Ganoderic acid protects against diabetic retinal injury via modulating inflammatory, apoptotic, and antioxidant signaling pathways

Abstract

Objective: To investigate whether ganoderic acid can alleviate streptozotocin-induced diabetic retinopathy and explore its underlying mechanisms. Methods: Streptozotocin (55 mg/kg) combined with nicotinamide (100 mg/kg body weight) was used to establish a diabetes mellitus rat model. Rats were then orally administered ganoderic acid at doses of 12.5, 25, and 50 mg/kg. Body weight, blood glucose, organ weights, and serum insulin levels were determined. Hepatic and renal biochemical indices, as well as markers related to oxidative stress, angiogenesis, inflammation, and apoptosis in retinal tissues, were also assessed. Results: Ganoderic acid treatment significantly (P<0.001) lowered blood glucose and improved insulin levels and body and organ weights. The treatment remarkably attenuated blood-retinal barrier disruption, reduced acellular capillaries, and ameliorated hepatic and renal pathological changes, accompanied by decreased levels of IL-1β, TNF-α, IL-6, IL-17, COX-2, and PGE₂. In addition, ganoderic acid upregulated Nrf2 and HO-1 and modulated the mRNA expression of Bax and Bcl-2. Conclusions: Ganoderic acid ameliorates streptozotocin-induced diabetic retinopathy by inhibiting inflammation and apoptosis and enhancing antioxidant activities.

Keywords

Diabetic retinopathy / Ganoderic acid / Glucose / Nrf2/HO-1 / Insulin

References

[1] Roy B. Pathophysiological mechanisms of diabetes-induced macrovascular and microvascular complications: The role of oxidative stress. Med Sci (Basel) 2025; 13(3). doi: 10.3390/medsci13030087.

[2] Alam A, Kumar R, Kumari A, Sahu B. A review on diabetes mellitus: Type 1 & Type 2. Int J Res Pharm Allied Sci 2025; 4(4): 18-36.

[3] Giri B, Dey S, Das T, Sarkar M, Banerjee J, Dash SK. Chronic hyperglycemia mediated physiological alteration and metabolic distortion leads to organ dysfunction, infection, cancer progression and other pathophysiological consequences: An update on glucose toxicity. Biomed Pharmacother 2018; 107: 306-328.

[4] Reynoso-Roa AS, Gutiérrez-Rubio SA, Magallón-Gastélum E, García-Iglesias T, Suárez-Rico DO, García-Cobián TA. The role of resistin in macrovascular and microvascular complications of type 2 diabetes. Life 2025; 15(4). doi: 10.3390/life15040585.

[5] Tigchelaar C, van Zuylen ML, Hulst AH, Preckel B, van Beek AP, Kema IP, et al. Elevated cerebrospinal fluid glucose levels and diabetes mellitus are associated with activation of the neurotoxic polyol pathway. Diabetologia 2022; 65(7): 1098-1107.

[6] Sinha SK, Nicholas SB. Pathomechanisms of diabetic kidney disease. J Clin Med 2023; 12(23): 7349.

[7] Yameny AA. Diabetes mellitus overview 2024. J Biosci Appl Res 2024; 10(3): 641-645.

[8] Fung THM, Patel B, Wilmot EG, Amoaku WMK. Diabetic retinopathy for the non-ophthalmologist. Clin Med (Lond) 2022; 22(2): 112-116.

[9] Guo L, Jiang B, Li D, Xiao X. Nephroprotective effect of adropinin against streptozotocin-induced diabetic nephropathy in rats: Inflammatory mechanism and yap/taz factor. Drug Des Devel Ther 2021; 15: 589-600.

[10] Grauslund J, Andersen N, Andresen J, Bek T, Brandi S, Hajari J, et al. Diabetic retinopathy. Ugeskr Laeger 2024; 186(37): 1-9.

[11] Duan H, Huang J, Li W, Tang M. Protective effects of Fufang Xueshuantong on diabetic retinopathy in rats. Evid Based Complement Alternat Med 2013; 2013. doi: 10.1155/2013/408268.

