Serum COMP-C3b complexes in rheumatic diseases and relation to anti-TNF-alpha treatment

Introduction: Cartilage oligomeric matrix protein (COMP) is found at elevated concentrations in sera of patients with joint diseases such as rheumatoid arthritis (RA) and osteoarthritis (OA). We recently showed that COMP activates complement via the alternative pathway and that COMP-C3b complexes are present in sera of RA patients, but not in healthy controls. We now set out to elaborate on the information provided by this marker in a variety of diseases and larger patient cohorts. Methods: COMP-C3b levels in sera were measured by using an enzyme-linked immunosorbent assay (ELISA) capturing COMP and detecting C3b. Serum COMP was measured by using ELISA. Results: COMP-C3b levels were significantly elevated in patients with RA as well as in systemic lupus erythematosus (SLE), compared with healthy controls. SLE patients with arthritis had significantly higher COMP-C3b levels than did those without. COMP-C3b was furthermore elevated in patients with ankylosing spondylitis (AS), psoriatic arthritis (PsA), reactive arthritis, systemic sclerosis, and OA. COMP-C3b did not correlate with COMP in any of the patient groups. COMP-C3b correlated with disease activity in RA, but not in other diseases. COMP-C3b levels in RA patients decreased on treatment with tumor necrosis factor (TNF)-alpha inhibitors, whereas the levels increased in patients with AS or PsA. The changes of COMP-C3b did not parallel the changes of C-reactive protein (CRP). Conclusions: COMP-C3b levels are elevated in several rheumatologic diseases and correlate with inflammatory measures in RA. COMP-C3b levels in RA decrease during TNF-alpha inhibition differently from those of CRP, suggesting that formation of COMP-C3b relates to disease features not reflected by general inflammation measures

Engineered mesoporous silica reduces long-term blood glucose and HbA1c, and improves metabolic parameters in prediabetics

Aim: To investigate the effect of oral consumption of engineered mesoporous silica particles, SiPore15 (R), on long-term blood glucose levels and other metabolic parameters in individuals with prediabetes and newly diagnosed Type 2 diabetes. Method: An open-label, single-arm, multicenter trial was conducted in which SiPore15 was consumed three times daily for 12 weeks. Hemoglobin A1c (HbA1c, primary end point) and an array of metabolic parameters were measured at baseline and throughout the trial. Result: SiPore15 treatment significantly reduced HbA1c by a clinically meaningful degree and improved several disease-associated parameters with minimal side effects. Conclusion: The results from this study demonstrate the potential use of SiPore15 as a treatment for prediabetes that may also delay or prevent the onset of Type 2 diabetes.Peer reviewe

Role of G protein‐coupled receptor kinases (GRKs) in β2‐adrenoceptor‐mediated glucose uptake

Truncation of the C‐terminal tail of the β2‐AR, transfection of βARKct or over‐expression of a kinase‐dead GRK mutant reduces isoprenaline‐stimulated glucose uptake, indicating that GRK is important for this response. We explored whether phosphorylation of the β2‐AR by GRK2 has a role in glucose uptake or if this response is related to the role of GRK2 as a scaffolding protein. CHO‐GLUT4myc cells expressing wild‐type and mutant β2‐ARs were generated and receptor affinity for [3H]‐CGP12177A and density of binding sites determined together with the affinity of isoprenaline and BRL37344. Following receptor activation by β2‐AR agonists, cAMP accumulation, GLUT4 translocation, [3H]‐2‐deoxyglucose uptake, and β2‐AR internalization were measured. Bioluminescence resonance energy transfer was used to investigate interactions between β2‐AR and β‐arrestin2 or between β2‐AR and GRK2. Glucose uptake after siRNA knockdown or GRK inhibitors was measured in response to β2‐AR agonists. BRL37344 was a poor partial agonist for cAMP generation but displayed similar potency and efficacy to isoprenaline for glucose uptake and GLUT4 translocation. These responses to β2‐AR agonists occurred in CHO‐GLUT4myc cells expressing β2‐ARs lacking GRK or GRK/PKA phosphorylation sites as well as in cells expressing the wild‐type β2‐AR. However, β2‐ARs lacking phosphorylation sites failed to recruit β‐arrestin2 and did not internalize. GRK2 knock‐down or GRK2 inhibitors decreased isoprenaline‐stimulated glucose uptake in rat L6 skeletal muscle cells. Thus, GRK phosphorylation of the β2‐AR is not associated with isoprenaline‐ or BRL37344‐stimulated glucose uptake. However, GRKs acting as scaffold proteins are important for glucose uptake as GRK2 knock‐down or GRK2 inhibition reduces isoprenaline‐stimulated glucose uptake

Shikonin Increases Glucose Uptake in Skeletal Muscle Cells and Improves Plasma Glucose Levels in Diabetic Goto-Kakizaki Rats

