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Natural Compounds in Kidney Disease: Therapeutic Potential and Drug Development

  • Vijayakumar Natesan (Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University) ;
  • Sung-Jin Kim (Department of Pharmacology and Toxicology, Metabolic Diseases Research Laboratory, School of Dentistry, Kyung Hee University)
  • Received : 2024.08.18
  • Accepted : 2024.10.17
  • Published : 2025.01.01

Abstract

Diabetic kidney disease (DKD) poses a major global health challenge, affecting millions of individuals and contributing to substantial morbidity and mortality. Traditional treatments have focused primarily on managing symptoms and slowing disease progression rather than reversing or halting kidney damage. However, recent advancements in natural compound research have unveiled promising new avenues for therapeutic development. Extensive research has been conducted to showcase the antioxidant advantages for kidney health, supporting the potential effectiveness of natural and synthetic products in clinical and experimental research. Bioactive substances found in large quantities in food, such as polyphenols, have emerged as adjuvants. This review manuscript aims to provide a comprehensive overview of natural compounds and their potential efficacy, mechanisms of action, and clinical applications in the prevention and treatment of various kidney diseases. This review emphasizes the connection between oxidative stress and inflammation in diabetic nephropathy (DN), which leads to harmful effects on kidney cells due to pathological damage. A lower incidence of DM2-related problems and a slower progression of end-stage renal disease have been associated with the consumption of these compounds.

Keywords

References

  1. Ahmed, S., Mundhe, N., Borgohain, M., Chowdhury, L., Kwatra, M., Bolshette, N., Ahmed, A. and Lahkar, M. (2016) Diosmin modulates the NF-kB signal transduction pathways and downregulation of various oxidative stress markers in alloxan-induced diabetic nephropathy. Inflammation 39, 1783-1797.
  2. Alam, W., Khan, H., Shah, M. A., Cauli, O. and Saso, L. (2020) Kaempferol as a dietary anti-inflammatory agent: current therapeutic standing. Molecules 25, 4073.
  3. Amalan, V., Vijayakumar, N., Indumathi, D. and Ramakrishnan, A. (2016) Antidiabetic and antihyperlipidemic activity of p-coumaric acid in diabetic rats, role of pancreatic GLUT 2: In vivo approach. Biomed. Pharmacother. 84, 230-236.
  4. American Diabetes Association (2010) Diagnosis and classification of diabetes mellitus. Diabetes Care 33, S62-S69.
  5. Amorim, R. G., Guedes, G. D. S., Vasconcelos, S. M. L. and Santos, J. C. F. (2019) Kidney disease in diabetes mellitus: cross-linking between hyperglycemia, redox imbalance and inflammation. Arq. Bras. Cardiol. 112, 577-587.
  6. Avila-Carrasco, L., García-Mayorga, E. A., Díaz-Avila, D. L., Garza Veloz, I., Martinez-Fierro, M. L. and González-Mateo, G. T. (2021) Potential therapeutic effects of natural plant compounds in kidney disease. Molecules 26, 6096.
  7. Baliou, S., Adamaki, M., Ioannou, P., Pappa, A., Panayiotidis, M. I., Christodoulou, I., Spandidos, D. A., Kyriakopoulos, A. M. and Zoumpourlis, V. (2021) Ameliorative effect of taurine against diabetes and renal-associated disorders (review). Med. Int. 1, 3.
  8. Borg, R., Carlson, N., Søndergaard, J. and Persson, F. (2023) The growing challenge of chronic kidney disease: an overview of current knowledge. Int. J. Nephrol. 2023, 9609266.
  9. Bülow, R. D. and Boor, P. (2019) Extracellular matrix in kidney fibrosis: more than just a scaffold. J. Histochem. Cytochem. 67, 643-661.
  10. Caturano, A., D'Angelo, M., Mormone, A., Russo, V., Mollica, M. P., Salvatore, T., Galiero, R., Rinaldi, L., Vetrano, E., Marfella, R., Monda, M., Giordano, A. and Sasso, F. C. (2023) Oxidative stress in type 2 diabetes: impacts from pathogenesis to lifestyle modifications. Curr. Issues Mol. Biol. 45, 6651-6666.
