Computational Analysis and Experimental Data Exploring the Role of Hesperetin in Ameliorating ADHD and SIRT1/Nrf2/Keap1/OH-1 Signaling
Abstract
:1. Introduction
2. Results
2.1. Bioinformatic Results Indicating the Relation between the Target Proteins
2.2. Effect of Hesperetin on OFT Behaviors
3. Discussion
4. Materials and Methods
4.1. The Bioinformatic Study
4.2. The Mouse Study
4.2.1. Chemicals
4.2.2. Animals
4.2.3. The Design of the Experiment
4.2.4. Behavioral Assessments
The Open Field Test (OFT)
Test of Y-Maze Discrimination Learning
Marble Burying Test (MBT)
4.2.5. Histopathological Examination and Photomicrography
4.2.6. Immunohistochemical Assessment of IL-1β Protein
4.2.7. Measuring of Whole Brain Oxidative Stress Parameters
4.2.8. Enzyme-Linked Immunosorbent Assays (ELISA)
4.2.9. Gene Expression Measurement of Nrf2, Keap1, SIRT1 and Hemoxygenase-1 by Quantitative Real-Time PCR (qPCR) Analysis
4.2.10. Statistical Analysis and Data Presentation
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Polanczyk, G.V.; Salum, G.A.; Sugaya, L.S.; Caye, A.; Rohde, L.A. Annual research review: A meta-analysis of the worldwide prevalence of mental disorders in children and adolescents. J. Child Psychol. Psychiatry 2015, 56, 345–365. [Google Scholar] [CrossRef]
- Barbaresi, W.J.; Colligan, R.C.; Weaver, A.L.; Voigt, R.G.; Killian, J.M.; Katusic, S.K. Mortality, ADHD, and psychosocial adversity in adults with childhood ADHD: A prospective study. Pediatrics 2013, 131, 637–644. [Google Scholar] [CrossRef] [PubMed]
- Do Austerman, J. ADHD and behavioral disorders: Assessment, management, and an update from DSM-5. Cleve Clin. J. Med. 2015, 82, 3. [Google Scholar] [CrossRef]
- Groenman, A.P.; Janssen, T.W.P.; Oosterlaan, J. Childhood psychiatric disorders as risk factor for subsequent substance abuse: A meta-analysis. J. Am. Acad. Child Adolesc. Psychiatry 2017, 56, 556–569. [Google Scholar] [CrossRef] [PubMed]
- Ambrosino, S.; De Zeeuw, P.; Wierenga, L.M.; van Dijk, S.; Durston, S. What can cortical development in attention-deficit/hyperactivity disorder teach us about the early developmental mechanisms involved? Cereb. Cortex 2017, 27, 4624–4634. [Google Scholar] [CrossRef] [PubMed]
- Allred, E.N.; Dammann, O.; Fichorova, R.N.; Hooper, S.R.; Hunter, S.J.; Joseph, R.M.; Kuban, K.; Leviton, A.; O’Shea, T.M.; Scott, M.N. Systemic inflammation during the first postnatal month and the risk of attention deficit hyperactivity disorder characteristics among 10 year-old children born extremely preterm. J. Neuroimmune Pharmacol. 2017, 12, 531–543. [Google Scholar] [CrossRef]
- Cai, Y.; Xing, L.; Yang, T.; Chai, R.; Wang, J.; Bao, J.; Shen, W.; Ding, S.; Chen, G. The neurodevelopmental role of dopaminergic signaling in neurological disorders. Neurosci. Lett. 2021, 741, 135540. [Google Scholar] [CrossRef]
