ROLE OF LUTEOLIN IN AUTOIMMUNE DISEASES

Year 2024, Volume: 48 Issue: 3, 1201 - 1218, 10.09.2024

Ali Eren Işkın , Muhammed Ali Kızmaz , Ferah Budak

https://doi.org/10.33483/jfpau.1459098

Abstract

Objective: Flavonoids, also known as crystalline compounds commonly found in plant foods, are compounds that exhibit optical activity. There are subtypes based on differences in their skeletal structure. Luteolin (LUT) is an important flavone obtained from dyer's catnip (Genista tinctoria) and lovebell (Reseda luteola) plants. In studies, it has been reported to exhibit many properties such as antioxidant, anti-inflammatory, immunomodulatory, anticancer and neuroprotective. Compounds derived from natural products such as LUTs have become the focus of numerous studies due to their important roles in the development of cancer, autoimmune, neurodegenerative and chronic diseases. Our aim in this review is to evaluate the therapeutic role of LUT compound in autoimmune diseases.
Result and Discussion: The compound LUT, characterized by a variable phenolic structure and found in various vegetables and fruits, has been reported to exhibit anti-inflammatory, antioxidant, immunomodulatory, and neuroprotective activities in several autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, asthma, multiple sclerosis, autoimmune encephalitis, ulcerative colitis, autoimmune diabetes, psoriasis, autoimmune thyroiditis, and uveitis. However, there have also been some concerning findings regarding the toxicity of the LUT compound. Future pharmacokinetic, toxicity, combination therapy, and molecular biology studies could help us better understand the health effects of the LUT compound.

Keywords

Antioxidant, autoimmune diseases, autoimmunity, flavonoid, luteolin

OTOİMMÜN HASTALIKLARDA LUTEOLİN BİLEŞİĞİNİN ROLÜ

Abstract

Amaç: Bitkisel gıdalarda yaygın olarak bulunan ve kristalik bileşikler olarak da bilinen flavonoidler, optik aktivite özelliği gösteren bileşiklerdir. İskelet yapılarının farklılıklarına dayalı olarak alt tipleri bulunmaktadır. Luteolin (LUT), boyacı katırtırnağı (Genista tinctoria) ve muhabbet çiçeği (Reseda luteola) bitkilerinden elde edilen önemli bir flavondur. Yapılan çalışmalarda, anti-oksidan, anti-enflamatuvar, immünomodülatör, anti-kanser ve nöroprotektif gibi birçok özellik sergilediği bildirilmiştir. LUT gibi doğal ürünlerden elde edilen bileşiklerin, kanser, otoimmün, nörodejeneratif ve kronik hastalıkların gelişiminde önemli rolleri nedeniyle çok sayıda araştırmanın odak noktası haline gelmiştir. Bu derlemedeki amacımız, otoimmün hastalıklarda LUT bileşiğinin terapötik rolünü değerlendirmektir.
Sonuç ve Tartışma: Çeşitli sebzelerde, meyvelerde bulunan ve değişken bir fenolik madde yapısına sahip olan LUT bileşiğinin; sistemik lupus eritematozus, romatoid artrit, astım, multipl skleroz, otoimmün ensefalit, ülseratif kolit, otoimmün diyabet, psoriasis, otoimmün tiroidit ve üveit gibi bazı otoimmün hastalıklarda anti-enflamatuvar, anti-oksidan, immünomodülatör ve nöroprotektif aktiviteler sergilediği bildirilmiştir. Ancak, LUT bileşiğinin toksisitesi ile ilgili endişe verici bazı bulgular da raporlanmaştır. Gelecekte yapılacak olan farmakokinetik, toksisite, kombine tedavi ve moleküler biyoloji çalışmaları LUT bileşiğinin sağlık üzerindeki etkilerini daha iyi anlamamıza yardımcı olabilir.

Keywords

Anti-oksidan, flavonoid, luteolin, otoimmün hastalıklar, otoimmünite

Ethical Statement

İlgili çalışmanın derleme yayını olması nedeniyle etik kurul onayı gerekmemektedir.