Glucose is the most common substrate for energy metabolism. Despite the varying demands for glucose, the body needs to regulate its internal environment and maintain a constant and stable condition. Glucose homeostasis requires harmonized interaction between several tissues, achieving equilibrium between glucose output and uptake. In this thesis we aimed to investigate factors modulating glucose homeostasis in a rat model of type 2 diabetes, the Goto-Kakizaki (GK) rat. In addition, we investigated sex differences in hepatic carbohydrate and lipid metabolism in healthy rats. In Paper I, three-week but not three-day treatment with a Southeast Asian herb, Gynostemma pentaphyllum (GP), significantly reduced plasma glucose (PG) levels in GK rats. An intra-peritoneal glucose tolerance test (IPGTT) was significantly improved in GP-treated compared to placebo-treated group. In the GP treated rats, the glucose response in an intra-peritoneal pyruvate tolerance test was significantly lower, indicating decreased gluconeogenesis, and hepatic glucose output (HGO) was reduced. GP-treatment significantly reduced hepatic glycogen content, but not glycogen synthase activity. The study provides evidence that the GP extract exerted anti-diabetic effect in GK rats, reducing PG levels and HGO, suggesting that GP improves the hepatic insulin sensitivity by suppressing gluconeogenesis. In Paper II, shikonin, a naphthoquinone derived from the Chinese plant Lithospermum erythrorhizon, increased glucose uptake in L6 myotubes, but did not phosphorylate Akt. Furthermore we found no evidence for the involvement of AMP activated protein kinase (AMPK) in shikonin induced glucose uptake. Shikonin increased the intracellular levels of calcium in these cells and stimulated the translocation of GLUT4 from intracellular vesicles to the cell surface in L6 myotubes. In GK rats treated with shikonin once daily for 4 days, PG levels were significantly decreased. In an insulin sensitivity test, the absolute PG levels were significantly lower in the shikonin-treated rats. These findings suggest that shikonin increases glucose uptake in muscle cells via an insulin-independent pathway dependent on calcium. In Paper III, GK and control Wistar rats were injected daily for up to 4 weeks with either a non-hematopoietic erythropoietin analog ARA290 or with placebo. PG levels in GK but not Wistar rats were significantly lower in ARA290-treated compared to placebo. After 2 and 4 weeks, the IPGTT was significantly improved in ARA290 treated GK rats. In insulin and pyruvate tolerance tests, glucose responses were similar in ARA290 and placebo groups. In isolated GK rat islets, glucose-stimulated insulin release was two-fold higher and islet intracellular calcium concentrations in response to several secretagogues were significantly higher in ARA290-treated than in placebo-treated GK rats. These findings indicate that treatment with ARA290 significantly improved glucose tolerance in diabetic GK rats, most likely due to improvement of insulin release. In Paper IV, sex differences in hepatic carbohydrate and lipid metabolism were characterized in healthy rats. No sex-differences were observed regarding hepatic triglyceride content, fatty acid oxidation rates or insulin sensitivity. Male rats had higher ratios of insulin to glucagon levels, increased hepatic glycogen content, a lower degree of AMPK phosphorylation, a higher rate of glucose production and higher expression levels of gluconeogenic genes, as compared to female rats. A sex-dependent response to mild starvation was observed with males being more sensitive. In conclusion, sex-differences reflect a higher capacity of the healthy male rat liver to respond to increased energy demands. Key words: glucose homeostasis, type 2 diabetes, GK rats, L6 myotubes, hepatic glucose output, insulin sensitivity, sex differences

β-Adrenergic Inhibition of Contractility in L6 Skeletal Muscle Cells

The β-adrenoceptors (β-ARs) control many cellular processes. Here, we show that β-ARs inhibit calcium depletion-induced cell contractility and subsequent cell detachment of L6 skeletal muscle cells. The mechanism underlying the cell detachment inhibition was studied by using a quantitative cell detachment assay. We demonstrate that cell detachment induced by depletion of extracellular calcium is due to myosin- and ROCK-dependent contractility. The β-AR inhibition of L6 skeletal muscle cell detachment was shown to be mediated by the β2-AR and increased cAMP but was surprisingly not dependent on the classical downstream effectors PKA or Epac, nor was it dependent on PKG, PI3K or PKC. However, inhibition of potassium channels blocks the β2-AR mediated effects. Furthermore, activation of potassium channels fully mimicked the results of β2-AR activation. In conclusion, we present a novel finding that β2-AR signaling inhibits contractility and thus cell detachment in L6 skeletal muscle cells by a cAMP and potassium channel dependent mechanism

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Populationsundersökningen av kvinnor i Göteborg (Kvinnoundersökningen, KVUS) - undersökning 1974