- Ernst, M.; Zametkin, A.J.; Matochik, J.A.; Pascualvaca, D.; Jons, P.H.; Cohen, R.M. High midbrain [18F] DOPA accumulation in children with attention deficit hyperactivity disorder. Am. J. Psychiatry 1999, 156, 1209–1215. [Google Scholar] [CrossRef]
- Volkow, N.D.; Wang, G.-J.; Newcorn, J.; Fowler, J.S.; Telang, F.; Solanto, M.V.; Logan, J.; Wong, C.; Ma, Y.; Swanson, J.M. Brain dopamine transporter levels in treatment and drug naive adults with ADHD. Neuroimage 2007, 34, 1182–1190. [Google Scholar] [CrossRef]
- Lou, H.C.; Rosa, P.; Pryds, O.; Karrebæk, H.; Lunding, J.; Cumming, P.; Gjedde, A. ADHD: Increased dopamine receptor availability linked to attention deficit and low neonatal cerebral blood flow. Dev. Med. Child Neurol. 2004, 46, 179–183. [Google Scholar] [CrossRef]
- Volkow, N.D.; Wang, G.-J.; Newcorn, J.; Telang, F.; Solanto, M.V.; Fowler, J.S.; Logan, J.; Ma, Y.; Schulz, K.; Pradhan, K. Depressed dopamine activity in caudate and preliminary evidence of limbic involvement in adults with attention-deficit/hyperactivity disorder. Arch. Gen. Psychiatry 2007, 64, 932–940. [Google Scholar] [CrossRef]
- Neto, P.R.; Lou, H.; Cumming, P.; Pryds, O.; Gjedde, A. Methylphenidate-Evoked Potentiation of Extracellular Dopamine in the Brain of Adolescents with Premature Birth: Correlation with Attentional Deficit. Ann. N. Y. Acad. Sci. 2002, 965, 434–439. [Google Scholar] [CrossRef]
- Tripp, G.; Wickens, J.R. Neurobiology of ADHD. Neuropharmacology 2009, 57, 579–589. [Google Scholar] [CrossRef]
- Biederman, J.; Spencer, T. Attention-deficit/hyperactivity disorder (ADHD) as a noradrenergic disorder. Biol. Psychiatry 1999, 46, 1234–1242. [Google Scholar] [CrossRef]
- de Oliveira, J.M.P.F.; Santos, C.; Fernandes, E. Therapeutic potential of hesperidin and its aglycone hesperetin: Cell cycle regulation and apoptosis induction in cancer models. Phytomedicine 2020, 73, 152887. [Google Scholar] [CrossRef]
- Wilmsen, P.K.; Spada, D.S.; Salvador, M. Antioxidant activity of the flavonoid hesperidin in chemical and biological systems. J. Agric. Food Chem. 2005, 53, 4757–4761. [Google Scholar] [CrossRef]
- Park, H.J.; Kim, M.J.; Ha, E.; Chung, J.H. Apoptotic effect of hesperidin through caspase3 activation in human colon cancer cells, SNU-C4. Phytomedicine 2008, 15, 147–151. [Google Scholar] [CrossRef]
- Elshazly, S.M.; Mahmoud, A.A.A. Antifibrotic activity of hesperidin against dimethylnitrosamine-induced liver fibrosis in rats. Naunyn-Schmiedeberg’s Arch. Pharmacol. 2014, 387, 559–567. [Google Scholar] [CrossRef]
- Zhu, C.; Dong, Y.; Liu, H.; Ren, H.; Cui, Z. Hesperetin protects against H2O2-triggered oxidative damage via upregulation of the Keap1-Nrf2/HO-1 signal pathway in ARPE-19 cells. Biomed. Pharmacother. 2017, 88, 124–133. [Google Scholar] [CrossRef]
- Ling, W.; Dai, T.; Zhang, J.; Liang, Y.; Yin, W.; Zhong, B.; Zhang, J. Evaluation of pomelo seed extracts as natural antioxidant, antibacterial, herbicidal agents, and their functional components. Chem. Biodivers. 2021, 18, e2100679. [Google Scholar] [CrossRef]
