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Esculetin is a coumarin-derived compound with antioxidant and anti-inflammatory properties. The current study aims to evaluate the therapeutic implications of esculetin on retinal dysfunction and uncover the underlying mechanisms. Tert -butyl hydroperoxide ( t -BHP) at a concentration of 300 μM was used to induce oxidative stress in human retinal pigment epithelial cell line (ARPE-19) cells. Esculetin at concentrations below 250 μM did not cause cytotoxicity to ARPE-19 cells. Cell viability analysis confirmed that t -BHP induced oxidative injury of ARPE-19 cells. However, ARPE-19 cells were protected from t -BHP-induced oxidative injury by esculetin in a concentration-dependent manner. As a result of the TUNEL assay to confirm apoptosis, esculetin treatment reduced the number of TUNEL-positive cells. Esculetin down-regulated the expression levels of Bax, Caspase-3, and PARP and up-regulated the expression level of Bcl2. Collectively, this study demonstrates that esculetin exerts potent antioxidant properties in ARPE-19 cells, inhibiting t -BHP-induced apoptosis under the regulation of apoptotic factors.

Exposure to particulate matter is a causative factor of dry eye disease. We aimed to investigate the beneficial effect of eye drops containing aucubin on dry eye disease induced by urban particulate matter (UPM). Dry eye was induced in male SD rats (6 weeks old) by topical exposure to UPM thrice a day for 5 d. Eye drops containing 0.1% aucubin or 0.5% aucubin were topically administered directly into the eye after UPM exposure for an additional 5 d. Tear secretion was evaluated using a phenol red thread tear test and corneal irregularity. The oxidative damage in the lacrimal gland was evaluated using TUNEL and immunohistochemical staining. The topical administration of aucubin significantly attenuated UPM-induced tear hyposecretion (control group: 9.25 ± 0.62 mm, UPM group: 4.55 ± 0.25 mm, 0.1% aucubin: 7.12 ± 0.58 mm, and 0.5% aucubin: 7.88 ± 0.75 mm) and corneal irregularity (control group: 0.00 ± 0.00, UPM group: 3.40 ± 0.29, 0.1% aucubin: 1.80 ± 0.27, and 0.5% aucubin: 1.15 ± 0.27). In addition, aucubin also reduced the UPM-induced apoptotic injury of lacrimal gland cells induced by oxidative stress through the increased expression of HMGB1 and RAGE. These findings indicate that the topical administration of aucubin eye drops showed a beneficial effect against UPM-induced abnormal ocular changes, such as tear hyposecretion and lacrimal gland damage. Therefore, our results reveal the pharmacological activities of aucubin in dry eye disease.

In the present study, we examined the potent retinoprotective effects of an ethanol-based extract of Aucuba japonica (AJE) and its active ingredient, aucubin, on N -methyl- N -nitrosourea (MNU)-induced retinal degeneration in mice. Retinal degeneration was induced by an intraperitoneal injection of MNU (60 mg/kg). AJE (250 mg/kg) and aucubin (15 mg/kg) were orally administered for 1 week after the MNU injection. Electroretinography (ERG) and histological examinations were performed. Retinal apoptosis and oxidative DNA damage were also quantified. The retinoprotective abilities of AJE and aucubin were also assessed in primary cultured retinal cells. Morphologically, MNU induced a remarkable decrease in the outer nuclear layer, which contains photoreceptor cells. However, this layer was well preserved in the AJE- and aucubin-administered mice. The ERG responses significantly decreased in both a- and b-wave amplitudes in the MNU-injected mice. In the AJE and aucubin-treated mice, ERG responses were significantly increased. In addition, a terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) assay and immunohistochemical staining for 8-hydroxydeoxyguanosine (8-OHdG) revealed that both AJE and aucubin attenuated MNU-induced photoreceptor cell apoptosis and oxidative DNA damage. Furthermore, the in vitro assay also showed that AJE and aucubin have potent anti-oxidative and anti-apoptotic activities in primary cultured retinal cells. These results indicate that AJE and aucubin have potent retinoprotective effects, and that this retinoprotective activity is as a result of the potency of the bioactive compound, aucubin. These pharmacological characteristics suggest the additional application of AJE or aucubin in the treatment of patients with retinal degenerative diseases.

Advanced glycation end products (AGEs) is a causative factor of various chronic diseases, including chronic kidney disease and atherosclerosis. AGE inhibitors, such as aminoguanidine and pyridoxamine, have the therapeutic activities for reversing the increase in AGEs burden. This study evaluated the inhibitory effects of aucubin on the formation of methylglyoxal (MGO)-modified AGEs in vitro. We also determined the potential activity of aucubin in reducing the AGEs burden in the kidney, blood vessel, heart, and retina of exogenously MGO-injected rats. Aucubin inhibited the formation of MGO-modified AGE-bovine serum albumin (IC 50 = 0.57 ± 0.04 mmol/L) and its cross-links to collagen (IC 50 = 0.55 ± 0.02 mmol/L) in a dose-dependent manner. In addition, aucubin directly trapped MGO (IC 50 = 0.22 ± 0.01 mmol/L) in vitro. In exogenous MGO-injected rats, aucubin suppressed the formation of circulating AGEs and its accumulation in various tissues. These activities of aucubin on the MGO-derived AGEs in vitro and in vivo showed its pharmacological potential for inhibiting AGEs-related various chronic diseases.