 2023. Protective effect of dendropanoxide against cadmium-induced hepatotoxicity via anti-inflammatory activities in Sprague-Dawley rats. Toxicol Mech Methods.1–15
Abu-El-Zahab HS, Hamza RZ, Montaser MM, El-Mahdi MM, Al-Harthi WA (2019) Antioxidant, anti-apoptotic, antigenotoxic, and hepatic ameliorative effects of L-carnitine and selenium on cadmium-induced hepatotoxicity and alterations in liver cell structure in male mice. Ecotoxicol Environ Saf 173:419–428
pubmed: 30798185
doi: 10.1016/j.ecoenv.2019.02.041
Alharbi N, Elobeid M, Virk P (2019) Protective effect of Quercetin treatment against cadmiuminduced oxidative stress in a male rat model. Pakistan J Zool 51:2287–2296
doi: 10.17582/journal.pjz/2019.51.6.2287.2296
Oboh G, Adebayo AA, Ademosun AO, Olowokere OG (2019) Rutin alleviates cadmium-induced neurotoxicity in Wistar rats: involvement of modulation of nucleotide-degrading enzymes and monoamine oxidase. Metab Brain Dis 34(4):1181–1190
pubmed: 30972687
doi: 10.1007/s11011-019-00413-4
Caselli A, Cirri P, Santi A, Paoli P (2016) Morin: a promising natural drug. Curr Med Chem 23(8):774–791
pubmed: 26018232
doi: 10.2174/0929867323666160106150821
Kuzu M, Yıldırım S, Kandemir FM, Küçükler S, Çağlayan C, Türk E, Dörtbudak MB (2019) Protective effect of Morin on doxorubicin-induced hepatorenal toxicity in rats. Chem-Biol Interact 308:89–100
pubmed: 31100273
doi: 10.1016/j.cbi.2019.05.017
Chen Y, Li Y, Xu H, Li G, Ma Y, Pang YJ (2017) Morin mitigates oxidative stress, apoptosis and inflammation in cerebral ischemic rats. Afr J Tradit Complement Altern Med 14(2):348–355
pubmed: 28573251
pmcid: 5446461
doi: 10.21010/ajtcam.v14i2.36
Nowak E, Sypniewski D, Bednarek I (2020) Morin exerts anti-metastatic, anti-proliferative and anti-adhesive effect in ovarian cancer cells: An in vitro studies. Mol Biol Rep 47(3):1965–1978
pubmed: 32020427
doi: 10.1007/s11033-020-05293-x
Ma SH, Zhang LL, Jiang QQ (2017) Protective effect of bioflavonoid Morin on cadmium induced oxidative neuropathy. Biomed Res 28(3):1148–1154
Dkhil MA, Al-Quraishy S, Diab MM, Othman MS, Aref AM, Moneim AEA (2014) The potential protective role of Physalis peruviana L. fruit in cadmium-induced hepatotoxicity and nephrotoxicity. FCT 74:98–106
Sengul E, Gelen V, Yildirim S, Tekin S, Dag Y (2021) The effects of selenium in acrylamide-induced nephrotoxicity in rats: roles of oxidative stress, inflammation, apoptosis, and DNA damage. Biol Trace Elem Res 199(1):173–184
pubmed: 32166561
doi: 10.1007/s12011-020-02111-0
Cinar I, Halici Z, Dincer B, Sirin B, Cadirci E (2020) The role of 5-HT7 receptors on isoproterenol-induced myocardial infarction in rats with high-fat diet exacerbated coronary endothelial dysfunction. Hum Exp Toxicol 39(8):1005–1018
pubmed: 32329363
doi: 10.1177/0960327120916821
Sanjeev S, Bidanchi RM, Murthy MK, Gurusubramanian G, Roy VK (2019) Influence of ferulic acid consumption in ameliorating the cadmium-induced liver and renal oxidative damage in rats. ESPR 26(20):20631–20653
pubmed: 31104231
Abarikwu SO, Njoku RC, Lawrence CJ, Charles IA, Ikewuchi JC (2017) Rutin ameliorates oxidative stress and preserves hepatic and renal functions following exposure to cadmium and ethanol. Pharm Biol 55(1):2161–2169