- Razick, D.I.; Akhtar, M.; Wen, J.; Alam, M.; Dean, N.; Karabala, M.; Ansari, U.; Ansari, Z.; Tabaie, E.; Siddiqui, S. The Role of Sirtuin 1 (SIRT1) in Neurodegeneration. Cureus 2023, 15, e40463. [Google Scholar] [CrossRef] [PubMed]
- Qushawy, M.; Mortagi, Y.; Alshaman, R.; Mokhtar, H.I.; Hisham, F.A.; Alattar, A.; Liang, D.; Enan, E.T.; Eltrawy, A.H.; Alamrani, Z.H. Formulation and characterization of O/W nanoemulsions of hemp seed oil for protection from steatohepatitis: Analysis of hepatic free fatty acids and oxidation markers. Pharmaceuticals 2022, 15, 864. [Google Scholar] [CrossRef]
- Jiang, Y.; Chen, D.; Gong, Q.; Xu, Q.; Pan, D.; Lu, F.; Tang, Q. Elucidation of SIRT-1/PGC-1α-associated mitochondrial dysfunction and autophagy in nonalcoholic fatty liver disease. Lipids Health Dis. 2021, 20, 40. [Google Scholar] [CrossRef]
- Uzun Cicek, A.; Mercan Isik, C.; Bakir, S.; Ulger, D.; Sari, S.A.; Bakir, D.; Cam, S. Evidence supporting the role of telomerase, MMP-9, and SIRT1 in attention-deficit/hyperactivity disorder (ADHD). J. Neural Transm. 2020, 127, 1409–1418. [Google Scholar] [CrossRef] [PubMed]
- Li, L.; Zhu, N.; Zhang, L.; Kuja-Halkola, R.; D’Onofrio, B.M.; Brikell, I.; Lichtenstein, P.; Cortese, S.; Larsson, H.; Chang, Z. ADHD pharmacotherapy and mortality in individuals with ADHD. JAMA 2024, 331, 850–860. [Google Scholar] [CrossRef]
- Schirm, E.; Tobi, H.; Zito, J.M.; de Jong-van den Berg, L.T.W. Psychotropic medication in children: A study from the Netherlands. Pediatrics 2001, 108, e25. [Google Scholar] [CrossRef] [PubMed]
- Coghill, D. Use of stimulants for attention deficit hyperactivity disorder: FOR. BMJ 2004, 329, 907–908. [Google Scholar] [CrossRef]
- Faber, A.; Kalverdijk, L.J.; Berg, L.T.W.d.J.-v.d.; Hugtenburg, J.G.; Minderaa, R.B.; Tobi, H. Parents report on stimulant-treated children in the Netherlands: Initiation of treatment and follow-up care. J. Child Adolesc. Psychopharmacol. 2006, 16, 432–440. [Google Scholar] [CrossRef]
- Faraone, S.V.; Biederman, J.; Morley, C.P.; Spencer, T.J. Effect of stimulants on height and weight: A review of the literature. J. Am. Acad. Child Adolesc. Psychiatry 2008, 47, 944–1009. [Google Scholar] [CrossRef]
- Meijer, W.M.; Faber, A.; van den Ban, E.; Tobi, H. Current issues around the pharmacotherapy of ADHD in children and adults. Pharm. World Sci. 2009, 31, 509–516. [Google Scholar] [CrossRef]
- Rapport, M.D.; Moffitt, C. Attention deficit/hyperactivity disorder and methylphenidate: A review of height/weight, cardiovascular, and somatic complaint side effects. Clin. Psychol. Rev. 2002, 22, 1107–1131. [Google Scholar] [CrossRef] [PubMed]
