Methylglyoxal Drives a Distinct, Nonclassical Macrophage Activation Status

2021 ◽  
Author(s):  
Foivos-Filippos Tsokanos ◽  
Carolin Muley ◽  
Sajjad Khani ◽  
Daniela Hass ◽  
Thomas Fleming ◽  
...  
Keyword(s):  
Macrophage Activation ◽  
Mapk Pathway ◽  
Polarization State ◽  
Reactive Metabolites ◽  
Diabetic Patients ◽  
Metabolic Complications ◽  
Inflammatory Processes ◽  
Toxic Byproduct ◽  
Activation Status ◽  
Classically Activated

AbstractMetabolic complications in diabetic patients are driven by a combination of increased levels of nutrients and the presence of a proinflammatory environment. Methylglyoxal (MG) is a toxic byproduct of catabolism and has been strongly associated with the development of such complications. Macrophages are key mediators of inflammatory processes and their contribution to the development of metabolic complications has been demonstrated. However, a direct link between reactive metabolites and macrophage activation has not been demonstrated yet. Here, we show that acute MG treatment activated components of the p38 MAPK pathway and enhanced glycolysis in primary murine macrophages. MG induced a distinct gene expression profile sharing similarities with classically activated proinflammatory macrophages as well as metabolically activated macrophages usually found in obese patients. Transcriptomic analysis revealed a set of 15 surface markers specifically upregulated in MG-treated macrophages, thereby establishing a new set of targets for diagnostic or therapeutic purposes under high MG conditions, including diabetes. Overall, our study defines a new polarization state of macrophages that may specifically link aberrant macrophage activation to reactive metabolites in diabetes.

Macrophage activation status rather than repolarization is associated with enhanced checkpoint activity in combination with PI3Kg inhibition

2021 ◽  
pp. molcanther.0961.2020
Author(s):  
Larissa S. Carnevalli ◽  
Molly A. Taylor ◽  
Matthew King ◽  
Anna ML Coenen-Stass ◽  
Adina M Hughes ◽  
...  
Keyword(s):  
Macrophage Activation ◽  
Activation Status

scholarly journals BCAT1 affects mitochondrial metabolism independently of leucine transamination in activated human macrophages

2020 ◽  
Vol 133 (22) ◽  
pp. jcs247957
Author(s):  
Jeong-Hun Ko ◽  
Antoni Olona ◽  
Adonia E. Papathanassiu ◽  
Norzawani Buang ◽  
Kwon-Sik Park ◽  
...  
Keyword(s):  
Macrophage Activation ◽  
Polarization State ◽  
Tca Cycle ◽  
Metabolic Adaptation ◽  
Human Macrophages ◽  
Relative Contribution ◽  
The Tca Cycle ◽  
Nutrient Consumption ◽  
Anti Oxidant ◽  
Branched Chain

ABSTRACTIn response to environmental stimuli, macrophages change their nutrient consumption and undergo an early metabolic adaptation that progressively shapes their polarization state. During the transient, early phase of pro-inflammatory macrophage activation, an increase in tricarboxylic acid (TCA) cycle activity has been reported, but the relative contribution of branched-chain amino acid (BCAA) leucine remains to be determined. Here, we show that glucose but not glutamine is a major contributor of the increase in TCA cycle metabolites during early macrophage activation in humans. We then show that, although uptake of BCAAs is not altered, their transamination by BCAT1 is increased following 8 h lipopolysaccharide (LPS) stimulation. Of note, leucine is not metabolized to integrate into the TCA cycle in basal or stimulated human macrophages. Surprisingly, the pharmacological inhibition of BCAT1 reduced glucose-derived itaconate, α-ketoglutarate and 2-hydroxyglutarate levels without affecting succinate and citrate levels, indicating a partial inhibition of the TCA cycle. This indirect effect is associated with NRF2 (also known as NFE2L2) activation and anti-oxidant responses. These results suggest a moonlighting role of BCAT1 through redox-mediated control of mitochondrial function during early macrophage activation.

