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A stroke is a medical emergency characterized by the sudden interruption of blood flow to the brain, leading to cell death from oxygen deprivation. As a leading cause of mortality and longterm disability worldwide, strokes present a growing socioeconomic challenge, exacerbated by demographic shifts and an increasing incidence in younger populations. Analyzing post-stroke conditions is essential for predicting recovery trajectories and guiding personalized treatments. The process is crucial for mitigating long-term cognitive deficits and improving the quality of life for stroke survivors and their families. Epigenetic mechanisms are emerging as key influencers, with four significant modulators—miRNAs, lncRNAs, DNA methylation, and histone modifications—being identified as central to modulating neuronal repair and regeneration. However, this is a lack of knowledge as to how major epigenetic signatures affect post-stroke recovery. The paper systematically reviews the capacity of miRNAs to fine-tune neuroprotective responses and the broader regulatory functions of lncRNAs. Additionally, we examine how shifts in DNA methylation patterns and histone modifications correlate with stroke outcomes, presenting a case for precise epigenetic therapies. In this review, we highlight that these modulators offer promising therapeutic targets for enhancing recovery and provide novel insights into stroke pathology and treatment. We also offer a comparative analysis of the four modulators and present the challenges and future perspectives for each one. The review sets forth a trajectory for future research, underscoring the development of novel epigenetic-based therapeutics as a groundbreaking approach to enhance post-stroke neurorehabilitation and improve patient prognoses. [ABSTRACT FROM AUTHOR]

Hypoxia occurs in situations of disbalance between metabolic needs and the supply of oxygen to organs and tissues of the body. In this regard, tissue hypoxia and ischemia are essential components of the pathogenesis of many diseases. One of the promising areas of research into the mechanisms of ischemia is attempting to weaken the negative effect of hypoxia and ischemia in the brain by using a variety of techniques that activate neuroprotective mechanisms. Here, we aimed to assess the dynamics of restoration of motor activity control in an experimental model of ischemic stroke in rats (cerebral ischemia, CI) after intranasal perineural implantation of mesenchymal stem cells into the receptive field of the olfactory nerve. It was found that the perineural administration of MSCs to rats in the acute period of cerebral ischemia was accompanied by clear signs of recovery of cognitive and motor functions within 1 and 3 days after the operation. On the seventh day after ischemia modeling, rats with the introduction of MSCs had no distinctive features in the control of motor activity compared to the period before the operation in the same rats. In the hippocampus of rats after modeling ischemia, a significant decrease in the content of NO by about 50% relative to the initial level is observed after 1 day. In the hippocampus of rats in which ischemia was modeled with simultaneous intranasal administration of MSC, a significant decrease in NO content by 39% relative to the initial level was also observed after 1 day. The content of NO increases slightly, but the difference in the level of NO relative to ischemic rats was not significant. The copper content in the hippocampus in the rats of these two groups did not change. There was a tendency to increase the efficiency of the antioxidant system 1 day after ischemia in both studied groups, and this effect was more pronounced with intranasal administration of MSC. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy (DN) is an emerging public health and clinical issue linked to heart failure, ESRD, and other negative effects, including renal replacement therapy. A systematic search of five major databases, including PubMed, Web of Science, Science Direct, EBSCO, and Cochrane library, was conducted to comprise eligible literature for research. This systematic review studies the risk factors associated with the development of DN and albuminuria in adolescents suffering from T1DM. A total of 13 study articles with 1489 patients were included in this review. Hypertension in association with albuminuria was found in six studies, high mean HbA1c in association with DN was demonstrated in all the included studies, and dyslipidemia/ high total cholesterol level was reported in three studies. Hypertension, high HbA1C (poor glycemic control), dyslipidemia, high cholesterol levels, and high BMI indicating overweight or obesity are risk factors for the incidence of microalbuminuria and DN in adolescents with T1DM. [ABSTRACT FROM AUTHOR]