  11. Chen, J., Guo, R., Yan, H., Tian, L., You, Q., Li, S., Huang, R. and Wu, K. (2014) Naringin inhibits ROS-activated MAPK pathway in high glucose-induced injuries in H9c2 cardiac cells. Basic Clin. Pharmacol. Toxicol. 114, 293-304.
  12. Chen, L. Y., Cheng, H. L., Liao, C. K., Kuan, Y. H., Liang, T. J., Tseng, T. J. and Lin, H. C. (2023) Luteolin improves nephropathy in hyperglycemic rats through anti-oxidant, anti-inflammatory, and antiapoptotic mechanisms. J. Funct. Foods 102, 105461.
  13. Chen, Y. J., Kong, L., Tang, Z. Z., Zhang, Y. M., Liu, Y., Wang, T. Y. and Liu, Y. W. (2019) Hesperetin ameliorates diabetic nephropathy in rats by activating Nrf2/ARE/glyoxalase 1 pathway. Biomed. Pharmacother. 111, 1166-1175.
  14. Cory, H., Passarelli, S., Szeto, J., Tamez, M. and Mattei, J. (2018) The role of polyphenols in human health and food systems: a mini review. Front. Nutr. 5, 87.
  15. Donate-Correa, J., Ferri, C. M., Sánchez-Quintana, F., Pérez-Castro, A., González-Luis, A., Martín-Núñez, E., Mora-Fernández, C. and Navarro-González, J. F. (2021) Inflammatory cytokines in diabetic kidney disease: pathophysiologic and therapeutic implications. Front. Med. 7, 628289.
  16. Dong, R., Zhang, X., Liu, Y., Zhao, T., Sun, Z., Liu, P., Xiang, Q., Xiong, J., Du, X., Yang, X., Gui, D. and Xu, Y. (2023) Rutin alleviates EndMT by restoring autophagy through inhibiting HDAC1 via PI3K/AKT/mTOR pathway in diabetic kidney disease. Phytomedicine 112, 154700.
  17. Duraisamy, S., Vijayakumar, N., Rajendran, J., Venkatesan, A., Kartha, B., Kandasamy, S. P., Nicoletti, M., Alharbi, N. S., Kadaikunnan, S., Khaled, J. M. and Govindarajan, M. (2022) Facile synthesis of silver nanoparticles using the Simarouba glauca leaf extract and their impact on biological outcomes: a novel perspective for nano-drug development. J. Drug Deliv. Sci. Technol. 69, 103160.
  18. Evans, J. A., Mendonca, P. and Soliman, K. F. (2023) Involvement of Nrf2 activation and NF-kB pathway inhibition in the antioxidant and anti-inflammatory effects of hesperetin in activated BV-2 microglial cells. Brain Sci. 13, 1144.
  19. Fakhruddin, S., Alanazi, W. and Jackson, K. E. (2017) Diabetes-induced reactive oxygen species: mechanism of their generation and role in renal injury. J. Diabetes Res. 9, 2017.
  20. Gai, Z., Wang, T., Visentin, M., Kullak-Ublick, G. A., Fu, X. and Wang, Z. (2019) Lipid accumulation and chronic kidney disease. Nutrients 11, 722.
  21. Gál, R., Halmosi, R., Gallyas, F., Jr., Tschida, M., Mutirangura, P., Tóth, K., Alexy, T. and Czopf, L. (2023) Resveratrol and beyond: the effect of natural polyphenols on the cardiovascular system: a narrative review. Biomedicines 11, 2888.
  22. Ganesan, D., Albert, A., Paul, E., Ananthapadmanabhan, K., Andiappan, R. and Sadasivam, S. G. (2020) Rutin ameliorates metabolic acidosis and fibrosis in alloxan induced diabetic nephropathy and cardiomyopathy in experimental rats. Mol. Cell. Biochem. 471, 41-50.
  23. Gheith, O., Farouk, N., Nampoory, N., Halim, M. A. and Al-Otaibi, T. (2016) Diabetic kidney disease: worldwide difference of prevalence and risk factors. J. Nephropharmacol. 5, 49.