Impact of metformin on outcomes in patients (pts) with metastatic renal cell carcinoma (mRCC): Results from a pooled clinical trials database.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 531-531
Author(s):  
Lana Hamieh ◽  
Rana R. McKay ◽  
Suzanne S Mickey ◽  
Xun Lin ◽  
Ronit Simantov ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Cox Regression ◽  
Mapk Pathway ◽  
Risk Groups ◽  
Diabetic Patients ◽  
First Line Therapy ◽  
Kaplan Meier ◽  
Tumor Types ◽  
Phase Ii And Iii

531 Background: Metformin has been shown to confer anti-neoplastic properties in several tumor types. Its effect on outcomes in mRCC patients has not been completely characterized. In this study, we evaluated the role of metformin on survival outcomes in pts with mRCC. Methods: We conducted a retrospective study of pts with mRCC treated on several phase II and III clinical trials from 2003-2013. We analyzed overall survival (OS) in the metformin users versus non-users using the Cox regression model and the Kaplan-Meier method. Results: We identified 4,736 pts with mRCC including 486 diabetic pts of whom 218 (4.6%) were metformin users. The majority were <65 years of age (69%), male (71%), with clear-cell histology (89%) and prior nephrectomy (70%). With regard to IMDC risk groups, 14%, 42%, and 24% had favorable, intermediate, and poor-risk disease, respectively. Pts received treatment with sunitinib (n=1,059), sorafenib (n=772), axitinib (n=896), temsirolimus (TEM) (n=457), TEM + interferon (IFN)-α (n=208), bevacizumab (BEV) + TEM (n=393), BEV + IFN-α (n=391), or IFN-α (n=560); overall 3,044 (64%) received first-line therapy. In the total cohort, metformin use did not impact OS when compared to users of other anti-diabetic agents (p=0.17) or non-diabetics (p=0.69). In diabetic pts, metformin use did not confer a survival advantage when stratified by type of therapy and IMDC risk group. However, in the cohort of diabetic pts receiving sunitinib (n=128), metformin use was associated with an improvement in OS when compared to users of non-metformin anti-diabetic agents (29.3 versus 20.9 months, respectively, p=0.0008, HR 0.051, 95% CI 0.009, 0.292). Conclusions: This is the largest study to date investigating the role of metformin on outcomes in mRCC pts. In this analysis, we demonstrate that concomitant use of metformin may improve survival in diabetic pts with mRCC treated with sunitinib. Based on preclinical data, we hypothesize that the mechanism underlying this survival benefit may be related to synergistic inhibition of the MAPK pathway. However, the study is limited by the small number of diabetic patients. Larger prospective studies are warranted to validate these results.

scholarly journals The Effects of Thiazolidinediones on Metabolic Complications and Lipodystrophy in HIV-Infected Patients

PPAR Research ◽  
2009 ◽  
Vol 2009 ◽  
pp. 1-15 ◽  
Author(s):  
Jussi Sutinen
Keyword(s):  
Highly Active Antiretroviral Therapy ◽  
Blood Lipids ◽  
Current Data ◽  
Diabetic Patients ◽  
Metabolic Complications ◽  
Highly Active ◽  
The Poor ◽  
Subcutaneous Adipose ◽  
Harmful Effects