Supporting Institution

Destekleyen kurum bulunmamaktadır

References

• 1. Shen, P., Lin, W., Deng, X., Ba, X., Han, L., Chen, Z., Qin, K., Huang, Y., Tu, S. (2021). Potential implications of quercetin in autoimmune diseases. Frontiers In Immunology, 12, 689044. [CrossRef]
• 2. Liu, X., Wang, Z., Qian, H., Tao, W., Zhang, Y., Hu, C., Mao, W., Guo, Q. (2022). Natural medicines of targeted rheumatoid arthritis and its action mechanism. Frontiers In Immunology, 13, 945129. [CrossRef]
• 3. Ntalouka, F., Tsirivakou, A. (2023). Luteolin: A promising natural agent in management of pain in chronic conditions. Frontiers In Pain Research (Lausanne, Switzerland), 4, 1114428. [CrossRef]
• 4. Badshah, S.L., Faisal, S., Muhammad, A., Poulson, B.G., Emwas, A.H., Jaremko, M. (2021). Antiviral activities of flavonoids. Biomedicine & Pharmacotherapy, 140, 111596. [CrossRef]
• 5. Kozłowska, A., Szostak-Wegierek, D. (2014). Flavonoids-food sources and health benefits. Roczniki Państwowego Zakładu Higieny, 65(2), 79-85.
• 6. Guven, H., Arici, A., Simsek, O. (2019). Flavonoids in our foods: a short review. Journal of Basic and Clinical Health Sciences, 3(2), 96-106. [CrossRef]
• 7. Panche, A.N., Diwan, A.D., Chandra, S.R. (2016). Flavonoids: an overview. Journal of Nutritional Science, 5, e47. [CrossRef]
• 8. Al-Khayri, J.M., Sahana, G.R., Nagella, P., Joseph, B.V., Alessa, F.M., Al-Mssallem, M.Q. (2022). Flavonoids as potential anti-inflammatory molecules: A review. Molecules, 27(9), 2901. [CrossRef]
• 9. Kozłowska A., Szostak-Węgierek D. Flavonoids-Food sources, health benefits, and mechanisms involved. In: Mérillon J.M., Ramawat K., editors. Bioactive Molecules in Food. Springer; Cham, Switzerland: 2017. (Reference Series in Phytochemistry), pp:53-78. [CrossRef]
• 10. Harborne, J.B., Williams, C.A. (2000). Advances in flavonoid research since 1992. Phytochemistry, 55(6), 481-504. [CrossRef]
• 11. Agati, G., Azzarello, E., Pollastri, S., Tattini, M. (2012). Flavonoids as antioxidants in plants: location and functional significance. Plant Science, 196, 67-76. [CrossRef]
• 12. Aziz, N., Kim, M.Y., Cho, J.Y. (2018). Anti-inflammatory effects of luteolin: A review of in vitro, in vivo, and in silico studies. Journal of Ethnopharmacology, 225, 342-358. [CrossRef]
• 13. Lin, Y., Shi, R., Wang, X., Shen, H. (2008). Luteolin, a flavonoid with potentials for cancer prevention and therapy, Currrent Cancer Drug Targets, 8, 634-646. [CrossRef]
• 14. Lien E.J., Ren, S., Bui, H.H., Wang R. (1999). Quantitative structure-activity relationship analysis of phenolic antioxidants. Free Radical Biology and Medicine, 26(3-4), 285-294. [CrossRef]
• 15. Shimoi, K., Masuda, S., Furugori, M., Esaki, S., Kinae, N. (1994). Radioprotective effect of antioxidative flavonoids in gamma-ray irradiated mice. Carcinogenesis, 15(11), 2669-2672. [CrossRef]
• 16. Ross, J.A., Kasum, C.M. (2002). Dietary flavonoids: Bioavailability, metabolic effects, and safety. Annual Review of Nutrition, 22, 19-34. [CrossRef]
• 17. Manju, V., Nalini, N. (2005). Chemopreventive potential of luteolin during colon carcinogenesis induced by 1,2-dimethylhydrazine. The Italian Journal of Biochemistry, 54(3-4), 268-275.
• 18. Leung, H.W., Kuo, C.L., Yang, W.H., Lin, C.H., Lee, H.Z. (2006). Antioxidant enzymes activity involvement in luteolin-induced human lung squamous carcinoma CH27 cell apoptosis. European Journal of Pharmacology, 534(1-3), 12–18. [CrossRef]
• 19. Wruck, C.J., Claussen, M., Fuhrmann, G., Römer, L., Schulz, A., Pufe, T., Waetzig, V., Peipp, M., Herdegen, T., Götz, M.E. (2007). Luteolin protects rat PC 12 and C6 cells against MPP+ induced toxicity via an ERK dependent Keapl-Nrf2-ARE pathway. Neuropsychiatr Disord Integrative Approach, 72, 57-67 [CrossRef]
• 20. Harris, G.K., Qian, Y., Leonard, S.S., Sbarra, D.C., Shi, X. (2006). Luteolin and chrysin differentially inhibit cyclooxygenase-2 expression and scavenge reactive oxygen species but similarly inhibit prostaglandin-E2 formation in RAW 264.7 cells. The Journal of Nutrition, 136, 1517-21 [CrossRef]