pubmed: 29025321
pmcid: 6130732
doi: 10.1080/13880209.2017.1387575
Hogervorst J, Plusquin M, Vangronsveld J, Nawrot T, Cuypers A, Van Hecke E, Staessen JA (2007) House dust as possible route of environmental exposure to cadmium and lead in the adult general population. Environ Res 103(1):30–37
pubmed: 16843453
doi: 10.1016/j.envres.2006.05.009
Kandemir FM, Yıldırım S, Kucukler S, Caglayan C, Darendelioğlu E, Dortbudak MB (2020) Protective effects of Morin against acrylamide-induced hepatotoxicity and nephrotoxicity: A multi-biomarker approach. FCT 138:111190
De S, Sen T, Chatterjee M (2015) Reduction of oxidative stress by an ethanolic extract of leaves of Piper betle (Paan) Linn. decreased methotrexate-induced toxicity. Mol Cell Biochem 409(1):191–197
pubmed: 26276309
doi: 10.1007/s11010-015-2524-x
Kaur G, Shivanandappa TB, Kumar M, Kushwah AS (2020) Fumaric acid protect the cadmium-induced hepatotoxicity in rats: owing to its antioxidant, anti-inflammatory action and aid in recast the liver function. Naunyn-Schmiedeb Arch Pharmacol 393(10):1911–1920
doi: 10.1007/s00210-020-01900-7
Rizvi F, Mathur A, Kakkar P (2015) Morin mitigates acetaminophen-induced liver injury by potentiating Nrf2 regulated survival mechanism through molecular intervention in PHLPP2-Akt-Gsk3β axis. Apoptosis 20(10):1296–1306
pubmed: 26286854
doi: 10.1007/s10495-015-1160-y
Cai Q, Rahn RO, Zhang R (1997) Dietary flavonoids, quercetin, luteolin and genistein, reduce oxidative DNA damage and lipid peroxidation and quench free radicals. Cancer lett 119(1):99–107
pubmed: 18372528
doi: 10.1016/S0304-3835(97)00261-9
Xue-Yan D, Shi-Yong Z, Jian C, Mu-Zi L, Yi Z, Milton T, Jin-Long L (2022) Lycopene alleviates di(2-ethylhexyl) phthalate-induced splenic injury by activating P62-Keap1-NRF2 signaling. FCT 168:113324
Das SC, Al-Naemi HA (2019) Cadmium toxicity: oxidative stress, inflammation and tissue injury. Occup Environ Med 7:144–163
Kahkeshani N, Saeidnia S, Abdollahi M (2015) Role of antioxidants and phytochemicals on acrylamide mitigation from food and reducing its toxicity. JFST 52(6):3169–3186
Fang J, Yin H, Yang Z, Tan M, Wang F, Chen K, Liu W (2021) Vitamin E protects against cadmium-induced sub-chronic liver injury associated with the inhibition of oxidative stress and activation of Nrf2 pathway. Ecotoxicol Environ Saf 208:111610
pubmed: 33396130
doi: 10.1016/j.ecoenv.2020.111610
Gong ZG, Wang XY, Wang JH, Fan RF, Wang L (2019) Trehalose prevents cadmium-induced hepatotoxicity by blocking Nrf2 pathway, restoring autophagy and inhibiting apoptosis. J Inorg Biochem 192:62–71
pubmed: 30599315
doi: 10.1016/j.jinorgbio.2018.12.008
Çelik H, Kucukler S, Çomaklı S, Özdemir S, Caglayan C, Yardım A, Kandemir FM (2020) Morin attenuates ifosfamide-induced neurotoxicity in rats via suppression of oxidative stress, neuroinflammation and neuronal apoptosis. Neurotoxicology 76:126–137
pubmed: 31722249
doi: 10.1016/j.neuro.2019.11.004
Özdemir S, Kucukler S, Çomaklı S, Kandemir FM (2022) The protective effect of Morin against ifosfamide-induced acute liver injury in rats associated with the inhibition of DNA damage and apoptosis. Drug Chem Toxicol 45(3):1308–1317
