Timokinon’un sıçanların pankreas dokusunda valproik asidin neden olduğu hasarı iyileştirmeye etkisi
Yıl 2022,
, 350 - 359, 31.03.2022
Sebile Azirak
,
Sedat Bilgiç
,
Deniz Taştemir Korkmaz
,
Murat Sevimli
,
Mehmet Kaya Özer
Öz
Amaç: Bu çalışmanın amacı timokinonun (TQ) valproik asit (VPA) kaynaklı pankreas hasarını önleme veya tedavi etmedeki potansiyel etkisinin, sıçanların pankreas dokusundaki gen ekspresyonlarının ve histopatolojik değişikliklerin değerlendirilmesidir.
Gereç ve Yöntem: 21 erkek Spraque-Dawley sıçanı 3 gruba ayrıldı (n = 7): Kontrol, VPA, VPA + TQ. Sıçanlar, 14 gün boyunca oral yoldan VPA (500 mg/kg/gün) ve TQ (50 mg/kg/gün) ile muamele edildi. Muamelenin 15. gününde, histon deasetilaz (HDAC1 ve HDAC2) genlerinin ekspresyon seviyelerinin analizi için pankreas dokusu çıkarıldı. Pankreas dokularındaki yapısal değişiklikler incelendi.
Bulgular: VPA + TQ grubunun, VPA grubuna göre anlamlı derecede daha yüksek HDAC1 ve HDAC2 gen ekspresyonuna sahip olduğu görüldü. Ayrıca bulgularımız, TQ tedavisinin pankreas dokusunu VPA'nın HDAC1 ve HDAC2 gen ekspresyonu üzerindeki olumsuz etkilerine karşı koruyabildiğini göstermektedir. Ayrıca TQ NADPH oksidaz-4 (NOX-4) ve kaspaz-3 (CAS-3) düzeylerini de düşürdü. VPA+TQ grubunda VPA grubuna göre oksidatif stres azaldı, antioksidan aktivite arttı ve histopatolojik değişiklikler azaldı. VPA'nın neden olduğu pankreas hasarı, TQ'nun antioksidatif ve antiapoptotik etkileri nedeniyle hafifletildi.
Sonuç: TQ, VPA'nın neden olduğu pankreas hasarının şiddetini azaltmada faydalı olabilir.
Kaynakça
- Kumar R, Vidaurre J, Gedela S. Valproic acid-induced coagulopathy. Ped Neurol. 2019;98:25-30.
- Zhu MM, Li HL, Shi LH, Chen XP, Luo J, Zhang ZL. The pharmacogenomics of valproic acid. J Hum Genet. 2017;62:1009-14.
- Gerstner T, Bell N, König S. Oral valproic acid for epilepsy--long-term experience in therapy and side effects. Expert Opin Pharmacother. 2008;9:285-92.
- Hamed SA. The effect of antiepileptic drugs on the kidney function and structure. Expert Rev Clin Pharmacol. 2017;10:993-1006.
- Mai A, Massa S, Rotili D, Cerbara I, Valente S, Pezzi R et al. Histone deacetylation in epigenetics: an attractive target for anticancer therapy. Med Res Rev. 2005;25:261-309.
- Bahl S, Seto E. Regulation of histone deacetylase activities and functions by phosphorylation and its physiological relevance. Cell Moll Life Sci. 2021;78:427-45.
- Sixto-López Y, Bello M, Correa-Basurto J. Exploring the inhibitory activity of valproic acid against the HDAC family using an MMGBSA approach. J Comput Aided Mol Des. 2020;34:857-78.
- Miller KM, Tjeertes JV, Coates J, Legube G, Polo SE, Britton S et al. Human HDAC1 and HDAC2 function in the DNA-damage response to promote DNA nonhomologous end-joining. Nat Struct Mol Biol. 2010;17:1144-51.
- Dovey OM, Foster CT, Conte N, Edwards SA, Edwards JM, Singh R, et al. Histone deacetylase 1 and 2 are essential for normal T-cell development and genomic stability in mice. Blood. 2013;121:1335-44.
