scholarly journals Dominant Role of PI3K p110α over p110β in Insulin and β-Adrenergic Receptor Signalling

2021 ◽  
Vol 22 (23) ◽  
pp. 12813
Author(s):  
Biqin Zhang ◽  
Cheukyau Luk ◽  
Joyce Valadares ◽  
Christos Aronis ◽  
Lazaros C. Foukas
Keyword(s):  
Insulin Receptor ◽  
Adrenergic Receptor ◽  
Metabolic Regulation ◽  
Insulin Signalling ◽  
Dominant Role ◽  
Selective Inhibitors ◽  
Relative Contribution ◽  
Regulation Of Metabolism ◽  
A Cell

Attribution of specific roles to the two ubiquitously expressed PI 3-kinase (PI3K) isoforms p110α and p110β in biological functions they have been implicated, such as in insulin signalling, has been challenging. While p110α has been demonstrated to be the principal isoform activated downstream of the insulin receptor, several studies have provided evidence for a role of p110β. Here we have used isoform-selective inhibitors to estimate the relative contribution of each of these isoforms in insulin signalling in adipocytes, which are a cell type with essential roles in regulation of metabolism at the systemic level. Consistent with previous genetic and pharmacological studies, we found that p110α is the principal isoform activated downstream of the insulin receptor under physiological conditions. p110α interaction with Ras enhanced the strength of p110α activation by insulin. However, this interaction did not account for the selectivity for p110α over p110β in insulin signalling. We also demonstrate that p110α is the principal isoform activated downstream of the β-adrenergic receptor (β-AR), another important signalling pathway in metabolic regulation, through a mechanism involving activation of the cAMP effector molecule EPAC1. This study offers further insights in the role of PI3K isoforms in the regulation of energy metabolism with implications for the therapeutic application of selective inhibitors of these isoforms.

scholarly journals Formation of hydroxyl radical from San Joaquin Valley particles extracted in a cell-free surrogate lung fluid

2011 ◽  
Vol 11 (18) ◽  
pp. 9671-9682 ◽  
Author(s):  
H. Shen ◽  
C. Anastasio
Keyword(s):  
Hydroxyl Radical ◽  
Dominant Role ◽  
San Joaquin Valley ◽  
Lung Fluid ◽  
Adverse Health Effects ◽  
Quantitative Studies ◽  
A Cell ◽  
Lung Lining Fluid ◽  
Phosphate Buffered Saline

Abstract. Previous studies have suggested that the adverse health effects from ambient particulate matter (PM) are linked to the formation of reactive oxygen species (ROS) by PM in cardiopulmonary tissues. While hydroxyl radical (•OH) is the most reactive of the ROS species, there are few quantitative studies of •OH generation from PM. Here we report on •OH formation from PM collected at an urban (Fresno) and rural (Westside) site in the San Joaquin Valley (SJV) of California. We quantified •OH in PM extracts using a cell-free, phosphate-buffered saline (PBS) solution with or without 50 μM ascorbate (Asc). The results show that generally the urban Fresno PM generates much more •OH than the rural Westside PM. The presence of Asc at a physiologically relevant concentration in the extraction solution greatly enhances •OH formation from all the samples. Fine PM (PM2.5) generally makes more •OH than the corresponding coarse PM (PMcf, i.e. with diameters of 2.5 to 10 μm) normalized by air volume collected, while the coarse PM typically generates more •OH normalized by PM mass. •OH production by SJV PM is reduced on average by (97 ± 6) % when the transition metal chelator desferoxamine (DSF) is added to the extraction solution, indicating a dominant role of transition metals. By measuring calibration curves of •OH generation from copper and iron, and quantifying copper and iron concentrations in our particle extracts, we find that PBS-soluble copper is primarily responsible for •OH production by the SJV PM, while iron often makes a significant contribution. Extrapolating our results to expected burdens of PM-derived •OH in human lung lining fluid suggests that typical daily PM exposures in the San Joaquin Valley are unlikely to result in a high amount of pulmonary •OH, although high PM events could produce much higher levels of •OH, which might lead to cytotoxicity.

scholarly journals Stress kinases in the modulation of metabolism and energy balance

2015 ◽  
Vol 55 (2) ◽  
pp. R11-R22 ◽  
Author(s):  
Elisa Manieri ◽  
Guadalupe Sabio
Keyword(s):  
Metabolic Stress ◽  
Cellular Responses ◽  
Cell Type ◽  
Global Pandemic ◽  
Increased Risk ◽  
Regulation Of Metabolism ◽  
A Cell ◽  
Cell Type Specific ◽  
Jnk Isoforms

