scholarly journals Faulty homocysteine recycling in diabetic retinopathy

2020 ◽  
Vol 7 (1) ◽  
Author(s):  
Renu A. Kowluru ◽  
Ghulam Mohammad ◽  
Nikhil Sahajpal
Keyword(s):  
Dna Methylation ◽  
Diabetic Retinopathy ◽  
Methylenetetrahydrofolate Reductase ◽  
Epigenetic Modification ◽  
Mitochondrial Dynamics ◽  
Methylation Status ◽  
Mitochondrial Damage ◽  
Diabetic Patients ◽  
Retinal Microvasculature ◽  
Increased Risk

Abstract 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 cystathionine β-synthase (CBS) to form cysteine. CBS and other transsulfuration enzyme cystathionine-γ-lyase (CSE), through desulfuration, generates H2S. 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 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.

scholarly journals DNA methylome signatures of prenatal exposure to synthetic glucocorticoids in hippocampus and peripheral whole blood of female guinea pigs in early life

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Aya Sasaki ◽  
Margaret E. Eng ◽  
Abigail H. Lee ◽  
Alisa Kostaki ◽  
Stephen G. Matthews
Keyword(s):  
Dna Methylation ◽  
Whole Blood ◽  
Guinea Pigs ◽  
Critical Role ◽  
Methylation Status ◽  
Peripheral Tissues ◽  
Epigenetic Biomarkers ◽  
Differentially Methylated Genes ◽  
Increased Risk ◽  
Synthetic Glucocorticoids

AbstractSynthetic glucocorticoids (sGC) are administered to women at risk of preterm delivery, approximately 10% of all pregnancies. In animal models, offspring exposed to elevated glucocorticoids, either by administration of sGC or endogenous glucocorticoids as a result of maternal stress, show increased risk of developing behavioral, endocrine, and metabolic dysregulation. DNA methylation may play a critical role in long-lasting programming of gene regulation underlying these phenotypes. However, peripheral tissues such as blood are often the only accessible source of DNA for epigenetic analyses in humans. Here, we examined the hypothesis that prenatal sGC administration alters DNA methylation signatures in guinea pig offspring hippocampus and whole blood. We compared these signatures across the two tissue types to assess epigenetic biomarkers of common molecular pathways affected by sGC exposure. Guinea pigs were treated with sGC or saline in late gestation. Genome-wide modifications of DNA methylation were analyzed at single nucleotide resolution using reduced representation bisulfite sequencing in juvenile female offspring. Results indicate that there are tissue-specific as well as common methylation signatures of prenatal sGC exposure. Over 90% of the common methylation signatures associated with sGC exposure showed the same directionality of change in methylation. Among differentially methylated genes, 134 were modified in both hippocampus and blood, of which 61 showed methylation changes at identical CpG sites. Gene pathway analyses indicated that prenatal sGC exposure alters the methylation status of gene clusters involved in brain development. These data indicate concordance across tissues of epigenetic programming in response to alterations in glucocorticoid signaling.

scholarly journals Epigenome-wide association study of whole blood gene expression in Framingham Heart Study participants provides molecular insight into the potential role of CHRNA5 in cigarette smoking-related lung diseases

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Chen Yao ◽  
Roby Joehanes ◽  
Rory Wilson ◽  
Toshiko Tanaka ◽  
Luigi Ferrucci ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lung Cancer ◽  
Dna Methylation ◽  
Cigarette Smoking ◽  
Association Study ◽  
Whole Blood ◽  
Lung Diseases ◽  
Epigenetic Modification ◽  
Blood Gene Expression ◽  
Increased Risk

Abstract Background DNA methylation is a key epigenetic modification that can directly affect gene regulation. DNA methylation is highly influenced by environmental factors such as cigarette smoking, which is causally related to chronic obstructive pulmonary disease (COPD) and lung cancer. To date, there have been few large-scale, combined analyses of DNA methylation and gene expression and their interrelations with lung diseases. Results We performed an epigenome-wide association study of whole blood gene expression in ~ 6000 individuals from four cohorts. We discovered and replicated numerous CpGs associated with the expression of cis genes within 500 kb of each CpG, with 148 to 1,741 cis CpG-transcript pairs identified across cohorts. We found that the closer a CpG resided to a transcription start site, the larger its effect size, and that 36% of cis CpG-transcript pairs share the same causal genetic variant. Mendelian randomization analyses revealed that hypomethylation and lower expression of CHRNA5, which encodes a smoking-related nicotinic receptor, are causally linked to increased risk of COPD and lung cancer. This putatively causal relationship was further validated in lung tissue data. Conclusions Our results provide a large and comprehensive association study of whole blood DNA methylation with gene expression. Expression platform differences rather than population differences are critical to the replication of cis CpG-transcript pairs. The low reproducibility of trans CpG-transcript pairs suggests that DNA methylation regulates nearby rather than remote gene expression. The putatively causal roles of methylation and expression of CHRNA5 in relation to COPD and lung cancer provide evidence for a mechanistic link between patterns of smoking-related epigenetic variation and lung diseases, and highlight potential therapeutic targets for lung diseases and smoking cessation.