- Yang WB, Hsu CC, Hsu TI, Liou JP, Chang KY, Chen PY et al. Increased activation of HDAC1/2/6 and Sp1 underlies therapeutic resistance and tumor growth in glioblastoma. Neuro-Oncol. 2020;22:1439-51.
- Seto E, Yoshida M. Erasers of histone acetylation: the histone deacetylase enzymes. Cold Spring Harb Perspect Biol. 2014;6:a018713.
- Mazzoccoli G, Longhitano C, Vinciguerra M. Cardio-hepatic metabolic derangements and valproic acid. Curr Clin Pharmacol. 2014;9:165-70.
- Cornago M, Garcia-Alberich C, Blasco-Angulo N, Vall-Llaura N, Nager M, Herreros J et al. Histone deacetylase inhibitors promote glioma cell death by G2 checkpoint abrogation leading to mitotic catastrophe. Cell Death Dis. 2014;5:e1435.
- Lorberbaum DS, Docherty FM, Sussel L. Animal models of pancreas development, developmental disorders, and disease. Adv Exp Med Biol. 2020;1236:65-85.
- Lankisch PG, Apte M, Banks PA. Acute pancreatitis. Lancet. 2015;386:85-96.
- Wang GJ, Gao CF, Wei D, Wang C, Ding SQ. Acute pancreatitis: etiology and common pathogenesis. World J Gastroenterol. 2009;15:1427-30.
- Eisses JF, Criscimanna A, Dionise ZR, Orabi AI, Javed TA, Sarwar S et al. Valproic acid limits pancreatic recovery after pancreatitis by inhibiting histone deacetylases and preventing acinar redifferentiation programs. Am J Pathol. 2015;185:3304-15.
- Mederos MA, Reber HA, Girgis MD. Acute pancreatitis: a review. JAMA. 2021;325:382-90.
- Głuszek S, Nawacki Ł, Matykiewicz J, Kot M, Kuchinka J. Severe vascular complications of acute pancreatitis. Pol Przegl Chir. 2015;87:485-90.
- Shaterzadeh-Yazdi H, Noorbakhsh MF, Hayati F, Samarghandian S, Farkhondeh T. Immunomodulatory and anti-inflammatory effects of thymoquinone. Cardiovasc Hematol Disord - Drug Targets. 2018;18:52-60.
- Glamočlija U, Padhye S, Špirtović-Halilović S, Osmanović A, Veljović E, Roca S et al. Synthesis, biological evaluation and docking studies of benzoxazoles derived from thymoquinone. Molecules. 2018;23:3297.
- Bimonte S, Albino V, Barbieri A, Tamma ML, Nasto A, Palaia R et al. Dissecting the roles of thymoquinone on the prevention and the treatment of hepatocellular carcinoma: an overview on the current state of knowledge. Infect Agents Cancer. 2019;14:10.
- Dariani S, Baluchnejadmojarad T, Roghani M. Thymoquinone attenuates astrogliosis, neurodegeneration, mossy fiber sprouting, and oxidative stress in a model of temporal lobe epilepsy. J Mol Neursci. 2013;51:679-86.
- Almatroodi SA, Almatroudi A, Alsahli MA, Khan AA, Rahmani AH. Thymoquinone, an active compound of Nigella sativa: role in prevention and treatment of cancer. Curr Pharm Biotechnol. 2020;21:1028-41.
- Raza M, Alghasham AA, Alorainy MS, El-Hadiyah TM. Potentiation of valproate-induced anticonvulsant response by Nigella sativa seed constituents: the role of GABA receptors. Int J Health Sci. 2008;2:15-25.
- Ozdemir H, Kara MI, Erciyas K, Ozer H, Ay S. Preventive effects of thymoquinone in a rat periodontitis model: a morphometric and histopathological study. J Periodontal Res. 2012;47:74-80.
- Talebi M, Talebi M. Biological and therapeutic activities of thymoquinone: focus on the Nrf2 signaling pathway. Phytother Res. 2021;35:1739-53.
- Yi T, Cho SG, Yi Z, Pang X, Rodriguez M, Wang Y et al. Thymoquinone inhibits tumor angiogenesis and tumor growth through suppressing AKT and extracellular signal-regulated kinase signaling pathways. Mol Cancer Ther. 2008;7:1789-96.