Obesity is a new global pandemic, with growing incidence and prevalence. This disease is associated with increased risk of several pathologies, including diabetes, cardiovascular diseases, and cancer. The mechanisms underlying obesity-associated metabolic changes are the focus of efforts to identify new therapies. Stress-activated protein kinases (SAPK), including cJun N-terminal kinases (JNKs) and p38, are required for cellular responses to metabolic stress and therefore might contribute to the pathogenesis of obesity. Tissue-specific knockout models support a cell-type-specific role for JNK isoforms, in particular JNK1, highlighting its importance in cell homeostasis and organ crosstalk. However, more efforts are needed to elucidate the specific roles of other JNK isoforms and p38 family members in metabolism and obesity. This review provides an overview of the role of SAPKs in the regulation of metabolism.

scholarly journals Metabolic Regulation of Hypoxia-Inducible Factors in Hypothalamus

2021 ◽  
Vol 12 ◽  
Author(s):  
Dan Du ◽  
Yugang Zhang ◽  
Canjun Zhu ◽  
Hong Chen ◽  
Jia Sun
Keyword(s):  
Metabolic Regulation ◽  
Molecular Mechanisms ◽  
Hypoxia Inducible Factor ◽  
Central Regulation ◽  
Hypoxic Conditions ◽  
Regulation Of Metabolism ◽  
Single Effect ◽  
Single Part ◽  
Main Influence

The earliest hypoxia-inducible factor (HIF) function was to respond to hypoxia or hypoxic conditions as a transcription factor. Recent studies have expanded our understanding of HIF, and a large amount of evidence indicates that HIF has an essential effect on central regulation of metabolism. The central nervous system’s response to glucose, inflammation, and hormones’ main influence on systemic metabolism are all regulated by HIF to varying degrees. In the hypothalamus, HIF mostly plays a role in inhibiting energy uptake and promoting energy expenditure, which depends not only on the single effect of HIF or a single part of the hypothalamus. In this paper, we summarize the recent progress in the central regulation of metabolism, describe in detail the role of HIF in various functions of the hypothalamus and related molecular mechanisms, and reveal that HIF is deeply involved in hypothalamic-mediated metabolic regulation.

Amazon River influence on nitrogen fixation in the western tropical North Atlantic

2019 ◽  
Vol 77 (2) ◽  
pp. 191-213
Author(s):  
Joseph P. Montoya ◽  
Jason P. Landrum ◽  
Sarah C. Weber
Keyword(s):  
North Atlantic ◽  
Suspended Particle ◽  
Dominant Role ◽  
Amazon River ◽  
N Fixation ◽  
Particulate Nitrogen ◽  
Biological N Fixation ◽  
Relative Contribution ◽  
Tropical North Atlantic

We measured rates of N- and C-fixation with a direct tracer method in regions of the western tropical North Atlantic influenced by the Amazon River plume during the high flow period of 2010 (May–June 2010). We found distinct regional variations in N-fixation activity, with the lowest rates in the plume proper and the highest rates in the plume margins and in offshore waters. A comparison of our N- and C-fixation measurements showed that the relative contribution of N-fixation to total primary production increased from the plume core toward oceanic waters, and that most of the C-fixation in this system was supported by sources of nitrogen other than those derived from biological N-fixation, or diazotrophy. We complemented these rate experiments with measurements of the δ15N of suspended particles (δ15PN), which documented the important and often dominant role of diazotrophs in supplying nitrogen to particulate organic matter in the water column. These coupled measurements revealed that small phytoplankton contributed more new nitrogen to the particulate nitrogen pool than larger phytoplankton. We used a habitat classification method to assess the fac- tors that control diazotrophic activity and contribution to the suspended particle pool, both of which increased from the plume toward oceanic waters. Our findings provide an important constraint on the role of the Amazon plume in creating distinct niches and roles for diazotrophs in the nutrient and carbon budgets of the western tropical North Atlantic.

scholarly journals Predominant role of catalase in the disposal of hydrogen peroxide within human erythrocytes

Blood ◽  
1996 ◽  
Vol 87 (4) ◽  
pp. 1595-1599 ◽  
Author(s):  
GF Gaetani ◽  
AM Ferraris ◽  
M Rolfo ◽  
R Mangerini ◽  
S Arena ◽  
...  
Keyword(s):  
Hydrogen Peroxide ◽  
Glutathione Peroxidase ◽  
Human Erythrocytes ◽  
Predominant Role ◽  
Intact Cells ◽  
Free System ◽  
Major Function ◽  
Relative Contribution ◽  
A Cell

