{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:39:14Z","timestamp":1785425954473,"version":"3.56.0"},"reference-count":62,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T00:00:00Z","timestamp":1778803200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Gazi University Projects of Scientific Investigation","award":["TDK-2023-8876"],"award-info":[{"award-number":["TDK-2023-8876"]}]},{"award":["TDK-2023-8876"],"award-info":[{"award-number":["TDK-2023-8876"]}],"id":[{"id":"https:\/\/ror.org\/054xkpr46","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: Parkinson\u2019s disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic neuronal loss, oxidative stress, and mitochondrial dysfunction. Although levodopa (L-Dopa) remains the main symptomatic treatment, prolonged administration can lead to adverse effects. Safranal, a bioactive constituent of Crocus sativus, has antioxidant and anti-apoptotic properties. This study evaluated the neuroprotective potential of L-Dopa and safranal, individually and in combination, in an in vitro cell-culture PD model. Methods: SH-SY5Y human neuroblastoma cells were treated with 6-hydroxydopamine (6-OHDA, 50 \u00b5M) to induce cytotoxicity. Cells were pretreated with L-Dopa (5\u2013500 \u00b5M) and safranal (1\u2013500 \u00b5M and 1\u20135 mM) for 4 or 24 h. Cell viability was assessed using 3-(4, 5-dimethylthiazol-2-yl)2,5-diphenyl-tetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. Mitochondrial membrane potential (MMP), caspase-3\/7 activity, and autophagy markers were also evaluated. Synergy was analyzed using Combination Index (CI) analysis. Furthermore, mRNA levels of circadian rhythm associated genes were also evaluated. Results: 6-OHDA significantly impaired cell viability and mitochondrial function. Pretreatment with low doses of L-Dopa and safranal partially improved cell viability and reduced apoptosis and showed a tendency to decrease autophagy-associated marker levels. Higher L-Dopa concentrations caused mild cytotoxicity, while high-dose safranal exhibited pronounced concentration-dependent toxicity. CI analysis confirmed synergistic interaction between both drugs in mitigating 6-OHDA-induced toxicity. Combined treatment markedly improved cell survival preserved mitochondrial function, and reduced caspase-3\/7 activity compared with monotherapy. A significant increase in the mRNA levels of Per1, Clock, Bmal1 and Cry1 genes was observed in groups treated with L-Dopa and safranal together. Conclusions: L-Dopa and safranal exerted concentration-dependent neuroprotective effects in SH-SY5Y cells. Their combination enhanced cytoprotection, which was associated with modulation of mitochondrial function, oxidative stress, apoptosis, and autophagy-related responses.<\/jats:p>","DOI":"10.3390\/ph19050773","type":"journal-article","created":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T13:12:08Z","timestamp":1779455528000},"page":"773","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Investigation of the Effects of Saffron on Neuroprotection and Circadian Rhythm in an In Vitro Parkinson\u2019s Model"],"prefix":"10.3390","volume":"19","author":[{"given":"Ayse","family":"Aksoy","sequence":"first","affiliation":[{"name":"Department of Medical Biology and Genetics, Faculty of Medicine, Gazi University, 06500 Ankara, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duygu Deniz","family":"Usta","sequence":"additional","affiliation":[{"name":"Department of Medical Biology and Genetics, Faculty of Medicine, Gazi University, 06500 Ankara, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atiye Seda","family":"Yar","sequence":"additional","affiliation":[{"name":"Department of Medical Biology and Genetics, Faculty of Medicine, Gazi University, 06500 Ankara, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Silva, J., Alves, C., Martins, A., Susano, P., Sim\u00f5es, M., Guedes, M., Rehfeldt, S., Pint\u00e9us, S., Gaspar, H., and Rodrigues, A. (2021). Loliolide, a new therapeutic option for neurological diseases? In vitro neuroprotective and anti-inflammatory activities of a monoterpenoid lactone isolated from Codium tomentosum. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22041888"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1038\/s41531-025-01009-9","article-title":"Circadian clock dysfunction in Parkinson\u2019s disease: Mechanisms, consequences, and therapeutic strategy","volume":"11","author":"Grande","year":"2025","journal-title":"NPJ Park. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Lucchesi, M., Biso, L., Bonaso, M., Longoni, B., Buchignani, B., Battini, R., Santorelli, F., Doccini, S., and Scarselli, M. (2025). Mitochondrial dysfunction in genetic and non-genetic Parkinson\u2019s disease. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26094451"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1136\/jnnp-2019-322338","article-title":"Parkinson\u2019s disease: Etiopathogenesis and treatment","volume":"91","author":"Jankovic","year":"2020","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Di Biase, L., Pecoraro, P., Carbone, S., Caminiti, M., and Lazzaro, V. (2023). Levodopa-induced dyskinesias in Parkinson\u2019s disease: An overview on pathophysiology, clinical manifestations, therapy management strategies and future directions. J. Clin. Med., 12.","DOI":"10.3390\/jcm12134427"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1038\/s41531-025-01081-1","article-title":"Revamping Parkinson\u2019s disease therapy using PLGA-based drug delivery systems","volume":"11","author":"Lababidi","year":"2025","journal-title":"NPJ Park. Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s13024-021-00504-w","article-title":"Sleep and circadian rhythms in Parkinson\u2019s disease and preclinical models","volume":"17","author":"Hunt","year":"2022","journal-title":"Mol. Neurodegener."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Shoaib, S., Ansari, M.A., Fatease, A.A., Safhi, A.Y., Hani, U., Jahan, R., Alomary, M.N., Ansari, M.N., Ahmed, N., and Wahab, S. (2023). Plant-derived bioactive compounds in the management of neurodegenerative disorders: Challenges, future directions and molecular mechanisms involved in neuroprotection. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15030749"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"El Midaoui, A., Ghzaiel, I., Vervandier-Fasseur, D., Ksila, M., Zarrouk, A., Nury, T., Khallouki, F., El Hessni, A., Ibrahimi, S.O., and Latruffe, N. (2022). Saffron (Crocus sativus L.): A source of nutrients for health and for the treatment of neuropsychiatric and age-related diseases. Nutrients, 14.","DOI":"10.3390\/nu14030597"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"100448","DOI":"10.1016\/j.phanu.2025.100448","article-title":"Neuroprotective potential of saffron metabolites in Parkinson\u2019s disease","volume":"33","author":"Aboudlou","year":"2025","journal-title":"PharmaNutrition"},{"key":"ref_11","first-page":"1786","article-title":"Advances in the pharmacological and non-pharmacological management of non-motor symptoms in Parkinson\u2019s disease: An update since 2017","volume":"21","author":"Rukavina","year":"2022","journal-title":"Curr. Neuropharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"11","DOI":"10.14715\/cmb\/2016.62.14.2","article-title":"Safranal prevents rotenone-induced oxidative stress and apoptosis in an in vitro model of Parkinson\u2019s disease through regulating Keap1\/Nrf2 signaling pathway","volume":"62","author":"Pan","year":"2016","journal-title":"Cell. Mol. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Chia, S., Tan, E., and Chao, Y. (2020). Historical Perspective: Models of Parkinson\u2019s Disease. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21072464"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Stevanovic, D., Vu\u010di\u0107evi\u0107, L., Misirkic-Marjanovic, M., Martinovi\u0107, T., Mandic, M., Harhaji-Trajkovi\u0107, L., and Trajkovi\u0107, V. (2024). Trehalose attenuates in vitro neurotoxicity of 6-hydroxydopamine by reducing oxidative stress and activation of MAPK\/AMPK signaling pathways. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms251910659"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Siwecka, N., Galita, G., Granek, Z., Wiese, W., Majsterek, I., and Rozp\u0119dek-Kami\u0144ska, W. (2024). IRE1\/JNK is the leading UPR pathway in 6-OHDA-induced degeneration of differentiated SH-SY5Y cells. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25147679"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1038\/s41419-020-2322-6","article-title":"Pharmacological enhancement of TFEB-mediated autophagy alleviated neuronal death in oxidative stress-induced Parkinson\u2019s disease models","volume":"11","author":"Zhuang","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"11738","DOI":"10.18632\/aging.202868","article-title":"Administration of quercetin improves mitochondria quality control and protects the neurons in 6-OHDA-lesioned Parkinson\u2019s disease models","volume":"13","author":"Wang","year":"2021","journal-title":"Aging"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Barata-Antunes, S., Teixeira, F., Mendes-Pinheiro, B., Domingues, A., Vila\u00e7a-Faria, H., Marote, A., Silva, D., Sousa, R., and Salgado, A. (2020). Impact of Aging on the 6-OHDA-Induced Rat Model of Parkinson\u2019s Disease. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21103459"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e05342","DOI":"10.1016\/j.heliyon.2020.e05342","article-title":"Sesaminol prevents Parkinson\u2019s disease by activating the Nrf2-ARE signaling pathway","volume":"6","author":"Kaji","year":"2020","journal-title":"Heliyon"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Sim\u00f5es, A.T., Gon\u00e7alves, R.A., Agostinho, P., Cunha, R.A., and Oliveira, C.R. (2022). Evaluation of 6-hydroxydopamine and rotenone in vitro neurotoxicity on differentiated SH-SY5Y cells using applied computational statistics. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23063009"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"9260748","DOI":"10.1155\/2020\/9260748","article-title":"Nitroxide radical-containing redox nanoparticles protect neuroblastoma SH-SY5Y cells against 6-hydroxydopamine toxicity","volume":"2020","author":"Pichla","year":"2020","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Lai, M., Liu, W., Liou, S., and Liu, I. (2022). p-Hydroxybenzyl Alcohol Antagonized the ROS-Dependent JNK\/Jun\/Caspase-3 Pathway to Produce Neuroprotection in a Cellular Model of Parkinson\u2019s Disease. Nutrients, 14.","DOI":"10.3390\/nu14235002"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1038\/s41419-020-2473-5","article-title":"Exosomes derived from mesenchymal stem cells repair a Parkinson\u2019s disease model by inducing autophagy","volume":"11","author":"Chen","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/j.tiv.2005.01.006","article-title":"Effects of 6-hydroxydopamine on mitochondrial function and glutathione status in SH-SY5Y human neuroblastoma cells","volume":"19","author":"Tirmenshtein","year":"2005","journal-title":"Toxicol. In Vitr."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Ceccarini, M., Ceccarelli, V., Codini, M., Fettucciari, K., Calvitti, M., Cataldi, S., Albi, E., Vecchini, A., and Beccari, T. (2022). The Polyunsaturated Fatty Acid EPA, but Not DHA, Enhances Neurotrophic Factor Expression through Epigenetic Mechanisms and Protects against Parkinsonian Neuronal Cell Death. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232416176"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Silva, J., Alves, C., Pinteus, S., Mendes, S., and Pedrosa, R. (2018). Neuroprotective effects of seaweeds against 6-hydroxydopamine-induced cell death on an in vitro human neuroblastoma model. BMC Complement. Altern. Med., 18.","DOI":"10.1186\/s12906-018-2103-2"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2150","DOI":"10.1007\/s11064-012-0838-6","article-title":"Differential Toxicity of 6-Hydroxydopamine in SH-SY5Y Human Neuroblastoma Cells and Rat Brain Mitochondria: Protective Role of Catalase and Superoxide Dismutase","volume":"37","author":"Rose","year":"2012","journal-title":"Neurochem. Res."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Zhong, S., Chen, Y., Fang, M., Zhu, X., Zhao, Y., and Liu, X. (2014). Low-Dose Levodopa Protects Nerve Cells from Oxidative Stress and Up-Regulates Expression of pCREB and CD39. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0095387"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Xie, L., Hu, L., Teo, X., Tiong, C., Tazzari, V., Sparatore, A., Soldato, P., Dawe, G., and Bian, J. (2013). Therapeutic Effect of Hydrogen Sulfide-Releasing L-Dopa Derivative ACS84 on 6-OHDA-Induced Parkinson\u2019s Disease Rat Model. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0060200"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Ferlazzo, N., Cirmi, S., Maugeri, A., Russo, C., Lombardo, G., Gangemi, S., Calapai, G., Mollace, V., and Navarra, M. (2020). Neuroprotective Effect of Bergamot Juice in 6-OHDA-Induced SH-SY5Y Cell Death, an In Vitro Model of Parkinson\u2019s Disease. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12040326"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.nutres.2021.09.003","article-title":"Tocotrienols protect differentiated SH-SY5Y human neuroblastoma cells against 6-hydroxydopamine-induced cytotoxicity by ameliorating dopamine biosynthesis and dopamine receptor D2 gene expression","volume":"98","author":"Magalingam","year":"2021","journal-title":"Nutr. Res."