Introduction: The dose-dependent effect of reactive oxygen species (ROS) in tissues in preconditioning (PreC) and oxidative stress, as well as NO-synthase participation in mitochondrial ROS production determined the study aim - to assess the impact of the neuroprotective method of combined preconditioning (CPreC) on free radical reactions (FRRs) in brain in normoxia and in cerebral ischemia, including in NO-synthase blockade. Materials and methods: The intensity of FRR by iron-induced chemiluminescence (CL), the content of lipid peroxidation products and antioxidant enzyme activity were investigated 1 hr (early period) and 48 hrs (delayed period) after CPreC (amtizol and hypobaric hypoxia) in Wistar rat brain. Some animal groups were operated (common carotid artery bilateral ligation) 1 hr and 48 hrs after CPreC, as well as with preliminary introduction of L-NAME and aminoguanidine. Results and discussion: In normoxia, CPreC led to increase the CL maximum level (Fmax) in the delayed PreC period. The amount of thiobarbituric acid reactive products (TBA-RP), activity of superoxide dismutase (SOD) and catalase in mitochondrial fraction of rat brain did not change in comparison with the intact control in both PreC periods. In cerebral ischemia, oxidative stress was observed. The CPreC use before ischemia caused a decrease in CL parameters and TBA-RP in brain, the maintenance of SOD and high catalase activity. NO-synthase inhibitors partially abolished the antioxidant effect of CPreC in ischemia. Conclusion: CPreC had no influence on FRRs in brain tissue in normoxia, but prevented their excessive activation after ischemia, especially in the delayed period. NO-synthase was involved in the CPreC neuroprotection. [ABSTRACT FROM AUTHOR]

Mortality from perinatal hypoxic–ischemic (HI) brain injury reached 1.15 million worldwide in 2010 and is also a major factor for neurological disability in infants. HI directly influences the oxidative phosphorylation enzyme complexes in mitochondria, but the exact mechanism of HI-reoxygenation response in brain remains largely unresolved. After induction of HI-reoxygenation in postnatal day 10 rats, activities of mitochondrial respiratory chain enzymes were analysed and complexome profiling was performed. The effect of conformational state (active/deactive (A/D) transition) of mitochondrial complex I on H2O2 release was measured simultaneously with mitochondrial oxygen consumption. In contrast to cytochrome c oxidase and succinate dehydrogenase, HI-reoxygenation resulted in inhibition of mitochondrial complex I at 4 h after reoxygenation. Immediately after HI, we observed a robust increase in the content of deactive (D) form of complex I. The D-form is less active in reactive oxygen species (ROS) production via reversed electron transfer, indicating the key role of the deactivation of complex I in ischemia/reoxygenation. We describe a novel mechanism of mitochondrial response to ischemia in the immature brain. HI induced a deactivation of complex I in order to reduce ROS production following reoxygenation. Delayed activation of complex I represents a novel mitochondrial target for pathological-activated therapy. [ABSTRACT FROM AUTHOR]

The content of regulatory proteins involved in adaptation to hypoxia and ischemia was studied in brain rat homogenate under conditions of normoxia and after bilateral ligation of the common carotid arteries. Preconditioning with amtizole in combination with moderate hypoxia increased the levels of HIF-1α, erythropoietin, vascular endothelial growth factor under conditions of normoxia. During experimental ischemia, combined preconditioning led to stabilization of the content of these regulatory proteins at the level of intact control and to a decrease in glycogen synthase-3β kinase activity. This pattern of changes in regulatory proteins was noted during the early and late periods of preconditioning. [ABSTRACT FROM AUTHOR]