  24. Giacco, F. and Brownlee, M. (2010) Oxidative stress and diabetic complications. Circ. Res. 107, 1058-1070.
  25. Gitanjali, J., Ram, D. S. D., Kavitha, R., Amalan, V., Alahmadi, T. A., Alharbi, S. A., Kandasamy, S., Shanmuganthan, R. and Vijayakumar, N. (2023) Antimicrobial, antioxidant, anticancer, and antithrombotic, competency of saponins from the root of Decalepis hamiltonii. Environ. Res. 231, 116096.
  26. Gomathi, D., Kalaiselvi, M., Ravikumar, G., Devaki, K. and Uma, C. (2014) Evaluation of antioxidants in the kidney of streptozotocin induced diabetic rats. Indian J. Clin. Biochem. 29, 221-226.
  27. Gomes, I. B., Porto, M. L., Santos, M. C., Campagnaro, B. P., Gava, A. L., Meyrelles, S. S., Pereira, T. M. and Vasquez, E. C. (2015) The protective effects of oral low-dose quercetin on diabetic nephropathy in hypercholesterolemic mice. Front. Physiol. 6, 247.
  28. Guerreiro, Í., Ferreira-Pêgo, C., Carregosa, D., Santos, C. N., Menezes, R., Fernandes, A. S. and Costa, J. G. (2022) Polyphenols and their metabolites in renal diseases: an overview. Foods 11, 1060.
  29. Han, X., Shen, T. and Lou, H. (2007) Dietary polyphenols and their biological significance. Int. J. Mol. Sci. 8, 950-988.
  30. Hao, H. H., Shao, Z. M., Tang, D. Q., Lu, Q., Chen, X., Yin, X. X., Wu, J. and Chen, H. (2012) Preventive effects of rutin on the development of experimental diabetic nephropathy in rats. Life Sci. 91, 959-967.
  31. Hoogeveen, E. K. (2022) The epidemiology of diabetic kidney disease. Kidney Dial. 2, 433-442.
  32. Huang, J., Huang, K., Lan, T., Xie, X., Shen, X., Liu, P. and Huang, H. (2013) Curcumin ameliorates diabetic nephropathy by inhibiting the activation of the SphK1-S1P signaling pathway. Mol. Cell. Endocrinol. 365, 231-240.
  33. Huang, Q. L., Huang, L. N., Zhao, G. Y., Liu, C., Pan, X. Y., Li, Z. R., Jing, X. H., Qiu, Z. Y. and Xin, R. H. (2024) Naringin attenuates Actinobacillus pleuropneumoniae-induced acute lung injury via MAPK/NF-κB and Keap1/Nrf2/HO-1 pathway. BMC Vet. Res. 20, 204.
  34. Iriondo, M. N., Etxaniz, A., Varela, Y. R., Ballesteros, U., Lázaro, M., Valle, M., Fracchiolla, D., Martens, S., Montes, L. R., Goñi, F. M. and Alonso, A. (2023) Effect of ATG12-ATG5-ATG16L1 autophagy E3-like complex on the ability of LC3/GABARAP proteins to induce vesicle tethering and fusion. Cell. Mol. Life Sci. 80, 56.
  35. Jain, D., Bansal M. K., Dalvi, R., Upganlawar, A. and Somani, R. (2014) Protective effect of diosmin against diabetic neuropathy in experimental rats. J. Integr. Med. 12, 35-41.
  36. Jain, D. and Saha, S. (2017) Antioxidant and antihyperglycaemic effects of naringenin arrest the progression of diabetic nephropathy in diabetic rats. Egypt. Pharm. 16, 144-151.
  37. Jankowski, J., Floege, J., Fliser, D., Bohm, M. and Marx, N. (2021) Cardiovascular disease in chronic kidney disease: pathophysiological insights and therapeutic options. Circulation 143, 1157-1172.
  38. Jha, J. C., Banal, C., Chow, B. S., Cooper, M. E. and Jandeleit-Dahm, K. (2016) Diabetes and kidney disease: role of oxidative stress. Antioxid. Redox Signal. 25, 657-684.
  39. Jin, Q., Liu, T., Qiao, Y., Liu, D., Yang, L., Mao, H., Ma, F., Wang, Y., Peng, L. and Zhan, Y. (2023) Oxidative stress and inflammation in diabetic nephropathy: role of polyphenols. Front. Immunol. 14, 1185317.
