Contrasting DCIS and invasive breast cancer by subtype suggests basal-like DCIS as distinct lesions.
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Coccolini Federico, Roberts Derek, Ansaloni Luca, Ivatury Rao, Gamberini Emiliano, Kluger Yoram, Moore Ernest E, Coimbra Raul, Kirkpatrick Andrew W, Pereira Bruno M, Montori Giulia, Ceresoli Marco, Abu-Zidan Fikri M, Sartelli Massimo, Velmahos George, Fraga Gustavo Pereira, Leppaniemi Ari, Tolonen Matti, Galante Joseph, Razek Tarek, Maier Ron, Bala Miklosh, Sakakushev Boris, Khokha Vladimir, Malbrain Manu, Agnoletti Vanni, Peitzman Andrew, Demetrashvili Zaza, Sugrue Michael, Di Saverio Salomone, Martzi Ingo, Soreide Kjetil, Biffl Walter, Ferrada Paula, Parry Neil, Montravers Philippe, Melotti Rita Maria, Salvetti Francesco, Valetti Tino M, Scalea Thomas, Chiara Osvaldo, Cimbanassi Stefania, Kashuk Jeffry L, Larrea Martha, Hernandez Juan Alberto Martinez, Lin Heng-Fu, Chirica Mircea, Arvieux Catherine, Bing Camilla, Horer Tal, De Simone Belinda, Masiakos Peter, Reva Viktor, DeAngelis Nicola, Kike Kaoru, Balogh Zsolt J, Fugazzola Paola, Tomasoni Matteo, Latifi Rifat, Naidoo Noel, Weber Dieter, Handolin Lauri, Inaba Kenji, Hecker Andreas, Kuo-Ching Yuan, Ordoñez Carlos A, Rizoli Sandro, Gomes Carlos Augusto, De Moya Marc, Wani Imtiaz, Mefire Alain Chichom, Boffard Ken, Napolitano Lena, Catena Fausto
Аннотация
METHODS: Homocysteine and H2S levels were analyzed in the retina, and CBS, CSE and MTHFR in the retinal microvasculature from human donors with established diabetic retinopathy. Mitochondrial damage was evaluated in retinal microvessels by quantifying enzymes responsible for maintaining mitochondrial dynamics (fission-fusion-mitophagy). DNA methylation status of CBS and MTHFR promoters was examined using methylated DNA immunoprecipitation technique. The direct effect of homocysteine on mitochondrial damage was confirmed in human retinal endothelial cells (HRECs) incubated with 100 μM L-homocysteine.
RESULTS: Compared to age-matched nondiabetic control human donors, retina from donors with established diabetic retinopathy had ~ 3-fold higher homocysteine levels and ~ 50% lower H2S levels. The enzymes important for both transsulfuration and remethylation of homocysteine including CBS, CSE and MTHFR, were 40-60% lower in the retinal microvasculature from diabetic retinopathy donors. While the mitochondrial fission protein, dynamin related protein 1, and mitophagy markers optineurin and microtubule-associated protein 1A/1B-light chain 3 (LC3), were upregulated, the fusion protein mitofusin 2 was downregulated. In the same retinal microvessel preparations from donors with diabetic retinopathy, DNA at the promoters of CBS and MTHFR were hypermethylated. Incubation of HRECs with homocysteine increased reactive oxygen species and decreased transcripts of mtDNA-encoded CYTB.
CONCLUSIONS: Compromised transsulfuration and remethylation processes play an important role in the poor removal of retinal homocysteine in diabetic patients. Thus, regulation of their homocysteine levels should ameliorate retinal mitochondrial damage, and by regulating DNA methylation status of the enzymes responsible for homocysteine transsulfuration and remethylation, should prevent excess accumulation of homocysteine.