Glycogen synthase kinase 3β (GSK-3β) is a key downstream protein in the PI3K/Akt pathway. Phosphorylation of serine 9 of GSK-3β (GSK-3β activity inhibition) promotes cell survival. In this study, we examined changes in expressions of GSK-3β and phosphorylation of GSK-3β (p-GSK-3β) in the gerbil hippocampal CA1 area after 5 min of transient cerebral ischemia. GSK-3β immunoreactivity in the CA1 area was increased in pyramidal cells at 6 h after ischemia-reperfusion. It was decreased in CA1 pyramidal cells from 12 h after ischemia-reperfusion, and hardly detected in the CA1 pyramidal cells at 5 days after ischemia-reperfusion. p-GSK-3β immunoreactivity was slightly decreased in CA1 pyramidal cells at 6 and 12 h after ischemia-reperfusion. It was significantly increased in these cells at 1 and 2 days after ischemia-reperfusion. Five days after ischemia-reperfusion, p-GSK-3β immunoreactivity was hardly found in CA1 pyramidal cells. However, p-GSK-3β immunoreactivity was strongly expressed in astrocytes primarily distributed in strata oriens and radiatum. In conclusion, GSK-3β and p-GSK-3β were significantly changed in pyramidal cells and/or astrocytes in the gerbil hippocampal CA1 area following 5 min of transient cerebral ischemia. This finding indicates that GSK-3β and p-GSK-3β are closely related to delayed neuronal death. [ABSTRACT FROM AUTHOR]

We studied combined effect of moderate hypoxia and compounds pQ-4, pQ-915, pQ-1032, and pQ-1104 on neurological deficit and survival of rats after bilateral ligation of common carotid arteries. Preconditioning including moderate hypoxia and treatment with compound pQ-4 produced a neuroprotective effect and increased animal survival during the early (by 51%) and late (by 33.5%) periods of modeled ischemia and reduced neurological deficit (by 50% and 41%, respectively). Moreover, this combination of preconditioning factors prevented postischemic excessive activation of free radical oxidation in brain hemispheres and blood serum. [ABSTRACT FROM AUTHOR]

Ischemic stroke is a major cause of death and disability all over the world. Ischemic stroke results from a temporary or permanent reduction of cerebral blood flow that leads to functional and structural damage in different brain regions. Despite decades of intense research, the beneficial treatment of stroke remains limited. In light of this, the search for effective means ameliorating cerebral ischemia-reperfusion injury (CIRI) is one of the major problems of experimental medicine and biology. Recently, the 5-Lipoxygenase (5-LO, a key enzyme metabolizing arachidonic acid to produce leukotrienes) inhibitors have been showed to protect brain against ischemic damage in animal model of cerebral ischemia. Caffeic acid, an inhibitor of 5-LO, is a phenolic compound widely distributed in medicinal plants. The aim of this study was to investigate the effect of caffeic acid on global cerebral ischemia-reperfusion injury in rats. The study was carried out on 45 rats that were randomly divided into five groups: the sham group (n = 9), I/R non-treated group (n = 9), I/R-caffeic acid group (10 mg·kg-1) (n = 9), I/R-caffeic acid group (30mg·kg-1) (n=9) and I/R-caffeic acid group (50mg·kg-1) (n=9). Global cerebral ischemia was induced by bilateral carotid artery occlusion for 20 min followed by reperfusion. Spatial learning and memory was evaluated using Morris water maze. Histopathological changes of hippocampus neurons was observed using HE staining. Superoxide dismutase (SOD, the antioxidant enzyme) activities and malondialdehyde (MDA, an oxidative stress biomarker) contents were detected. NF-kBp65 expression was detected by the methods of immunohistochemistry. Caffeic acid markedly reduced the escape latency, relieved hippocampal neurons injury and increased neuron count compared with those of I/R non-treated rat. NF-kBp65 expression and MDA content decreased significantly, and SOD activities increased significantly in hippocampus. Compared with sham group, 5-LO expression increase significantly in I/R non-treated group rat, and caffeic acid markedly reduced 5-LO expression. The results of the study suggest that caffeic acid has a significant protective effect on global cerebral ischemia-reperfusion injury in rats. The neuroprotective effects is likely to be mediated through the inhibition of 5-LO. [ABSTRACT FROM AUTHOR]