- Peng L, Liu A, Shen Y, Xu HZ, Yang SZ, Ying XZ et al. Antitumor and anti-angiogenesis effects of thymoquinone on osteosarcoma through the NF-κB pathway. Oncol Rep. 2013;29:571-8.
- Banerjee S, Kaseb AO, Wang Z, Kong D, Mohammad M, Padhye S et al. Antitumor activity of gemcitabine and oxaliplatin is augmented by thymoquinone in pancreatic cancer. Cancer Res. 2009;69:5575-83.
- Ijaz H, Tulain UR, Qureshi J, Danish Z, Musayab S, Akhtar MF et al. Review: Nigella sativa (prophetic medicine): a review. Pak J Pharm Sci. 2017;30:229-34.
- Kanter M, Demir H, Karakaya C, Ozbek H. Gastroprotective activity of Nigella sativa L oil and its constituent, thymoquinone against acute alcohol-induced gastric mucosal injury in rats. World J Gastroenterol. 2005;11:6662-6.
- Erdemli ME, Yigitcan B, Erdemli Z, Gül M, Gözükara Bağ HG, Gül S. Thymoquinone protection against 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin induced nephrotoxicity in rats. Biotech Histochem. 2020;95:567-74.
- Barrett CE, Hennessey TM, Gordon KM, Ryan SJ, McNair ML, Ressler KJ et al. Developmental disruption of amygdala transcriptome and socioemotional behavior in rats exposed to valproic acid prenatally. Mol Autism. 2017;8:42.
- Atta MS, Almadaly EA, El-Far AH, Saleh RM, Assar DH, Al Jaouni SK et al. Thymoquinone defeats diabetes-induced testicular damage in rats targeting antioxidant, inflammatory and aromatase expression. Int J Mol Sci. 2017;18:919.
- Pitetzis DA, Spilioti MG, Yovos JG, Yavropoulou MP. The effect of VPA on bone: from clinical studies to cell cultures-the molecular mechanisms revisited. Seizure. 2017;48:36-43.
- Inoue T, Tanaka Y, Otani R, Itabashi H, Murakami N, Nagai T et al. Three cases of Fanconi syndrome associated with valproate sodium treatment. No Hattatsu. 2011;43:233-7.
- Oztopuz O, Turkon H. Melatonin ameliorates sodium valproate-induced hepatotoxicity in rats. Mol Biol Rep. 2020;47:317-25.
- Haumaitre C, Lenoir O, Scharfmann R. Histone deacetylase inhibitors modify pancreatic cell fate determination and amplify endocrine progenitors. Mol Cell Biol. 2008;28:6373-83.
- Leggatt GR, Gabrielli B. Histone deacetylase inhibitors in the generation of the anti-tumour immune response. Immunol Cell Biol. 2012;90:33-8.
- Demyanenko S, Neginskaya M, Berezhnaya E. Expression of class I histone deacetylases in ipsilateral and contralateral hemispheres after the ocal photothrombotic infarction in the mouse brain. Transl Stroke Res. 2018;9:471-83.
- Kayarthodi S, Fujimura Y, Fang J, Morsalin S, Rao VN, Reddy ES. Anti-epileptic drug targets ewing sarcoma. J Pharm Sci. 2014;1:87-100.
- Yazdani K, Lippmann M, Gala I. Fatal pancreatitis associated with valproic acid: review of the literature. Medicine. 2002;81:305-10.
- Komariah K, Manalu W, Kiranadi B, Winarto A, Handharyani E, Roeslan MO. Valproic acid exposure of pregnant rats during organogenesis disturbs pancreas development in insulin synthesis and secretion of the offspring. Toxicol Res. 2018;34:173-82.
- Iwahashi S, Ishibashi H, Utsunomiya T, Morine Y, Ochir TL, Hanaoka J et al. Effect of histone deacetylase inhibitor in combination with 5-fluorouracil on pancreas cancer and cholangiocarcinoma cell lines. J Med Invest. 2011;58:106-9.
- Li L, Bonneton F, Tohme M, Bernard L, Chen XY, Laudet V. In vivo screening using transgenic zebrafish embryos reveals new effects of HDAC inhibitors trichostatin A and valproic acid on organogenesis. PloS One. 2016;11:e0149497.