• 21. Reudhabibadh, R., Binlateh, T., Chonpathompikunlert, P., Nonpanya, N., Prommeenate, P., Chanvorachote, P., Hutamekalin, P. (2021). Suppressing Cdk5 Activity by Luteolin Inhibits MPP+ -Induced Apoptotic of Neuroblastoma through Erk/Drp1 and Fak/Akt/GSK3β Pathways. Molecules, 26, 1307. [CrossRef]
• 22. Seelinger, G., Merfort, I., Schempp, C.M. (2008). Anti-oxidant, anti-inflammatory and anti-allergic activities of luteolin. Planta Medica, 74(14), 1667-1677. [CrossRef]
• 23. Chen, L., Deng, H., Cui, H., Fang, J., Zuo, Z., Deng, J., Li, Y., Wang, X., Zhao, L. (2017). Inflammatory responses and inflammation-associated diseases in organs. Oncotarget, 9(6), 7204-7218. [CrossRef]
• 24. Brody, J.S., Spira, A. (2006). State of the art. Chronic obstructive pulmonary disease, inflammation, and lung cancer. Proceedings of the American Thoracic Society, 3, 535-537. [CrossRef]
• 25. Karin, M., Lawrence, T., Nizet, V. (2006). Innate immunity gone awry: Linking microbial infections to chronic inflammation and cancer. Cell, 124, 823-835. [CrossRef]
• 26. Huang, L., Kim, M.Y., Cho, J.Y. (2023). Immunopharmacological activities of luteolin in chronic diseases. International Journal of Molecular Sciences, 24(3), 2136. [CrossRef]
• 27. Gendrisch, F., Esser, P.R., Schempp, C.M., Wölfle, U. (2021). Luteolin as a modulator of skin aging and inflammation. Biofactors, 47(2), 170-180. [CrossRef]
• 28. Singh Tuli, H., Rath, P., Chauhan, A., Sak, K., Aggarwal, D., Choudhary, R., Sharma, U., Vashishth, K., Sharma, S., Kumar, M., Yadav, V., Singh, T., Yerer, M.B., Haque, S. (2022). Luteolin, a potent anticancer compound: From chemistry to cellular interactions and synergetic perspectives. Cancers, 14(21), 5373. [CrossRef]
• 29. Weng, Z., Patel, A.B., Vasiadi, M., Therianou, A., Theoharides, T.C. (2014). Luteolin inhibits human keratinocyte activation and decreases NF-κB induction that is increased in psoriatic skin. PLoS One, 9, e90739. [CrossRef]
• 30. Wölfle, U., Haarhaus, B., Schempp, C.M., Wölfle, U., Heinemann, A., Esser, P.R., Haarhaus, B., Martin, S.F., Schempp, C.M. (2012). Luteolin prevents solar radiation-induced matrix metalloproteinase-1 activation in human fibroblasts: a role for p38 mitogen-activated protein kinase and interleukin-20 released from keratinocytes. Rejuvenation Research, 15(5), 466-475. [CrossRef]
• 31. Taliou, A., Zintzaras, E., Lykouras, L., Francis, K. (2013). An open-label pilot study of a formulation containing the anti-iflammatory flavonoid luteolin and its effects on behavior in children with autism spectrum disorders. Clin. Therapeutics, 35, 592-602. [CrossRef]
• 32. Zhou, F., Chen, S., Xiong, J., Li, Y., Qu, L. (2012). Luteolin reduces zincinduced tau phosphorylation at Ser262/356 in an ROS-dependent manner in SH-SY5Y cells. Biological Trace Element Research, 149(2), 273-279 [CrossRef]
• 33. Kou, J., Shi, J., He, Y., Hao, J., Zhang, H., Luo, D., Song, J., Yan, Y., Xie, X., Du, G. (2022). Luteolin alleviates cognitive impairment in Alzheimer’s disease mouse model via ınhibiting endoplasmic reticulum stress-dependent neuroinflammation. Acta Pharmacologica Sinica, 43, 840-849. [CrossRef]
• 34. Gendrisch, F., Esser, P.R., Schempp, C.M., Wölfle, U. (2021). Luteolin as a modulator of skin aging and inflammation. Biofactors, 47(2), 170-180. [CrossRef]
• 35. Erdoğan, M.K., Ağca, C.A., Aşkın, H. (2022). Quercetin and luteolin improve the anticancer effects of 5-fluorouracil in human colorectal adenocarcinoma in vitro model: A mechanistic insight. Nutrition and Cancer, 74(2), 660-676. [CrossRef]
• 36. Zhao, J., Jiao, W., Sui, X., Zou, J., Wang, J., Lin, Z. (2023). Construction of a prognostic model of luteolin for endometrial carcinoma. American Journal of Translational Research, 15(3), 2122-2139.