The association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and diabetic nephropathy (DN) or diabetes mellitus (DM) risk has been widely reported, but the results are still debatable. To investigate the role of MTHFR C677T polymorphism on DM or DN, 13 separate studies in the Chinese population on the relation between MTHFR C677T polymorphism and DM or DN were analyzed by a meta-analysis. Five genetic models were used to estimate the association between MTHFR C677T polymorphism and the risk of DM or DN. Overall, our meta-analysis for DN versus healthy controls produced significant results for all genetic contrasts except for the co-dominant model (allele contrast: OR = 2.24, 95%CI: 1.88-2.65, p < 0.00001, Pheterogeneity = 0.49). However, the meta-analysis for DM versus healthy controls produced non-significant results for all contrasts (allele contrast: OR = 1.12, 95%CI: 0.92-1.35, p = 0.25, Pheterogeneity = 0.07). In addition, the meta-analysis for DM versus DN produced significant results for all contrasts (allele contrast: OR = 1.88, 95%CI: 1.65-2.15, p < 0.00001, Pheterogeneity = 0.83). The current meta-analysis suggested that MTHFR C677T polymorphism might influence DN risk, but not for DM in the Chinese population. [ABSTRACT FROM AUTHOR]

In the past decade, a number of case-control studies have been carried out to investigate the relationship between the ApoE polymorphism and diabetic nephropathy. However, the results have been inconclusive. To investigate this inconsistency, we performed a meta-analysis of all available studies dealing with the relationship between the ApoE polymorphism and DN. The 23 studies in the meta- analysis included 6,012 diabetic patients with ( n = 2,979) and without ( n = 3,033) DN. The ApoE ε2 allele was significantly associated with DN (OR = 1.64, 95% CI: 1.26-2.13; P( Z) = 0.00027), whereas the ε4 allele was non-significantly associated with DN (OR = 0.93, 95% CI: 0.78-1.11; P( Z) = 0.418). However, significant heterogeneity was detected. In further subgroup analyses, genotyping methods, outcome of cases and duration of diabetes in controls were found to explain some of the heterogeneity. Genotypic analysis also found a strong association between the ε2 carriers and DN (OR = 1.61, 95% CI: 1.22-2.13; P( Z) = 0.001) and indicated that ε4 tended to have a marginally significant protective effect for DN (OR = 0.82, 95% CI: 0.65-1.03; P( Z) = 0.085). The results of our meta-analysis support a genetic association between the ApoE polymorphism and DN. ε2 increases the risk of DN in diabetes patients, while ε4 trends to be protective. These findings may have implications for therapeutic intervention in diabetic nephropathy. [ABSTRACT FROM AUTHOR]

Minimal change nephrotic syndrome (MCNS) is a common progressive renal disorder occurring in childhood that is characterized by alterations of permselectivity at the glomerular capillary wall, resulting in its inability to restrict the urinary loss of protein. Hyperlipidemia (HLP) is not only an important clinical manifestation of MCNS but is also involved in cardiovascular disease and in progressive renal damage. ApoE is a polymorphic protein. Besides modulation of lipid metabolism, apoE can also elevate the sulfate-proteoglycan in glomerular filtration membrane and inhibit the proliferation of mesengial cells. The present study aimed mainly to determine whether genetic polymorphism of apoE is involved in the HLP secondary to childhood MCNS. Genomic DNA was extracted from 250 children diagnosed with MCNS and 200 healthy controls. ApoE genotype was determined by PCR-restriction fragment length polymorphism (RFLP) analysis. The fasting serum lipoprotein (a) [Lp(a)], total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A1 (apoA1), and apoB were measured. Serum concentrations of Lp(a), TC, TG, HDL-C, nonHDL-C, LDL-C, and apoB were higher in the MCNS than in the control group ( P < 0.05). No significant differences in genotypes and alleles frequencies were observed for the apoE Hha I restriction sites in MCNS patients as compared to controls ( P > 0.05). No significant differences in serum lipid levels were observed for variant genotypes and alleles of apoE Hha I restriction site in both MCNS and healthy children ( P > 0.05). Genetic variation of apoE does not contribute to the lipid abnormalities secondary to childhood MCNS. [ABSTRACT FROM AUTHOR]