The effect of insulin pump therapy in retinal vasculature in type 1 diabetic patients

2021 ◽  
pp. 112067212199057
Author(s):  
Tomás de Oliveira Loureiro ◽  
João Nobre Cardoso ◽  
Carlos Diogo Pinheiro Lima Lopes ◽  
Ana Rita Carreira ◽  
Sandra Rodrigues-Barros ◽  
...  
Keyword(s):  
Diabetic Retinopathy ◽  
Metabolic Control ◽  
Insulin Pump Therapy ◽  
Vascular Density ◽  
Diabetic Patients ◽  
Retinal Vasculature ◽  
Increased Risk ◽  
The Mean ◽  
Type 1 Diabetic Patients

Background/objectives: Continuous subcutaneous insulin infusion (CSII) is a treatment for type 1 diabetes that improves metabolic control and reduces micro and macrovascular complications. The aim of this study was to compare the effect of CSII versus traditional multiple daily injections (MDI) therapy on retinal vasculature. Methods: We performed a prospective study with type 1 diabetic patients with no prior history of ocular pathology other than mild diabetic retinopathy. The patients were divided into two groups according to their therapeutic modality (CSII vs MDI). The retinal nerve fiber layers thickness and vascular densities were compared between groups in both macula and optic disc. The correlations between vascular density and clinical features were also determined. Statistical significance was defined as p < 0.05. Results: The study included 52 eyes, 28 in the insulin CSII group. The mean age was 36.66 ± 12.97 years, with no difference between groups ( p = 0.49). The mean glycated hemoglobin (HbA1c) was found to be lower in the CSII group (7.1% ± 0.7 vs 7.5% ± 0.7 p < 0.01). The parafoveal vascular density was found to be higher in the CSII group (42.5% ± 0.4 vs 37.7% ± 0.6, p < 0.01). We found an inverse correlation between HbA1c value and parafoveal vascular densities ( p < 0.01, r = −0.50). Conclusion: We found that CSII provided better metabolic control than MDI and this seemed to result in higher parafoveal vascular density. As lower vascular density is associated with an increased risk of diabetic retinopathy, these results suggest that CSII could be the safest therapeutic option to prevent retinopathy.

Hepatic IGF1 DNA methylation is influenced by gender but not by intrauterine growth restriction in the young lamb

2015 ◽  
Vol 6 (6) ◽  
pp. 558-572 ◽  
Author(s):  
D. J. Carr ◽  
J. S. Milne ◽  
R. P. Aitken ◽  
C. L. Adam ◽  
J. M. Wallace
Keyword(s):  
Dna Methylation ◽  
Growth Hormone ◽  
Sexual Dimorphism ◽  
Mrna Expression ◽  
Intrauterine Growth Restriction ◽  
Messenger Rna ◽  
Methylation Status ◽  
Growth Restriction ◽  
Intrauterine Growth ◽  
Increased Risk

Intrauterine growth restriction (IUGR) and postnatal catch-up growth confer an increased risk of adult-onset disease. Overnourishment of adolescent ewes generates IUGR in ∼50% of lambs, which subsequently exhibit increased fractional growth rates. We investigated putative epigenetic changes underlying this early postnatal phenotype by quantifying gene-specific methylation at cytosine:guanine (CpG) dinucleotides. Hepatic DNA/RNA was extracted from IUGR [eight male (M)/nine female (F)] and normal birth weight (12 M/9 F) lambs. Polymerase chain reaction was performed using primers targeting CpG islands in 10 genes: insulin, growth hormone, insulin-like growth factor (IGF)1, IGF2, H19, insulin receptor, growth hormone receptor, IGF receptors 1 and 2, and the glucocorticoid receptor. Using pyrosequencing, methylation status was determined by quantifying cytosine:thymine ratios at 57 CpG sites. Messenger RNA (mRNA) expression of IGF system genes and plasma IGF1/insulin were determined. DNA methylation was independent of IUGR status but sexual dimorphism in IGF1 methylation was evident (M<F, P=0.008). IGF1 mRNA:18S and plasma IGF1 were M>F (both P<0.001). IGF1 mRNA expression correlated negatively with IGF1 methylation (r=−0.507, P=0.002) and positively with plasma IGF1 (r=0.884, P<0.001). Carcass and empty body weights were greater in males (P=0.002–0.014) and this gender difference in early body conformation was mirrored by sexual dimorphism in hepatic IGF1 DNA methylation, mRNA expression and plasma IGF1 concentrations.