- Sun J, Piao J, Li N, Yang Y, Kim KY, Lin Z. Valproic acid targets HDAC1/2 and HDAC1/PTEN/Akt signalling to inhibit cell proliferation via the induction of autophagy in gastric cancer. FEBS J. 2020;287:2118-33.
- Krämer OH, Göttlicher M, Heinzel T. Histone deacetylase as a therapeutic target. Trends Endocrinol Metab. 2001;12:294-300.
- Imran M, Rauf A, Khan IA, Shahbaz M, Qaisrani TB, Fatmawati S et al. Thymoquinone: a novel strategy to combat cancer: a review. Biomed Pharmacother. 2018;106:390-402.
- Siveen KS, Mustafa N, Li F, Kannaiyan R, Ahn KS, Kumar AP et al. Thymoquinone overcomes chemoresistance and enhances the anticancer effects of bortezomib through abrogation of NF-κB regulated gene products in multiple myeloma xenograft mouse model. Oncotarget. 2014;5:634-8.
- Rocca G, Gaia E, Iuliano R, Caselle MT, Rocca N, Calcamuggi G et al. Increased incidence of cancer in chronic pancreatitis. J Clin Gastroenterol. 1987;9:175-9.
- Chehl N, Chipitsyna G, Gong Q, Yeo CJ, Arafat HA. Anti-inflammatory effects of the Nigella sativa seed extract, thymoquinone, in pancreatic cancer cells. HPB (Oxford). 2009;11:373-81.
- Rahmani AH, Alzohairy MA, Khan MA, Aly SM. Therapeutic implications of black seed and its constituent thymoquinone in the prevention of cancer through inactivation and activation of molecular pathways. eCAM. 2014;2014:724658.
- Barkat MA, Harshita, Ahmad J, Khan MA, Beg S, Ahmad FJ. Insights into the targeting potential of thymoquinone for therapeutic intervention against triple-negative breast cancer. Curr Drug Targets. 2018;19:70-80.
- Dash SK, Chattopadhyay S, Ghosh T, Dash SS, Tripathy S, Das B et al. Self-assembled betulinic acid protects doxorubicin induced apoptosis followed by reduction of ROS-TNF-α-caspase-3 activity. Biomed Pharmacother. 2015;72:144-57.
- Moongkarndi P, Srisawat C, Saetun P, Jantaravinid J, Peerapittayamongkol C, Soi-ampornkul R et al. Protective effect of mangosteen extract against beta-amyloid-induced cytotoxicity, oxidative stress and altered proteome in SK-N-SH cells. J Proteome Res. 2010;9:2076-86.
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Effect of thymoquinone on ameliorating valproic acid-induced damage in pancreatic tissue of rats
Yıl 2022,
, 350 - 359, 31.03.2022
Sebile Azirak
,
Sedat Bilgiç
,
Deniz Taştemir Korkmaz
,
Murat Sevimli
,
Mehmet Kaya Özer
Öz
Purpose: The aim of this study was to evaluate the potential effect of thymoquinone (TQ) in preventing or treating valproic acid (VPA)-induced pancreatic injury, gene expressions and histopathological changes in pancreatic tissue of rats..
Materials and Methods: 21 male Spraque-Dawley rats were divided into 3 groups (n = 7): Control, VPA, VPA + TQ. Rats were treated orally with VPA (500 mg/kg/day) and TQ (50 mg/kg/day) for 14 days. On the 15th day of treatment, pancreatic tissue was resected for the analysis of the expression levels of histone deacetylase (HDAC1 and HDAC2) genes. Structural changes in pancreatic tissues were examined.
Results: It was observed that VPA + TQ group had significantly higher HDAC1 and HDAC2 genes expression compared to the VPA group. Furthermore, the findings show that TQ therapy can protect pancreatic tissue against the negative effects of VPA on HDAC1 and HDAC2 gene expression. It also decreased the levels of NADPH oxidase-4 (NOX-4) and caspase-3 (CAS-3). Oxidative stress decreased, antioxidant activity increased and histopathological changes decreased in the VPA + TQ group compared to the VPA group. Pancreatic damage caused by VPA was attenuated due to TQ's antioxidative and antiapoptotic effects.