• 37. İskin, A. E., Budak, F. (2023). Enfeksiyon hastalıklarında ferroptozun rolü. Uludağ Üniversitesi Tıp Fakültesi Dergisi, 49(3), 425-438. [CrossRef]
• 38. Han, S., Lin, F., Qi, Y., Liu, C., Zhou, L., Xia, Y., Chen, K., Xing, J., Liu, Z., Yu, W., Zhang, Y., Zhou, X., Rao, T., Cheng, F. (2022). HO-1 contributes to luteolin-triggered ferroptosis in clear cell renal cell carcinoma via increasing the labile iron pool and promoting lipid peroxidation. Oxidative Medicine and Cellular Longevity, 2022(1), 3846217. [CrossRef]
• 39. Xie, K., Chai, Y.S., Lin, S.H., Xu, F., Wang, C.J. (2021). Luteolin regulates the differentiation of regulatory T cells and activates IL-10-dependent macrophage polarization against acute lung Injury. Journal of Immunology Research, 8883962. [CrossRef]
• 40. Huang, X., Bhugul, P.A., Fan, G., Ye, T., Huang, S., Dai, S., Chen, B., Zhou, M. (2018). Luteolin inhibits pancreatitis-induced acinar-ductal metaplasia, proliferation and epithelial-mesenchymal transition of acinar cells. Molecular Medicine Reports, 17, 3681-3689. [CrossRef]
• 41. Lv, L., Lv, L., Zhang, Y., Kong, Q. (2011). Luteolin prevents LPS-induced TNF-α expression in cardiac myocytes through inhibiting NF-κB signaling pathway. Inflammation 34, 620-629. [CrossRef]
• 42. Wu, W., Li, D., Zong, Y., Zhu, H., Pan, D., Xu, T., Wang, T., Wang, T. (2013). Luteolin inhibits inflammatory responses via p38/MK2/TTP-mediated mRNA stability. Molecules, 18, 8083-8094. [CrossRef]
• 43. Xie, M., Wang, H., Gao, T., Peng, J., Meng, P., Zhang, X., Guo, D., Liu, G., Shi, J., Peng, Q. (2023). The protective effect of luteolin on the depression-related dry eye disorder through Sirt1/NF-κB/NLRP3 pathway. Aging (Albany NY), 15(1), 261. [CrossRef]
• 44. Griffith, J.W., Sokol, C.L., Luster, A.D. (2014). Chemokines and chemokine receptors: Positioning cells for host defense and immunity. Annual Review of Immunology, 32, 659-702. [CrossRef]
• 45. Rakoczy, K., Kaczor, J., Sołtyk, A., Szymańska, N., Stecko, J., Sleziak, J., Kulbacka, Baczyńska, D. (2023). Application of luteolin in neoplasms and nonneoplastic diseases. International Journal of Molecular Sciences, 24(21), 15995. [CrossRef]
• 46. Theoharides, T. C., Kempuraj, D., Iliopoulou, B. P. (2007). Mast cells, T cells, and inhibition by luteolin: Implications for the pathogenesis and treatment of multiple sclerosis. Immune-Mediated Diseases: From Theory to Therapy, 423-430. [CrossRef]
• 47. Yang, D., Tan, X., Lv, Z., Liu, B., Baiyun, R., Lu, J., Zhang, Z. (2016). Regulation of Sirt1/Nrf2/TNF-α signaling pathway by luteolin is critical to attenuate acute mercuric chloride exposure induced hepatotoxicity. Scientific Reports, 6, 37157. [CrossRef]
• 48. Zhang, Z.T., Zhang, D.Y., Xie, K., Wang, C.J., Xu, F. (2021). Luteolin activates tregs to promote IL-10 expression and alleviating caspase-11-dependent pyroptosis in sepsis-induced lung injury. International Immunopharmacology, 99, 107914. [CrossRef]
• 49. Pollard, K.M., Hultman, P., Kono, D.H. (2010). Toxicology of autoimmune diseases. Chemical Research in Toxicology, 23(3), 455-466. [CrossRef]
• 50. Akoğlu, T., Ar, M.C., Patıroğlu, T., Al, E. (2016). Hematologlar ı̇çı̇n İmmunoloji. Akoğlu T, Ar MC, Patıroğlu T, editors. Vol. 97.
• 51. Erol, Ç., Turgay, M. (2011). İç Hastalıkları İmmunoloji ve Romatoloji. 1st ed. Erol Ç, Turgay M, editors. Ankara: MN Meidkal & Nobel Basım Yayın.
• 52. Hou, W., Xu, G., Wang, H. (2011). Chapter 1-Basic immunology and immune system disorders, Editor(s): Wanzhu Hou, Guangpi Xu, Hanjie Wang, Treating Autoimmune Disease with Chinese Medicine, Churchill Livingstone, Pages 1-12, ISBN 9780443069741, [CrossRef]
• 53. Pisetsky D.S. (2023). Pathogenesis of autoimmune disease. Nature reviews. Nephrology, 19(8), 509-524. [CrossRef]
• 54. Nagafuchi, Y., Yanaoka, H., Fujio, K. (2022). Lessons from transcriptome analysis of autoimmune diseases. Frontiers in Immunology, 13, 857269. [CrossRef]
• 55. Ray, D., Yung, R. (2018). Immune senescence, epigenetics and autoimmunity. Clinical Immunology, 196, 59-63. [CrossRef]
