Elevated Levels of Plasma IgA Autoantibodies against Oxidized LDL Found in Proliferative Diabetic Retinopathy but Not in Nonproliferative Retinopathy

Aims. This study investigated the association of autoantibodies binding to oxidized low-density lipoproteins (oxLDL) in diabetic retinopathy (DR). Methods. Plasma from 229 types 1 and 2 patients with DR including diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) was analysed with ELISA-based assay to determine IgA, IgG, and IgM autoantibody levels binding to oxLDL. The controls were 106 diabetic patients without retinopathy (NoDR) and 139 nondiabetic controls (C). Results. PDR group had significantly higher IgA autoantibody levels than DME or NoDR: mean 94.9 (SD 54.7) for PDR, 75.5 (41.8) for DME ( = 0.001), and 76.1 (48.2) for NoDR ( = 0.008). There were no differences in IgG, IgM, or IgA that would be specific for DR or for DME. Type 2 diabetic patients had higher levels of IgA autoantibodies than type 1 diabetic patients (86.0 and 65.5, resp., = 0.004) and the highest levels in IgA were found in type 2 diabetic patients with PDR (119.1, > 0.001). Conclusions. IgA autoantibodies were increased in PDR, especially in type 2 diabetes. The high levels of IgA in PDR, and especially in type 2 PDR patients, reflect the inflammatory process and enlighten the role of oxLDL and its autoantibodies in PDR

Elevated Levels of Plasma IgA Autoantibodies against Oxidized LDL Found in Proliferative Diabetic Retinopathy but Not in Nonproliferative Retinopathy

Peer reviewe

Ceramide stearic to palmitic acid ratio predicts incident diabetes

Aims/hypothesis Ceramide lipids have a role in the development of insulin resistance, diabetes and risk of cardiovascular disease. Here we investigated four ceramides and their ratios to find the best predictors of incident diabetes. Methods A validated mass-spectrometric method was applied to measure Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:0) and Cer(d18:1/24:1) from serum or plasma samples. These ceramides were analysed in a population-based risk factor study (FINRISK 2002, n = 8045), in a cohort of participants undergoing elective coronary angiography for suspected stable angina pectoris (Western Norway Coronary Angiography Cohort [WECAC], n = 3344) and in an intervention trial investigating improved methods of lifestyle modification for individuals at high risk of the metabolic syndrome (Prevent Metabolic Syndrome [PrevMetSyn], n = 371). Diabetes risk score models were developed to estimate the 10 year risk of incident diabetes. Results Analysis in FINRISK 2002 showed that the Cer(d18:1/18:0)/Cer(d18:1/16:0) ceramide ratio was predictive of incident diabetes (HR per SD 2.23, 95% CI 2.05, 2.42), and remained significant after adjustment for several risk factors, including BMI, fasting glucose and HbA1c (HR 1.34, 95% CI 1.14, 1.57). The finding was validated in the WECAC study (unadjusted HR 1.81, 95% CI 1.53, 2.14; adjusted HR 1.39, 95% CI 1.16, 1.66). In the intervention trial, the ceramide ratio and diabetes risk scores significantly decreased in individuals who had 5% or more weight loss. Conclusions/interpretation The Cer(d18:1/18:0)/Cer(d18:1/16:0) ratio is an independent predictive biomarker for incident diabetes, and may be modulated by lifestyle intervention.publishedVersio

Impaired HDL2-mediated cholesterol efflux is associated with metabolic syndrome in families with early onset coronary heart disease and low HDL-cholesterol level

<div><p>Objective</p><p>The potential of high-density lipoproteins (HDL) to facilitate cholesterol removal from arterial foam cells is a key function of HDL. We studied whether cholesterol efflux to serum and HDL subfractions is impaired in subjects with early coronary heart disease (CHD) or metabolic syndrome (MetS) in families where a low HDL-cholesterol level (HDL-C) predisposes to early CHD.</p><p>Methods</p><p>HDL subfractions were isolated from plasma by sequential ultracentrifugation. THP-1 macrophages loaded with acetyl-LDL were used in the assay of cholesterol efflux to total HDL, HDL2, HDL3 or serum.</p><p>Results</p><p>While cholesterol efflux to serum, total HDL and HDL3 was unchanged, the efflux to HDL2 was 14% lower in subjects with MetS than in subjects without MetS (p<0.001). The efflux to HDL2 was associated with components of MetS such as plasma HDL-C (r = 0.76 in men and r = 0.56 in women, p<0.001 for both). The efflux to HDL2 was reduced in men with early CHD (p<0.01) only in conjunction with their low HDL-C. The phospholipid content of HDL2 particles was a major correlate with the efflux to HDL2 (r = 0.70, p<0.001). A low ratio of HDL2 to total HDL was associated with MetS (p<0.001).</p><p>Conclusion</p><p>Our results indicate that impaired efflux to HDL2 is a functional feature of the low HDL-C state and MetS in families where these risk factors predispose to early CHD. The efflux to HDL2 related to the phospholipid content of HDL2 particles but the phospholipid content did not account for the impaired efflux in cardiometabolic disease, where a combination of low level and poor quality of HDL2 was observed.</p></div

