301 research outputs found
Regulation of podocyte survival and endoplasmic reticulum stress by fatty acids and its modification by Stearoyl-CoA desaturases and cyclic AMP
No full textPodocyte apoptosis is a hallmark in the development and progression of diabetic nephropathy (DN). Several factors of the diabetic milieu are known to induce podocyte apoptosis. Currently, the role of free fatty acids (FFAs) for podocytopathy and podocyte cell death is unknown, although FFAs are considered to be crucially involved in the development of diabetes mellitus type II. It is well known that FFAs are toxic to several cell types including pancreatic § cells and they may contribute to the development of insulin resistance. The aims of this study were to elucidate the role of the saturated palmitic acid and the monounsaturated palmitoleic and oleic acid on podocyte cell death and endoplasmic reticulum (ER)-stress, to investigate more specifically the impact of ER-stress on podocyte survival as well as to elaborate strategies to protect podocytes from lipotoxicity.
The present study uncovered that palmitic acid induces podocyte apoptosis and necrosis and leads to ER-stress as reflected by induction of the unfolded protein response (UPR), i.e. upregulation of the ER chaperone immunoglobulin heavy chain binding protein (BiP), X-box protein 1 (XBP-1) mRNA splicing, and a strong upregulation of the proapoptotic transcription factor C/EBP homologous protein (CHOP). Gene silencing experiments of CHOP support a crucial involvment of CHOP and ER-stress in mediating the proapoptotic effect of palmitic acid in podocytes. Contrariwise, monounsaturated FFAs (MUFAs) such as palmitoleic and oleic acid prevent palmitic acid-induced podocyte death and attenuate ER-stress.
This study further revealed that the liver X receptor (LXR) agonist TO901317 (TO) ameliorates survival of palmitic acid-treated podocytes. Mechanistically, this beneficial effect can be explained mainly by the induction of stearoyl-CoA desaturase (SCD-) 1 and 2 as shown by gene silencing experiments and further supported from overexpression studies of SCD-1. Moreover, palmitic acid tracing experiments revealed a higher incorporation of palmitic acid into the triglyceride (TG) fraction in podocytes treated with TO or oleic acid, which is at least compatible with a benefit of increased fatty acid storage, by TO, i.e. SCDs, and MUFAs, respectively.
In addition, this study provides some preliminary data that adenylate cyclases (AC) may be an interesting target to protect podocytes from ER-stress in general and in particular from palmitic acid-induced podocytopathy and cell death. Experiments with forskolin, a specific AC agonist, and cyclic AMP (cAMP) analogons protect from palmitic acid-induced podocyte lipotoxicity. The effect cannot be explained by an involvment of PKA-CREB signaling as overexpression of a dominant negative CREB mutant could not abrogate the protective effect of forskolin. Furthermore, the beneficial impact of forskolin is not influencing the intrinisic (mitochondrial) apoptotic pathway. However, in addition to the protection from palmitic acid-induced cell death, forskolin is suppressing podocyte death caused by other independent ER-stressors such as tunicamycin and thapsigargin. These findings suggest a direct role of forskolin and increased cAMP levels for a protection from ER-stress in podocytes.