pubmed: 32957801
doi: 10.1080/01480545.2020.1822390
Ince S, Arslan-Acaroz D, Demirel HH, Varol N, Ozyurek HA, Zemheri F, Kucukkurt I (2017) Taurine alleviates malathion induced lipid peroxidation, oxidative stress, and pro-inflammatory cytokine gene expressions in rats. Biomed Pharmacother 96:263–268
pubmed: 28987951
doi: 10.1016/j.biopha.2017.09.141
Al Olayan EM, Aloufi AS, Al Amri OD, Ola H, Moneim AEA (2020) Protocatechuic acid mitigates cadmium-induced neurotoxicity in rats: role of oxidative stress, inflammation and apoptosis. Sci Total Environ 723:137969
pubmed: 32392679
doi: 10.1016/j.scitotenv.2020.137969
Kumar A, Siddiqi NJ, Alrashood ST, Khan HA, Dubey A, Sharma B (2021) Protective effect of eugenol on hepatic inflammation and oxidative stress induced by cadmium in male rats. Biomed Pharmacother 139:111588
pubmed: 33862491
doi: 10.1016/j.biopha.2021.111588
Gur C, Kandemir FM, Darendelioglu E, Caglayan C, Kucukler S, Kandemir O, Ileriturk M (2021) Morin protects against acrylamide-induced neurotoxicity in rats: an investigation into different signal pathways. ESPR 28(36):49808–49819
pubmed: 33939091
Shah A, Vaidya NK, Bhat HK, Kumar A (2016) HIV-1 gp120 induces type-1 programmed cell death through ER stress employing IRE1α, JNK and AP-1 pathway. Sci Rep 6(1):1–13
doi: 10.1038/srep18929
Xiaoyu W, Chenghong X, Guyue L, Xueyan D, Xiaona G, Yu Z, Huabin C, Guoliang H, Xiaoquan G, Fan Y (2023) The key role of proteostasis at mitochondria-associated endoplasmic reticulum membrane in vanadium-induced nephrotoxicity using a proteomic strategy. Sci Total Environ 869:161741
doi: 10.1016/j.scitotenv.2023.161741
Malhi H, Kaufman RJ (2011) Endoplasmic reticulum stress in liver disease. J Hepatol 54(4):795–809
pubmed: 21145844
doi: 10.1016/j.jhep.2010.11.005
Guo Y, Guo R, Su Y, Fu J, Wang S, Kong Y, Zhao B (2020) The PERK/eIF2α/ATF4/CHOP pathway plays a role in regulating monocrotaline-induced endoplasmic reticulum stress in rat liver. Res Vet Sci 130:237–239
pubmed: 32224353
doi: 10.1016/j.rvsc.2020.03.021
Pandey VK, Mathur A, Khan MF, Kakkar P (2019) Activation of PERK-eIF2α-ATF4 pathway contributes to diabetic hepatotoxicity: attenuation of ER stress by Morin. Cell Signal 59:41–52
pubmed: 30877037
doi: 10.1016/j.cellsig.2019.03.008
Varışlı B, Caglayan C, Kandemir FM, Gür C, Bayav İ, Genç A (2022) The impact of Nrf2/HO-1, caspase-3/Bax/Bcl2 and ATF6/IRE1/PERK/GRP78 signaling pathways in the ameliorative effects of Morin against methotrexate-induced testicular toxicity in rats. Mol Biol Rep 49(10):9641–9649
pubmed: 36057755
doi: 10.1007/s11033-022-07873-5
Zhang Q, Liu J, Chen S, Liu J, Liu L, Liu G, Yuan X (2016) Caspase-12 is involved in stretch-induced apoptosis mediated endoplasmic reticulum stress. Apoptosis 21(4):432–442
pubmed: 26801321
doi: 10.1007/s10495-016-1217-6
Yuan Y, Yang J, Chen J, Zhao S, Wang T, Zou H, Liu Z (2019) Alpha-lipoic acid protects against cadmium-induced neuronal injury by inhibiting the endoplasmic reticulum stress eIF2α-ATF4 pathway in rat cortical neurons in vitro and in vivo. Toxicology 414:1–13
pubmed: 30605698
doi: 10.1016/j.tox.2018.12.005