  40. Kang, M. K., Park, S. H., Choi, Y. J., Shin, D. and Kang, Y. H. (2015) Chrysin inhibits diabetic renal tubulointerstitial fibrosis through blocking epithelial to mesenchymal transition. J. Mol. Med. (Berl.) 93, 759-772.
  41. Kandemir, F. M., Ozkaraca, M., Küçükler, S., Caglayan, C. and Hanedan, B. (2018) Preventive effects of hesperidin on diabetic nephropathy induced by streptozotocin via modulating TGF-β1 and oxidative DNA damage. Toxin Rev. 37, 287-293.
  42. Khan, M. F., Mathur, A., Pandey, V. K. and Kakkar, P. (2022) Naringenin alleviates hyperglycemia-induced renal toxicity by regulating activating transcription factor 4-C/EBP homologous protein mediated apoptosis. J. Cell Commun. Signal. 16, 271-291.
  43. Khattar, S., Khan, S. A., Zaidi, S. A. A., Darvishikolour, M., Farooq, U., Naseef, P. P., Kurunian, M. S., Khan, M. Z., Shamim, A., Khan, M. M. U., Iqbal, Z. and Mirza, M. A. (2022) Resveratrol from dietary supplement to a drug candidate: an assessment of potential. Pharmaceuticals (Basel) 15, 957.
  44. Kim, K. K., Sheppard, D. and Chapman, H. A. (2018) TGF-β1 signaling and tissue fibrosis. Cold Spring Harb. Perspect Biol. 10, a022293.
  45. Kim, K. P., Williams, C. E. and Lemmon, C. A. (2022) Cell-matrix interactions in renal fibrosis. Kidney Dial. 2, 607-624.
  46. Kolluru, G. K., Bir, S. C. and Kevil, C. G. (2012) Endothelial dysfunction and diabetes: effects on angiogenesis, vascular remodeling, and wound healing. Int. J. Vasc. Med. 2012, 918267.
  47. Kottaisamy, C. P. D., Raj, D. S., Prasanth Kumar, V. and Sankaran, U. (2021) Experimental animal models for diabetes and its related complications-a review. Lab. Anim. Res. 37, 23.
  48. Koushki, M., Amiri-Dashatan, N., Ahmadi, N., Abbaszadeh, H. A. and Rezaei-Tavirani, M. (2018) Resveratrol: a miraculous natural compound for diseases treatment. Food Sci. Nutr. 6, 2473-2490.
  49. Kumari, S., Kamboj, A., Wanjari, M. and Sharma, A. K. (2021) Nephroprotective effect of Vanillic acid in STZ-induced diabetic rats. J. Diabetes Metab. Disord. 20, 571-582.
  50. Lai, P. B., Zhang, L. and Yang, L. Y. (2012) Quercetin ameliorates diabetic nephropathy by reducing the expressions of transforming growth factor-β1 and connective tissue growth factor in streptozotocin-induced diabetic rats. Ren. Fail. 34, 83-87.
  51. Lee, E. J., Kang, M. K., Kim, D. Y., Kim, Y. H., Oh, H. and Kang, Y. H. (2018) Chrysin inhibits advanced glycation end products-induced kidney fibrosis in renal mesangial cells and diabetic kidneys. Nutrients 10, 882.
  52. Lee, O. Y. A., Wong, A. N. N., Ho, C. Y., Tse, K. W., Chan, A. Z., Leung, G. P. H., Kwan, Y. W. and Yeung, M. H. Y. (2024) Potentials of natural antioxidants in reducing inflammation and oxidative stress in chronic kidney disease. Antioxidants 13, 751.
  53. Leon, B. M. and Maddox, T. M. (2015) Diabetes and cardiovascular disease: epidemiology, biological mechanisms, treatment recommendations and future research. World J. Diabetes 6, 1246.
  54. Liang, J., Wang, C., Peng, J., Li, W., Jin, Y., Liu, Q., Meng, Q., Liu, K. and Sun, H. (2016) Naringin regulates cholesterol homeostasis and inhibits inflammation via modulating NF-κB and ERK signaling pathways in vitro. Pharmazie 71, 101-108.
  55. Mahfoz, A. M., El-Latif, H. A. A., Ahmed, L. A., Hassanein, N. M. and Shoka, A. A. (2016) Anti-diabetic and renoprotective effects of aliskiren in streptozotocin-induced diabetic nephropathy in female rats. Naunyn Schmiedebergs Arch. Pharmacol. 389, 1315-1324.
