Thymoquinone Prevents Valproic Acid-Induced Nephrotoxicity in Rat Kidney
Yıl 2022,
Cilt: 5 Sayı: 2, 77 - 84, 28.12.2022
Sebile Azirak
,
Deniz Taştemir Korkmaz
,
Sedat Bilgiç
,
Meltem Özgöçmen
,
Mehmet Kaya Özer
Öz
Valproic acid (VA), widely used as an antiepileptic, causes structural and functional kidney disorders. Whether thymoquinone (TQ) has a beneficial effect on valproic acid (VA)-induced nephrotoxicity has been investigated. Twenty-one male Spraque Dawley rats were grouped into control, VA, and VA + TQ groups (n=7 for per group). VA (500 mg/kg/day) and TQ (50 mg/kg/day) were applied to the rats orally for 14 days. They were euthanized on the 15th day of the treatment. The cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX-2) gene expression levels, biochemical parameters, total antioxidant/oxidant statuses (TAS/TOS), oxidative stress index (OSI), histological and immunohistochemical analysis were performed to evaluate kidney toxicity. In the VA + TQ group, COX-1 expression levels increased, while COX-2 expression levels decreased. While the creatinine (Cr) and blood urea nitrogen (BUN) levels, production of caspase-3 (CAS-3) and NADPH oxidase-4 (NOX-4) were increased in the VA-treated group, they were decreased in VA + TQ group. Treatment with TQ against VA administration decreased TOS and OSI levels while increasing TAS. TQ protects the kidney against the toxic effects of VA.
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Projeye destek veren bir kurum bulunmamaktadır.
Kaynakça
- Abdel-Wahhab MA, Nada SA, Arbid MS. 1999. Ochratoxicosis: prevention of developmental toxicity by L-methionine in rats. J Appl Toxicol. 19(1): 7-12.
- Altunbaşak S, Yildizaş D, Anarat A, Burgut HR. 2001. Renal tubular dysfunction in epileptic children on valproic acid therapy. Pediatr Nephrol. 16(3): 256-259.
- Asconapé JJ. 2014. Use of antiepileptic drugs in hepatic and renal disease. Handb Clin Neurol. 119: 417-432.
- Atta MS, Almadaly EA, El-Far AH, Saleh RM, Assar DH, Jaouni SKA, Mousa SA. 2017. Thymoquinone Defeats Diabetes-Induced Testicular Damage in Rats Targeting Antioxidant, Inflammatory and Aromatase Expression. Int J Mol Sci. 18(5): 919.
- Azirak S, Bilgiç S, Taştemir Korkmaz D, Sevimli M, Özer MK. 2022. Effect of thymoquinone on ameliorating valproic acid-induced damage in pancreatic tissue of rats. Cukurova Med J. 47: 350-359.
- Badary OA, Abdel-Naim AB, Abdel-Wahab MH, Hamada FM. 2000. The influence of thymoquinone on doxorubicin-induced hyperlipidemic nephropathy in rats. Toxicology. 143(3): 219-226.
- Barbalho PG, Carvalho BS, Lopes-Cendes I, Maurer-Morelli CV. 2016. Cyclooxygenase-1 as a Potential Therapeutic Target for Seizure Suppression: Evidences from Zebrafish Pentylenetetrazole-Seizure Model. Front Neurol. 7: 200.
- Barrett CE, Hennessey TM, Gordon KM, Ryan SJ, McNair ML, Ressler KJ, Rainnie DG. 2017. Developmental disruption of amygdala transcriptome and socioemotional behavior in rats exposed to valproic acid prenatally. Mol Autism. 8: 42.
- Bilgiç S, Korkmaz DT, Azirak S, Güvenç AN, Kocaman N, Özer MK. 2017. Risperidone-Induced Renal Damage and Metabolic Side Effects: The Protective Effect of Resveratrol. Oxid Med Cell Longev. 8709521.
- Blumenfeld A, Gennings C, Cady R. 2012. Pharmacological synergy: the next frontier on therapeutic advancement for migraine. Headache. 52(4): 636-647.
