Resveratrol prevents hypoxia-induced retinal ganglion cell death related with ErbB2

AIM: To confirm the changes in proteins related with hypoxia-induced retinal cell death and to assess the effects of resveratrol(Res).METHODS: The therapeutic effect of Res was verified using an ischemic/reperfusion(I/R) model in vivo and a hypoxia modelin retinal ganglion cells(RGCs) in vitro.Death of RGCs were confirmed by TUNEL assay.Protein expression was confirmed by Western blotting and immunohistochemistry.In addition, flow cytometric analysis was used to confirm the response in the cell unit to obtain more accurate data.RESULTS: ErbB2 expression and apoptosis in the ganglion cell layer(GCL) increased after I/R injury.Treatment of Res rescued I/R-induced ganglion cell death, downregulated apoptosis and ErbB2 protein expression in the retina.In subsequent in vitro models, Res affects apoptosis by regulating the phosphorylation and expression of mouse double minute 2 homolog(MDM2), along with those of ErbB2.These results suggest that Res reverses GCL-specific apoptosis via downregulation of ErbB2 in ischemic injury.CONCLUSION: In light of Res favorable properties, it should be evaluated in the treatment of RGC death and related retinal disease characterized by ErbB2 and MDM2 expression.Therefore, Res is appropriate therapeutic agent for treating ischemic injury-related eye diseases by targeting the expression of ErbB2 and MDM2.

Suppression of laser-induced choroidal neovascularization by intravitreal injection of tristetraprolin

AIM: To examine the effect of intravitreal adenoviral vector-mediated tristetraprolin(Ad-TTP) on VEGF m RNA expression in a rat model of laser-induced choroidal neovascularization.METHODS: Ad-TTP was prepared using a commercial kit. Retinal laser-induced photocoagulation(10 spots per eye) was performed on rats in this experimental choroidal neovascularization(CNV) model. Rats were divided into four groups: control(single intravitreal injection of balanced salt solution, n =10), laser-induced CNV(photocoagulation only, n =20), laser-induced CNV plus Ad-TTP injection(photocoagulation plus a single intravitreal Ad-TTP injection, n =20) and Ad-TTP injection only(n =10). Changes in choroidal morphology were evaluated in ten rats in the laser only and the laser plus Ad-TTP groups. Two weeks after laser injury, the size of CNV was calculated by perfusion with high-molecular-weight fluorescein isothiocyanate(FITC)-dextran. VEGF m RNA expression in retina-choroid tissue from ten rats in each group was measured by reverse transcription polymerase chain reaction(RT-PCR). RESULTS: Two weeks after treatment, the area of laser-induced CNV was reduced by approximately 60% in the rats given the Ad-TTP injection compared with that in the laser-only group. There was a tendency toward decreased VEGF m RNA expression in the Ad-TTP injection groups.CONCLUSION: A single intravitreal injection of Ad-TTP significantly suppressed CNV size in this experimental laser-induced CNV model. Ad-TTP injection also decreased VEGF m RNA expression compared with that inthe laser-induced CNV group. The present study is meaningful as the first study to investigate the effect of tristetraprolin delivered via intravitreal injection.

A novel IRAK4/PIM1 inhibitor ameliorates rheumatoid arthritis and lymphoid malignancy by blocking the TLR/MYD88-mediated NF-κB pathway

Interleukin-1 receptor-associated kinase 4(IRAK4)is a pivotal enzyme in the Toll-like receptor(TLR)/MYD88 dependent signaling pathway,which is highly activated in rheumatoid arthritis tissues and activated B cell-like diffuse large B-cell lymphoma(ABC-DLBCL).Inflammatory responses followed by IRAK4 activation promote B-cell proliferation and aggressiveness of lymphoma.Moreover,proviral integration site for Moloney murine leukemia virus 1(PIM1)functions as an anti-apoptotic kinase in propagation of ABC-DLBCL with ibrutinib resistance.We developed a dual IRAK4/PIM1 inhibitor KIC-0101 that potently suppresses the NF-κB pathway and proinflammatory cytokine induction in vitro and in vivo.In rheumatoid arthritis mouse models,treatment with KIC-0101 significantly ameliorated cartilage damage and inflammation.KIC-0101 inhibited the nuclear translocation of NF-κB and activation of JAK/STAT pathway in ABC-DLBCLs.In addition,KIC-0101 exhibited an anti-tumor effect on ibrutinib-resistant cells by synergistic dual suppression of TLR/MYD88-mediated NF-κB pathway and PIM1 kinase.Our results suggest that KIC-0101 is a promising drug candidate for autoimmune diseases and ibrutinib-resistant B-cell lymphomas.