• 56. Saurin, S., Meineck, M., Erkel, G., Opatz, T., Weinmann-Menke, J., Pautz, A. (2022). Drug candidates for autoimmune diseases. Pharmaceuticals, 15(5), 503. [CrossRef]
• 57. Yu, H., Nagafuchi, Y., Fujio, K. (2021). Clinical and immunological biomarkers for systemic lupus erythematosus. Biomolecules, 11(7), 928. [CrossRef]
• 58. Almaani, S., Meara, A., Rovin, B. H. (2017). Update on lupus nephritis. Clinical journal of the American Society of Nephrology: CJASN, 12(5), 825. [CrossRef]
• 59. Ding, T., Yi, T., Li, Y., Zhang, W., Wang, X., Liu, J., Fan, Y., Ji, J., Xu, L. (2023). Luteolin attenuates lupus nephritis by regulating macrophage oxidative stress via HIF-1α pathway. European Journal of Pharmacology, 175823. [CrossRef]
• 60. Liu, W., Li, S., Tao, F., Wu, L., Luo, F., Sun, T., Zhao, J., Li, J., Li, C. (2022). The mechanism of jieduquyuziyin prescription in the treatment of systemic lupus erythematosus via Nek7-NLRP3 signaling pathway. Journal of Biomedical Nanotechnology, 18(7), 1782-1792. [CrossRef]
• 61. Radu, A.F., Bungau, S.G. (2021). Management of rheumatoid arthritis: An overview. Cells, 10(11), 2857. [CrossRef]
• 62. Jang, S., Kwon, E.J., Lee, J.J. (2022). Rheumatoid arthritis: Pathogenic roles of diverse immune cells. International Journal of Molecular Sciences, 23(2), 905. [CrossRef]
• 63. Shi, F., Zhou, D., Ji, Z., Xu, Z., Yang, H. (2015). Anti-arthritic activity of luteolin in Freund’s complete adjuvant-induced arthritis in rats by suppressing P2X4 pathway. Chemico-biological Interactions, 226, 82-87. [CrossRef]
• 64. Lou, L., Liu, Y., Zhou, J., Wei, Y., Deng, J., Dong, B., Chai, L. (2015). Chlorogenic acid and luteolin synergistically inhibit the proliferation of interleukin-1β-induced fibroblast-like synoviocytes through regulating the activation of NF-κ B and JAK/STAT-signaling pathways. Immunopharmacology and Immunotoxicology, 37(6), 499-507. [CrossRef]
• 65. Yang, S.C., Chen, P.J., Chang, S.H., Weng, Y.T., Chang, F.R., Chang, K.Y., Chen, C.Y., Kao T., Hwang, T.L. (2018). Luteolin attenuates neutrophilic oxidative stress and inflammatory arthritis by inhibiting Raf1 activity. Biochemical Pharmacology, 154, 384-396. [CrossRef]
• 66. Hou, Y., Wu, J., Huang, Q., Guo, L. (2009). Luteolin inhibits proliferation and affects the function of stimulated rat synovial fibroblasts. Cell Biology International, 33(2), 135-147. [CrossRef]
• 67. Xiao, B., Li, J., Qiao, Z., Yang, S., Kwan, H. Y., Jiang, T., Zhang, M., Xia, Q., Liu, Z., Su, T. (2023). Therapeutic effects of Siegesbeckia orientalis L. and its active compound luteolin in rheumatoid arthritis: Network pharmacology, molecular docking and experimental validation. Journal of Ethnopharmacology, 317, 116852. [CrossRef]
• 68. Impellizzeri, D., Esposito, E., Di Paola, R., Ahmad, A., Campolo, M., Peli, A., Morittu, V.M., Britti, D., Cuzzocrea, S. (2013). Palmitoylethanolamide and luteolin ameliorate development of arthritis caused by injection of collagen type II in mice. Arthritis Research & Therapy, 15(6), 1-14. [CrossRef]
• 69. Alizadeh, Z., Mortaz, E., Adcock, I., Moin, M. (2017). Role of epigenetics in the pathogenesis of Asthma. Iranian Journal of Allergy, Asthma and Immunology, 82-91.
• 70. Jang, T.Y., Jung, A.Y., Kyung, T.S., Kim, D.Y., Hwang, J.H., Kim, Y.H. (2017). Anti-allergic effect of luteolin in mice with allergic asthma and rhinitis. Central European Journal of Immunology, 42(1), 24-29. [CrossRef]
• 71. Kim, S.H., Saba, E., Kim, B.K., Yang, W.K., Park, Y.C., Shin, H.J., Han, C.K., Lee, Y.C., Rhee, M.H. (2018). Luteolin attenuates airway inflammation by inducing the transition of CD4+ CD25– to CD4+ CD25+ regulatory T cells. European Journal of Pharmacology, 820, 53-64. [CrossRef]
• 72. Wang, S., Wuniqiemu, T., Tang, W., Teng, F., Bian, Q., Yi, L., Qin, J., Zhu, X., Wei, Y., Dong, J. (2021). Luteolin inhibits autophagy in allergic asthma by activating PI3K/Akt/mTOR signaling and inhibiting Beclin-1-PI3KC3 complex. International Immunopharmacology, 94, 107460. [CrossRef]