In summary, this study unveiled antagonistic effects of palmitic acid versus monounsaturated FFAs for podocyte survival, ER-stress and the UPR. They support an important role of CHOP in the regulation of podocyte death by FFAs. Similarly to exogenous MUFAs, induction of SCDs partially protects podocytes from palmitic acid-induced ER-stress and podocyte death. The protective effect of MUFAs may be related to increased incorporation of palmitic acid into TGs. Additional, preliminary data indicate that AC agonists such as forskolin may be interesting compounds to protect podocytes from ER-stress and from the toxic effects of FFAs. The results of this study offer a rationale for interventional studies aimed at testing whether dietary shifting of the FFA balance toward MUFAs, or tissue- (podocyte-) specific stimulation or overexpression of SCDs can delay the progression of DN. Similarly, the results of this study should encourage more studies to evaluate the therapeutic potential of AC agonists or phosphodiesterase inhibitors for the prevention and treatment of DN
Perception, attitudes and knowledge regarding the 2009 swine-origin influenza A (H1N1) virus pandemic among health-care workers in Australia
No full textAim: To determine the perceptions, attitudes and knowledge of Australian health-care workers (HCWs) regarding the novel, swine-origin influenza A (H1N1) virus (S-OIV) outbreak that reached the country in early May 2009.Methods: Self-administered, anonymous Web-based survey conducted during the early stages of the S-OIV pandemic. Participants comprised hospital- and community-based medical and nursing staff, medical students, allied health professionals, laboratory staff and administrative personnel.Results: Of the 947 participants surveyed, 59.4% were not convinced that Australia was sufficiently prepared for an influenza pandemic. Only 17.6% of the participants stated they were prepared to work unconditionally during a pandemic; 36.5% stated they would work if they had access to antiviral treatment; 27.9% would if provided with antiviral prophylaxis; and 7.5% would refuse to work. In addition, 37.5% of the participants responded they would refuse or avoid being involved in screening suspected cases. A total of 47.7% admitted to possessing a personal supply of antivirals or having considered this option. Only 48.0% provided a realistic estimate of the mortality associated with an influenza pandemic at a population level. HCWs overestimating the mortality risk and HCWs believing the efficacy of antiviral prophylaxis to be low were significantly less likely to be prepared to work (P= 0.04 and P= 0.0004, respectively).Conclusions: To ensure adequate staffing during an influenza pandemic, preparedness plans should anticipate significant levels of absenteeism by choice. Interventions aimed at increasing staff retention during a pandemic require further evaluation
Model-Based Assessment of C-Peptide Secretion and Kinetics in Post Gastric Bypass Individuals Experiencing Postprandial Hyperinsulinemic Hypoglycemia
No full textAssessment of insulin secretion is key to diagnose postprandial hyperinsulinemic hypoglycemia (PHH), an increasingly recognized complication following bariatric surgery. To this end, the Oral C-peptide Minimal Model (OCMM) can be used. This usually requires fixing C-peptide (CP) kinetics to the ones derived from the Van Cauter population model (VCPM), which has never been validated in PHH individuals. The objective of this work was to test the validity of the OCMM coupled with the VCPM in PHH subjects and propose a method to overcome the observed limitations. Two cohorts of adults with PHH after gastric bypass (GB) underwent either a 75 g oral glucose (9F/3M; age=42±9 y; BMI=28.3±6.9 kg/m2) or a 60 g mixed-meal (7F/3M; age = 43 ± 11 y; BMI=27.5±4.2 kg/m2) tolerance test. The OCMM was identified on CP concentration data with CP kinetics fixed to VCPM (VC approach). In both groups, the VC approach underestimated CP-peak and overestimated CP-tail suggesting CP kinetics predicted by VCPM to be inaccurate in this population. Thus, the OCMM was identified using CP kinetics estimated from the data (DB approach) using a Bayesian Maximum a Posteriori estimator. CP data were well predicted in all the subjects using the DB approach, highlighting a significantly faster CP kinetics in patients with PHH compared to the one predicted by VCPM. Finally, a simulation study was used to validate the proposed approach. The present findings question the applicability of the VCPM in patients with PHH after GB and call for CP bolus experiments to develop a reliable CP kinetic model in this population
Palosuran: clinical pharmacology of a urotensin-II receptor antagonist in type 2 diabetes mellitus
No full textType 2 Diabetes Mellitus (Type 2 DM) is a growing global public health threat, leading to a significant cost burden to society.
Type 2 DM increases the risk of hypertension and associated macro- and microcardiovascular diseases, affecting the eyes, brain, kidneys, and cardiovasculature. Cardiovascular disease accounts for up to 80% of the deaths in individuals with Type 2 DM. The mechanistic background for the disease is an imbalance between increased insulin requirement (insulin resistance) versus insufficient insulin availability (insulin deficiency) resulting in hyperglycemia and increased circulatory fatty acids. Treatment of Type 2 DM is aimed at increasing pancreatic ß-cell function and lowering insulin resistance in order to lower blood glucose levels. While in first line life style changes such as weight loss and exercise should be implemented, various antidiabetic drugs are available that are can be used either as mono- or combination therapy. Overall, these agents are well tolerated. However, some risks remain which could affect patient's compliance and safety. Therefore, there is a need for better and safer antidiabetic drugs.