Background Poor glycaemic control, hypertension and duration of diabetes are risk factors for the development of diabetic nephropathy, but there may be genetic factors. Recently, a common C to T mutation at nucleotide position 677 of the MTHFR gene (MTHFR677C > T) has been reported to be correlated with hyperhomocysteinemia and the severity of coronary artery disease as macroangiopathy. We aim to investigate Turkish type 2 diabetic patients with/without diabetic nephropathy and healthy group and examine the contribution of the MTHFR gene polymorphism to the development of diabetic nephropathy. Methods DNA was extracted from peripheral leukocytes of the subjects. Genotyping of the MTHFR C677T polymorphism for all individuals was performed by melting curve analysis of the generated amplicons after real-time online PCR. Results This genotype distribution did not differ between control subjects and type 2 diabetic patients in which 6.8% were TT, 43.7% were CT and 49.5% were CC (χ2 = 0.201, p > 0.05). The frequency of the mutant T allele was 23.4% in diabetic patients with nephropathy versus 33.0% in those without nephropathy. The genotype frequencies were TT, 2.1%; CT, 46.6%; CC, 55.3% in diabetic patients with nephropathy versus TT, 10.7%; CT, 44.6%; CC, 44.6% in those without nephropathy. Conclusions The MTHFR genotype and allele frequencies were not different between diabetic patients with and without nephropathy (χ2 = 3, 386, p > 0.005; χ2 = 2.320, p > 0.005, respectively). Therefore, we conclude that the MTHFR gene polymorphism is not associated with the development of diabetic nephropathy in Turkish type 2 diabetic patients. Copyright © 2007 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Investigations into the association between diabetic nephropathy (DN) and MTHFR C677T gene polymorphism in several case–control studies has yielded contradictory results. To shed light on these inconclusive findings, a meta-analysis of all available studies relating the C677T polymorphism to the risk of developing DN was conducted. The PubMed database was searched, and case–control studies investigating the association between MTHFR C677T gene polymorphism and DN were included in the meta-analysis. The meta-analysis included 15 studies, of which 8 involved Caucasians and 5 East Asians; 11 studies involved subjects with type 2 diabetes and 4 with type 1 diabetes. The main analysis (all studies) revealed significant heterogeneity between the studies ( P Q < 0.01) and a marginal association between the 677T allele and the risk of developing DN; the random effects (RE) pooled odds ratio (OR) was 1.30 (1.03–1.64). However, the sensitivity analysis (exclusion of studies not in Hardy–Weinberg equilibrium) produced non-significant results. The recessive model derived significant results in main analysis [fixed effects (FE) OR = 1.32 (1.10–1.58), P Q = 0.27], and in type 2 diabetes [FE OR = 1.30 (1.06–1.60), P Q = 0.38]. The additive model produced significant association in main analysis [RE OR = 1.65 (1.13–2.42), P Q < 0.01] in Caucasians [FE OR = 1.48 (1.11–1.98), P Q = 0.17] and in type 2 diabetes [RE OR = 1.65 (1.03–2.67), P Q < 0.01]. However, sensitivity analysis diminished the significant results in type 2 diabetes. There is no differential magnitude of effect in large versus small studies. In conclusion, although there is some evidence of association between MTHFR C677T gene polymorphism and DN, the above findings reinforce the need for further and more rigorous association studies. [ABSTRACT FROM AUTHOR]

