Cholesteryl ester transfer protein (CETP) I405V polymorphism and cardiovascular disease in eastern European Caucasians – a cross-sectional study

Methods A cross-sectional study was conducted to genotype 1028 healthy blood donors and 1517 clinically well characterized elderly for CETP I405V. Results We could not find any association of this polymorphism with age for both, males or females, in any of these cohorts (P = 0.71 and P = 0.57, respectively, for males and P = 0.55 and P = 0.88, respectively, for females). In addition, no association with cardiovascular diseases could be observed in the elderly cohort (males OR = 1.12 and females OR = 0.88). In the same cohort, the CETP V405V genotype was associated with significantly enhanced HDL levels (P = 0.03), mostly owing to the female sex (P = 0.46 for males, P = 0.02 for females), whereas LDL and triglyceride levels were unchanged (P = 0.62 and P = 0.18, respectively). Conclusion Our data support the recent hypothesis that variations enhancing HDL levels without affecting LDL levels are not associated with the risk for cardiovascular diseases

TLR-6 SNP P249S is associated with healthy aging in nonsmoking Eastern European Caucasians - A cohort study

Background To investigate mechanisms that determine healthy aging is of major interest in the modern world marked by longer life expectancies. In addition to lifestyle and environmental factors genetic factors also play an important role in aging phenotypes. The aged immune system is characterized by a chronic micro-inflammation, known as inflamm-aging, that is suspected to trigger the onset of age-related diseases such as cardiovascular disease, Alzheimer’s disease, cancer, and Diabetes Mellitus Type 2 (DMT2). We have recently shown that a Toll-like receptor 6 variant (P249S) is associated with susceptibility to cardiovascular disease and speculated that this variant may also be associated with healthy aging in general by decreasing the process of inflamm- aging. Results Analyzing the PolSenior cohort we show here that nonsmoking S allele carriers are significantly protected from age-related diseases (P = 0.008, OR: 0.654). This association depends not only on the association with cardiovascular diseases (P = 0.018, OR: 0.483) for homozygous S allele carriers, but is also driven by a protection from Diabetes Mellitus type 2 (P = 0.010, OR: 0.486) for S allele carriers. In addition we detect a trend but no significant association of this allele with inflamm-aging in terms of baseline IL-6 levels. Conclusion We confirm our previous finding of the TLR-6 249S variant to be protective regarding cardiovascular diseases. Furthermore, we present first evidence of TLR-6 249S being involved in DMT2 susceptibility and may be in general associated with healthy aging possibly by reducing the process of inflamm-aging

GLP-2 as Beneficial Factor in the Glucose Homeostasis in Mice Fed a High Fat Diet

Glucagon like peptide-2 (GLP-2) is a gastrointestinal hormone released in response to dietary nutrients, which acts through a specific receptor, the GLP-2 receptor (GLP-2R). The physiological effects of GLP-2 are multiple, involving also the intestinal adaptation to high fat diet (HFD). In consideration of the well-known relationship between chronic HFD and impaired glucose metabolism, in the present study we examined if the blocking of the GLP-2 signaling by chronic treatment with the GLP-2R antagonist, GLP-2 (3-33), leads to functional consequences in the regulation of glucose metabolism in HFD-fed mice. Compared with animals fed standard diet (STD), mice at the 10th week of HFD showed hyperglycaemia, glucose intolerance, high plasma insulin level after glucose load, increased pancreas weight and β cell expansion, but not insulin resistance. In HFD fed mice, GLP-2 (3-33) treatment for 4 weeks (from the 6th to the 10th week of diet) did not affect fasting glycaemia, but it significantly increased the glucose intolerance, both fasting and glucose-induced insulin levels, and reduced the sensitivity to insulin leading to insulin-resistance. In GLP-2 (3-33)-treated HFD mice pancreas was significantly heavier and displayed a significant increase in β-cell mass in comparison with vehicle-treated HFD mice. In STD mice, the GLP-2 (3-33) treatment did not affect fasted or glucose-stimulated glycemia, insulin, insulin sensitivity, pancreas weight and beta cell mass. The present study suggests that endogenous GLP-2 may act as a protective factor against the dysregulation of the glucose metabolism that occurs in HFD mice, because GLP-2 (3-33) worsens glucose metabolism disorders. J. Cell. Physiol. 230: 3029-3036, 2015. © 2015 Wiley Periodicals, Inc