  56. Martemucci, G., Costagliola, C., Mariano, M., D'andrea, L., Napolitano, P. and D'Alessandro, A. G. (2022) Free radical properties, source and targets, antioxidant consumption and health. Oxygen 2, 48-78.
  57. Meng, F., Li, J., Yang, X., Yuan, X. and Tang, X. (2018) Role of Smad3 signaling in the epithelial mesenchymal transition of the lens epithelium following injury. Int. J. Mol. Med. 42, 851-860.
  58. Nasri, H. and Rafieian-Kopaei, M. (2015) Diabetes mellitus and renal failure: prevention and management. Res. J. Med. Sci. 20, 1112-1120.
  59. Nentwich, M. M. and Ulbig, M. W. (2015) Diabetic retinopathy-ocular complications of diabetes mellitus. World J. Diabetes 6, 489.
  60. Nie, K., Gao, Y., Chen, S., Wang, Z., Wang, H., Tang, Y., Su, H., Lu, F., Dong, H. and Fang, K. (2023) Diosgenin attenuates non-alcoholic fatty liver disease in type 2 diabetes through regulating SIRT6-related fatty acid uptake. Phytomedicine 111, 154661.
  61. Pandey, K. B. and Rizvi, S. I. (2009) Plant polyphenols as dietary antioxidants in human health and disease. Oxid. Med. Cell. Longev. 2, 270-278.
  62. Pasupuleti, V. R., Arigela, C. S., Gan, S. H., Salam, S. K., Krishnan, K. T., Rahman, N. A. and Jeffree, M. S. (2020) A review on oxidative stress, diabetic complications, and the roles of honey polyphenols. Oxid. Med. Cell. Longev. 2020, 8878172.
  63. Pizzino, G., Irrera, N., Cucinotta, M., Pallio, G., Mannino, F., Arcoraci, V., Squadrito, F., Altavilla, D. and Bitto, A. (2017) Oxidative stress: harms and benefits for human health. Oxid. Med. Cell. Longev. 2017, 8416763.
  64. Rangel, É. B., de Sá, J. R., Melaragno, C. S., Gonzalez, A. M., Linhares, M. M., Salzedas, A. and Medina-Pestana, J. O. (2009) Kidney transplant in diabetic patients: modalities, indications and results. Diabetol. Metab. Syndr. 1, 2.
  65. Reiss, A. B., Jacob, B., Zubair, A., Srivastava, A., Johnson, M. and De Leon, J. (2024) Fibrosis in chronic kidney disease: pathophysiology and therapeutic targets. J. Clin. Med. 13, 1881.
  66. Ren, J., Lu, Y., Qian, Y., Chen, B., Wu, T. and Ji, G. (2019) Recent progress regarding kaempferol for the treatment of various diseases. Exp. Ther. Med. 18, 2759-2776.
  67. Rudrapal, M., Khairnar, S. J., Khan, J., Dukhyil, A. B., Ansari, M. A., Palai, S. and Devi, R. (2022) Dietary polyphenols and their role in oxidative stress-induced human diseases: insights into protective effects, antioxidant potentials and mechanism(s) of action. Front. Pharmacol. 13, 806470.
  68. Runwal, G., Stamatakou, E., Siddiqi, F. H., Puri, C., Zhu, Y. and Rubinsztein, D. C. (2019) LC3-positive structures are prominent in autophagy-deficient cells. Sci. Rep. 9, 10147.
  69. Saeedi, P., Petersohn, I., Salpea, P., Malanda, B., Karuranga, S., Unwin, N., Colagiuri, S., Guariguata, L., Motala, A. A., Ogurtsova, K. and Shaw, J. E. (2019) Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: results from the International Diabetes Federation Diabetes Atlas. Diabetes Res. Clin. Pract. 157, 107843.
  70. Samy, J. V. R. A., Kumar, N., Singaravel, S., Krishnamoorthy, R., Alshuniaber, M. A., Gatasheh, M. K., Venkatesan, A., Natesan, V. and Kim, S. J. (2023) Effect of prunetin on streptozotocin-induced diabetic nephropathy in rats - a biochemical and molecular approach. Biomol. Ther. (Seoul) 31, 619-628.