Urotensin-II (U-II) has been described as one of the most potent vasoconstrictors up to date, though its function in humans is not fully understood.
In humans, U-II receptors (UT receptor) have been identified in various tissues; amongst others the kidney and pancreas. These organs have a crucial role in glucose regulation and cardiovascular homeostasis, mechanisms which are disrupted in diabetic patients. Increases in U-II concentrations have also been observed in diabetic patients. Therefore, antagonism of U-II could be beneficial in treatment of this disease. Palosuran is a potent, selective, oral antagonist of the human UT receptor. In healthy subjects, palosuran was well tolerated after single- and multiple-dose administration over a wide dose range. The pharmacokinetics were indicative of a twice daily dosing regimen. Two absorption peaks could be detected at approximately 1 and 4 h after drug administration. Following peak plasma concentrations, elimination was biphasic with a faster and slower elimination phase resulting in low plasma concentrations at 12 h after drug administration. The intake of food had a minor effect on drug exposure when expressed in area under the curve, but is not considered to be of clinical relevance. Therefore palosuran can be administered with and without food.
In an open-label study in patients with Type 2 diabetic nephropathy, 2-week treatment with palosuran significantly reduced the 24-hour urinary albumin excretion rate, an accepted clinical marker for cardiorenal disease progression. Surprisingly, in this study, no effects on other renal hemodynamic parameters (i.e., glomerular filtration rate, renal blood flow, filtration fraction) were observed, which hampered the understanding of the mechanism underlying the reduction of 24-h UAER. In a proof-of-concept, randomized, double-blind, placebo-controlled study, 4-week treatment with palosuran did not show any effect on insulin secretion or blood glucose levels in diet-treated patients with Type 2 DM.
These studies suggest that palosuran is not efficacious in subjects with diabetic nephropathy and Type 2 DM. However, based on the expression of UT receptors in humans, there is enough reason to believe that UT receptor antagonists can have therapeutic value in various other cardiovascular, pulmonary, renal, and oncologic indications
Author Co-Citation Analysis (ACA): a powerful tool for representing implicit knowledge of scholar knowledge workers
No full textIn the last decade, knowledge has emerged as one of the most important and valuable organizational assets. Gradually this importance caused to emergence of new discipline entitled ―knowledge management‖. However one of the major challenges of knowledge management is conversion implicit or tacit knowledge to explicit knowledge. Thus Making knowledge visible so that it can be better accessed, discussed, valued or generally managed is a long-standing objective in knowledge management. Accordingly in this paper author co- citation analysis (ACA) will be proposed as an efficient technique of knowledge visualization in academia (Scholar knowledge workers)
New Philharmonia Chorus, de Londres, director adjunto: Russell Burgess, Orquesta Nacional, Rafael Frübeck de Burgos director
No full textPrograma dels concerts que va dur a terme l'Orquestra Nacional d'Espanya amb el New Philharmonia Chorus de Londres, dirigits per R. Frühbeck de Burgos i R. Burgess respectivament. En primer lloc van interpretar "Elies" de F. Mendelssohn, amb E. Speiser, N. Procter, W. Hollweg i H. Hagegard com a solistes, i amb M. Torrent a l'orgue. El proper concert van interpretar "La Creació" de J. Haydn, amb H. Donath, W. Hollweg i S. Nimsgern com a solistes. Els concerts es van celebrar en el marc de la XIV temporada musical del patronat pro musica de Barcelon
Physiological synergy between IL-1β and insulin on glucose disposal and macrophage activity
No full textType 2 diabetes (T2D) is an inflammatory disease associated with infiltration of immune cells into various tissues and increased levels of inflammatory factors including Interleukin-1 β (IL-1β). In pancreatic islets elevated glucose levels stimulate IL-1β production resulting in impaired function and survival of β cells.
Blockade of IL-1β improves T2D, pointing on a major role for IL-1β in the
development and T2D. While the deleterious role of chronic activation of the IL-1 system in T2D is well documented, little is known about its potential physiological role(s).
The aim of the present study is to reveal the physiological role of inflammation
and specifically of IL-1β in metabolism.
In vivo acutely administered IL-1β dose dependently induced insulin secretion even at IL-1β concentrations in the circulation that are below the detection limit.
