Prophylaxis of posterior capsule opacification through autophagy activation with indomethacin-eluting intraocular lens

Posterior capsule opacification(PCO)is the most common long-term postoperative complication of cataract surgery,leading to secondary vision loss.Optimized intraocular lens(IOL)structure and appropriate pharmacological intervention,which provides physical barriers and biological inhibition,respectively,can block the migration,proliferation,and epithelial-mesenchymal transition(EMT)of lens epithelial cells(LECs)for PCO prophylaxis.Herein,a novel indomethacin-eluting IOL(INDOM-IOL)with an optimized sharper edge and a sustained drug release behavior was developed for PCO prevention.Indomethacin(INDOM),an ophthalmic non-steroidal anti-inflammatory drug(NSAID)used for postoperative ocular inflammation,was demonstrated to not only be able to suppress cell migration and down-regulate the expression of cyclooxygenase-2(COX-2)and EMT markers,including alpha-smooth muscle actin(α-SMA)and cyclin D1,but also promote the autophagy activation in LECs.Additionally,autophagy was also verified to be a potential therapeutic target for the down-regulation of EMT in LECs.The novel IOL,serving as a drug delivery platform,could carry an adjustable dose of hydrophobic indomethacin with sustained drug release ability for more than 28 days.In the rabbit PCO model,the indomethacin-eluting IOL showed excellent anti-inflammatory and anti-PCO effects.In summary,indomethacin is an effective pharmacological intervention in PCO prophylaxis,and the novel IOL we developed prevented PCO in vivo under its sustained indomethacin release property,which provided a promising approach for PCO prophylaxis in clinical application.

Role of Rapamycin and 3-MA in oxidative damage of HLECs caused by two doses of UVB radiation

Background:This study compared the role of autophagy regulators Rapamycin and 3-MA in oxidative damage and apoptosis of human lens epithelial cells(HLECs)caused by two doses of Ultraviolet Radiation B(UVB).Methods:HLECs were irradiated with UVB,and two doses of UVB damage models were constructed.After treatment with autophagy regulators,cell damage tests such as CCK-8,LDH activity,and Ros detection were performed.Western blotting was used to detect the levels of autophagy-related proteins and apoptosis-related proteins.Quantitative real-time PCR(RT-qPCR)was used to detect the mRNA leve of secondary antioxidant enzymes.Flow cytometry was used to examine cell viability and apoptosis.Finally,the proportion of autophagy and apoptosis was observed by electron microscope.Results:Autophagy inhibitor 3-MA promoted oxidative damage and apoptosis of HLECs at low doses of UVB(5 mJ/cm2),which corresponds to 1.3 h of exposure to sunlight in human eyes.Under the high dose of UVB(50mJ/cm2),which is equivalent to 13 h of exposure to sunlight in human eyes,the autophagy inducer Rapamycin caused more extensive oxidative damage and apoptosis of HLECs.3-MA was able to reduce this damage,indicating that moderate autophagy is necessary for HLECs to cope with mild oxidative stress.For high dose UVBinduced oxidative stress,the use of 3-MA inhibiting autophagy is more beneficial to reduce cell damage and apoptosis.The mechanisms include degradation of damaged organelles,regulation of the expression of antioxidant enzymes HO-1,NQO1,GCS and regulation of apoptosis-related proteins.Conclusions:Autophagy played different roles in HLECs oxidative stress induced by two doses of UVB.It provides new ideas for reducing oxidative damage and apoptosis of HLECs to prevent or delay the progression of agerelated cataract(ARC).