• 73. Gong, B., Zheng, Y., Li, J., Lei, H., Liu, K., Tang, J., Peng, Y. (2022). Luteolin activates M2 macrophages and suppresses M1 macrophages by upregulation of hsa_circ_0001326 in THP-1 derived macrophages. Bioengineered, 13(3), 5079-5090. [CrossRef]
• 74. Qiao, X.R., Feng, T., Zhang, D., Zhi, L.L., Zhang, J.T., Liu, X. F., Pan, Y., Xu, J.W., Cui, W.J., Dong, L. (2023). Luteolin alleviated neutrophilic asthma by inhibiting IL-36γ secretion-mediated MAPK pathways. Pharmaceutical biology, 61(1), 165-176. [CrossRef]
• 75. Shen, M.L., Wang, C.H., Lin, C.H., Zhou, N., Kao, S.T., Wu, D.C. (2016). Luteolin attenuates airway mucus overproduction via inhibition of the GABAergic system. Scientific Reports, 6, 32756. [CrossRef]
• 76. Tafti, D., Ehsan, M., Xixis, K.L. (2022). Multiple Sclerosis, in StatPearls. StatPearls Publishing Copyright © 2022, StatPearls Publishing LLC.: Treasure Island (FL).
• 77. Kempuraj, D., Thangavel, R., Kempuraj, D.D., Ahmed, M.E., Selvakumar, G.P., Raikwar, S.P., Zaheer, S.A., Iyer, S.S., Govindarajan, R., Chandrasekaran, P.N., Zaheer, A. (2021). Neuroprotective effects of flavone luteolin in neuroinflammation and neurotrauma. Biofactors, 47(2), 190-197. [CrossRef]
• 78. Kempuraj, D., Tagen, M., Iliopoulou, B.P., Clemons, A., Vasiadi, M., Boucher, W., House, M., Wolfberg, A., Theoharides, T.C. (2008). Luteolin inhibits myelin basic protein‐induced human mast cell activation and mast cell‐dependent stimulation of Jurkat T cells. British Journal of Pharmacology, 155(7), 1076-1084. [CrossRef]
• 79. Sternberg, Z., Chadha, K., Lieberman, A., Drake, A., Hojnacki, D., Weinstock-Guttman, B., Munschauer, F. (2009). Immunomodulatory responses of peripheral blood mononuclear cells from multiple sclerosis patients upon in vitro incubation with the flavonoid luteolin: Additive effects of IFN-β. Journal of Neuroinflammation, 6, 1-8. [CrossRef]
• 80. El‐Deeb, O.S., Ghanem, H.B., El‐Esawy, R.O., Sadek, M.T. (2019). The modulatory effects of luteolin on cyclic AMP/Ciliary neurotrophic factor signaling pathway in experimentally induced autoimmune encephalomyelitis. IUBMB Life, 71(9), 1401-1408. [CrossRef]
• 81. Hébert, J., Muccilli, A., Wennberg, R.A., Tang-Wai, D.F. (2022). Autoimmune encephalitis and autoantibodies: A review of clinical implications. Journal of Applied Laboratory Medicine, 7(1), 81-98. [CrossRef]
• 82. Contarini, G., Franceschini, D., Facci, L., Barbierato, M., Giusti, P., Zusso, M. (2019). A co-ultramicronized palmitoylethanolamide/luteolin composite mitigates clinical score and disease-relevant molecular markers in a mouse model of experimental autoimmune encephalomyelitis. Journal of Neuroinflammation, 16, 1-13. [CrossRef]
• 83. Actis, G.C., Pellicano, R., Fagoonee, S., Ribaldone, D.G. (2019). History of inflammatory bowel diseases. Journal of Clinical Medicine, 8(11), 1970. [CrossRef]
• 84. Kornbluth, A., Sachar, D.B., The Practice Parameters Committee of the American College of Gastroenterology. (2010). Ulcerative colitis practice guidelines in adults: American College of Gastroenterology, Practice Parameters Committee. American Journal of Gastroenterology, 105, 501-523. [CrossRef]
• 85. Li, B., Du, P., Du, Y., Zhao, D., Cai, Y., Yang, Q., Guo, Z. (2021). Luteolin alleviates inflammation and modulates gut microbiota in ulcerative colitis rats. Life Sciences, 269, 119008. [CrossRef]
• 86. Li, B., Guo, Y., Jia, X., Cai, Y., Zhang, Y., Yang, Q. (2023). Luteolin alleviates ulcerative colitis in rats via regulating immune response, oxidative stress, and metabolic profiling. Open Medicine, 18(1), 20230785. [CrossRef]
• 87. Kim, W.S., Song, H.Y., Han, J.M., Byun, E.B. (2019). GLM, a novel luteolin derivative, attenuates inflammatory responses in dendritic cells: Therapeutic potential against ulcerative colitis. Biochemical and Biophysical Research Communications, 518(1), 87-93. [CrossRef]