- Contesse, T.; Ayrault, M.; Mantegazza, M.; Studer, M.; Deschaux, O. Hyperactive and anxiolytic-like behaviors result from loss of COUP-TFI/Nr2f1 in the mouse cortex. Genes Brain Behav. 2019, 18, e12556. [Google Scholar] [CrossRef]
- Castellanos, F.X.; Proal, E. Large-scale brain systems in ADHD: Beyond the prefrontal–striatal model. Trends Cogn. Sci. 2012, 16, 17–26. [Google Scholar] [CrossRef] [PubMed]
- Norman, L.J.; Carlisi, C.; Lukito, S.; Hart, H.; Mataix-Cols, D.; Radua, J.; Rubia, K. Structural and functional brain abnormalities in attention-deficit/hyperactivity disorder and obsessive-compulsive disorder: A comparative meta-analysis. JAMA Psychiatry 2016, 73, 815–825. [Google Scholar] [CrossRef] [PubMed]
- Shaw, P.; Eckstrand, K.; Sharp, W.; Blumenthal, J.; Lerch, J.P.; Greenstein, D.; Clasen, L.; Evans, A.; Giedd, J.; Rapoport, J.L. Attention-deficit/hyperactivity disorder is characterized by a delay in cortical maturation. Proc. Natl. Acad. Sci. USA 2007, 104, 19649–19654. [Google Scholar] [CrossRef]
- Guney, E.; Cetin, F.H.; Alisik, M.; Tunca, H.; Torun, Y.T.; Iseri, E.; Taner, Y.I.; Cayci, B.; Erel, O. Attention deficit hyperactivity disorder and oxidative stress: A short term follow up study. Psychiatry Res. 2015, 229, 310–317. [Google Scholar] [CrossRef]
- Ceylan, M.F.; Sener, S.; Bayraktar, A.C.; Kavutcu, M. Changes in oxidative stress and cellular immunity serum markers in attention-deficit/hyperactivity disorder. Psychiatry Clin. Neurosci. 2012, 66, 220–226. [Google Scholar] [CrossRef]
- Owoeye, O.; Salami, O.A. Monosodium glutamate toxicity: Sida acuta leaf extract ameliorated brain histological alterations, biochemical and haematological changes in wistar rats. Afr. J. Biomed. Res. 2017, 20, 173–182. [Google Scholar]
- Aboul Fotouh, G.I.; Eldin Sayed, S.S.; Altayeb, Z.M.; Zaher, E.A. The Possible Neuroprotective Effect of Astaxanthin on Monosodium Glutamate and Aspartame Induced Hippocampal Changes in Albino Rats:(Histological and Immuno-histochemical Study). Egypt. J. Histol. 2020, 43, 684–701. [Google Scholar]
- Onaolapo, O.J.; Onaolapo, A.Y.; Akanmu, M.A.; Gbola, O. Evidence of alterations in brain structure and antioxidant status following ‘low-dose’monosodium glutamate ingestion. Pathophysiology 2016, 23, 147–156. [Google Scholar] [CrossRef]
- Khan, A.; Ikram, M.; Hahm, J.R.; Kim, M.O. Antioxidant and anti-inflammatory effects of citrus flavonoid hesperetin: Special focus on neurological disorders. Antioxidants 2020, 9, 609. [Google Scholar] [CrossRef] [PubMed]
- De Andrade Teles, R.B.; Diniz, T.C.; Pinto, T.C.C.; de Oliveira Junior, R.G.; e Silva, M.G.; de Lavor, É.M.; Fernandes, A.W.C.; de Oliveira, A.P.; de Almeida Ribeiro, F.P.R.; da Silva, A.A.M. Flavonoids as therapeutic agents in Alzheimer’s and Parkinson’s diseases: A systematic review of preclinical evidences. Oxidative Med. Cell. Longev. 2018, 2018, 7043213. [Google Scholar] [CrossRef] [PubMed]