Our hypothesis is that impairment of peroxisome proliferator-activated receptor-γ (PPARγ) initiates renal dysfunction by increasing renal glomerular matrix metalloproteinase-2 (MMP-2) activity because of increased renal homocysteine (Hcy) and decreased nitric oxide (NO) levels. C57BL/6J mice were made diabetic (D) by being fed a high-fat-calorie diet, and an increase in PPARγ activity was induced by adding pioglitazone (Pi) to the diet. Mice were grouped as follows: normal calorie diet (N), D, N+Pi, and D+Pi (n = 6/group). The glomerular filtration rate (GFR), renal artery blood flow and pressure, and plasma glucose were measured. Renal glomeruli and preglomerular arterioles were isolated. Plasma and glomerular levels of NO, Hcy, and MMP activity were measured. The contractile response to phenylephrine and the dilatation response to acetylcholine in renal arteriolar rings were measured in a tissue myobath. In N, D, N+Pi, and D+Pi groups, respectively, GFR was 9.4 ± 1.2, 3.9 ± 1.1, 9.2 ± 1.6, and 8.4 ± 1.4 μl·min-1·g body wt-1. Renovascular resistance was 140 ± 3, 367 ± 21, 161 ± 9, and 153 ± 10 mmHg·ml·min-1. Levels of Hcy were increased from 5.8 ± 1.5 in the N to 18.0 ± 4.0 μmol/l in the D group. Glomerular levels of MMP-2 were increased in D mice compared with N mice, and there was no change in levels of MMP-9. Treatment with Pi ameliorated glomerular levels of MMP-2 and Hcy in the D group. Renal artery ring contraction and relaxation by phenylephrine and acetylcholine, respectively, were attenuated in the D groups compared with the N groups. Results suggest that a PPARγ agonist ameliorates preglomerular arteriole remodeling in diabetes by decreasing tissue levels of Hcy and MMP-2 activity and increasing NO. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. In DN patients, triglyceride (TG) level is elevated and lipoprotein lipase (LPL) activity, which hydrolyzes TG, is decreased. The LPL S447X and apolipoprotein E ( APOE) exon 4 polymorphisms affect TG levels, and the APOC3−455T>C polymorphism affects LPL activity. Our aim was to examine the association of these polymorphisms with nephropathy in type 2 diabetes. We examined these polymorphisms in a case-control study of type 2 diabetic patients including 374 with DN and 392 without DN. LPL 447X-containing genotypes (447X+) were significantly decreased in DN patients [18.6 vs 25.6%, odds ratio (OR) = 0.66, p = 0.02], as were APOEɛ3/ɛ3 genotypes (64.8 vs 73.1%, OR = 0.68, p = 0.01). In addition, combinations of genotypes [ APOEɛ3/ɛ3 and LPL 447X+ (OR = 0.56), APOC3 CC and LPL 447X+ (OR = 0.31), APOEɛ3/ɛ3 and APOC3 CC (OR = 0.61] were protective for DN compared with the most common combination of the respective polymorphisms. Our findings suggest the importance of interactions among lipid genes in modulating the risk of DN. [ABSTRACT FROM AUTHOR]

Background: The pathogenesis of hypertensive nephropathy is multifactoral and in addition to BP, other factors contribute to the development of this renal pathology and its progression to end-stage renal disease. These include genetic predisposition and increased pleasure level of homocysteine-intermediate protein catabolism product known to induce kidney injury. The 677C → T polymorphism in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene is associated with elevated homocysteine level in the general population, and therefore it has been hypothesized to be a risk factor for the development of renal failure in the course of essential hypertension. Methods: In this case-control, cross-sectional study the frequency of the MTHFR 677C → T and the 1298A → C polymorphism was compared between patients with hypertension-related chronic renal failure (n = 90), patients with essential hypertension without kidney injury (n = 90), and healthy individuals (n = 90) who were matched for age and gender. In addition, the influence of these polymorphisms on homocysteine concentration in individuals with essential hypertension was examined. Results: The frequency of the MTHFR 677 TT genotype did not differ between groups (4.5%, 12.3%, and 11.1%, respectively). Patients with hypertension and the 677TT genotype showed significantly higher homocysteine levels as compared to individuals having CC and CT. In the multivariate correlation analysis the MTHFR 677TT genotype (P < .01; β = 0.27), age (P < .001; β = 0.33), and body mass index (P < .01; β = 0.3) were independent predictors for total homocysteine level. Conclusions: Plasma homocysteine levels in individuals with essential hypertension is affected by the MTHFR 677C → T polymorphism. However, we did not prove the hypothesis that MTHFR 677C → T influences the risk of development of renal failure in the course of hypertension. [Copyright &y& Elsevier]