The population study of women in Gothenburg is a population study based at the University of Gothenburg. The study started as a cross-sectional study in 1968 including 1462 women aged 38, 46, 50 and 60 years. The participants have after that been followed-up with regular examinations in 1974-75, 1980-81, 1992-1993, 2000-2001, 2004-2005, 2009-2010 and 2016-2017. In addition, new participants have been included. During the examinations 2004-2005 and 2016-2017, only women 38 and 50 years old were invited to participate with the purpose of enabling comparison of these age cohorts. The study comprises physical and mental disease as well as health, social and psychological circumstances and data regarding food and dental health. To study determinants among middle age women that have importance for the development of cardiovascular disease, diabetes, cancer, dementia and other mental illness in high age is possible because of the long running follow-ups, high participant rates, and thorough mapping of non-participants and data regarding morbidity and mortality. The study covers both longitudinal trends (change in individuals over time) and secular trends (changes in the population over time). This implies the possibility to study e.g. whether the increased consumption of oestrogenic hormones and new antidepressive agents in the population has influenced the occurrence of cardiovascular disease, dementia, depression and the proportion that are under treatment. The long-running follow-up has also made it possible to study the long term prognosis for these diseases and whether the risk for prolonged illness increases with older age. In addition, women from different birth cohorts are examined at certain ages to investigate secular trends in health related variables, such as obesity and dental health. The questionnaires have been changed as little as possible between each survey. Data from 1968 and 1974 are available from SND. The population study of women in Gothenburg collaborates with the H70 study which started in 1971, a cross-sectional study of men and women in Gothenburg aged 70 years. It is coordinated by several researcher groups, especially the groups handling general medicine, epidemiology, psychiatry and geriatrics. When the participants turned 70 years old, they were invited to participate in the H70 study (1992, 2000), and a follow-up examination of 75 years old participants 2005-2006. Purpose: The purpose of this study was initially to investigate anemia and health factors related to menopause, but has later also included examination of determinants among middle age women that have importance for the development of cardiovascular disease, diabetes, cancer, dementia and other mental illness in high age.Kvinnoundersökningen i Göteborg är en populationsstudie som bedrivs vid Göteborgs universitet. Studien startade 1968 som en tvärsnittsstudie omfattande 1462 kvinnor i åldrarna 38, 46, 50, 54 och 60 år. Sedan dess har deltagarna genomgått regelbundna uppföljningar 1974-75, 1980-81, 1992-1993, 2000-2001, 2004-2005, 2009-2010 och 2016-2017. Samtidigt har nya deltagare tillkommit. Vid undersökningarna 2004-2005 samt 2016-2017 inbjöds endast kvinnor 38 och 50 år gamla att delta för att möjliggöra en jämförelse av dessa ålderskohorter. Studien omfattar såväl kroppsliga och psykiska sjukdomar, hälsa, sociala och psykologiska faktorer som tand- och kostdata. Att studera faktorer hos kvinnor i medelåldern som har betydelse för utveckling av bland annat hjärtkärlsjukdom, diabetes, cancer, demens och andra psykiska sjukdomar i hög ålder är möjligt i kvinnostudien tack vare en lång uppföljningstid, hög deltagarfrekvens, och noggrann kartläggning av bortfall samt sjukdoms- och dödlighetsdata. Studien ger möjlighet att studera både longitudinella trender (förändring över tid hos individer) och sekulära trender (förändring i befolkningen över tid). Man har bl. a. studerat huruvida den ökade förbrukningen av östrogena hormoner och nya antidepressiva läkemedel i befolkningen har påverkat förekomsten av hjärtkärlsjukdom, demens och depression samt andelen som har behandling. De långa uppföljningstiderna har också gjort det möjligt att studera långtidsprognosen för dessa sjukdomar och om risken för långvarig sjukdom ökar med stigande ålder. I studien jämförs även kvinnor från olika födelsekohorter vid vissa åldrar för att studera sekulära trender i hälsorelaterade variabler, som exempelvis fetma och tandhälsa. Frågorna i enkäterna har i så så liten grad som möjligt ändrats mellan varje undersökningsomgång. Data från undersökningen 1968 och 1974 finns hos SND. Kvinnoundersökningen samarbetar med H70-studien som startade 1971, en studie av manliga och kvinnliga 70-åringar i Göteborg och koordineras av flera forskargrupper, framför allt inom allmänmedicin, epidemiologi, psykiatri och geriatrik. Kvinnor i Kvinnoundersökningen erbjöds de åren de fyllde 70 år att delta i H70-studien (1992, 2000) samt till en uppföljning av 75-åringar som genomfördes 2005-2006. Syfte: Syftet med studien var från början att undersöka anemi och hälsofaktorer relaterad till menopaus, men har sedan omfattat även att undersöka faktorer hos kvinnor i medelåldern som har betydelse för utveckling av bland annat hjärtkärlsjukdom, diabetes, cancer, demens och andra psykiska sjukdomar i hög ålder