- Ikram, M.; Muhammad, T.; Rehman, S.U.; Khan, A.; Jo, M.G.; Ali, T.; Kim, M.O. Hesperetin confers neuroprotection by regulating Nrf2/TLR4/NF-κB signaling in an Aβ mouse model. Mol. Neurobiol. 2019, 56, 6293–6309. [Google Scholar] [CrossRef] [PubMed]
- Kiasalari, Z.; Khalili, M.; Baluchnejadmojarad, T.; Roghani, M. Protective effect of oral hesperetin against unilateral striatal 6-hydroxydopamine damage in the rat. Neurochem. Res. 2016, 41, 1065–1072. [Google Scholar] [CrossRef]
- Li, H. Sirtuin 1 (SIRT1) and oxidative stress. Syst. Biol. Free Radic. Antioxid. 2014, 19, 417–435. [Google Scholar]
- Kao, C.-L.; Chen, L.-K.; Chang, Y.-L.; Yung, M.-C.; Hsu, C.-C.; Chen, Y.-C.; Lo, W.-L.; Chen, S.-J.; Ku, H.-H.; Hwang, S.-J. Resveratrol protects human endothelium from H2O2-induced oxidative stress and senescence via SirT1 activation. J. Atheroscler. Thromb. 2010, 17, 970–979. [Google Scholar] [CrossRef]
- Qadri, R.; Goyal, V.; Behari, M.; Subramanian, A.; Datta, S.K.; Mukhopadhyay, A.K. Alteration of mitochondrial function in oxidative stress in parkinsonian neurodegeneration: A cross-sectional study. Ann. Indian Acad. Neurol. 2021, 24, 506–512. [Google Scholar]
- Bustamante-Barrientos, F.A.; Luque-Campos, N.; Araya, M.J.; Lara-Barba, E.; de Solminihac, J.; Pradenas, C.; Molina, L.; Herrera-Luna, Y.; Utreras-Mendoza, Y.; Elizondo-Vega, R. Mitochondrial dysfunction in neurodegenerative disorders: Potential therapeutic application of mitochondrial transfer to central nervous system-residing cells. J. Transl. Med. 2023, 21, 613. [Google Scholar] [CrossRef]
- Checa, J.; Aran, J.M. Reactive oxygen species: Drivers of physiological and pathological processes. J. Inflamm. Res. 2020, 61, 1057–1073. [Google Scholar] [CrossRef]
- Zhang, Z.; Liu, C.; Zhou, X.; Zhang, X. The Critical Role of Sirt1 in Subarachnoid Hemorrhages: Mechanism and Therapeutic Considerations. Brain Sci. 2023, 13, 674. [Google Scholar] [CrossRef]
- Sun, Z.; Zhao, S.; Suo, X.; Dou, Y. Sirt1 protects against hippocampal atrophy and its induced cognitive impairment in middle-aged mice. BMC Neurosci. 2022, 23, 33. [Google Scholar] [CrossRef] [PubMed]
- Khan, R.S.; Fonseca-Kelly, Z.; Callinan, C.; Zuo, L.; Sachdeva, M.M.; Shindler, K.S. SIRT1 activating compounds reduce oxidative stress and prevent cell death in neuronal cells. Front. Cell. Neurosci. 2012, 6, 63. [Google Scholar] [CrossRef]
- Liao, D.; Lv, C.; Cao, L.; Yao, D.; Wu, Y.; Long, M.; Liu, N.; Jiang, P. Curcumin attenuates chronic unpredictable mild stress-induced depressive-like behaviors via restoring changes in oxidative stress and the activation of Nrf2 signaling pathway in rats. Oxidative Med. Cell. Longev. 2020, 2020, 9268083. [Google Scholar] [CrossRef] [PubMed]
- Tian, W.; de la Vega, M.R.; Schmidlin, C.J.; Ooi, A.; Zhang, D.D. Kelch-like ECH-associated protein 1 (KEAP1) differentially regulates nuclear factor erythroid-2–related factors 1 and 2 (NRF1 and NRF2). J. Biol. Chem. 2018, 293, 2029–2040. [Google Scholar] [CrossRef]
