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| 1 | Faulty homocysteine recycling in diabetic retinopathy显示文摘Background:Although hyperglycemia is the main instigator in the development of diabetic retinopathy,elevated circulating levels of a non-protein amino acid,homocysteine,are also associated with an increased risk of retinopathy.Homocysteine is recycled back to methionine by methylenetetrahydrofolate reductase(MTHFR)and/or transsulfurated by cystathionineβ-synthase(CBS)to form cysteine.CBS and other transsulfuration enzyme cystathionine-γ-lyase(CSE),through desulfuration,generates H_(2)S.Methionine cycle also regulates DNA methylation,an epigenetic modification associated with the gene suppression.The aim of this study was to investigate homocysteine and its metabolism in diabetic retinopathy.Methods:Homocysteine and H_(2)S 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-fusionmitophagy).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 100μM 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 H_(2)S 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. | Renu A.Kowluru Ghulam Mohammad Nikhil Sahajpal | 2020 | Eye and Vision2020，7，1： | 2 |
| 2 | Treatment of heterotopic ossification of the elbow following burn injury:recommenda- tions for surgical excision and perioperative prophylaxis u- sing radiation therapy 显示文摘 | Maender C Sahajpal D Wright TW | 2010 | J Shoulder Elbow Surg2010，19，8： | 1 |
| 3 | Arthroscopic release of the stiff elbow 显示文摘 | Sahajpal D Choi T Wright TW | 2009 | J Hand Surg Am2009，34，3： | 1 |
| 4 | Proximal ulna fractures 显示文摘 | Sahajpal D Wright TW | 2009 | J Hand Surg Am2009，34，2： | 1 |
| 5 | An aggressive surgical approach leads to improved survival in patients with gallbladder cancer: a 12year study at a North American Center显示文摘 | Dixon E Vnllmer CM Sahajpal A el al | 2005 | Ann Surg2005，241，3： | 1 |
| 6 | An aggressive surgical approach leads to improved survival in patients with gallbladder cancer: a 12-year study at a North American Center 显示文摘 | DIXON E VOLLMER C M JR SAHAJPAL A | 2005 | Ann Surg2005，241，3： | 1 |
| 7 | PERCUTANEOUS NEPHROLITHOTOMY OF A PELVIC KIDNEY: A POSTERIOR APPROACH THROUGH THE GREATER SCIATIC FORAMEN显示文摘 | JAMES D. WATTERSON ANTHONY COOK RIKI SAHAJPAL JOHN BENNETT JOHN D. DENSTEDT | 2001 | The Journal of Urology2001，，1： | 1 |
| 8 | An aggressive surgical approach leads to improved survival in patients with gallbladder cancer: a 12-year study at a North American Center 显示文摘 | Dixon E Vollmer CM Sahajpal A | 2005 | Ann Surg2005，241，30： | 1 |
| 9 | Accuracy and safety of pedi- cle screw fixation in thoracic spine trauma 显示文摘 | Fisher CG Sahajpal V Keynan O | 2006 | J Neurosurg Spine2006，6，： | 1 |
| 10 | Accuracy and safety of pedicle screw fixation in thoracic spine trauma显示文摘 | Fisher CG Sahajpal V Keynan O | 2006 | J Neumsurg Spine2006，5，6： | 1 |
| 11 | Proximal ulna fractures 显示文摘 | Sahajpal D Wfight TW | 2009 | J Hand Surg Am2009，34，： | 1 |
| 12 | Arthroscopic release of the stiff elbow显示文摘 | Sahajpal D Choi T Wright TW | 2009 | J Hand Surg Am2009，34，3： | 1 |
| 13 | An aggressive approach leads to improved survival in patients with gallbladder cancer显示文摘 | Dixon E Vollmer CM Sahajpal A | 2005 | Ann Surg2005，241，3： | 1 |
| 14 | An aggressive surgical approach leads to improved survival in patients with gallbladder cancer:a 12-year study at a North American Center显示文摘 | Dixon E Vollmer CM Jr Sahajpal A | 2005 | Ann Surg2005，241，3： | 1 |
| 15 | Sustainable bioenergy production from marginal lands in the US Midwest显示文摘 | Gelfand I Sahajpal R Zhang X C | 2013 | Nature2013，，493： | 1 |
| 16 | Percutaneous nephrolithotomy of a pelvic kidney: a posterior approach through the greater sciatic foramen显示文摘 | Watterson JD Cook A Sahajpal R | 2001 | J Urol2001，166，1： | 1 |
| 17 | Arthroscopic release of theswtiff elbow显示文摘 | Deenesh Sahajpal MD Tony Choi MD | 2009 | J Hand Surg2009，34，： | 1 |
| 18 | Transduodenal Resection of Peri-Ampullary Lesions显示文摘 | Elijah Dixon M.D. Charles M. Vollmer Jr. M.D. Ajay Sahajpal M.D. Mark S. Cattral M.D. M.Sc. David R. Grant M.D. Bryce R. Taylor M.D. Bernard Langer MD. Steven Gallinger M.D. M.Sc. Paul D. Greig M.D | 2005 | World Journal of Surgery2005，，5： | 1 |
| 19 | Sustainable bioenergy production from marginal lands in the US Midwest显示文摘 | GELFAND I SAHAJPAL R ZHANG X | 2013 | Nature2013，493，7433： | 1 |
| 20 | Identification of mongoose (Genus:Herpestes) species from hair through band pattern studies using discriminate functional analysis (DFA) and microscopic examination显示文摘 | Sahajpal V Goyal S Raza R | 2008 | Science and Justice2008，49，3： | 1 |
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