[12] Mrugacz M, Bryl A, Zorena K. Retinal vascular endothelial cell dysfunction and neuroretinal degeneration in diabetic patients. J Clin Med 2021; 10(3): 1-18.

[13] Alsabaani NA, Osman OM, Dallak MA, Morsy MD, Al-Dhibi HA. Maslinic acid protects against streptozotocin-induced diabetic retinopathy by activating Nrf2 and suppressing NF-κB. J Ophthalmol 2022; 2022. doi: 10.1155/2022/3044202.

[14] Rohilla M, Rishabh, Bansal S, Garg A, Dhiman S, Dhankhar S, et al. Discussing pathologic mechanisms of diabetic retinopathy & therapeutic potentials of curcumin and β-glucogallin in the management of diabetic retinopathy. Biomed Pharmacother 2023; 169. doi: 10.1016/j.biopha.2023.115881.

[15] Ansari P, Tabasumma N, Snigdha NN, Siam NH, Panduru RVNRS, Azam S, et al. Diabetic retinopathy: An overview on mechanisms, pathophysiology and pharmacotherapy. Diabetology 2022; 3(1): 159-175.

[16] Elkhateeb WA. A review on ganoderic acid, cordycepin and usnic acid, an interesting natural compounds from mushrooms and lichens. Open Access J Pharm Res 2021; 5(4): 1-9.

[17] Song HY, Yang W, Liu LW, Cheng XY, Yang DF, Yang ZQ. Biosynthesis of ganoderic acid and its derivatives. Zhongguo Zhongyao Zazhi 2025; 50(5): 1155-1163.

[18] Zhou J, Chen B. Retinal cell damage in diabetic retinopathy. Cells 2023; 12(9). doi: 10.3390/cells12091342.

[19] Rahman M, Al-Ghamdi SA, Alharbi KS, Beg S, Sharma K, Anwar F, et al. Ganoderic acid loaded nano-lipidic carriers improvise treatment of hepatocellular carcinoma. Drug Deliv 2019; 26(1): 782-793.

[20] Kumar V, Sachan R, Rahman M, Sharma K, Al-Abbasi FA, Anwar F. Prunus amygdalus extract exert antidiabetic effect via inhibition of DPP-IV: In-silico and in-vivo approaches. J Biomol Struct Dyn 2021; 39(11): 4160-4174.

[21] Bora K, Kushwah N, Maurya M, Pavlovich MC, Wang Z, Chen J. Assessment of inner blood-retinal barrier: Animal models and methods. Cells 2023; 12(20). doi: 10.3390/cells12202443.

[22] Si YF, Wang J, Guan J, Zhou L, Sheng Y, Zhao J. Treatment with hydrogen sulfide alleviates streptozotocin-induced diabetic retinopathy in rats. Br J Pharmacol 2013; 169(3): 619-631.

[23] Elks CM, Mariappan N, Haque M, Guggilam A, Majid DSA, Francis J. Chronic NF-κB blockade reduces cytosolic and mitochondrial oxidative stress and attenuates renal injury and hypertension in SHR. Am J Physiol Ren Physiol 2009; 296(2): F298-F305.

[24] Alqahtani QH, Alshehri S, Alhusaini AM, Sarawi WS, Alqarni SS, Mohamed R, et al. Protective effects of sitagliptin on streptozotocin-induced hepatic injury in diabetic rats: A possible mechanisms. Diseases 2023; 11(4). doi: 10.3390/diseases11040184.

[25] Karimi R, Bakhshi A, Dayati P, Abazari O, Shahidi M, Savaee M, et al. Silymarin reduces retinal microvascular damage in streptozotocin-induced diabetic rats. Sci Rep 2022; 12(1). doi: 10.1038/s41598-022-20297-2.

[26] Zhang C, Gu L, Xie H, Liu Y, Huang P, Zhang J, et al. Glucose transport, transporters and metabolism in diabetic retinopathy. Biochim Biophys Acta Mol Basis Dis 2024; 1870(3). doi: 10.1016/j.bbadis.2023.166995.