- Chang TK and Abbott FS. 2006. Oxidative stress as a mechanism of valproic acid-associated hepatotoxicity. Drug Metab Rev. 38(4): 627-639.
- Cole-Edwards KK and Bazan NG. 2005. Lipid signaling in experimental epilepsy. Neurochem Res. 30(6-7): 847-853.
- Crofford LJ. 1997. COX-1 and COX-2 tissue expression: implications and predictions. J Rheumatol Suppl. 49:15-19.
- de Leval X, Delarge J, Somers F, de Tullio P, Henrotin Y, Pirotte B, Dogné JM. 2000. Recent advances in inducible cyclooxygenase (COX-2) inhibition. Curr Med Chem. 7(10):1041-1062.
- Dhir A. 2019. An update of cyclooxygenase (COX)-inhibitors in epilepsy disorders. Expert Opin Investig Drugs. 28(2):191-205.
- Eirin A, Lerman A, Lerman LO. 2017. The Emerging Role of Mitochondrial Targeting in Kidney Disease. Handb Exp Pharmacol. 240: 229-250.
- El Sabbahy M and Vaidya VS. 2011. Ischemic kidney injury and mechanisms of tissue repair. Wiley Interdiscip Rev Syst Biol Med. 3(5): 606-618.
- Endo A, Fujita Y, Fuchigami T, Takahashi S, Mugishima H. 2010. Fanconi syndrome caused by valproic acid. Pediatr Neurol. 42(4): 287-290.
- Erdemli ME and Yigitcan B. 2020. Thymoquinone protection against 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin induced nephrotoxicity in rats. Biotech Histochem. 95(8): 567-574.
- Fanos V and Cataldi L. 2002. Drug misadventuring in neonatal nephrology. Pediatr Med Chir. 24(2): 150-156.
- Faria J, Ahmed S, Gerritsen KGF, Mihaila SM, Masereeuw R. 2019. Kidney-based in vitro models for drug-induced toxicity testing. Arch Toxicol. 93(12): 3397-3418.
- Gezginci-Oktayoglu S, Turkyilmaz IB, Ercin M, Yanardag R, Bolkent S. 2016. Vitamin U has a protective effect on valproic acid-induced renal damage due to its anti-oxidant, anti-inflammatory, and anti-fibrotic properties. Protoplasma. 253(1):127-135.
- Gul F, Muderris T, Yalciner G, Sevil E, Bercin S, Ergin M, Babademez MA, Kiris M. 2017. A comprehensive study of oxidative stress in sudden hearing loss. Eur Arch Otorhinolaryngol. 274(3): 1301-1308.
- Hamed SA. 2017. The effect of antiepileptic drugs on kidney function and structure. Expert Rev Clin Pharmacol. 10(9): 993-1006.
- Heidari R, Jafari F, Khodaei F, Yeganeh BS, Niknahad H. 2018. Mechanism of valproic acid-induced Fanconi syndrome involves mitochondrial dysfunction and oxidative stress in rat kidney. Nephrology (Carlton). 23(4): 351-361.
- Irazabal MV and Torres VE. 2020. Reactive Oxygen Species and Redox Signaling in Chronic Kidney Disease. Cells. 9(6): 1342.
- Jalili C, Salahshoor MR, Hoseini M, Roshankhah S, Sohrabi M, Shabanizadeh A. 2017. Protective Effect of Thymoquinone Against Morphine Injuries to Kidneys of Mice. Iran J Kidney Dis. 11(2): 142-150.
- Junge W, Wilke B, Halabi A, Klein G. 2004. Determination of reference intervals for serum creatinine, creatinine excretion and creatinine clearance with an enzymatic and a modified Jaffé method. Clin Chim Acta. 344(1-2): 137-148.
- Karimi Z and Mirza Alizadeh A. 2019. Nigella sativa and its Derivatives as Food Toxicity Protectant Agents. 9(1): 22-37.