Cell lineage specific expression of matrix metalloproteinases -2 and -9 in transgenic mice

Abstract Mammalian extracellular matrix metalloproteinases, MMPs, are a family of enzymes capable of degrading components of the connective tissue. The in vivo regulation of the cell lineage-specific expression of MMPs, however, is not well known. This study used transgenic mice to identify cell-specific elements in the upstream regulatory regions of MMP-2 and MMP-9. Transgenic mice were generated by pronuclear microinjections into fertilised oocytes using lacZ as a reporter gene. The reporter gene constructs containing varying lengths of the MMP-9 5'-upstream region revealed an area that allowed for expression in osteoclasts and migrating keratinocytes, the cells that also express MMP-9 in vivo. The sequence driving the cell specific expression included the nucleotides from -2722 to -7745. When the same upstream regulatory fragment of MMP-9 was used to drive the expression of the human tissue specific inhibitor of MMPs, TIMP-1, instead of lacZ, the transgenic mice developed normally and the animals were fertile with normal post-embryonic growth. However, cutaneous wound healing was remarkably retarded, but not totally prevented, and the migration of keratinocytes over the wound was slow. The mice expressed the human TIMP-1 in keratinocytes during wound healing and in situ zymography revealed a total blockage of the gelatinolytic activity of MMP-2 and MMP-9, the main gelatinases active in the healing wound tissues. By using a sequence of 6500 base pairs from the 5'-upstream regulatory region of the MMP-2 gene it was possible to drive the expression of lacZ in mesenchymal cells of the developing transgenic mouse embryo. The expression pattern was similar to that found in previous in situ hybridization studies, following the different stages of tissue morphogenesis and being present in the areas of basement membrane degradation and epithelial cell invasion. Computer analyses of the sequence revealed three regulatory upstream regions conserved between human, mouse, and rat, and possibly responsible for the cell-and tissue specificity. New transgene constructs containing fragments of the conserved regions will provide a more detailed profile of the in vivo MMP-2 regulation in the future. This study defined a fragment in the upstream regulatory region of MMP-9 that is essential for expression in osteoclasts and migrating keratinocytes. Furthermore, the keratinocyte derived MMPs, including MMP-9, were found to play important role in epithelial cell migration in the area of the healing wound

lnfotech Oulu Focus lnstitute periodic report 2018–2021

Director’s preface Infotech Oulu Focus Institute promotes research in the University of Oulu’s strategic focus area of “Digitalization and smart society”. Being one of the University of Oulu’s four focus institutes, Infotech Oulu promotes multidisciplinary and internationally significant research, cross-faculty research cooperation, and researcher interaction and community spirit. Infotech Oulu supports multidisciplinary spearhead projects, engages in foresight work and initiating new research projects, develops doctoral education, strengthens international networking, and promotes the popularization of science and participating in stakeholder cooperation. Infotech Oulu’s organization was renewed in January 2022 with new directorial appointments for the period 2022–2026. Professor Dr. Simo Saarakkala, who was the the Director of Infotech in 2018–2021, continues as the Scientific Director of Infotech Oulu in the next period. University Researcher Dr. Marja Matinmikko-Blue has started as the new Research Director at Infotech Oulu. Dr. Mirjami Jutila continues as the Coordinator of Infotech Oulu. In addition, Dr. Tuire Salonurmi, Coordinator of the Digital Health research profiling area, has been actively participating the coordination actions of Infotech Oulu. Within the University of Oulu’s strategic focus area of “Digitalization and smart society”, strategic research projects coordinated under Infotech Oulu Institute have included 12 spearhead projects in 2018–2021 and 5 emerging projects in 2019–2022. These projects have accomplished 300+ publications including books, conference proceedings, book sections and journal articles. During the four-year project duration, seven doctoral theses have been finalized and more is expected in late 2022 and 2023. The results of these projects are presented in this periodic report, establishing close connections with UN SDGs. Twelve new spearhead projects started in January 2022 for a 4-year period after a competitive call where 44 proposals were reviewed via international evaluation. Additionally, 5 new emerging projects are about to start in early 2023. These new spearhead and emerging projects will form the core of Infotech Oulu Institute’s research activities for the next period. Research in the digitalization and smart society strategic research area at the University of Oulu has taken major global leaps during the current reporting period. The 6G Flagship research program launched by the Academy of Finland at the University of Oulu, started global 6G R&D in May 2018, and is the world’s first and leading 6G research program. 6G, which is aimed for deployment in the 2030s, will be a major new avenue of innovation in the entire digitalization and smart society research area. Furthermore, the University of Oulu’s research profiling activities have allowed recruitment of several high-quality researchers in this focus area. Excellence in research was well quantified in the latest international evaluation of research at the University of Oulu in Research Assessment Exercise in 2020 (RAE2020) report published in 2021, where 4 research units contributing to the strategic area of digitalization and smart society were awarded full scores and marked “outstanding”. On behalf of the Infotech Oulu Focus Institute, we would like to express our gratitude to the research community around digitalization and smart society at the University of Oulu for the excellent research. We wish the best of success to the new Infotech Oulu research projects as well as all activities around the focus area of digitalization and smart society. Oulu, Finland, 10.10.2022 Prof. Simo Saarakkala Scientific Director of Infotech (2018–2026) Dr. Marja Matinmikko-Blue Research Director of Infotech (2022–2026