scholarly journals Comparative gene expression profile and DNA methylation status in diabetic patients of Kazak and Han people

Medicine ◽  
2018 ◽  
Vol 97 (36) ◽  
pp. e11982 ◽  
Author(s):  
Cuizhe Wang ◽  
Xiaodan Ha ◽  
Wei Li ◽  
Peng Xu ◽  
Zhiwei Zhang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Gene Expression Profile ◽  
Expression Profile ◽  
Methylation Status ◽  
Diabetic Patients

scholarly journals Diabetic Retinopathy: Mitochondria Caught in a Muddle of Homocysteine

2020 ◽  
Vol 9 (9) ◽  
pp. 3019
Author(s):  
Renu A. Kowluru
Keyword(s):  
Oxidative Stress ◽  
Dna Methylation ◽  
Diabetic Retinopathy ◽  
Diabetic Patients ◽  
Vicious Cycle ◽  
Protein Amino Acid ◽  
Mtdna Damage ◽  
Mitochondrial Homeostasis ◽  
Systemic Factors ◽  
Adenosyl Methionine

Diabetic retinopathy is one of the most feared complications of diabetes. In addition to the severity of hyperglycemia, systemic factors also play an important role in its development. Another risk factor in the development of diabetic retinopathy is elevated levels of homocysteine, a non-protein amino acid, and hyperglycemia and homocysteine are shown to produce synergistic detrimental effects on the vasculature. Hyperhomocysteinemia is associated with increased oxidative stress, and in the pathogenesis of diabetic retinopathy, oxidative stress-mitochondrial dysfunction precedes the development of histopathology characteristic of diabetic retinopathy. Furthermore, homocysteine biosynthesis from methionine forms S-adenosyl methionine (SAM), and SAM is a co-substrate of DNA methylation. In diabetes, DNA methylation machinery is activated, and mitochondrial DNA (mtDNA) and several genes associated with mitochondrial homeostasis undergo epigenetic modifications. Consequently, high homocysteine, by further affecting methylation of mtDNA and that of genes associated with mtDNA damage and biogenesis, does not give any break to the already damaged mitochondria, and the vicious cycle of free radicals continues. Thus, supplementation of sensible glycemic control with therapies targeting hyperhomocysteinemia could be valuable for diabetic patients to prevent/slow down the development of this sight-threatening disease.

Diabetic Retinopathy—Update on Prevention Techniques, Present Therapies, and New Leads

2014 ◽  
Vol 10 (01) ◽  
pp. 25
Author(s):  
Lauren M Marozas ◽  
Patrice E Fort ◽  
◽  
Keyword(s):  
Diabetic Retinopathy ◽  
Vision Loss ◽  
Developed Countries ◽  
Detection Methods ◽  
Retinal Microvasculature ◽  
Increased Risk ◽  
Patients With Diabetes ◽  
Combined Control ◽  
Working Age ◽  
Proactive Measures

Diabetic retinopathy is the major ocular complication associated with diabetes, and represents the leading cause of legal blindness in the working-age population of developed countries. Although classically diagnosed based on abnormalities of the retinal microvasculature, diabetic retinopathy is now widely recognized as a neurovascular disease. While all patients with diabetes are at increased risk for eye disease including diabetic retinopathy, proactive measures, and timely intervention can prevent or delay subsequent vision loss. Systemic management of diabetes by combined control of glycemia, blood pressure, and serum lipid levels remains the most important method of preventing diabetic retinopathy onset and progression. Once detected, surgical and medical interventions including photocoagulation, vitrectomy, and intravitral drug injection can help preserve vision. However, the need for improved detection methods and therapies that will allow earlier diagnosis and treatment remains apparent. This review summarizes current techniques for the prevention and intervention for diabetic retinopathy, and examines ongoing developments in the search for new endpoints and therapies as they apply to preventing vision loss associated with diabetes.

The C677T Methylenetetrahydrofolate Reductase Polymorphism and Insulin Resistance in Childhood Cancer Survivors.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1400-1400
Author(s):  
Lisa Ann Bishop ◽  
Lyn M Steffen ◽  
Alex Tsai ◽  
Naomi Hanson ◽  
K. Scott Baker ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Cancer Survivors ◽  
Vitamin B12 ◽  
Childhood Cancer ◽  
Methylenetetrahydrofolate Reductase ◽  
Methylation Status ◽  
Childhood Cancer Survivors ◽  
Mthfr C677t Polymorphism ◽  
Mthfr Polymorphisms ◽  
Increased Risk