- Kis B, Snipes JA, Isse T, Nagy K, Busija DW. 2003. Putative cyclooxygenase-3 expression in rat brain cells. J Cereb Blood Flow Metab. 23(11): 1287-1292.
- Knights MJ and Finlay E. 2014. The effects of sodium valproate on the renal function of children with epilepsy. Pediatr Nephrol. 29(7):1131-1138.
- Makris K and Spanou L. 2016. Acute Kidney Injury: Definition, Pathophysiology and Clinical Phenotypes. Clin Biochem Rev. 37(2): 85-98.
- Malyszko J, Kozlowska K, Kozlowski L, Malyszko J. 2017. Nephrotoxicity of anticancer treatment. Nephrol Dial Transplant. 32(6): 924-936.
- Oksuz E, Atalar F, Tanırverdi G, Bilir A, Shahzadi A, Yazici Z. 2016. Therapeutic potential of cyclooxygenase-3 inhibitors in the management of glioblastoma. J Neurooncol. 126(2): 271-278.
- Ornoy A, Becker M, Weinstein-Fudim L, Ergaz Z. 2020. S-Adenosine Methionine (SAMe) and Valproic Acid (VPA) as Epigenetic Modulators: Special Emphasis on their Interactions Affecting Nervous Tissue during Pregnancy. Int J Mol Sci. 21(10): 3721.
- Polascheck N, Bankstahl M, Löscher W. 2010. The COX-2 inhibitor parecoxib is neuroprotective but not antiepileptogenic in the pilocarpine model of temporal lobe epilepsy. Exp Neurol. 224(1): 219-233.
- Qiao L-N, Wang J-Y, Yang Y-S, Chen S-P, Gao Y-H, Zhang J-L, Liu J-L. 2013. Effect of Electroacupuncture Intervention on Expression of CGRP, SP, COX-1, and PGE2 of Dorsal Portion of the Cervical Spinal Cord in Rats with Neck-Incision Pain. Evid Based Complement Alternat Med. 2013:294091.
- Ragheb A, Attia A, Eldin WS, Elbarbry F, Gazarin S, Shoker A. 2009. The protective effect of thymoquinone, an anti-oxidant and anti-inflammatory agent, against renal injury: a review. Saudi J Kidney Dis Transpl. 20(5): 741-752.
- Rana SV. 2008. Metals and apoptosis: recent developments. J Trace Elem Med Biol. 22(4): 262-284.
- Savran M, Ascı H, Armagan İ, Erzurumlu Y, Azırak S, Ozer MK, Bilgic S, Korkmaz DT. 2020. Thymoquinone could be protective against valproic acid-induced testicular toxicity by antioxidant and anti-inflammatory mechanisms. Andrologia. 52 (7): e13623.
- Shalini S, Dorstyn L, Dawar S, Kumar S. 2015. Old, new and emerging functions of caspases. Cell Death Differ. 22(4): 526-539.
- Shaterzadeh-Yazdi H, Noorbakhsh MF, Samarghandian S, Farkhondeh T. 2018. An Overview on Renoprotective Effects of Thymoquinone. Kidney Dis (Basel). 4(2): 74-82.
- Sher Y, Miller Cramer AC, Ament A, Lolak S, Maldonado JR. 2015. Valproic Acid for Treatment of Hyperactive or Mixed Delirium: Rationale and Literature Review. Psychosomatics. 56(6): 615-625.
- Takemiya T, Matsumura K, Yamagata K. 2007. Roles of prostaglandin synthesis in excitotoxic brain diseases. Neurochem Int. 51(2-4): 112-120.
- Takeuchi K, Tanaka A, Hayashi Y, Yokota A. 2005. COX inhibition and NSAID-induced gastric damage--roles in various pathogenic events. Curr Top Med Chem. 5(5): 475-486.
- Talebi M, Talebi M, Farkhondeh T, Samarghandian S. 2021. Biological and therapeutic activities of thymoquinone: Focus on the Nrf2 signaling pathway. Phytother Res. 35(4): 1739-1753.