Conclusion: TQ may be useful for reducing the severity of VPA-induced pancreatic damage.
Kaynakça
- Kumar R, Vidaurre J, Gedela S. Valproic acid-induced coagulopathy. Ped Neurol. 2019;98:25-30.
- Zhu MM, Li HL, Shi LH, Chen XP, Luo J, Zhang ZL. The pharmacogenomics of valproic acid. J Hum Genet. 2017;62:1009-14.
- Gerstner T, Bell N, König S. Oral valproic acid for epilepsy--long-term experience in therapy and side effects. Expert Opin Pharmacother. 2008;9:285-92.
- Hamed SA. The effect of antiepileptic drugs on the kidney function and structure. Expert Rev Clin Pharmacol. 2017;10:993-1006.
- Mai A, Massa S, Rotili D, Cerbara I, Valente S, Pezzi R et al. Histone deacetylation in epigenetics: an attractive target for anticancer therapy. Med Res Rev. 2005;25:261-309.
- Bahl S, Seto E. Regulation of histone deacetylase activities and functions by phosphorylation and its physiological relevance. Cell Moll Life Sci. 2021;78:427-45.
- Sixto-López Y, Bello M, Correa-Basurto J. Exploring the inhibitory activity of valproic acid against the HDAC family using an MMGBSA approach. J Comput Aided Mol Des. 2020;34:857-78.
- Miller KM, Tjeertes JV, Coates J, Legube G, Polo SE, Britton S et al. Human HDAC1 and HDAC2 function in the DNA-damage response to promote DNA nonhomologous end-joining. Nat Struct Mol Biol. 2010;17:1144-51.
- Dovey OM, Foster CT, Conte N, Edwards SA, Edwards JM, Singh R, et al. Histone deacetylase 1 and 2 are essential for normal T-cell development and genomic stability in mice. Blood. 2013;121:1335-44.
- Yang WB, Hsu CC, Hsu TI, Liou JP, Chang KY, Chen PY et al. Increased activation of HDAC1/2/6 and Sp1 underlies therapeutic resistance and tumor growth in glioblastoma. Neuro-Oncol. 2020;22:1439-51.
- Seto E, Yoshida M. Erasers of histone acetylation: the histone deacetylase enzymes. Cold Spring Harb Perspect Biol. 2014;6:a018713.
- Mazzoccoli G, Longhitano C, Vinciguerra M. Cardio-hepatic metabolic derangements and valproic acid. Curr Clin Pharmacol. 2014;9:165-70.
- Cornago M, Garcia-Alberich C, Blasco-Angulo N, Vall-Llaura N, Nager M, Herreros J et al. Histone deacetylase inhibitors promote glioma cell death by G2 checkpoint abrogation leading to mitotic catastrophe. Cell Death Dis. 2014;5:e1435.
- Lorberbaum DS, Docherty FM, Sussel L. Animal models of pancreas development, developmental disorders, and disease. Adv Exp Med Biol. 2020;1236:65-85.
- Lankisch PG, Apte M, Banks PA. Acute pancreatitis. Lancet. 2015;386:85-96.
- Wang GJ, Gao CF, Wei D, Wang C, Ding SQ. Acute pancreatitis: etiology and common pathogenesis. World J Gastroenterol. 2009;15:1427-30.
- Eisses JF, Criscimanna A, Dionise ZR, Orabi AI, Javed TA, Sarwar S et al. Valproic acid limits pancreatic recovery after pancreatitis by inhibiting histone deacetylases and preventing acinar redifferentiation programs. Am J Pathol. 2015;185:3304-15.
- Mederos MA, Reber HA, Girgis MD. Acute pancreatitis: a review. JAMA. 2021;325:382-90.
- Głuszek S, Nawacki Ł, Matykiewicz J, Kot M, Kuchinka J. Severe vascular complications of acute pancreatitis. Pol Przegl Chir. 2015;87:485-90.
- Shaterzadeh-Yazdi H, Noorbakhsh MF, Hayati F, Samarghandian S, Farkhondeh T. Immunomodulatory and anti-inflammatory effects of thymoquinone. Cardiovasc Hematol Disord - Drug Targets. 2018;18:52-60.