Abstract Abstract 1400 Poster Board I-422 Introduction: Childhood cancer survivors have increased risk for cardiovascular disease and insulin resistance. Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and low folate are associated with higher levels of homocysteine and changes in methylation status; these factors, in particular the TT and CT genotypes have been associated with insulin resistance in animal and human models. The CT genotype is present in about 25 % of the healthy US population. Vitamin B12 is an important co-factor in this association. The homocysteine/methionine ratio has been used as an indirect marker of methylation status and MTHFR function. Population and Methods: This analysis includes children (n=156) who survived ≥ 5-yrs following diagnosis of acute lymphoblastic leukemia (ALL) (n=55), acute myeloid leukemia (AML) (n=4), and non-Hodgkin's lymphoma (NHL) (n=13), central nervous system tumors (38) and other cancers (n=46). Mean age at diagnosis was 10.3 yrs (5.7-15.8) and mean age at evaluation was 15.0 yrs (9.9-17.9). Anthropometric measurements, blood pressure (BP), fasting glucose, insulin, lipids, folate, vitamin B12, homocysteine, and methionine were collected. Insulin resistance was assessed by euglycemic hyperinsulinemic clamp, adjusted for lean body mass (low Mlbm represents insulin resistance, less than 50% of distribution). Genetic polymorphisms, of MTHFR CC (wildtype) CT (heterozygous) and TT (homozygous) were identified; comparisons between MTHFR polymorphisms were adjusted for age, gender, and Tanner stage. Results: CC genotype was present in 44%, CT in 47.3 %, and TT in 8.7 % of survivors. Folate and B12 levels were lowest in the TT group, although not statistically significant (P value >0.05). Insulin resistance was most prevalent in the CT group and least prevalent in the TT group. The homocysteine/ methionine ratio was lowest in the CT group and highest in the TT group. Measures of adiposity were similar in all three groups (Table). Conclusion: This study suggests an increased frequency of the CT genotype in this study population of childhood cancer survivors compared to the healthy US population. Insulin resistance was most prevalent in the CT group; however, this was not associated with low levels of folate, B12, or high homocysteine/methionine ratio. The low frequency of insulin resistance in the TT group likely reflects the small number of participants with this genotype. Further study of these variables in larger populations is needed to provide sufficient power in assessing these relationships in childhood cancer survivors. Disclosures: No relevant conflicts of interest to declare.

scholarly journals 0027 Adolescent Sleep Timing And Dietary Patterns In Relation To Dna Methylation Of Core Clock Genes

SLEEP ◽  
2019 ◽  
Vol 42 (Supplement_1) ◽  
pp. A11-A11
Author(s):  
Erica C Jansen ◽  
Dana Dolinoy ◽  
Ronald D Chervin ◽  
Karen E Peterson ◽  
Louise M O'Brien ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Dietary Patterns ◽  
Dietary Habits ◽  
Clock Genes ◽  
Epigenetic Modification ◽  
Shift Workers ◽  
Wake Time ◽  
Cpg Sites ◽  
Sleep Timing ◽  
Increased Risk

Abstract Introduction Mistimed sleep/wake and eating patterns put adult shift workers at increased risk for chronic disease, and epigenetic modification of core clock genes has been proposed as a mechanism. Although not as extreme as shift workers, adolescents often have delayed sleep timing. Our aim was to assess whether sleep midpoints in adolescents are associated with DNA methylation of circadian genes. A secondary aim was to examine associations between dietary patterns and circadian gene methylation. Methods The study population included 142 Mexican youth (average age 14.0 (SD=2.0) years, 49% male) enrolled in a cohort study. Average sleep midpoint (between bed time and wake time) over 7 days was estimated with actigraphy. Diet was assessed with a semi-quantitative food frequency questionnaire, and three dietary patterns were derived from principal components analysis (a vegetable-based pattern, a meat and starch-based pattern, and a breakfast pattern). DNA methylation was quantified in blood leukocytes with the Infinium MethylatinEPIC BeadChip. We selected 166 loci (CpG sites) within CpG islands of core ‘clock’ genes known to regulate circadian rhythms (CLOCK, BMAL, PER1, PER2, PER3, CRY1, CRYI2, RORA, RORB, REV-VERBA, REV-VERBB). Linear regression was used to analyze associations between sleep midpoint or dietary patterns and logit-transformed percent methylation at the 166 CpG sites. All models were adjusted for sex and age. Results The average midpoint was 3:41 AM (SD=1 hr 15 min); average bed time was 11:29 PM (SD=68 min) and average wake time was 7:53 AM (SD=97 min). Sleep midpoint was positively associated with DNA methylation of CpG sites from the genes REV-VERBA and RORB at the Bonferroni-corrected significance level of p&lt;0.005. The breakfast dietary pattern (rich in eggs, milk, and bread) was inversely associated with DNA methylation at RORA (P=0.003). Conclusion Sleep timing and dietary habits are associated with DNA methylation of core clock genes in adolescents. Epigenetic modification of clock genes could in part underlie relationships between sleep, diet, and metabolic health among adolescents. Support (If Any) Dr. Jansen is supported by the NIH/NHLBI grant 5T32HL110952-05.

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