Quantum dot loaded immunomicelles for tumor imaging

<p>Abstract</p> <p>Background</p> <p>Optical imaging is a promising method for the detection of tumors in animals, with speed and minimal invasiveness. We have previously developed a lipid coated quantum dot system that doubles the fluorescence of PEG-grafted quantum dots at half the dose. Here, we describe a tumor-targeted near infrared imaging agent composed of cancer-specific monoclonal anti-nucleosome antibody 2C5, coupled to quantum dot (QD)-containing polymeric micelles, prepared from a polyethylene glycol/phosphatidylethanolamine (PEG-PE) conjugate. Its production is simple and involves no special equipment. Its imaging potential is great since the fluorescence intensity in the tumor is twofold that of non-targeted QD-loaded PEG-PE micelles at one hour after injection.</p> <p>Methods</p> <p>Para-nitrophenol-containing (5%) PEG-PE quantum dot micelles were produced by the thin layer method. Following hydration, 2C5 antibody was attached to the PEG-PE micelles and the QD-micelles were purified using dialysis. 4T1 breast tumors were inoculated subcutaneously in the flank of the animals. A lung pseudometastatic B16F10 melanoma model was developed using tail vein injection. The contrast agents were injected via the tail vein and mice were depilated, anesthetized and imaged on a Kodak Image Station. Images were taken at one, two, and four hours and analyzed using a methodology that produces normalized signal-to-noise data. This allowed for the comparison between different subjects and time points. For the pseudometastatic model, lungs were removed and imaged <it>ex vivo </it>at one and twenty four hours.</p> <p>Results</p> <p>The contrast agent signal intensity at the tumor was double that of the passively targeted QD-micelles with equally fast and sharply contrasted images. With the side views of the animals only tumor is visible, while in the dorsal view internal organs including liver and kidney are visible. <it>Ex vivo </it>results demonstrated that the agent detects melanoma nodes in a lung pseudometastatic model after a 24 hours wash-out period, while at one hour, only a uniform signal is detected.</p> <p>Conclusions</p> <p>The targeted agent produces ultrabright tumor images and double the fluorescence intensity, as rapidly and at the same low dose as the passively targeted agents. It represents a development that may potentially serve to enhance early detection for metastases.</p

COVID-19 severity and thrombo-inflammatory response linked to ethnicity

Although there is strong evidence that SARS-CoV-2 infection is associated with adverse outcomes in certain ethnic groups, the association of disease severity and risk factors such as comorbidities and biomarkers with racial disparities remains undefined. This retrospective study between March 2020 and February 2021 explores COVID-19 risk factors as predictors for patients&rsquo; disease progression through country comparison. Disease severity predictors in Germany and Japan were cardiovascular-associated comorbidities, dementia, and age. We adjusted age, sex, body mass index, and history of cardiovascular disease comorbidity in the country cohorts using a propensity score matching (PSM) technique to reduce the influence of differences in sample size and the surprisingly young, lean Japanese cohort. Analysis of the 170 PSM pairs confirmed that 65.29% of German and 85.29% of Japanese patients were in the uncomplicated phase. More German than Japanese patients were admitted in the complicated and critical phase. Ethnic differences were identified in patients without cardiovascular comorbidities. Japanese patients in the uncomplicated phase presented a suppressed inflammatory response and coagulopathy with hypocoagulation. In contrast, German patients exhibited a hyperactive inflammatory response and coagulopathy with hypercoagulation. These differences were less pronounced in patients in the complicated phase or with cardiovascular diseases. Coagulation/fibrinolysis-associated biomarkers rather than inflammatory-related biomarkers predicted disease severity in patients with cardiovascular comorbidities: platelet counts were associated with severe illness in German patients. In contrast, high D-dimer and fibrinogen levels predicted disease severity in Japanese patients. Our comparative study indicates that ethnicity influences COVID-19-associated biomarker expression linked to the inflammatory and coagulation (thrombo-inflammatory) response. Future studies will be necessary to determine whether these differences contributed to the less severe disease progression observed in Japanese COVID-19 patients compared with those in Germany

Review article: a comparison of glucagon-like peptides 1 and 2.

BACKGROUND: Recent advancements in understanding the roles and functions of glucagon-like peptide 1 (GLP-1) and 2 (GLP-2) have provided a basis for targeting these peptides in therapeutic strategies. AIM: To summarise the preclinical and clinical research supporting the discovery of new therapeutic molecules targeting GLP-1 and GLP-2. METHODS: This review is based on a comprehensive PubMed search, representing literature published during the past 30 years related to GLP-1 and GLP-2. RESULTS: Although produced and secreted together primarily from L cells of the intestine in response to ingestion of nutrients, GLP-1 and GLP-2 exhibit distinctive biological functions that are governed by the expression of their respective receptors, GLP-1R and GLP-2R. Through widespread expression in the pancreas, intestine, nervous tissue, et cetera, GLP-1Rs facilitates an incretin effect along with effects on appetite and satiety. GLP-1 analogues resistant to degradation by dipeptidyl peptidase-IV and inhibitors of dipeptidyl peptidase-IV have been developed to aid treatment of diabetes and obesity. The GLP-2R is expressed almost exclusively in the stomach and bowel. The most apparent role for GLP-2 is its promotion of growth and function of intestinal mucosa, which has been targeted for therapies that promote repair and adaptive growth. These are used as treatments for intestinal failure and related conditions. CONCLUSIONS: Our growing understanding of the biology and function of GLP-1, GLP-2 and corresponding receptors has fostered further discovery of fundamental biological function as well as new categories of potent therapeutic medicines