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Rehfeldt, S., Silva, J., Alves, C., Pint\u00e9us, S., Pedrosa, R., Laufer, S., and Goettert, M. (2022). Neuroprotective Effect of Luteolin-7-O-Glucoside against 6-OHDA-Induced Damage in Undifferentiated and RA-Differentiated SH-SY5Y Cells. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23062914"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/0065-2571(84)90007-4","article-title":"Quantitative analysis of dose-effect relationships: The combined effects of multiple drugs or enzyme inhibitors","volume":"22","author":"Chou","year":"1984","journal-title":"Adv. Enzym. Regul."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1763","DOI":"10.1089\/ars.2009.3074","article-title":"Cellular Stress Responses, The Hormesis Paradigm, and Vitagenes: Novel Targets for Therapeutic Intervention in Neurodegenerative Disorders","volume":"13","author":"Calabrese","year":"2010","journal-title":"Antioxid. Redox Signal."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1080\/10408440801981965","article-title":"Dose-Response Features of Neuroprotective Agents: An Integrative Summary","volume":"38","author":"Calabrese","year":"2008","journal-title":"Crit. Rev. Toxicol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1296","DOI":"10.1038\/s41598-018-37972-y","article-title":"High doses of synthetic antioxidants induce premature senescence in cultivated mesenchymal stem cells","volume":"9","author":"Kornienko","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"8947","DOI":"10.1021\/acssensors.5c03024","article-title":"Ultrasensitive and Selective Iontronic H2O2 Nanosensor Reveals the Biphasic Redox Dynamics Invoked by l-DOPA at a Single-Cell Level","volume":"10","author":"Zhao","year":"2025","journal-title":"ACS Sens."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1016\/j.neuropharm.2013.11.026","article-title":"Naringenin protects against 6-OHDA-induced neurotoxicity via activation of the Nrf2\/ARE signaling pathway","volume":"79","author":"Lou","year":"2014","journal-title":"Neuropharmacology"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1016\/j.phrs.2016.09.004","article-title":"Palmitoylethanolamide protects mice against 6-OHDA-induced neurotoxicity and endoplasmic reticulum stress: In vivo and in vitro evidence","volume":"113","author":"Avagliano","year":"2016","journal-title":"Pharmacol. Res."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Tang, H., Zheng, Z., Wang, H., Wang, L., Zhao, G., and Wang, P. (2022). Vitamin K2 Modulates Mitochondrial Dysfunction Induced by 6-Hydroxydopamine in SH-SY5Y Cells via Mitochondrial Quality-Control Loop. Nutrients, 14.","DOI":"10.3390\/nu14071504"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/s40035-015-0033-1","article-title":"Wnt3a protects SH-SY5Y cells against 6-hydroxydopamine toxicity by restoration of mitochondria function","volume":"4","author":"Wei","year":"2015","journal-title":"Transl. Neurodegener."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1016\/j.bbrc.2016.01.102","article-title":"Activated cathepsin L is associated with the switch from autophagy to apoptotic death of SH-SY5Y cells exposed to 6-hydroxydopamine","volume":"470","author":"Li","year":"2016","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Kwon, S., Lee, S., Park, Y., Ra, M., Lee, Y., Pang, C., and Kim, K. (2019). Suppression of 6-Hydroxydopamine-Induced Oxidative Stress by Hyperoside Via Activation of Nrf2\/HO-1 Signaling in Dopaminergic Neurons. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20235832"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1038\/s41419-024-06670-1","article-title":"Protective effect of increased O-GlcNAc cycling against 6-OHDA induced Parkinson\u2019s disease pathology","volume":"15","author":"Kim","year":"2024","journal-title":"Cell Death Dis."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Perlikowska, R., Silva, J., Alves, C., Susano, P., and Pedrosa, R. (2022). The Therapeutic Potential of Naturally Occurring Peptides in Counteracting SH-SY5Y Cells Injury. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231911778"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Wu, C., Chang, H., Cheng, Y., Lan, W., Yang, S., and Ching, H. (2018). Aqueous Extract of Davallia mariesii Attenuates 6-Hydroxydopamine-Induced Oxidative Damage and Apoptosis in B35 Cells Through Inhibition of Caspase Cascade and Activation of PI3K\/AKT\/GSK-3\u03b2 Pathway. Nutrients, 10.","DOI":"10.3390\/nu10101449"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1038\/s41419-018-1229-y","article-title":"Dysregulated autophagy contributes to caspase-dependent neuronal apoptosis","volume":"9","author":"Chung","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Yun, H., Jo, Y., Kim, J., Shin, Y., Kim, S., and Choi, T. (2020). Roles of Autophagy in Oxidative Stress. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21093289"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Kuatov, R., Takano, J., Arie, H., Kominami, M., Tateishi, N., Wakabayashi, K., Takemoto, D., Izumo, T., Nakao, Y., and Nakamura, W. (2024). Urolithin A Modulates PER2 Degradation via SIRT1 and Enhances the Amplitude of Circadian Clocks in Human Senescent Cells. Nutrients, 17.","DOI":"10.3390\/nu17010020"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"5389","DOI":"10.1172\/JCI70317","article-title":"Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration","volume":"123","author":"Musiek","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"100232","DOI":"10.1016\/j.advnut.2024.100232","article-title":"Effects of (Poly)phenols on Circadian Clock Gene\u2013Mediated Metabolic Homeostasis in Cultured Mammalian Cells: A Scoping Review","volume":"15","author":"Sulaimani","year":"2024","journal-title":"Adv. Nutr."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"12036","DOI":"10.1073\/pnas.1108125108","article-title":"Regulation of apoptosis by the circadian clock through NF-kappaB signaling","volume":"108","author":"Lee","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Su, H., Sun, Y., Yang, M., Wu, C., and Hsu, C. (2023). Dihydroisotanshinone I and BMAL-SIRT1 Pathway in an In Vitro 6-OHDA-Induced Model of Parkinson\u2019s Disease. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241311088"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/S0301-0082(01)00003-X","article-title":"Molecular pathways involved in the neurotoxicity of 6-OHDA, dopamine and MPTP: Contribution to the apoptotic theory in Parkinson\u2019s disease","volume":"65","author":"Blum","year":"2001","journal-title":"Prog. Neurobiol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1038\/s41580-019-0173-8","article-title":"Mitochondria as multifaceted regulators of cell death","volume":"21","author":"Bock","year":"2019","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"4854732","DOI":"10.1155\/2018\/4854732","article-title":"Disruption of the Circadian Clock Alters Antioxidative Defense via the SIRT1-BMAL1 Pathway in 6-OHDA-Induced Models of Parkinson\u2019s Disease","volume":"2018","author":"Wang","year":"2018","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1007\/s10856-025-06951-x","article-title":"A review of cytotoxicity testing methods and in vitro study of biodegradable Mg-1%Sn-2%HA composite by elution method","volume":"36","author":"Jhamb","year":"2025","journal-title":"J. Mater. Sci. Mater. Med."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"e45","DOI":"10.1093\/nar\/29.9.e45","article-title":"A new mathematical model for relative quantification in real-time RT-PCR","volume":"29","author":"Pfaffl","year":"2001","journal-title":"Nucleic Acids Res."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"George, D., and Mallery, P. (2019). IBM SPSS Statistics 26 Step by Step, Routledge.","DOI":"10.4324\/9780429056765"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"172","DOI":"10.5395\/rde.2015.40.2.172","article-title":"Statistical notes for clinical researchers: Post-hoc multiple comparisons","volume":"40","author":"Kim","year":"2015","journal-title":"Restor. Dent. Endod."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"407","DOI":"10.4103\/aca.ACA_94_19","article-title":"Application of Student\u2019s t-test, analysis of variance, and covariance","volume":"22","author":"Mishra","year":"2019","journal-title":"Ann. Card. Anaesth."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/5\/773\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T13:19:31Z","timestamp":1779455971000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/5\/773"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,15]]},"references-count":62,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["ph19050773"],"URL":"https:\/\/doi.org\/10.3390\/ph19050773","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,15]]}}}