Together with glucose IL-1β promotes insulin secretion via parasympathetic nerve stimulation. In vitro IL-1β had a dual effect on glucose stimulated insulin secretion: it was beneficial at low doses and deleterious at high doses. The endotoxin lipopolysaccharide (LPS) strongly induced IL-1β, stimulated insulin secretion and improved glucose tolerance. Interestingly, the improvement of glucose tolerance was not only a consequence of increased insulin levels but was also due to direct IL-1β mediated glucose uptake into various tissues. One of the compartments responding to IL-1β with elevated glucose uptake was the cells of the immune system, mainly macrophages. We further show that macrophages significantly contribute to IL-1β mediated glucose disposal from the circulation. In addition, this work provides evidence for a role of insulin in mounting an immune response. Indeed, insulin increased the secretion of IL-1β via the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome preferentially in inflammatory M1 macrophages but not from alternatively activated M2 macrophages. In line with this response, M1 macrophages expressed higher levels of insulin receptors than naïve or M2. Further, insulin had an overall pro inflammatory effect in naïve and inflammatory macrophages, which could be attributed to increased glucose uptake via the GLUT1 glucose transporter
Fatty acids and their metabolism critically regulate podocyte survival
No full textDiabetic nephropathy (DN) is the most common cause of end-stage renal disease in industrialized countries, and most affected patients have type 2 diabetes. Podocyte injury and loss are considered critical in the development, and progression of DN. Several factors of the diabetic milieu are well known to impair function and survival of podocytes. However, the role of free fatty acids (FFAs), which are elevated in type 2 diabetes, and the role of their metabolism are just emerging in the pathogenesis of DN. FFAs were reported to regulate podocyte survival. Saturated FFAs, i.e. palmitic acid, were found to induce endoplasmic reticulum (ER) stress and podocyte death, whereas monounsaturated FFAs, i.e. palmitoleic acid or oleic acid, were protective.
The aims of the present study were to investigate whether FFA metabolism is regulated in glomeruli of type 2 diabetic patients with DN and whether regulation of FFA metabolism affects the susceptibility of podocytes towards palmitic acid. Particularly, I aimed to investigate whether regulation of fatty acid oxidation (FAO) modifies palmitic acid-induced podocyte death. As genome wide association studies suggest that acetyl CoA carboxylase (ACC) 2, an important enzyme in the regulation of FAO, is involved in the pathogenesis of DN, I performed detailed studies investigating the role of ACCs in podocytes. Furthermore, I explored the effect of palmitic acid on podocytes in combination with well-known proapoptotic stimuli of the diabetic milieu.
The present study uncovered that palmitic acid can aggravate the toxicity of other factors which are known to be important in the pathogenesis of DN and which are considered to cause podocyte loss. In particular the toxicity of high glucose concentrations and transforming growth factor (TGF)-β are substantially increased by palmitic acid, whereas the effect of palmitic acid on tumor necrosis factor (TNF)-α induced podocyte death is discret.
In the main part of this study FFA metabolism and its effect on palmitic acid induced podocyte death was investigated. The study finds that in glomeruli of type 2 diabetic patients mRNA expression levels of several key enzymes involved in fatty acid metabolism are altered. Of particular relevance for my detailed studies on FAO, a significant upregulation of all three isoforms of carnitine palmitoyltransferase (CPT)-1, the rate-limiting enzyme for FAO, and a downregulation of ACC-2, which catalyzes the formation of the CPT-1 inhibitor malonyl-CoA, are found which suggest a disposition for increased FAO. In vitro, stimulation of FAO by aminoimidazole-4-carboxamide-1β-D-ribofuranoside (Aicar) or by adiponectin, activators of the low-energy sensor AMP-activated protein kinase (AMPK), protect from palmitic acid induced podocyte death. Conversely, inhibition of CPT-1, a downstream target of AMPK, by etomoxir augments palmitic acid toxicity and impedes the protective Aicar effect. Etomoxir blocked the Aicar induced FAO measured with tritium labeled palmitic acid. Of note, only double knockdown of ACC1 and ACC2 has a protective effect on palmitic acid induced cell death, which indicates that both isoforms contribute to the regulation of FAO in podocytes. Furthermore, the effect of Aicar is associated with a reduction of ER-stress as indicated by a significant attenuation of the palmitic acid induced upregulation of immunoglobulin heavy chain binding protein (BiP), an ER chaperone, and of the proapoptotic transcription factor C/EBP homologous protein (CHOP).