Molecular mechanisms of incretin hormone secretion

Incretin peptides (glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)) are secreted from enteroendocrine cells in the intestinal epithelium, and help to coordinate metabolic responses to food ingestion. A number of molecular mechanisms have recently been defined that underlie carbohydrate, lipid and protein sensing in gut endocrine cells. Knockout mice lacking sodium glucose tranporter-1 (SGLT-1) or the short chain fatty acid sensing receptor FFAR2 (GPR43), for example, have highlighted the importance of these molecules in incretin secretion. This review outlines our current understanding of sensory pathways in incretin secreting cells and highlights the therapeutic potential of targeting them for the development of novel therapies for obesity and diabetes

The importance of Protein Kinase C isoforms PKCα and PKCβ for the acetylcholine-induced Calcium Signal in the native murine pancreatic β-cells

Titelblatt und Inhaltsverzeichnis Einleitung Material und Methoden Ergebnisse Diskussion LiteraturverzeichnisZusammenfassend konnten wir mit Hilfe der drei untersuchten Maus- Modelle mit PKCα-, PKCβ\- und PKCα-/PKCβ-Defizienz die Beteiligung der beiden Isozyme am ACh-vermittelten intrazellulären Ca2+-Signal in den insulinsezernierenden β-Zellen nachweisen. Hierbei zeigte es sich eine Kombination aus hemmenden, aber auch fördernden Einflüssen dieser PKCIsoformen auf das Ca2+-Signal, wobei vor allem der Einstrom des Ca2+ aus dem extrazellulären Raum beeinträchtigt wurde. Die Freisetzung der Ca2+- Ionen aus den intrazellulären Speichern blieb in unseren Experimenten in allen knock-out-Modellen unbeeinträchtigt. Während die PKCα-Defizienz nur zu einer leichten Verminderung des ACh-bedingten Ca2+-Signals in der Plateau-Phase führte, kam es in den PKCβ-/- β-Zellen zu deutlicher Vergrößerung des Ca2+-Signals nach ACh-Stimulation. Die PKCβ- Defizienz führte hierbei vor allem zur Vermehrung des Ca2+-Einstroms über die spannungsunabhängigen Ca2+-Kanäle, wie in der Versuchsreihe mit Thapsigargin- Blockade der intrazellulären Ca2+-ATPasen nachgewiesen werden konnte. Die PKCβ scheint vorwiegend eine hemmende Wirkung auf den Ca2+-Einstrom auszuüben. Die PKCαβ-/- β-Zellen zeigten eine signifikante Erhöhung des Initial-Peaks nach ACh-Stimulation, der vermehrte Ca2+-Einstrom über spannungsunabhängige Kanäle konnte in den PKCαβ-/- β-Zellen nicht nachgewiesen werden. Während in den PKCα-/- und PKCβ-/- β-Zellen der Ca2+-Einstrom über CaVKanäle nach der Depolarisation der Zellmembran unverändert blieb, zeigten die PKCαβ-/- β-Zellen eine deutliche Verminderung des Ca2+-Einstroms über CaV (CaV 1.2, CaV 1.3) nach der Depolarisation der Zellmembran mit K+- Ionen. Offensichtlich verfügen die cPKC-Enzyme β-Zelle über die Möglichkeit, einander zu kompensieren. Dennoch handelt es sich um Enzyme mit spezifischer Funktion. Die weitere Erforschung dieser Zusammenhänge würde zum besseren Verständnis der physiologischen aber auch der pathophysiologischen Vorgänge in der β-Zelle führen und langfristig auch neue Möglichkeiten zur Entwicklung nächster Generationen unterschiedlicher Antidiabetika führen, die zur Behandlung vom Diabetes Typ 2 beitragen könnten.PKCα-, PKCβ\- and PKCαβ-deficient mice were used to establish the importance of classical PKC isoforms for the intracellular calcium signaling in pancreatic β-cells. PKC-deficient β-cells showed distinct isoform-dependent changes in calcium signaling, especially the calcium influx through the membrane calcium channels. The intracellular calcium stores were not affected. PKCα deficiency caused minimal decrease in calcium influx in the second phase of intracellular calcium signal due to acetylcholine stimulation. PKCβ deficiency, however, induced increased global calcium influx in acetylcholine associated calcium signaling. Especially the voltage-independent calcium channels (SOC) showed increased influx, as detected by thapsigargin treatment in β-cells. The PKCβ isoform appears to be involved into a negative feedback mechanism of calcium signal regulation due to acetylcholine stimulation. Global cPKC deficiency (PKCαβ-knockout) caused increased initial calcium signal in acetylcholine-treated β-cells. Additionally, global calcium influx through voltage-dependent calcium channels (CaV) was significantly decreased. Therefore, the classical PKC isoforms are able to compensate each other in CaV channel regulation. The better understanding of mechanisms underlying the physiological and pathophysiological regulation in the β-cell is absolutely necessary for future development of novel therapy strategies for type 2 diabetes