Purified enzymes were mixed to form a cell-free system that simulated the conditions for removal of hydrogen peroxide within human erythrocytes. Human glutathione peroxidase disposed of hydrogen peroxide (H2O2) at a rate that was only 17% of the rate at which human catalase simultaneously removed hydrogen peroxide. The relative rates observed were in agreement with the relative rates predicted from the kinetic constants of the two enzymes. These results confirm two earlier studies on intact erythrocytes, which refuted the notion that glutathione peroxidase is the primary enzyme for removal of hydrogen peroxide within erythrocytes. The present findings differ from the results with intact cells, however, in showing that glutathione peroxidase accounts for even less than 50% of the removal of hydrogen peroxide. A means is proposed for calculating the relative contribution of glutathione peroxidase and catalase in other cells and species. The present results raise the possibility that the major function of glutathione peroxidase may be the disposal of organic peroxides rather than the removal of hydrogen peroxide.

scholarly journals Formation of hydroxyl radical from San Joaquin Valley particles extracted in a cell-free solution

2011 ◽  
Vol 11 (6) ◽  
pp. 16861-16894 ◽  
Author(s):  
H. Shen ◽  
C. Anastasio
Keyword(s):  
Hydroxyl Radical ◽  
Dominant Role ◽  
San Joaquin Valley ◽  
Ambient Particulate Matter ◽  
Adverse Health Effects ◽  
Quantitative Studies ◽  
A Cell ◽  
Lung Lining Fluid ◽  
Phosphate Buffered Saline

Abstract. Previous studies have suggested that the adverse health effects from ambient particulate matter (PM) are linked to the formation of reactive oxygen species (ROS) by PM. While hydroxyl radical (•OH) is the most reactive of the ROS species, there are few quantitative studies of •OH generation from PM. Here we report on •OH formation from PM collected at an urban (Fresno) and rural (Westside) site in the San Joaquin Valley (SJV) of California. We quantified •OH in PM extracts using a cell-free, phosphate-buffered saline (PBS) solution with or without 50 μM ascorbate (Asc). The results show that generally the urban Fresno PM generates much more •OH than the rural Westside PM. The presence of Asc at a physiologically relevant concentration in the extraction solution greatly enhances •OH formation from all the samples. Fine PM (PM2.5) generally makes more •OH than the corresponding coarse PM (PMcf, i.e., 2.5 to 10 μm) normalized by air volume collected, while the coarse PM typically generates more •OH normalized by PM mass. •OH production by SJV PM is reduced on average by (97 ± 6) % when the transition metal chelator desferoxamine (DSF) is added to the extraction solution, indicating a dominant role of transition metals. By measuring calibration curves of •OH generation from copper and iron, and quantifying copper and iron concentrations in our particle extracts, we find that PBS-soluble copper is primarily responsible for •OH production by the SJV PM, while iron often makes a significant contribution. Extrapolating our results to expected burdens of PM-derived •OH in human lung lining fluid suggests that typical daily PM exposures in the San Joaquin Valley are unlikely to result in a high amount of pulmonary •OH, although high PM events could produce much higher levels of •OH, which might lead to cytotoxicity.

Chronic Pain: Fundamental Scientific Considerations, Specifically for Legal Claims

2013 ◽  
Vol 18 (1) ◽  
pp. 1-18 ◽  
Author(s):  
Robert J. Barth
Keyword(s):  
Health Outcomes ◽  
Pain Perception ◽  
Driving Forces ◽  
Psychological Treatment ◽  
Dominant Role ◽  
Meta Analysis ◽  
General Medicine ◽  
Pain Syndrome ◽  
Problematic Relationship

Abstract Scientific findings have indicated that psychological and social factors are the driving forces behind most chronic benign pain presentations, especially in a claim context, and are relevant to at least three of the AMA Guides publications: AMA Guides to Evaluation of Disease and Injury Causation, AMA Guides to Work Ability and Return to Work, and AMA Guides to the Evaluation of Permanent Impairment. The author reviews and summarizes studies that have identified the dominant role of financial, psychological, and other non–general medicine factors in patients who report low back pain. For example, one meta-analysis found that compensation results in an increase in pain perception and a reduction in the ability to benefit from medical and psychological treatment. Other studies have found a correlation between the level of compensation and health outcomes (greater compensation is associated with worse outcomes), and legal systems that discourage compensation for pain produce better health outcomes. One study found that, among persons with carpal tunnel syndrome, claimants had worse outcomes than nonclaimants despite receiving more treatment; another examined the problematic relationship between complex regional pain syndrome (CRPS) and compensation and found that cases of CRPS are dominated by legal claims, a disparity that highlights the dominant role of compensation. Workers’ compensation claimants are almost never evaluated for personality disorders or mental illness. The article concludes with recommendations that evaluators can consider in individual cases.

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