- Glamočlija U, Padhye S, Špirtović-Halilović S, Osmanović A, Veljović E, Roca S et al. Synthesis, biological evaluation and docking studies of benzoxazoles derived from thymoquinone. Molecules. 2018;23:3297.
- Bimonte S, Albino V, Barbieri A, Tamma ML, Nasto A, Palaia R et al. Dissecting the roles of thymoquinone on the prevention and the treatment of hepatocellular carcinoma: an overview on the current state of knowledge. Infect Agents Cancer. 2019;14:10.
- Dariani S, Baluchnejadmojarad T, Roghani M. Thymoquinone attenuates astrogliosis, neurodegeneration, mossy fiber sprouting, and oxidative stress in a model of temporal lobe epilepsy. J Mol Neursci. 2013;51:679-86.
- Almatroodi SA, Almatroudi A, Alsahli MA, Khan AA, Rahmani AH. Thymoquinone, an active compound of Nigella sativa: role in prevention and treatment of cancer. Curr Pharm Biotechnol. 2020;21:1028-41.
- Raza M, Alghasham AA, Alorainy MS, El-Hadiyah TM. Potentiation of valproate-induced anticonvulsant response by Nigella sativa seed constituents: the role of GABA receptors. Int J Health Sci. 2008;2:15-25.
- Ozdemir H, Kara MI, Erciyas K, Ozer H, Ay S. Preventive effects of thymoquinone in a rat periodontitis model: a morphometric and histopathological study. J Periodontal Res. 2012;47:74-80.
- Talebi M, Talebi M. Biological and therapeutic activities of thymoquinone: focus on the Nrf2 signaling pathway. Phytother Res. 2021;35:1739-53.
- Yi T, Cho SG, Yi Z, Pang X, Rodriguez M, Wang Y et al. Thymoquinone inhibits tumor angiogenesis and tumor growth through suppressing AKT and extracellular signal-regulated kinase signaling pathways. Mol Cancer Ther. 2008;7:1789-96.
- Peng L, Liu A, Shen Y, Xu HZ, Yang SZ, Ying XZ et al. Antitumor and anti-angiogenesis effects of thymoquinone on osteosarcoma through the NF-κB pathway. Oncol Rep. 2013;29:571-8.
- Banerjee S, Kaseb AO, Wang Z, Kong D, Mohammad M, Padhye S et al. Antitumor activity of gemcitabine and oxaliplatin is augmented by thymoquinone in pancreatic cancer. Cancer Res. 2009;69:5575-83.
- Ijaz H, Tulain UR, Qureshi J, Danish Z, Musayab S, Akhtar MF et al. Review: Nigella sativa (prophetic medicine): a review. Pak J Pharm Sci. 2017;30:229-34.
- Kanter M, Demir H, Karakaya C, Ozbek H. Gastroprotective activity of Nigella sativa L oil and its constituent, thymoquinone against acute alcohol-induced gastric mucosal injury in rats. World J Gastroenterol. 2005;11:6662-6.
- Erdemli ME, Yigitcan B, Erdemli Z, Gül M, Gözükara Bağ HG, Gül S. Thymoquinone protection against 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin induced nephrotoxicity in rats. Biotech Histochem. 2020;95:567-74.
- Barrett CE, Hennessey TM, Gordon KM, Ryan SJ, McNair ML, Ressler KJ et al. Developmental disruption of amygdala transcriptome and socioemotional behavior in rats exposed to valproic acid prenatally. Mol Autism. 2017;8:42.
- Atta MS, Almadaly EA, El-Far AH, Saleh RM, Assar DH, Al Jaouni SK et al. Thymoquinone defeats diabetes-induced testicular damage in rats targeting antioxidant, inflammatory and aromatase expression. Int J Mol Sci. 2017;18:919.
- Pitetzis DA, Spilioti MG, Yovos JG, Yavropoulou MP. The effect of VPA on bone: from clinical studies to cell cultures-the molecular mechanisms revisited. Seizure. 2017;48:36-43.
