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Search Results: 1 - 10 of 6596 matches for " Philip Newsholme "
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Unsaturated fatty acids suppress interleukin-2 production and transferrin receptor expression by concanavalin A-stimulated rat Iymphocytes
Philip C. Calder,Eric A. Newsholme
Mediators of Inflammation , 1992, DOI: 10.1155/s0962935192000188
Abstract:
Mathematical Model of Metabolism and Electrophysiology of Amino Acid and Glucose Stimulated Insulin Secretion: In Vitro Validation Using a β-Cell Line
Manuela Salvucci, Zoltan Neufeld, Philip Newsholme
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0052611
Abstract: We integrated biological experimental data with mathematical modelling to gain insights into the role played by L-alanine in amino acid-stimulated insulin secretion (AASIS) and in D-glucose-stimulated insulin secretion (GSIS), details important to the understanding of complex β-cell metabolic coupling relationships. We present an ordinary differential equations (ODEs) based simplified kinetic model of core metabolic processes leading to ATP production (glycolysis, TCA cycle, L-alanine-specific reactions, respiratory chain, ATPase and proton leak) and Ca2+ handling (essential channels and pumps in the plasma membrane) in pancreatic β-cells and relate these to insulin secretion. Experimental work was performed using a clonal rat insulin-secreting cell line (BRIN-BD11) to measure the consumption or production of a range of important biochemical parameters (D-glucose, L-alanine, ATP, insulin secretion) and Ca2+ levels. These measurements were then used to validate the theoretical model and fine-tune the parameters. Mathematical modelling was used to predict L-lactate and L-glutamate concentrations following D-glucose and/or L-alanine challenge and Ca2+ levels upon stimulation with a non metabolizable L-alanine analogue. Experimental data and mathematical model simulations combined suggest that L-alanine produces a potent insulinotropic effect via both a stimulatory impact on β-cell metabolism and as a direct result of the membrane depolarization due to Ca2+ influx triggered by L-alanine/Na+ co-transport. Our simulations indicate that both high intracellular ATP and Ca2+ concentrations are required in order to develop full insulin secretory responses. The model confirmed that K+ATP channel independent mechanisms of stimulation of intracellular Ca2+ levels, via generation of mitochondrial coupling messengers, are essential for promotion of the full and sustained insulin secretion response in β-cells.
A proteomic analysis of the functional effects of fatty acids in NIH 3T3 fibroblasts
Juliana Magdalon, Elaine Hatanaka, Talita Romanatto, Hosana G Rodrigues, Wilson MT Kuwabara, Caitriona Scaife, Philip Newsholme, Rui Curi
Lipids in Health and Disease , 2011, DOI: 10.1186/1476-511x-10-218
Abstract: Found in the majority of tissues of the body, fibroblasts are responsible for the synthesis and secretion of most extracellular matrix (ECM) components, such as proteoglycans, collagens, laminin and fibronectin, which bind to proteins expressed on cell surfaces thus modulating physiologic responses. Fibroblasts can also secrete proteinases, including matrix metalloproteinases and plasminogen, hence playing an important role in ECM degradation and tissue remodeling [1-3].The dysregulation of fibroblast biology is associated with several diseases and pathological states, including deficient wound healing [4-6], pulmonary diseases [7,8], cardiovascular diseases [9,10] and cancer [11]. Therefore, the discovery of new therapies modulating fibroblast biology could be a powerful target to develop treatment against such diseases. Oleic (18:1n-9), linoleic (18:2n-6) and palmitic (16:0) acids are the most abundant fatty acids in the western diets [12]. The latter is a saturated fatty acid found in palm oil, butter, milk, cheese and meats, whereas oleic acid is a monounsaturated fatty acid found in olive oil, meat, eggs and milk and linoleic acid is a polyunsaturated fatty acid found in soybean, sunflower, safflower and corn oils. The effects of prostaglandin derived from n-3 and n-6 fatty acids on specific protein expression (e.g. COX-2 and IL-6) in NIH 3T3 fibroblasts [13] and some aspects of the impact of fatty acids on process involving fibroblast function [14-16] have been reported. However, no systematic study has assessed the pleiotropic effects of fatty acids on fibroblast protein expression. Therefore, the aim of this study was to assess the effects of oleic (OLA), linoleic (LNA) or palmitic acids (PAM) on protein expression of NIH 3T3 fibroblasts, as determined by 2D-DIGE, i.e., separation of proteins by isoelectric focusing in the first dimension followed by SDS-PAGE in the second. This approach has been successful in elucidating the actions of palmitic acid on prot
Persistence of Inflammatory Response to Intense Exercise in Diabetic Rats
José Ricardo Bortolon,Antonio José de Almeida Silva Junior,Gilson Masahiro Murata,Philip Newsholme,Rui Curi,Tania Cristina Pithon-Curi,Elaine Hatanaka
Experimental Diabetes Research , 2012, DOI: 10.1155/2012/213986
Abstract: In this study we evaluated the onset and resolution of inflammation in control and streptozotocin-induced diabetic rats subjected to a single session of intense exercise. The following measurements were carried out prior to, immediately after, and 2 and 24 hours after exercise: plasma levels of proinflammatory cytokines (TNF-, IL-1, IL-6, CINC-2/, MIP-3, and IL-6), immunoglobulins (IgA and IgM), acute phase proteins (CRP and C3), and creatine kinase (CK) activity. We also examined the occurrence of macrophage death by measurements of macrophages necrosis (loss of membrane integrity) and DNA fragmentation. An increase was observed in the concentration of IL-1 (3.3-fold) and TNF- (2.0-fold) and in the proportion of necrotic macrophages (4.5-fold) in diabetic rats 24 hours after exercise, while the control group showed basal measurements. Twenty-four hours after the exercise, serum CK activity was elevated in diabetic rats but not in control animals. We concluded that lesion and inflammations resulting from intense exercise were greater and lasted longer in diabetic animals than in nondiabetic control rats.