  71. Schena, F. P. and Gesualdo, L. (2005) Pathogenetic mechanisms of diabetic nephropathy. J. Am. Soc. Nephrol. 16, S30-S33.
  72. Selby, N. M. and Taal, M. W. (2020) An updated overview of diabetic nephropathy: diagnosis, prognosis, treatment goals and latest guidelines. Diabetes Obes. Metab. 22, 3-15.
  73. Sharma, D., Gondaliya, P., Tiwari, V. and Kalia, K. (2019) Kaempferol attenuates diabetic nephropathy by inhibiting RhoA/Rho-kinase mediated inflammatory signalling. Biomed. Pharmacother. 109, 1610-1619.
  74. Singh, B., Kumar, A., Singh, H., Kaur, S., Arora, S. and Singh, B. (2022) Protective effect of vanillic acid against diabetes and diabetic nephropathy by attenuating oxidative stress and upregulation of NF-κB, TNF-α and COX-2 proteins in rats. Phytother. Res. 36, 1338-1352.
  75. Singh, V. P., Bali, A., Singh, N. and Jaggi, A. S. (2014) Advanced glycation end products and diabetic complications. Korean J. Physiol. Pharmacol. 18, 1-14.
  76. Sureshbabu, A., Muhsin, S. A. and Choi, M. E. (2016) TGF-β signaling in the kidney: profibrotic and protective effects. Am. J. Physiol. Renal Physiol . 310, F596-F606. Tr
  77. Trackman, P. C. (2016) Enzymatic and non-enzymatic functions of the lysyl oxidase family in bone. Matrix Biol. 52-54, 7-18.
  78. Unuofin, J. O. and Lebelo, S. L. (2020) Antioxidant effects and mechanisms of medicinal plants and their bioactive compounds for the prevention and treatment of type 2 diabetes: an updated review. Oxid. Med. Cell. Longev. 2020, 1356893.
  79. Venkatesan, A., Roy, A., Kulandaivel, S., Natesan, V. and Kim, S. J. (2022) p-Coumaric acid nanoparticles ameliorate diabetic nephropathy via regulating mRNA expression of KIM-1 and GLUT-2 in streptozotocin-induced diabetic rats. Metabolites 12, 1166.
  80. Venkatesan, A., Vinoth Raja Antony Samy, J., Balakrishnan, K., Natesan, V. and Kim, S. J. (2023) In vitro antioxidant, anti-inflammatory, antimicrobial, and antidiabetic activities of synthesized chitosan loaded p-coumaric acid nanoparticles. Curr. Pharm. Biotechnol. 24, 1178-1194.
  81. Wang, G. G., Lu, X. H., Li, W., Zhao, X. and Zhang, C. (2011) Protective effects of luteolin on diabetic nephropathy in STZ-induced diabetic rats. Evid. Based Complement. Alternat. Med. 2011, 323171.
  82. Wang, W., Sun, W., Cheng, Y., Xu, Z. and Cai, L. (2019) Role of sirtuin-1 in diabetic nephropathy. J. Mol. Med. (Berl.) 97, 291-309.
  83. Wang, Z., Wu, Q., Wang, H., Gao, Y., Nie, K., Tang, Y., Su, H., Hu, M., Gong, J., Fang, K. and Dong, H. (2022) Diosgenin protects against podocyte injury in early phase of diabetic nephropathy through regulating SIRT6. Phytomedicine 104, 154276.
  84. Yan, Z., Zhong, Y., Duan, Y., Chen, Q. and Li, F. (2020) Antioxidant mechanism of tea polyphenols and its impact on health benefits. Anim. Nutr. 6, 115-123.
  85. Yang, A., Hacheney, I. and Wu, Y. W. (2017) Semisynthesis of autophagy protein LC3 conjugates. Bioorg. Med. Chem. 25, 4971-4976.
  86. Yang, Y. and Xu, G. (2022) Update on pathogenesis of glomerular hyperfiltration in early diabetic kidney disease. Front. Endocrinol. 13, 872918.
  87. Yang, Y. L., Ji, C., Cheng, L., He, L., Lu, C. C., Wang, R. and Bi, Z. G. (2012) Sphingosine kinase-1 inhibition sensitizes curcumin-induced growth inhibition and apoptosis in ovarian cancer cells. Cancer Sci. 103, 1538-1545.