Context Apolipoprotein E (APOE) genetic variation has been implicated in diabetic nephropathy with the ε2 allele increasing and the ε4 allele decreasing risk. APOE allelic associations with chronic kidney disease beyond diabetic nephropathy are unknown, with no studies reported in high-risk African American populations. Objective To quantify the risk of chronic kidney disease progression associated with APOE in a population-based study including white, African American, diabetic, and nondiabetic individuals. Design, Setting, and Participants Prospective follow-up (through January 1, 2003) of Atherosclerosis Risk in Communities (ARIC) study participants, including 3859 African American and 10 661 white adults aged 45 to 64 years without severe renal dysfunction at baseline in 1987-1989, sampled from 4 US communities. Main Outcome Measures Incident chronic kidney disease progression, defined as hospitalization or death with kidney disease or increase in serum creatinine level of 0.4 mg/dL (35 μmol/L) or more above baseline, examined by APOE genotypes and alleles. Results During median follow-up of 14 years, chronic kidney disease progression developed in 1060 individuals (incidence per 1000 person-years: 5.5 overall; 8.8 in African Americans and 4.4 in whites). Adjusting for major chronic kidney disease risk factors, ε2 moderately increased and ε4 decreased risk of disease progression (likelihood ratio test, P = .03). Further adjustment for low- and high-density lipoprotein cholesterol and triglycerides did not attenuate relative risks (RRs) (ε2: 1.08 [95% CI, 0.93-1.25] and ε4: 0.85 [95% CI, 0.75-0.95] compared with ε3; likelihood ratio test, P = .008). ε4 decreased risk of end-stage renal disease (RR, 0.60 [95% CI, 0.43-0.84]). ε2 was associated with a decline in renal function (RR, 1.25 [95% CI, 1.02-1.53]), though not with events, such as hospitalizations or end-stage renal disease. Risks were similar stratified by race, sex, diabetes, and hypertension (all P values for interaction >.05). Excess risk of chronic kidney disease in African Americans was not explained by APOE alleles. Conclusions APOE variation predicts chronic kidney disease progression, independent of diabetes, race, lipid, and nonlipid risk factors. Our study suggests that nonlipid-mediated pathways, such as cellular mechanisms of kidney remodeling, may be involved in the association of APOE alleles and progression of chronic kidney disease. [ABSTRACT FROM AUTHOR]

Accumulation of oxidized-matrix (fibrosis) between the endothelium (the endothelial cells embedded among the myocytes) and cardiomyocytes is a hallmark of diabetes mellitus and causes diastolic impairment. In diabetes mellitus, elevated levels of homocysteine activate matrix metalloproteinase and disconnect the endothelium from myocytes. Extracellular matrix functionally links the endothelium to the cardiomyocyte and is important for their synchronization. However, in diabetes mellitus, a disconnection is caused by activated metalloproteinase, with subsequent accumulation of oxidized matrix between the endothelium and myocyte. This contributes to endothelial-myocyte uncoupling and leads to impaired diastolic relaxation of the heart in diabetes mellitus. Elevated levels of homocysteine in diabetes are attributed to impaired homocysteine metabolism by glucose and insulin and decreased renal clearance. Homocysteine induces oxidative stress and is inversely related to the expression of peroxisome proliferators activated receptor (PPAR). Several lines of evidence suggest that ablation of the matrix metalloproteinase (MMP-9) gene ameliorates the endothelial-myocyte uncoupling in diabetes mellitus. Homocysteine competes for, and decreases the PPARgammaactivity. In diabetes mellitus, endothelial-myocyte uncoupling is associated with matrix metalloproteinase activation and decreased PPARgamma activity. The purpose of this review is to discuss the role of endothelial-myocyte uncoupling in diabetes mellitus and increased levels of homocysteine, causing activation of latent metalloproteinases, decreased levels of thioredoxin and peroxiredoxin, and cardiac tissue inhibitor of metalloproteinase (CIMP) in response to antagonizing PPARgamma. [ABSTRACT FROM AUTHOR]