[27] He W, Tang P, Lv H. Targeting oxidative stress in diabetic retinopathy: Mechanisms, pathology, and novel treatment approaches. Front Immunol 2025; 16. doi: 10.3389/fimmu.2025.1571576.

[28] Georgescu A, Dascalu A, Stana D, Alexandrescu C, Bobirca A, Cristea BM, et al. The role of inflammation in diabetic retinopathy in patients with type II diabetes; potential therapeutic perspectives. J Mind Med Sci 2024; 11(1): 17-23.

[29] Peng H, Gao Y, Zeng C, Hua R, Guo Y, Wang Y, et al. Effects of Maillard reaction and its product AGEs on aging and age-related diseases. Food Sci Hum Wellness 2024; 13(3): 1118-1134.

[30] Feriani A, Tir M, Gómez-Caravaca AM, Contreras M del M, Talhaoui N, Taamalli A, et al. HPLC-DAD-ESI-QTOF-MS/MS profiling of Zygophyllum album roots extract and assessment of its cardioprotective effect against deltamethrin-induced myocardial injuries in rat, by suppression of oxidative stress-related inflammation and apoptosis via NF-κB signaling pathway. J Ethnopharmacol 2020; 247. doi: 10.1016/j.jep.2019.112266.

[31] Victor AA, Gondhowiardjo TD, Dharma R, Jusman SWA, Yandri VR, Yuneta R, et al. Intercellular adhesive molecule-1 (Icam-1) in proliferative diabetic retinopathy. Asian J Ophthalmol 2020; 17(1): 120-127.

[32] Zhang M, Zhou M, Cai X, Zhou Y, Jiang X, Luo Y, et al. VEGF promotes diabetic retinopathy by upregulating the PKC/ET/NF-κB/ICAM-1 signaling pathway. Eur J Histochem 2022; 66(4). doi: 10.4081/ejh.2022.3522.

[33] Siddiqui K, George TP, Mujammami M, Isnani A, Alfadda AA. The association of cell adhesion molecules and selectins (VCAM-1, ICAM-1, E-selectin, L-selectin, and P-selectin) with microvascular complications in patients with type 2 diabetes: A follow-up study. Front Endocrinol (Lausanne) 2023; 14. doi: 10.3389/fendo.2023.1072288.

[34] Forrester JV, Kuffova L, Delibegovic M. The role of inflammation in diabetic retinopathy. Front Immunol 2020; 11. doi: 10.3389/fimmu.2020.583687.

[35] Yue T, Shi Y, Luo S, Weng J, Wu Y, Zheng X. The role of inflammation in immune system of diabetic retinopathy: Molecular mechanisms, pathogenetic role and therapeutic implications. Front Immunol 2022; 13. doi: 10.3389/fimmu.2022.1055087.

[36] Kowluru RA, Mishra M. Oxidative stress, mitochondrial damage and diabetic retinopathy. Biochim Biophys Acta Mol Basis Dis 2015; 1852(11): 2474-2483.

[37] Değirmenci C, Afrashi F, Erbaş O, Aktuğ H, Taşkıran D. The preventive effect of oxytocin on retinopathy in streptozotocin-induced diabetic rats. Turkish J Ophthalmol 2019; 49(2): 68-72.

[38] Ghalehbandi S, Yuzugulen J, Pranjol MZI, Pourgholami MH. The role of VEGF in cancer-induced angiogenesis and research progress of drugs targeting VEGF. Eur J Pharm 2023; 949. doi: 10.1016/j.ejphar.2023.175586.

[39] Kang Y, Li H, Liu Y, Li Z. Regulation of VEGF-A expression and VEGF-A-targeted therapy in malignant tumors. J Cancer Res Clin Oncol 2024; 150(5): 221. doi: 10.1007/s00432-024-05714-5.

[40] Józkowiak M, Niebora J, Domagała D, Data K, Partyńska A, Kulus M, et al. New insights into endothelial cell physiology and pathophysiology. Biomed Pharmacother 2025; 190. doi: 10.1016/j.biopha.2025.118415.