- Tastemir Korkmaz D, Azirak S, Bilgic S, Bayram D, Ozer MK. 2021. Thymoquinone reduced RIPK1-dependent apoptosis caused by valproic acid in rat brain. Ann Med Res. 28(11): 2005-2011.
- Tavakkoli A, Mahdian V, Razavi BM, Hosseinzadeh H. 2017. Review on Clinical Trials of Black Seed (Nigella sativa ) and Its Active Constituent, Thymoquinone. J Pharmacopuncture. 20(3): 179-193.
- Tekbas A, Huebner J, Settmacher U, Dahmen U. 2018. Plants and Surgery: The Protective Effects of Thymoquinone on Hepatic Injury-A Systematic Review of In Vivo Studies. Int J Mol Sci. 19(4): 1085.
- Tung EW and Winn LM. 2011. Valproic acid increases formation of reactive oxygen species and induces apoptosis in postimplantation embryos: a role for oxidative stress in valproic acid-induced neural tube defects. Mol Pharmacol. 80(6): 979-987.
- Vane JR and Botting RM. 1998. Anti-inflammatory drugs and their mechanism of action. Inflamm Res. 47(2): 78-87.
- Vezzani A, Balosso S, Ravizza T. 2008. The role of cytokines in the pathophysiology of epilepsy. Brain Behav Immun. 22(6): 797-803.
- Wallace JL, McKnight W, Reuter BK, Vergnolle N. 2000. NSAID-induced gastric damage in rats: requirement for inhibition of both cyclooxygenase 1 and 2. Gastroenterology. 119(3): 706-714.
- Yaman A, Kendirli T, Odek C, Bektaş O, Kuloğlu Z, Koloğlu M, Ince E, Deda D. 2013. Valproic acid-induced acute pancreatitis and multiorgan failure in a child. Pediatr Emerg Care. 29(5): 659-661.
- Yan S, Li YZ, Zhu XW, Liu CL, Wang P, Liu YL. 2013. HuGE systematic review and meta-analysis demonstrate association of CASP-3 and CASP-7 genetic polymorphisms with cancer risk. Genet Mol Res. 12(2): 1561-1573.
- Yang Q, Wu F-R, Wang J-N, Gao L, Jiang L, Li H-D, Ma Q, Liu X-Q, Wei B, Zhou L, Wen J, Ma TT, Li J, Meng X-M. 2018. Nox4 in renal diseases: An update. Free Radic Biol Med. 124: 466-472.
- Zidar N, Odar K, Glavac D, Jerse M, Zupanc T, Stajer D. 2009. Cyclooxygenase in normal human tissues--is COX-1 really a constitutive isoform, and COX-2 an inducible isoform? J Cell Mol Med. 13(9b): 3753-3763.
Yıl 2022,
Cilt: 5 Sayı: 2, 77 - 84, 28.12.2022
Sebile Azirak
,
Deniz Taştemir Korkmaz
,
Sedat Bilgiç
,
Meltem Özgöçmen
,
Mehmet Kaya Özer
Kaynakça
- Abdel-Wahhab MA, Nada SA, Arbid MS. 1999. Ochratoxicosis: prevention of developmental toxicity by L-methionine in rats. J Appl Toxicol. 19(1): 7-12.
- Altunbaşak S, Yildizaş D, Anarat A, Burgut HR. 2001. Renal tubular dysfunction in epileptic children on valproic acid therapy. Pediatr Nephrol. 16(3): 256-259.
- Asconapé JJ. 2014. Use of antiepileptic drugs in hepatic and renal disease. Handb Clin Neurol. 119: 417-432.
- Atta MS, Almadaly EA, El-Far AH, Saleh RM, Assar DH, Jaouni SKA, Mousa SA. 2017. Thymoquinone Defeats Diabetes-Induced Testicular Damage in Rats Targeting Antioxidant, Inflammatory and Aromatase Expression. Int J Mol Sci. 18(5): 919.
- Azirak S, Bilgiç S, Taştemir Korkmaz D, Sevimli M, Özer MK. 2022. Effect of thymoquinone on ameliorating valproic acid-induced damage in pancreatic tissue of rats. Cukurova Med J. 47: 350-359.