Purpose: Folate deficiency is considered to increase the risk of developing esophageal cancer. Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme involved in folate metabolism. A single C → T substitution at nucleotide 677 of the MTHFR cDNA influences enzyme activity. The purpose of this study is to compare the association of the MTHFR C677T polymorphism with susceptibility to esophageal squamous cell carcinoma (ESCC). Methods: Using real-time PCR and melting curve analysis, the MTHFR C677T genotypes were determined in 430 patients with ESCC (241 German Caucasians and 189 northern Chinese) and 397 unrelated healthy controls (256 German Caucasians and 141 northern Chinese). Results: A significant difference in MTHFR C677T genotype distribution was observed between German Caucasian controls (C/C, 41.8%, C/T, 44.9%, T/T, 13.3%) and northern Chinese controls (C/C, 17.7%, C/T, 38.3%, T/T, 44.0%) (χ2=52.19, P<0.001). The distribution of the MTHFR C677T genotypes among German ESCC patients (C/C, 39.0%, C/T, 48.1%, T/T, 12.9%) was not significantly different from that among healthy controls (χ2=0.531, P=0.767). In contrast, the frequency of the C/C genotype among Chinese ESCC patients (8.5%) was significantly lower than among Chinese healthy controls (17.7%) (χ2=6.37, P=0.012). The C/C genotype was correlated with a significantly reduced risk for the development of ESCC as compared to the combination of C/T and T/T genotypes (adjusted OR=0.38, 95% CI=0.16-0.88). Conclusions: Our results suggest that, in contrast to German Caucasians, the MTHFR 677CC homozygous wild-type plays a protective role in the development of ESCC in the northern Chinese population. [ABSTRACT FROM AUTHOR]

Diabetic retinopathy is a sight-threatening complication of the retinal microvasculature. While important environmental factors have been clearly identified as influencing its development, increasing evidence suggests that diabetic retinopathy has a genetic component. A variety of studies have explored associations between candidate genes and frequency and severity of retinopathy. Overall, this review has found that the majority of candidate genes studied exhibit weak or no association with retinopathy status, and where associations have been detected these results have not been replicated in multiple populations. This may reflect inaccurate case definition, small subject numbers and possibly inadequate markers for genetic studies. [ABSTRACT FROM AUTHOR]

Higher erythrocyte sodium-lithium countertransport activity (SLC) is implicated in the development of diabetic nephropathy. Altered glucose homeostasis and genetic susceptibility are claimed to play a role in the elevation of SLC. We aimed to test whether metabolic control or the genetic variants of G protein beta 3 (Gb3) subunits determine SLC and other erythrocyte transport activities in complication-free stage of type 1 diabetes. A total of 96 complication-free type 1 diabetic children and adolescents were enrolled. SLC, Na+/K+-ATPase (NAK) and Ca2+-ATPase (CA) were measured by functional assays in erythrocytes. Gb3-C825T polymorphism was determined by PCR-RFLP. Results were related to HbA1c and were compared to those of 97 healthy controls. SLC activity was higher in diabetics (387±146 vs. 280±65 mmol/RBC · hour) and correlated with HbA1c levels (y=0.004x+6.42, r=0.33, n=96, p<0.01). NAK and CA activities were unaltered. The prevalence of 825T allele was similar in the patient and control groups (0.34 vs 0.37) and no differences in enzyme activities were observed between the 825T allele-positive and negative subjects. Although metabolic control correlated with SLC, other membrane functions were not affected. Therefore we hypothesize that the relationship between advanced glycation and SLC elevation is not causative. Rather, a genetic susceptibility for the coexistence of poor metabolic control and higher SLC is more likely. However, the presence of Gb3-C825T variant is not likely to be a risk factor for SLC-elevation and altered metabolic control diabetes. [ABSTRACT FROM AUTHOR]

Background: The gene encoding apolipoprotein E (APOE) has been proposed as a candidate gene for vascular complications in Type I diabetes. This study aimed to investigate the influence of three-allelic variations in the APOE gene for the development of diabeetic retinopathy and nephropathy. Results: Neither APOE alleles frequencies or APOE genotypes frequencies differed between Type I diabetic groups either with or without nephropathy. Similar results were found for patients with and without diabetic retinopathy. Conclusions: APOE gene polymorphism does not determine genetic susceptibility for the development of diabetic retinopathy in Type I diabetes patients. Association between APOE gene polymorphism and diabetic nephropathy may be weak or moderate, but not strong. [ABSTRACT FROM AUTHOR]

Reports that the frequency of DQB1 alleles in a white Polish population showed a significant positive association of DQB1*05 and pulmonary tuberculosis, with patients almost three times more likely to have DQB1*05 as controls. Provision of yet more evidence that variation in the HLA system affects response to infection in pulmonary TB.