- Suzuki, T.; Yamamoto, M. Molecular basis of the Keap1–Nrf2 system. Free Radic. Biol. Med. 2015, 88, 93–100. [Google Scholar] [CrossRef]
- Saha, S.; Buttari, B.; Panieri, E.; Profumo, E.; Saso, L. An overview of Nrf2 signaling pathway and its role in inflammation. Molecules 2020, 25, 5474. [Google Scholar] [CrossRef]
- Dang, R.; Wang, M.; Li, X.; Wang, H.; Liu, L.; Wu, Q.; Zhao, J.; Ji, P.; Zhong, L.; Licinio, J. Edaravone ameliorates depressive and anxiety-like behaviors via Sirt1/Nrf2/HO-1/Gpx4 pathway. J. Neuroinflam. 2022, 19, 41. [Google Scholar] [CrossRef]
- Loboda, A.; Damulewicz, M.; Pyza, E.; Jozkowicz, A.; Dulak, J. Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: An evolutionarily conserved mechanism. Cell. Mol. Life Sci. 2016, 73, 3221–3247. [Google Scholar] [CrossRef] [PubMed]
- Farina, M.; Vieira, L.E.; Buttari, B.; Profumo, E.; Saso, L. The Nrf2 pathway in ischemic stroke: A review. Molecules 2021, 26, 5001. [Google Scholar] [CrossRef]
- Jo, S.H.; Kim, M.E.; Cho, J.H.; Lee, Y.; Lee, J.; Park, Y.-D.; Lee, J.S. Hesperetin inhibits neuroinflammation on microglia by suppressing inflammatory cytokines and MAPK pathways. Arch. Pharmacal Res. 2019, 42, 695–703. [Google Scholar] [CrossRef]
- Muhammad, T.; Ikram, M.; Ullah, R.; Rehman, S.U.; Kim, M.O. Hesperetin, a citrus flavonoid, attenuates LPS-induced neuroinflammation, apoptosis and memory impairments by modulating TLR4/NF-κB signaling. Nutrients 2019, 11, 648. [Google Scholar] [CrossRef] [PubMed]
- Song, C.; Wang, Z.; Cao, J.; Dong, Y.; Chen, Y. Hesperetin protects hippocampal neurons from the neurotoxicity of Aflatoxin B1 in mice. Ecotoxicol. Environ. Saf. 2024, 269, 115782. [Google Scholar] [CrossRef] [PubMed]
- Song, H.; Ding, Z.; Chen, J.; Chen, T.; Wang, T.; Huang, J. The AMPK-SIRT1-FoxO1-NF-κB signaling pathway participates in hesperetin-mediated neuroprotective effects against traumatic brain injury via the NLRP3 inflammasome. Immunopharmacol. Immunotoxicol. 2022, 44, 970–983. [Google Scholar] [CrossRef]
- Thapar, A.; Cooper, M. Attention deficit hyperactivity disorder. Lancet 2016, 387, 1240–1250. [Google Scholar] [CrossRef] [PubMed]
- Chen, X.; Wei, W.; Li, Y.; Huang, J.; Ci, X. Hesperetin relieves cisplatin-induced acute kidney injury by mitigating oxidative stress, inflammation and apoptosis. Chem. Biol. Interact. 2019, 308, 269–278. [Google Scholar] [CrossRef]
- Onaolapo, A.Y.; Odetunde, I.; Akintola, A.S.; Ogundeji, M.O.; Ajao, A.; Obelawo, A.Y.; Onaolapo, O.J. Dietary composition modulates impact of food-added monosodium glutamate on behaviour, metabolic status and cerebral cortical morphology in mice. Biomed. Pharmacother. 2019, 109, 417–428. [Google Scholar] [CrossRef]