• 88. Xie, X., Zhao, M., Huang, S., Li, P., Chen, P., Luo, X., Wang, Q., Pan, Z., Li, X., Chen, J., Chen, B., Zhou, L. (2022). Luteolin alleviates ulcerative colitis by restoring the balance of NCR-ILC3/NCR+ ILC3 to repairing impaired intestinal barrier. International Immunopharmacology, 112, 109251. [CrossRef]
• 89. Li, Y., Shen, L., Luo, H. (2016). Luteolin ameliorates dextran sulfate sodium-induced colitis in mice possibly through activation of the Nrf2 signaling pathway. International Immunopharmacology, 40, 24-31. [CrossRef]
• 90. Xue, L., Jin, X., Ji, T., Li, R., Zhuge, X., Xu, F., Quan, Z., Tong, H., Yu, W. (2023). Luteolin ameliorates DSS-induced colitis in mice via suppressing macrophage activation and chemotaxis. International Immunopharmacology, 124, 110996. [CrossRef]
• 91. Vukelić, I., Detel, D., Batičić, L., Potočnjak, I., Domitrović, R. (2020). Luteolin ameliorates experimental colitis in mice through ERK-mediated suppression of inflammation, apoptosis and autophagy. Food and Chemical Toxicology, 145, 111680. [CrossRef]
• 92. Tan, C., Fan, H., Ding, J., Han, C., Guan, Y., Zhu, F., Wu, H., Liu, Y., Zhang, W., Hou, X., Tan, S., Tang, Q. (2022). ROS-responsive nanoparticles for oral delivery of luteolin and targeted therapy of ulcerative colitis by regulating pathological microenvironment. Materials Today Bio, 14, 100246. [CrossRef]
• 93. The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. (1997). Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care, 20, 1183-1197. [CrossRef]
• 94. Zhang Y., Xiao-Qin Tian., Xiang-Xin Song., Jia-Pu Ge., Yan-Cheng Xu. (2017). Luteolin protect against diabetic cardiomyopathy in rat model via regulating the AKT/GSK-3β signalling pathway. Biomedical Research, 28(3), 1359-1363.
• 95. Wang, G.G., Lu, X.H., Li, W., Zhao, X., Zhang, C. (2011). Protective effects of luteolin on diabetic nephropathy in STZ-induced diabetic rats. Evidence-Based Complementary And Alternative Medicine, 2011(1), 323171. [CrossRef]
• 96. Lu, H.E., Chen, Y., Sun, X.B., Tong, B., Fan, X.H. (2015). Effects of luteolin on retinal oxidative stress and inflammation in diabetes. Rsc Advances, 5(7), 4898-4904. [CrossRef]
• 97. Wang, G., Li, W., Lu, X., Bao, P., Zhao, X. (2012). Luteolin ameliorates cardiac failure in type I diabetic cardiomyopathy. Journal of Diabetes and its Complications, 26(4), 259-265. [CrossRef]
• 98. Li, X.B., Rekep, M., Tian, J.H., Wu, Q., Chen, M., Yang, S., Zhang, L., Zhang, G., Qin, Y., Yu, X., Xue, G., Liu, Y. H. (2023). Luteolin Attenuates Diabetic Myocardial Hypertrophy by Inhibiting Proteasome Activity. Pharmacology, 108(1), 47-60. [CrossRef]
• 99. Li, L., Wu, L., Yuanyuan, Q., Weiwei, Z., Jianchang, Q., Jieli, L., Yiyi, J., Xuzhong, X., Guang, L. (2019). Luteolin protects against diabetic cardiomyopathy by inhibiting NF-κB-mediated inflammation and activating the Nrf2-mediated antioxidant responses. Phytomedicine, 59, 152774. [CrossRef]
• 100. Birlea, S.A., Serota, M., Norris, D. A. (2020). Nonbullous skin diseases: Alopecia areata, vitiligo, psoriasis, and urticaria. In the autoimmune diseases (pp. 1211-1234). Academic Press. [CrossRef]
• 101. Vijayalakshmi, A., Geetha, M. (2014). Anti-psoriatic activity of Givotia rottle riformis in rats. Indian Journal of Pharmacology, 46, 386-390. [CrossRef]
• 102. Lv, J., Zhou, D., Wang, Y., Sun, W., Zhang, C., Xu, J., Yang, H., Zhou, T., Li, P. (2020). Effects of luteolin on treatment of psoriasis by repressing HSP90. International Immunopharmacology, 79, 106070. [CrossRef]
• 103. Wang, X., Yao, Y., Li, Y., Guo, S., Li, Y., Zhang, G. (2023). Experimental study on the effect of luteolin on the proliferation, apoptosis and expression of inflammation-related mediators in lipopolysaccharide-induced keratinocytes. International Journal of Immunopathology and Pharmacology, 37, 03946320231169175. [CrossRef]