Oleic, Linoleic and Linolenic Acids Increase ROS Production by Fibroblasts via NADPH Oxidase Activation
Elaine Hatanaka, Alexandre Dermargos, Aparecida Emiko Hirata, Marco Aurélio Ramirez Vinolo, Angelo Rafael Carpinelli, Philip Newsholme, Hugo Aguirre Armelin, Rui Curi
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0058626
Abstract: The effect of oleic, linoleic and γ-linolenic acids on ROS production by 3T3 Swiss and Rat 1 fibroblasts was investigated. Using lucigenin-amplified chemiluminescence, a dose-dependent increase in extracellular superoxide levels was observed during the treatment of fibroblasts with oleic, linoleic and γ-linolenic acids. ROS production was dependent on the addition of β-NADH or NADPH to the medium. Diphenyleneiodonium inhibited the effect of oleic, linoleic and γ-linolenic acids on fibroblast superoxide release by 79%, 92% and 82%, respectively. Increased levels of p47phox phosphorylation due to fatty acid treatment were detected by Western blotting analyses of fibroblast proteins. Increased p47phox mRNA expression was observed using real-time PCR. The rank order for the fatty acid stimulation of the fibroblast oxidative burst was as follows: γ-linolenic > linoleic > oleic. In conclusion, oleic, linoleic and γ-linolenic acids stimulated ROS production via activation of the NADPH oxidase enzyme complex in fibroblasts.
Persistence of Inflammatory Response to Intense Exercise in Diabetic Rats
José Ricardo Bortolon,Antonio José de Almeida Silva Junior,Gilson Masahiro Murata,Philip Newsholme,Rui Curi,Tania Cristina Pithon-Curi,Elaine Hatanaka
Journal of Diabetes Research , 2012, DOI: 10.1155/2012/213986
Abstract: In this study we evaluated the onset and resolution of inflammation in control and streptozotocin-induced diabetic rats subjected to a single session of intense exercise. The following measurements were carried out prior to, immediately after, and 2 and 24 hours after exercise: plasma levels of proinflammatory cytokines (TNF- , IL- , IL-6, CINC- , MIP-3 , and IL-6), immunoglobulins (IgA and IgM), acute phase proteins (CRP and C3), and creatine kinase (CK) activity. We also examined the occurrence of macrophage death by measurements of macrophages necrosis (loss of membrane integrity) and DNA fragmentation. An increase was observed in the concentration of IL- (3.3-fold) and TNF- (2.0-fold) and in the proportion of necrotic macrophages (4.5-fold) in diabetic rats 24 hours after exercise, while the control group showed basal measurements. Twenty-four hours after the exercise, serum CK activity was elevated in diabetic rats but not in control animals. We concluded that lesion and inflammations resulting from intense exercise were greater and lasted longer in diabetic animals than in nondiabetic control rats. 1. Introduction Moderate and regular aerobic exercise reduces insulin resistance and improves antioxidant and immune capacities, preventing the onset and progression of chronic diseases that present low-grade systemic inflammation (e.g., diabetes mellitus) [1–5]. On the other hand, high-intensity exercise imposes major acute endocrine, metabolic, and immune changes that may persist for a period of several hours after the exercise and may be detrimental to the health of diabetic patients [6]. The American College of Sports Medicine (ACSM), the American Diabetes Association (ADA), the European Association for the Study of Diabetes (EASD), and the American Heart Association (AHA) recommend regular aerobic and resistance exercising for patients with diabetes without major complications [7–10]. However, their guidelines do not specify the intensity or the most suitable type of physical exercise to maximize the benefits of exercise with minimal risk while ensuring the proper regulation of immune function and inflammatory control. Furthermore, there are no studies that have determined the time required for diabetic patients to recover from exercise-induced skeletal muscle injury. Strenuous physical exercise can result in muscle injury, promoting the release of skeletal muscle enzymes creatine kinase (CK) and lactate dehydrogenase (LDH) [11]. Inflammatory response begins by infiltration of fluid, plasma proteins, and leukocytes (e.g., macrophages) into the
Reducing consumption to avert catastrophic global climate change: The case of aviation  [PDF]
Philip Cafaro
Natural Science (NS) , 2013, DOI: 10.4236/ns.2013.51A016
Abstract:

Avoiding potentially catastrophic global climate change is a moral imperative, demanding significant reductions in greenhouse gas emissions from all important transport sectors, including aviation. However, because passenger flights and freight traffic are increasing much faster than efficiency improvements, the aviation sector will not be able to reduce emissions, or even stabilize them at current levels, without direct, forceful action to reduce demand. This paper reviews the ethical principles and empirical realities supporting the case for reducing worldwide aviation traffic. It argues that most passenger air travel and air freight shipping represents unnecessary luxury consumption, which responsible moral agents should willingly reduce in order to mitigate global climate change. It considers several mechanisms for doing so, and contends that they may succeed, but only if combined with an explicit recognition and binding commitment that for the foreseeable future, aviation must be a slow-growth or no-growth sector of the world economy.

Linking Regional Science and Urban Economics: Long-Run Interactions among Preferences for Amenities and Public Goods  [PDF]
Philip E. Philip E. Graves
Modern Economy (ME) , 2012, DOI: 10.4236/me.2012.33035
Abstract: The linked nature of long-term patterns of urban deconcentration and regional change (from rustbelt to sunbelt in the U.S., but with similar phenomena increasingly world-wide) is analyzed in a framework that emphasizes heterogeneous human preferences. The focus is on the important interactions that exist between local and regional amenities, whether exogenous or endogenous. The central thesis is that persistent exogenous amenity variation among regions provides an underlying pattern of regional growth and decline. However, inappropriate provision of local public goods in central cities is seen to lead both to non-optimally large levels of suburbanization and to rates of regional change that are also non-optimally large.
Metabolic fate of glutamine in lymphocytes, macrophages and neutrophils
Curi R.,Newsholme P.,Pithon-Curi T.C.,Pires-de-Melo M.
Brazilian Journal of Medical and Biological Research , 1999,
Abstract: Eric Newsholme's laboratory was the first to show glutamine utilization by lymphocytes and macrophages. Recently, we have found that neutrophils also utilize glutamine. This amino acid has been shown to play a role in lymphocyte proliferation, cytokine production by lymphocytes and macrophages and phagocytosis and superoxide production by macrophages and neutrophils. Knowledge of the metabolic fate of glutamine in these cells is important for the understanding of the role and function of this amino acid in the maintenance of the proliferative, phagocytic and secretory capacities of these cells. Glutamine and glucose are poorly oxidized by these cells and might produce important precursors for DNA, RNA, protein and lipid synthesis. The high rate of glutamine utilization and its importance in such cells have raised the question as to the source of this glutamine, which, according to current evidence, appears to be muscle.
Glutamine and glutamate as vital metabolites
Newsholme P.,Lima M.M.R.,Procopio J.,Pithon-Curi T.C.
Brazilian Journal of Medical and Biological Research , 2003,
Abstract: Glucose is widely accepted as the primary nutrient for the maintenance and promotion of cell function. This metabolite leads to production of ATP, NADPH and precursors for the synthesis of macromolecules such as nucleic acids and phospholipids. We propose that, in addition to glucose, the 5-carbon amino acids glutamine and glutamate should be considered to be equally important for maintenance and promotion of cell function. The functions of glutamine/glutamate are many, i.e., they are substrates for protein synthesis, anabolic precursors for muscle growth, they regulate acid-base balance in the kidney, they are substrates for ureagenesis in the liver and for hepatic and renal gluconeogenesis, they act as an oxidative fuel for the intestine and cells of the immune system, provide inter-organ nitrogen transport, and act as precursors of neurotransmitter synthesis, of nucleotide and nucleic acid synthesis and of glutathione production. Many of these functions are interrelated with glucose metabolism. The specialized aspects of glutamine/glutamate metabolism of different glutamine-utilizing cells are discussed in the context of glucose requirements and cell function.
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