- Badary OA, Abdel-Naim AB, Abdel-Wahab MH, Hamada FM. 2000. The influence of thymoquinone on doxorubicin-induced hyperlipidemic nephropathy in rats. Toxicology. 143(3): 219-226.
- Barbalho PG, Carvalho BS, Lopes-Cendes I, Maurer-Morelli CV. 2016. Cyclooxygenase-1 as a Potential Therapeutic Target for Seizure Suppression: Evidences from Zebrafish Pentylenetetrazole-Seizure Model. Front Neurol. 7: 200.
- Barrett CE, Hennessey TM, Gordon KM, Ryan SJ, McNair ML, Ressler KJ, Rainnie DG. 2017. Developmental disruption of amygdala transcriptome and socioemotional behavior in rats exposed to valproic acid prenatally. Mol Autism. 8: 42.
- Bilgiç S, Korkmaz DT, Azirak S, Güvenç AN, Kocaman N, Özer MK. 2017. Risperidone-Induced Renal Damage and Metabolic Side Effects: The Protective Effect of Resveratrol. Oxid Med Cell Longev. 8709521.
- Blumenfeld A, Gennings C, Cady R. 2012. Pharmacological synergy: the next frontier on therapeutic advancement for migraine. Headache. 52(4): 636-647.
- Chang TK and Abbott FS. 2006. Oxidative stress as a mechanism of valproic acid-associated hepatotoxicity. Drug Metab Rev. 38(4): 627-639.
- Cole-Edwards KK and Bazan NG. 2005. Lipid signaling in experimental epilepsy. Neurochem Res. 30(6-7): 847-853.
- Crofford LJ. 1997. COX-1 and COX-2 tissue expression: implications and predictions. J Rheumatol Suppl. 49:15-19.
- de Leval X, Delarge J, Somers F, de Tullio P, Henrotin Y, Pirotte B, Dogné JM. 2000. Recent advances in inducible cyclooxygenase (COX-2) inhibition. Curr Med Chem. 7(10):1041-1062.
- Dhir A. 2019. An update of cyclooxygenase (COX)-inhibitors in epilepsy disorders. Expert Opin Investig Drugs. 28(2):191-205.
- Eirin A, Lerman A, Lerman LO. 2017. The Emerging Role of Mitochondrial Targeting in Kidney Disease. Handb Exp Pharmacol. 240: 229-250.
- El Sabbahy M and Vaidya VS. 2011. Ischemic kidney injury and mechanisms of tissue repair. Wiley Interdiscip Rev Syst Biol Med. 3(5): 606-618.
- Endo A, Fujita Y, Fuchigami T, Takahashi S, Mugishima H. 2010. Fanconi syndrome caused by valproic acid. Pediatr Neurol. 42(4): 287-290.
- Erdemli ME and Yigitcan B. 2020. Thymoquinone protection against 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin induced nephrotoxicity in rats. Biotech Histochem. 95(8): 567-574.
- Fanos V and Cataldi L. 2002. Drug misadventuring in neonatal nephrology. Pediatr Med Chir. 24(2): 150-156.
- Faria J, Ahmed S, Gerritsen KGF, Mihaila SM, Masereeuw R. 2019. Kidney-based in vitro models for drug-induced toxicity testing. Arch Toxicol. 93(12): 3397-3418.
- Gezginci-Oktayoglu S, Turkyilmaz IB, Ercin M, Yanardag R, Bolkent S. 2016. Vitamin U has a protective effect on valproic acid-induced renal damage due to its anti-oxidant, anti-inflammatory, and anti-fibrotic properties. Protoplasma. 253(1):127-135.
- Gul F, Muderris T, Yalciner G, Sevil E, Bercin S, Ergin M, Babademez MA, Kiris M. 2017. A comprehensive study of oxidative stress in sudden hearing loss. Eur Arch Otorhinolaryngol. 274(3): 1301-1308.