- Inoue T, Tanaka Y, Otani R, Itabashi H, Murakami N, Nagai T et al. Three cases of Fanconi syndrome associated with valproate sodium treatment. No Hattatsu. 2011;43:233-7.
- Oztopuz O, Turkon H. Melatonin ameliorates sodium valproate-induced hepatotoxicity in rats. Mol Biol Rep. 2020;47:317-25.
- Haumaitre C, Lenoir O, Scharfmann R. Histone deacetylase inhibitors modify pancreatic cell fate determination and amplify endocrine progenitors. Mol Cell Biol. 2008;28:6373-83.
- Leggatt GR, Gabrielli B. Histone deacetylase inhibitors in the generation of the anti-tumour immune response. Immunol Cell Biol. 2012;90:33-8.
- Demyanenko S, Neginskaya M, Berezhnaya E. Expression of class I histone deacetylases in ipsilateral and contralateral hemispheres after the ocal photothrombotic infarction in the mouse brain. Transl Stroke Res. 2018;9:471-83.
- Kayarthodi S, Fujimura Y, Fang J, Morsalin S, Rao VN, Reddy ES. Anti-epileptic drug targets ewing sarcoma. J Pharm Sci. 2014;1:87-100.
- Yazdani K, Lippmann M, Gala I. Fatal pancreatitis associated with valproic acid: review of the literature. Medicine. 2002;81:305-10.
- Komariah K, Manalu W, Kiranadi B, Winarto A, Handharyani E, Roeslan MO. Valproic acid exposure of pregnant rats during organogenesis disturbs pancreas development in insulin synthesis and secretion of the offspring. Toxicol Res. 2018;34:173-82.
- Iwahashi S, Ishibashi H, Utsunomiya T, Morine Y, Ochir TL, Hanaoka J et al. Effect of histone deacetylase inhibitor in combination with 5-fluorouracil on pancreas cancer and cholangiocarcinoma cell lines. J Med Invest. 2011;58:106-9.
- Li L, Bonneton F, Tohme M, Bernard L, Chen XY, Laudet V. In vivo screening using transgenic zebrafish embryos reveals new effects of HDAC inhibitors trichostatin A and valproic acid on organogenesis. PloS One. 2016;11:e0149497.
- Sun J, Piao J, Li N, Yang Y, Kim KY, Lin Z. Valproic acid targets HDAC1/2 and HDAC1/PTEN/Akt signalling to inhibit cell proliferation via the induction of autophagy in gastric cancer. FEBS J. 2020;287:2118-33.
- Krämer OH, Göttlicher M, Heinzel T. Histone deacetylase as a therapeutic target. Trends Endocrinol Metab. 2001;12:294-300.
- Imran M, Rauf A, Khan IA, Shahbaz M, Qaisrani TB, Fatmawati S et al. Thymoquinone: a novel strategy to combat cancer: a review. Biomed Pharmacother. 2018;106:390-402.
- Siveen KS, Mustafa N, Li F, Kannaiyan R, Ahn KS, Kumar AP et al. Thymoquinone overcomes chemoresistance and enhances the anticancer effects of bortezomib through abrogation of NF-κB regulated gene products in multiple myeloma xenograft mouse model. Oncotarget. 2014;5:634-8.
- Rocca G, Gaia E, Iuliano R, Caselle MT, Rocca N, Calcamuggi G et al. Increased incidence of cancer in chronic pancreatitis. J Clin Gastroenterol. 1987;9:175-9.
- Chehl N, Chipitsyna G, Gong Q, Yeo CJ, Arafat HA. Anti-inflammatory effects of the Nigella sativa seed extract, thymoquinone, in pancreatic cancer cells. HPB (Oxford). 2009;11:373-81.
- Rahmani AH, Alzohairy MA, Khan MA, Aly SM. Therapeutic implications of black seed and its constituent thymoquinone in the prevention of cancer through inactivation and activation of molecular pathways. eCAM. 2014;2014:724658.
- Barkat MA, Harshita, Ahmad J, Khan MA, Beg S, Ahmad FJ. Insights into the targeting potential of thymoquinone for therapeutic intervention against triple-negative breast cancer. Curr Drug Targets. 2018;19:70-80.
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