• 104. Xu, H., Hu, H., Zhao, M., Shi, C., Zhang, X. (2023). Preparation of luteolin loaded nanostructured lipid carrier based gel and effect on psoriasis of mice. Drug Delivery and Translational Research, 14, 637-654. [CrossRef]
• 105. Zhou, W., Hu, M., Zang, X., Liu, Q., Du, J., Hu, J., Zhang, L., Du, Z., Xiang, Z. (2020). Luteolin attenuates imiquimod-induced psoriasis-like skin lesions in BALB/c mice via suppression of inflammation response. Biomedicine & Pharmacotherapy, 131, 110696. [CrossRef]
• 106. Hiromatsu, Y., Satoh, H., Amino, N. (2013). Hashimoto's thyroiditis: History and future outlook. Hormones (Athens, Greece), 12(1), 12-8. [CrossRef]
• 107. Li, Q., Yang, W., Li, J., Shan, Z. (2022). Emerging trends and hot spots in autoimmune thyroiditis research from 2000 to 2022: A bibliometric analysis. Frontiers in Immunology, 13, 953465. [CrossRef]
• 108. Xia, N., Chen, G., Liu, M., Ye, X., Pan, Y., Ge, J., Mao, Y., Wang, H., Xie, S. (2016). Anti-inflammatory effects of luteolin on experimental autoimmune thyroiditis in mice. Experimental and Therapeutic Medicine, 12(6), 4049-4054. [CrossRef]
• 109. Gan, X.X., Zhong, L.K., Shen, F., Feng, J.H., Li, Y.Y., Li, S.J., Cai, W.S., Xu, B. (2021). Network pharmacology to explore the molecular mechanisms of prunella vulgaris for treating Hashimoto’s thyroiditis. Frontiers in Pharmacology, 12, 700896. [CrossRef]
• 110. Hoy, S.M. (2017). Adalimumab: A review in non-infectious non-anterior uveitis. BioDrugs, 31, 135-142. [CrossRef]
• 111. Hasanreisoglu, M., Cubuk, M.O., Ozdek, S., Gurelik, M.D., Aktas, Z. Hasanreisoglu, B. (2017). Interferon alpha-2a therapy in patients with refractory Behçet Uveitis. Ocular Immunology and Inflammation, 25, 71-5. [CrossRef]
• 112. Ten Berge, J.C., Schreurs, M.W., Vermeer, J., Meester‐Smoor, M.A., Rothova, A. (2016). Prevalence and clinical impact of antiretinal antibodies in uveitis. Acta Ophthalmologica, 94(3), 282-288. [CrossRef]
• 113. Zhang, D., Hong, L., Zhang, R.S., Zhang, Q., Yao, J., Wang, J., Zhang, N. (2023). Identification of the key mechanisms of action of Si-Ni-San in uveitis using bioinformatics and network pharmacology. Medicine, 102(34), e34615. [CrossRef]
• 114. Kanai, K., Hatta, T., Nagata, S., Sugiura, Y., Sato, K., Yamashita, Y., Kimura, Y., Itoh, N. (2016). Luteolin attenuates endotoxin-induced uveitis in Lewis rats. Journal of Veterinary Medical Science, 78(8), 1229-1235. [CrossRef]
• 115. Kanai, K., Nagata, S., Hatta, T., Sugiura, Y., Sato, K., Yamashita, Y., Kimura, Y., Itoh, N. (2016). Therapeutic anti-inflammatory effects of luteolin on endotoxin-induced uveitis in Lewis rats. Journal of Veterinary Medical Science, 78(8), 1381-1384. [CrossRef]
• 116. Nordeen, S.K., Bona, B.J., Jones, D.N., Lambert, J.R., Jackson, T.A. (2013). Endocrine disrupting activities of the flavonoid nutraceuticals luteolin and quercetin. Horm Cancer, 4(5), 293-300 [CrossRef]
• 117. Xiong, J., Wang, K., Yuan, C., Xing, R., Ni, J., Hu, G., Chen, F., Wang, X. (2017). Inflammaluteolin protects mice from severe acute pancreatitis by exerting HO-1-mediated anti-inflammatory and antioxidant effects. International Journal of Molecular Medicine, 39, 113-125. [CrossRef]
• 118. De Leo, E., Elmonem, M.A., Berlingerio, S.P., Berquez, M., Festa, B.P., Raso, R., Bellomo, F., Starborg, T., Janssen, M.J., Abbaszadeh, Z., Cairoli, S., Goffredo, B.M., Masereeuw, R., Devuyst, O., Lowe, M., Levtchenko, E., Luciani, A., Emma, F., Rega, L.R. (2020). Cell-Based Phenotypic Drug Screening Identifies Luteolin as Candidate Therapeutic for Nephropathic Cystinosis. Journal of the American Society of Nephrology, 31, 1522-1537. [CrossRef]
• 119. Singh Tuli, H., Rath, P., Chauhan, A., Sak, K., Aggarwal, D., Choudhary, R., Sharma, U., Vashishth, K., Sharma, S., Kumar, M., Yadav, V., Singh, T., Yerer, M.B., Haque, S. (2022). Luteolin, a potent anticancer compound: From chemistry to cellular interactions and synergetic perspectives. Cancers, 14(21), 5373. [CrossRef]