Rizvi F, Mathur A, Krishna S, Siddiqi MI, Kakkar P (2015) Suppression in PHLPP2 induction by Morin promotes Nrf2-regulated cellular defenses against oxidative injury to primary rat hepatocytes. Redox biol 6:587–598
pubmed: 26513344
pmcid: 4633887
doi: 10.1016/j.redox.2015.10.002
Qu D, Jiang M, Huang D, Zhang H, Feng L, Chen Y, Han J (2019) Synergistic effects of the enhancements to mitochondrial ROS, p53 activation and apoptosis generated by aspartame and potassium sorbate in HepG2 cells. Molecules 24(3):457
pubmed: 30696035
pmcid: 6384600
doi: 10.3390/molecules24030457
Chen Y, Zhang W, Guo X, Ren J, Gao A (2019) The crosstalk between autophagy and apoptosis was mediated by phosphorylation of Bcl-2 and beclin1 in benzene-induced hematotoxicity. Cell death dis 10(10):1–15
doi: 10.1038/s41419-019-2004-4
Tartik M, Darendelioglu E, Aykutoglu G, Baydas G (2016) Turkish propolis suppresses MCF-7 cell death induced by homocysteine. Biomed Pharmacother 82:704–712
pubmed: 27470414
doi: 10.1016/j.biopha.2016.06.013
Adikwu E, Deo O, Geoffrey OBP (2013) Hepatotoxicity of cadmium and roles of mitigating agents. Br J Pharmacol Toxicol 4(6):222–231
doi: 10.19026/bjpt.4.5406
Banerjee S, Joshi N, Mukherjee R, Singh PK, Baxi D, Ramachandran AV (2017) Melatonin protects against chromium (VI) induced hepatic oxidative stress and toxicity: duration dependent study with realistic dosage. Interdiscip Toxicol 10(1):20–29
pubmed: 30123032
doi: 10.1515/intox-2017-0003
Oyinloye BE, Ajiboye BO, Ojo OA, Musa HM, Onikanni SA, Ojo AA (2016) Ameliorative potential of Aframomum melegueta extract in cadmium-induced hepatic damage and oxidative stress in male Wistar rats. JAPS 6(7):1–6
Ren L, Qi K, Zhang L, Bai Z, Ren C, Xu X, Li X (2019) Glutathione might attenuate cadmium-induced liver oxidative stress and hepatic stellate cell activation. Biol Trace Elem Res 191(2):443–452
pubmed: 30715683
doi: 10.1007/s12011-019-1641-x
Wang S, Ren X, Hu X, Zhou L, Zhang C, Zhang M (2019) Cadmium-induced apoptosis through reactive oxygen species-mediated mitochondrial oxidative stress and the JNK signaling pathway in TM3 cells, a model of mouse Leydig cells. Toxicol Appl Pharmacol 368:37–48
pubmed: 30796935
doi: 10.1016/j.taap.2019.02.012
Kuzu M, Kandemir FM, Yildirim S, Kucukler S, Caglayan C, Turk E (2018) Morin attenuates doxorubicin-induced heart and brain damage by reducing oxidative stress, inflammation and apoptosis. Biomed Pharmacother 106:443–453
pubmed: 29990832
doi: 10.1016/j.biopha.2018.06.161
Cinar I, Yayla M, Tavaci T, Toktay E, Ugan RA, Bayram P, Halici H (2022) In vivo and in vitro cardioprotective effect of gossypin against isoproterenol-induced myocardial infarction injury. Cardiovasc Toxicol 22(1):52–62
pubmed: 34599475
doi: 10.1007/s12012-021-09698-3
Ighodaro OM, Akinloye OA (2018) First line defence antioxidants-superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX): their fundamental role in the entire antioxidant defence grid. Alexandria J Med 54(4):287–293
doi: 10.1016/j.ajme.2017.09.001
Kunle-Alabi OT, Akindele OO, Odoh MI, Oghenetega BO, Raji Y (2017) Comparative effects of coconut water and N-Acetyl cysteine on the hypothalamo-pituitary-gonadal axis of male rats. SJST 39:6