Distinct Fatty Acid Compositions of HDL Phospholipids Are Characteristic of Metabolic Syndrome and Premature Coronary Heart Disease—Family Study

HDL particles can be structurally modified in atherosclerotic disorders associated with low HDL cholesterol level (HDL-C). We studied whether the lipidome of the main phosphatidylcholine (PC), lysophosphatidylcholine (LPC) and sphingomyelin (SM) species of HDL2 and HDL3 subfractions is associated with premature coronary heart disease (CHD) or metabolic syndrome (MetS) in families where common low HDL-C predisposes to premature CHD. The lipidome was analyzed by LC-MS. Lysophosphatidylcholines were depleted of linoleic acid relative to more saturated and shorter-chained acids containing species in MetS compared with non-affected subjects: the ratio of palmitic to linoleic acid was elevated by more than 30%. A minor PC (16:0/16:1) was elevated (28–40%) in MetS. The contents of oleic acid containing PCs were elevated relative to linoleic acid containing PCs in MetS; the ratio of PC (16:0/18:1) to PC (16:0/18:2) was elevated by 11–16%. Certain PC and SM ratios, e.g., PC (18:0/20:3) to PC (16:0/18:2) and a minor SM 36:2 to an abundant SM 34:1, were higher (11–36%) in MetS and CHD. The fatty acid composition of certain LPCs and PCs displayed a characteristic pattern in MetS, enriched with palmitic, palmitoleic or oleic acids relative to linoleic acid. Certain PC and SM ratios related consistently to CHD and MetS

Fto-Deficiency Affects the Gene and MicroRNA Expression Involved in Brown Adipogenesis and Browning of White Adipose Tissue in Mice

Genetic variants in the fat mass- and obesity-associated gene Fto are linked to the onset of obesity in humans. The causal role of the FTO protein in obesity is supported by evidence obtained from transgenic mice; however, the underlying molecular pathways pertaining to the role of FTO in obesity have yet to be established. In this study, we investigate the Fto gene in mouse brown adipose tissue and in the browning process of white adipose tissue. We analyze distinct structural and molecular factors in brown and white fat depots of Fto-deficient mice under normal and obesogenic conditions. We report significant alterations in the morphology of adipose tissue depots and the expression of mRNA and microRNA related to brown adipogenesis and metabolism in Fto-deficient mice. Furthermore, we show that high-fat feeding does not attenuate the browning process of Fto-deficient white adipose tissue as observed in wild-type tissue, suggesting a triggering effect of the FTO pathways by the dietary environment

Low eating self-efficacy is associated with unfavorable eating behavior tendencies among individuals with overweight and obesity

Abstract Success in long-term weight management depends partly on psychological and behavioral aspects. Understanding the links between psychological factors and eating behavior tendencies is needed to develop more effective weight management methods. This population-based cross-sectional study examined whether eating self-efficacy (ESE) is associated with cognitive restraint (CR), uncontrolled eating (UE), emotional eating (EE), and binge eating (BE). The hypothesis was that individuals with low ESE have more unfavorable eating behavior tendencies than individuals with high ESE. Participants were classified as low ESE and high ESE by the Weight-Related Self-Efficacy questionnaire (WEL) median cut-off point. Eating behavior tendencies were assessed with Three Factor Eating Questionnaire R-18 and Binge Eating Scale, and additionally, by the number of difficulties in weight management. The difficulties were low CR, high UE, high EE, and moderate or severe BE. Five hundred and thirty-two volunteers with overweight and obesity were included in the study. Participants with low ESE had lower CR (p < 0.03) and higher UE, EE, and BE (p < 0.001) than participants with high ESE. Thirty-nine percent of men with low ESE had at least two difficulties in successful weight control while this percentage was only 8% in men with high ESE. In women, the corresponding figures were 56% and 10%. The risk of low ESE was increased by high UE [OR 5.37 (95% CI 1.99–14.51)], high EE [OR 6.05 (95% CI 2.07–17.66)], or moderate or severe BE [OR 12.31 (95% CI 1.52–99.84)] in men, and by low CR [OR 5.19 (95% CI 2.22–12.18)], high UE [OR 7.20 (95% CI 2.41–19.22)], or high EE [OR 23.66 (95% CI 4.79–116.77)] in women. Low ESE was associated with unfavorable eating behavior tendencies and multiple concomitant difficulties in successful weight loss promotion. These eating behavior tendencies should be considered when counseling patients with overweight and obesity