- Alshaman, R.; Kolieb, E.; El-Sayed, R.M.; Gouda, S.G.; Alattar, A.; Zaitone, S.A.; Abdelmaogood, A.K.K.; Elabbasy, L.M.; Eltrawy, A.H.; Sayd, F.Y. Computational and Experimental Approaches Exploring the Role of Hesperetin in Improving Autophagy in Rat Diabetic Retinopathy. Biomedicines 2024, 12, 552. [Google Scholar] [CrossRef]
- El-Sayed, R.M.; Abdelaziz, A.M.; Zaki, H.F.; Rasheed, N.O.A. Cilostazol novel neuroprotective mechanism against rotenone-induced Parkinson’s disease in rats: Correlation between Nrf2 and HMGB1/TLR4/PI3K/Akt/mTOR signaling. Int. Immunopharmacol. 2003, 117, 109986. [Google Scholar] [CrossRef]
- ElSayed, M.H.; Atif, H.M.; Eladl, M.A.; Elaidy, S.M.; Helaly, A.M.N.; Hisham, F.A.; Farag, N.E.; Osman, N.M.S.; Ibrahiem, A.T.; Khella, H.W.Z. Betanin improves motor function and alleviates experimental Parkinsonism via downregulation of TLR4/MyD88/NF-κB pathway: Molecular docking and biological investigations. Biomed. Pharmacother. 2023, 164, 114917. [Google Scholar] [CrossRef]
- Stanford, S.C. The open field test: Reinventing the wheel. J. Psychopharmacol. 2007, 21, 134–135. [Google Scholar] [CrossRef]
- Xu, B.H.; Duan, H.F.; Liu, R.Y. The effect on learing and memory of application of RNAase to hippocampus of rats. Chin. Sci. Bull. 1979, 24, 182–185. [Google Scholar]
- Zhang, Y.; Yu, L.; Ma, R.; Zhang, X.; Yu, T. Comparison of the effects of perinatal and neonatal administration of sodium ferulate on repair following excitotoxic neuronal damages induced by maternal oral administration of monosodium glutamate at a late stage of pregnancy. World J. Neurosci. 2012, 2, 21853. [Google Scholar] [CrossRef]
- Deacon, R.M.J. Digging and marble burying in mice: Simple methods for in vivo identification of biological impacts. Nat. Protoc. 2006, 1, 122–124. [Google Scholar] [CrossRef] [PubMed]
- Alomar, S.Y.; Gheit, R.E.A.E.; Enan, E.T.; El-Bayoumi, K.S.; Shoaeir, M.Z.; Elkazaz, A.Y.; Al Thagfan, S.S.; Zaitone, S.A.; El-Sayed, R.M. Novel mechanism for memantine in attenuating diabetic neuropathic pain in mice via downregulating the spinal HMGB1/TRL4/NF-kB inflammatory axis. Pharmaceuticals 2021, 14, 307. [Google Scholar] [CrossRef]
- Alshaman, R.; Qushawy, M.; Mokhtar, H.I.; Ameen, A.M.; El-Sayed, R.M.; Alamri, E.S.; Elabbasy, L.M.; Helaly, A.M.N.; Elkhatib, W.F.; Alyahya, E.M. Marula oil nanoemulsion improves motor function in experimental parkinsonism via mitigation of inflammation and oxidative stress. Front. Pharmacol. 2023, 14, 1293306. [Google Scholar] [CrossRef]
- Ali, S.A.; Zaitone, S.A.; Moustafa, Y.M. Boswellic acids synergize antitumor activity and protect against the cardiotoxicity of doxorubicin in mice bearing Ehrlich’s carcinoma. Can. J. Physiol. Pharmacol. 2015, 93, 695–708. [Google Scholar] [CrossRef]
- Elsherbiny, N.M.; Abdel-Mottaleb, Y.; Elkazaz, A.Y.; Atef, H.; Lashine, R.M.; Youssef, A.M.; Ezzat, W.; El-Ghaiesh, S.H.; Elshaer, R.E.; El-Shafey, M. Carbamazepine alleviates retinal and optic nerve neural degeneration in diabetic mice via nerve growth factor-induced PI3K/Akt/mTOR activation. Front. Neurosci. 2019, 13, 1089. [Google Scholar] [CrossRef]