- Hamed SA. 2017. The effect of antiepileptic drugs on kidney function and structure. Expert Rev Clin Pharmacol. 10(9): 993-1006.
- Heidari R, Jafari F, Khodaei F, Yeganeh BS, Niknahad H. 2018. Mechanism of valproic acid-induced Fanconi syndrome involves mitochondrial dysfunction and oxidative stress in rat kidney. Nephrology (Carlton). 23(4): 351-361.
- Irazabal MV and Torres VE. 2020. Reactive Oxygen Species and Redox Signaling in Chronic Kidney Disease. Cells. 9(6): 1342.
- Jalili C, Salahshoor MR, Hoseini M, Roshankhah S, Sohrabi M, Shabanizadeh A. 2017. Protective Effect of Thymoquinone Against Morphine Injuries to Kidneys of Mice. Iran J Kidney Dis. 11(2): 142-150.
- Junge W, Wilke B, Halabi A, Klein G. 2004. Determination of reference intervals for serum creatinine, creatinine excretion and creatinine clearance with an enzymatic and a modified Jaffé method. Clin Chim Acta. 344(1-2): 137-148.
- Karimi Z and Mirza Alizadeh A. 2019. Nigella sativa and its Derivatives as Food Toxicity Protectant Agents. 9(1): 22-37.
- Kis B, Snipes JA, Isse T, Nagy K, Busija DW. 2003. Putative cyclooxygenase-3 expression in rat brain cells. J Cereb Blood Flow Metab. 23(11): 1287-1292.
- Knights MJ and Finlay E. 2014. The effects of sodium valproate on the renal function of children with epilepsy. Pediatr Nephrol. 29(7):1131-1138.
- Makris K and Spanou L. 2016. Acute Kidney Injury: Definition, Pathophysiology and Clinical Phenotypes. Clin Biochem Rev. 37(2): 85-98.
- Malyszko J, Kozlowska K, Kozlowski L, Malyszko J. 2017. Nephrotoxicity of anticancer treatment. Nephrol Dial Transplant. 32(6): 924-936.
- Oksuz E, Atalar F, Tanırverdi G, Bilir A, Shahzadi A, Yazici Z. 2016. Therapeutic potential of cyclooxygenase-3 inhibitors in the management of glioblastoma. J Neurooncol. 126(2): 271-278.
- Ornoy A, Becker M, Weinstein-Fudim L, Ergaz Z. 2020. S-Adenosine Methionine (SAMe) and Valproic Acid (VPA) as Epigenetic Modulators: Special Emphasis on their Interactions Affecting Nervous Tissue during Pregnancy. Int J Mol Sci. 21(10): 3721.
- Polascheck N, Bankstahl M, Löscher W. 2010. The COX-2 inhibitor parecoxib is neuroprotective but not antiepileptogenic in the pilocarpine model of temporal lobe epilepsy. Exp Neurol. 224(1): 219-233.
- Qiao L-N, Wang J-Y, Yang Y-S, Chen S-P, Gao Y-H, Zhang J-L, Liu J-L. 2013. Effect of Electroacupuncture Intervention on Expression of CGRP, SP, COX-1, and PGE2 of Dorsal Portion of the Cervical Spinal Cord in Rats with Neck-Incision Pain. Evid Based Complement Alternat Med. 2013:294091.
- Ragheb A, Attia A, Eldin WS, Elbarbry F, Gazarin S, Shoker A. 2009. The protective effect of thymoquinone, an anti-oxidant and anti-inflammatory agent, against renal injury: a review. Saudi J Kidney Dis Transpl. 20(5): 741-752.
- Rana SV. 2008. Metals and apoptosis: recent developments. J Trace Elem Med Biol. 22(4): 262-284.
- Savran M, Ascı H, Armagan İ, Erzurumlu Y, Azırak S, Ozer MK, Bilgic S, Korkmaz DT. 2020. Thymoquinone could be protective against valproic acid-induced testicular toxicity by antioxidant and anti-inflammatory mechanisms. Andrologia. 52 (7): e13623.