In conclusion, palmitic acid increases the toxicity of other factors known to contribute to podocyte loss, which underlines the potentially important contribution of elevated saturated FFAs in the pathogenesis of DN. An important role of FFAs and of their metabolism in the pathogenesis of DN is further suggested by profound changes in gene expression levels of key enzymes of FFA metabolism in glomerular extracts of type 2 diabetic patients. The changed expression profile indicates a compensatory, protective response. Moreover, the results of this study uncover that stimulation of FAO by modulating the AMPK-ACC-CPT-1 pathway protects from palmitic acid induced podocyte death. The results of this study should encourage further investigations to evaluate the therapeutic potential of interfering with FFA metabolism specifically with stimulating FAO for the prevention and therapy of DN
Metabolic Consequences of Adipocyte-specific Deletion of the IL-1 Receptor in Mice
No full textWith the increasing abundance of food and the deleterious consequences of overnutrition, metabolic stress may act on the immune system and trigger local and systemic inflammation. My host laboratory previously found that adipose tissue macrophages are the first immune cells responding to feeding after fasting by upregulating the interleukin-1 (IL-1) pathway. Therefore, we generated mice that lack the receptor for IL-1specifically in adipocytes (Il1r1fl/fl Adipoq-Cretg/0) and assessed metabolic consequences.
Despite unaltered body weight development under regular chow- and high-fat diet (HFD) feeding, we found Il1r1fl/fl Adipoq-Cretg/0 mice on chow diet to have metabolic changes indicative of pre-diabetes at 1 year of age. With HFD feeding, glucose intolerance was already apparent after 10 weeks of HFD feeding. Further, we found the gene encoding for IL-6 to be lower in adipocytes of knock out mice fed chow diet. Fluorescence-activated cell sorting (FACS) analysis revealed that the immune cell composition of the stromal vascular fraction of Il1r1fl/fl Adipoq-Cretg/0 mice are comparable to controls. Further, Il1r1fl/fl Adipoq-Cretg/0 mice pre-injected with IL-1β in a glucose tolerance test showed a blunted insulin response compared to control mice, suggesting that a part of the insulin secretagogue action of IL-1β signals via adipocytes. Interestingly, Il1r1fl/fl Adipoq-Cretg/0 mice on HFD showed an increased pancreas weight, which might point to a novel crosstalk of IL-1 signaling in fat tissue and the pancreas.
Overall, our adipocyte-specific Il1r1 knock out mice show similar body weight development as control mice but show signs of impaired glucose metabolism when aging or fed a HFD
Imatinib reduces non-alcoholic fatty liver disease in obese mice by targeting inflammatory and lipogenic pathways in macrophages and liver
No full textMacrophages have been recognized as key players in non-alcoholic fatty liver disease (NAFLD). Our aim was to assess whether pharmacological attenuation of macrophages can be achieved by imatinib, an anti-leukemia drug with known anti-inflammatory and antidiabetic properties, and how this impact on NAFLD. We analyzed the pro- and anti-inflammatory gene expression of murine macrophages and human monocytes in vitro in the presence or absence of imatinib. In a time-resolved study, we characterized metabolic disease manifestations such as hepatic steatosis, systemic and adipose tissue inflammation as well as lipid and glucose metabolism in obese mice at one and three months of imatinib treatment. Our results showed that imatinib lowered pro-inflammatory markers in murine macrophages and human monocytes in vitro. In obese mice, imatinib reduced TNFα-gene expression in peritoneal and liver macrophages and systemic lipid levels at one month. This was followed by decreased hepatic steatosis, systemic and adipose tissue inflammation and increased insulin sensitivity after three months. As the transcription factor sterol regulatory element-binding protein (SREBP) links lipid metabolism to the innate immune response, we assessed the gene expression of SREBPs and their target genes, which was indeed downregulated in the liver and partially in peritoneal macrophages. In conclusion, targeting both inflammatory and lipogenic pathways in macrophages and liver as shown by imatinib could represent an attractive novel therapeutic strategy for patients with NAFLD
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