- Beutler, E.; Duron, O.; Kelly, B.M. Improved method for determination of blood glutathione. J. Lab. Clin. Med. 1963, 61, 537–549. [Google Scholar]
- Livak, K.J.; Schmittgen, T.D. Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method. Methods 2001, 25, 402–408. [Google Scholar] [CrossRef]
Markers | Control | ADHD Model | ADHD/HSP-25 | ADHD/HSP-50 |
---|---|---|---|---|
Glutamate (ng/g) | 11.3 ± 1.28 | 42.04 ± 5.07 * | 38.6 ± 4.56 * | 42.6 ± 5.94 * |
Dopamine (ng/g) | 25.62 ± 3.94 | 7.38 ± 1.63 * | 12.12 ± 1.46 *# | 18.32 ± 1.99 *# |
Malondialdehyde | 6.26 ± 0.78 | 20.4 ± 2.78 * | 11.96 ± 2.04 *# | 7.98 ± 0.69 # |
Reduced glutathione | 90.8 ± 14.65 | 35.4 ± 9.45 * | 44.4 ± 9.37 * | 67.8 ± 10.80 *#$ |
SIRT1 (ng/g) | 12.25 ± 2.32 | 2.6 ± 0.82 * | 6.06 ± 1.06 # | 8.56 ± 1.77 *# |
Nrf2 (ng/g) | 66.4 ± 6.11 | 15.6 ± 5.77 * | 28.6 ± 15.95 *# | 46.2 ± 7.05 *#$ |
HO-1 (pg/g) | 206.2 ± 15.06 | 48.6 ± 20.79 * | 116.2 ± 16.12 *# | 156.2 ± 20.54 *#$ |
NFκB (pg/g) | 64.4 ± 16.73 | 482.8 ± 66.15 * | 404 ± 44.07 *# | 238.2 ± 42.90 *#$ |
IL-1β (pg/g) | 17.4 ± 3.21 | 74.2 ± 8.26 * | 51.4 ± 4.39 *# | 31.8 ± 5.72 *#$ |
The Target Gene | Primers | Accession Numbers |
---|---|---|
SIRT1 | F: 5′-GGAGCAGATTAGTAAGCGGCTTG-3′ R: 5′-GTTACTGCCACAGGAACTAGAGG-3′ | NM_019812 |
Keap1 | F: 5′-ATCCAGAGAGGAATGAGTGGCG-3′ R: 5′-TCAACTGGTCCTGCCCATCGTA-3′ | NM_001110305 |
β-actin | F: 5′-CATTGCTGACAGGATGCAGAAGG-3′ R: 5′-TGCTGGAAGGTGGACAGTGAGG-3′ | NM_007393 |
HO-1 | F: 5′-CCAGGCAGAGAATGCTGAGTTC-3′ R: 5′-AAGACTGGGCTCTCCTTGTTGC-3′ | NM_002133 |
Nrf2 | F: 5′-CAGCATAGAGCAGGACATGGAG-3′ R: 5′-GAACAGCGGTAGTATCAGCCAG-3′ | NM_010902 |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Mokhtar, H.I.; Abd El-Fadeal, N.M.; El-Sayed, R.M.; Hegazy, A.; El-Kherbetawy, M.K.; Hamad, A.G.; ElSayed, M.H.; Zaitone, S.A. Computational Analysis and Experimental Data Exploring the Role of Hesperetin in Ameliorating ADHD and SIRT1/Nrf2/Keap1/OH-1 Signaling. Int. J. Mol. Sci. 2024, 25, 9284. https://doi.org/10.3390/ijms25179284
Mokhtar HI, Abd El-Fadeal NM, El-Sayed RM, Hegazy A, El-Kherbetawy MK, Hamad AG, ElSayed MH, Zaitone SA. Computational Analysis and Experimental Data Exploring the Role of Hesperetin in Ameliorating ADHD and SIRT1/Nrf2/Keap1/OH-1 Signaling. International Journal of Molecular Sciences. 2024; 25(17):9284. https://doi.org/10.3390/ijms25179284
Chicago/Turabian StyleMokhtar, Hatem I., Noha M. Abd El-Fadeal, Rehab M. El-Sayed, Ann Hegazy, Mohamed K. El-Kherbetawy, Ahmed G. Hamad, Mohamed H. ElSayed, and Sawsan A. Zaitone. 2024. "Computational Analysis and Experimental Data Exploring the Role of Hesperetin in Ameliorating ADHD and SIRT1/Nrf2/Keap1/OH-1 Signaling" International Journal of Molecular Sciences 25, no. 17: 9284. https://doi.org/10.3390/ijms25179284