  88. Yang, Z. J., Wang, H. R., Wang, Y. I., Zhai, Z. H., Wang, L. W., Li, L., Zhang, C. and Tang, L. (2019) Myricetin attenuated diabetes-associated kidney injuries and dysfunction via regulating nuclear factor (erythroid derived 2)-like 2 and nuclear factor-κB signalling. Front. Pharmacol. 10, 647.
  89. Yao, M., Lian, D., Wu, M., Zhou, Y., Fang, Y., Zhang, S., Zhang, W., Yang, Y., Li, R., Chen, H., Chen, Y., Shen, A. and Peng, J. (2023) Isoliensinine attenuates renal fibrosis and inhibits TGF-β1/Smad2/3 signaling pathway in spontaneously hypertensive rats. Drug Des. Devel. Ther. 17, 2749-2762.
  90. Yi, X., Dong, M., Guo, N., Tian, J., Lei, P., Wang, S., Yang, Y. and Shi, Y. (2023) Flavonoids improve type 2 diabetes mellitus and its complications: a review. Front. Nutr. 10, 1192131.
  91. Yu, C., Wang, D., Yang, Z. and Wang, T. (2022) Pharmacological effects of polyphenol phytochemicals on the intestinal inflammation via targeting TLR4/NF-κB signaling pathway. Int. J. Mol. Sci. 23, 6939.
  92. Yu, L., Chen, Y. and Tooze, S. A. (2018) Autophagy pathway: cellular and molecular mechanisms. Autophagy 14, 207-215.
  93. Yu, X., Long, Y. C. and Shen, H. M. (2015) Differential regulatory functions of three classes of phosphatidylinositol and phosphoinositide 3-kinases in autophagy. Autophagy 11, 1711-1728.
  94. Yuan, T., Yang, T., Chen, H., Fu, D., Hu, Y., Wang, J., Yuan, Q., Yu, H., Xu, W. and Xie, X. (2019) New insights into oxidative stress and inflammation during diabetes mellitus-accelerated atherosclerosis. Redox Biol. 20, 247-260.
  95. Zabad, O. M., Samra, Y. A. and Eissa, L. A. (2019) P-coumaric acid alleviates experimental diabetic nephropathy through modulation of Toll like receptor-4 in rats. Life Sci. 238, 116965.
  96. Zakir, M., Ahuja, N., Surksha, M.A., Sachdev, R., Kalariya, Y., Nasir, M., Kashif, M., Shahzeen, F., Tayyab, A., Khan, M. S. M., Junejo, M., Manoj Kumar, F., Varrassi, G., Kumar, S., Khatri, M. and Mohamad, T. (2023) Cardiovascular complications of diabetes: from microvascular to macrovascular pathways. Cureus 15, e45835.
  97. Zhang, J., Yang, S., Li, H., Chen, F. and Shi, J. (2017) Naringin ameliorates diabetic nephropathy by inhibiting NADPH oxidase 4. Eur. J. Pharmacol. 804, 1-6.
  98. Zhao, L., Zou, Y. and Liu, F. (2020) Transforming growth factor-beta1 in diabetic kidney disease. Front. Cell. Dev. Biol. 8, 187.
  99. Zhao, W. M., Li, X. L., Zhu, Y., Shi, R., Wang, Z. J., Xiao, J. P. and Wang, D. G. (2024) Diosmin ameliorates renal fibrosis through inhibition of inflammation by regulating SIRT3-mediated NF-κB p65 nuclear translocation. BMC Complement. Med. Ther. 9, 29.
  100. Zhou, K., Zi, X., Song, J., Zhao, Q., Liu, J., Bao, H. and Li, L. (2022a) Molecular mechanistic pathways targeted by natural compounds in the prevention and treatment of diabetic kidney disease. Molecules 27, 6221.
  101. Zhou, Y., Tao, H., Xu, N., Zhou, S., Peng, Y., Zhu, J., Liu, S. and Chang, Y. (2022b) Chrysin improves diabetic nephropathy by regulating the AMPK-mediated lipid metabolism in HFD/STZ-induced DN mice. J. Food Biochem. 46, e14379.