- Shalini S, Dorstyn L, Dawar S, Kumar S. 2015. Old, new and emerging functions of caspases. Cell Death Differ. 22(4): 526-539.
- Shaterzadeh-Yazdi H, Noorbakhsh MF, Samarghandian S, Farkhondeh T. 2018. An Overview on Renoprotective Effects of Thymoquinone. Kidney Dis (Basel). 4(2): 74-82.
- Sher Y, Miller Cramer AC, Ament A, Lolak S, Maldonado JR. 2015. Valproic Acid for Treatment of Hyperactive or Mixed Delirium: Rationale and Literature Review. Psychosomatics. 56(6): 615-625.
- Takemiya T, Matsumura K, Yamagata K. 2007. Roles of prostaglandin synthesis in excitotoxic brain diseases. Neurochem Int. 51(2-4): 112-120.
- Takeuchi K, Tanaka A, Hayashi Y, Yokota A. 2005. COX inhibition and NSAID-induced gastric damage--roles in various pathogenic events. Curr Top Med Chem. 5(5): 475-486.
- Talebi M, Talebi M, Farkhondeh T, Samarghandian S. 2021. Biological and therapeutic activities of thymoquinone: Focus on the Nrf2 signaling pathway. Phytother Res. 35(4): 1739-1753.
- Tastemir Korkmaz D, Azirak S, Bilgic S, Bayram D, Ozer MK. 2021. Thymoquinone reduced RIPK1-dependent apoptosis caused by valproic acid in rat brain. Ann Med Res. 28(11): 2005-2011.
- Tavakkoli A, Mahdian V, Razavi BM, Hosseinzadeh H. 2017. Review on Clinical Trials of Black Seed (Nigella sativa ) and Its Active Constituent, Thymoquinone. J Pharmacopuncture. 20(3): 179-193.
- Tekbas A, Huebner J, Settmacher U, Dahmen U. 2018. Plants and Surgery: The Protective Effects of Thymoquinone on Hepatic Injury-A Systematic Review of In Vivo Studies. Int J Mol Sci. 19(4): 1085.
- Tung EW and Winn LM. 2011. Valproic acid increases formation of reactive oxygen species and induces apoptosis in postimplantation embryos: a role for oxidative stress in valproic acid-induced neural tube defects. Mol Pharmacol. 80(6): 979-987.
- Vane JR and Botting RM. 1998. Anti-inflammatory drugs and their mechanism of action. Inflamm Res. 47(2): 78-87.
- Vezzani A, Balosso S, Ravizza T. 2008. The role of cytokines in the pathophysiology of epilepsy. Brain Behav Immun. 22(6): 797-803.
- Wallace JL, McKnight W, Reuter BK, Vergnolle N. 2000. NSAID-induced gastric damage in rats: requirement for inhibition of both cyclooxygenase 1 and 2. Gastroenterology. 119(3): 706-714.
- Yaman A, Kendirli T, Odek C, Bektaş O, Kuloğlu Z, Koloğlu M, Ince E, Deda D. 2013. Valproic acid-induced acute pancreatitis and multiorgan failure in a child. Pediatr Emerg Care. 29(5): 659-661.
- Yan S, Li YZ, Zhu XW, Liu CL, Wang P, Liu YL. 2013. HuGE systematic review and meta-analysis demonstrate association of CASP-3 and CASP-7 genetic polymorphisms with cancer risk. Genet Mol Res. 12(2): 1561-1573.
- Yang Q, Wu F-R, Wang J-N, Gao L, Jiang L, Li H-D, Ma Q, Liu X-Q, Wei B, Zhou L, Wen J, Ma TT, Li J, Meng X-M. 2018. Nox4 in renal diseases: An update. Free Radic Biol Med. 124: 466-472.
- Zidar N, Odar K, Glavac D, Jerse M, Zupanc T, Stajer D. 2009. Cyclooxygenase in normal human tissues--is COX-1 really a constitutive isoform, and COX-2 an inducible isoform? J Cell Mol Med. 13(9b): 3753-3763.