Highly active antiretroviral therapy (HAART)-associated metabolic complications include lipoatrophy (loss of subcutaneous adipose tissue (SAT)) and insulin resistance. Thiazolidinediones are insulin-sensitizing antidiabetic agents which—as an untoward side effect in obese diabetic patients—increase SAT. Furthermore, troglitazone has improved lipoatrophy and glycemic control in non-HIV patients with various forms of lipodystrophy. These data have led to 14 clinical trials to examine whether thiazolidinediones could be useful in the treatment of HAART-associated metabolic complications. The results of these studies indicate very modest, if any, effect on lipoatrophic SAT, probably due to ongoing HAART negating the beneficial effect. The benefit might be more prominent in patients not taking thymidine analoges. Despite the poor effect on lipoatrophy, thiazolidin-ediones improved insulin sensitivity. However, especially rosiglitazone induced harmful effects on blood lipids. Current data do not provide evidence for the use of thiazolidinediones in the treatment of HAART-associated lipoatrophy, but treatment of lipoatrophy-associated diabetes may be warranted. The role of thiazolidinediones for novel indications, such as hepatosteatosis, should be studied in these patients.

scholarly journals Metformin prevents metabolic side effects during systemic glucocorticoid treatment

2017 ◽  
Vol 176 (3) ◽  
pp. 349-358 ◽  
Author(s):  
Eleonora Seelig ◽  
Stefanie Meyer ◽  
Katharina Timper ◽  
Nicole Nigro ◽  
Martina Bally ◽  
...  
Keyword(s):  
Side Effects ◽  
Glucose Tolerance Test ◽  
Controlled Trial ◽  
Tolerance Test ◽  
Oral Glucose ◽  
Diabetic Patients ◽  
Oral Glucose Tolerance ◽  
Glucocorticoid Treatment ◽  
Metabolic Complications ◽  
Systemic Glucocorticoid

Objectives Patients receiving glucocorticoid treatment are prone to develop metabolic complications. In preclinical studies, metformin prevented the development of the metabolic syndrome during glucocorticoid excess. We herein investigated the metabolic effect of metformin during glucocorticoid treatment in non-diabetic patients. Methods In a double-blind, placebo-controlled trial, patients starting glucocorticoid treatment (prednisone, prednisolone or methylprednisolone) for four weeks were randomised to concomitantly receive metformin (850 mg once daily for one week followed by 850 mg twice daily for three weeks) or placebo. All patients underwent a standardised oral glucose tolerance test at baseline and after four weeks. The primary endpoint was change in the 2-h area under the curve (AUC) of glucose during the oral glucose tolerance test between baseline and four weeks. Results 29 of 34 randomised non-diabetic patients completed the trial (17 metformin and 12 placebo). In patients allocated to placebo, median glucose 2-h AUC increased from baseline to four weeks (836 (IQR 770–966) to 1202 (1009–1271) mmol/L per min; P = 0.01). In contrast, glucose levels remained similar to baseline in the metformin group (936 (869–1003) to 912 (825–1011) mmol/L per min; P = 0.83). This change within four weeks was different between both groups (P = 0.005). Glucocorticoid equivalent doses were similar in both groups (placebo: 980.0 (560.0–3259.8) mg/28 days; metformin: 683.0 (437.5–1970.5) mg/28 days; P = 0.26). Conclusions In this first randomised controlled trial of metformin targeting metabolic complications in patients needing glucocorticoid therapy, we observed a beneficial effect of metformin on glycaemic control. Metformin thus seems to be a promising drug for preventing metabolic side effects during systemic glucocorticoid treatment.

scholarly journals Benfotiamine reduces pathology and improves muscle function in mdx mice

2018 ◽  
Author(s):  
Keryn G. Woodman ◽  
Chantal A. Coles ◽  
Su L Toulson ◽  
Elizabeth M. Gibbs ◽  
Matthew Knight ◽  
...  
Keyword(s):  
Calcium Influx ◽  
Dystrophin Gene ◽  
Mdx Mice ◽  
Diabetic Patients ◽  
Severe Reduction ◽  
Dystrophin Deficiency ◽  
Inflammatory Processes ◽  
Dystrophin Glycoprotein ◽  
And Oxidative Stress ◽  
Pro Inflammatory Cytokines

AbstractDuchenne Muscular Dystrophy (DMD) is a progressive and fatal neuromuscular disease which arises from mutations in the dystrophin gene (DMD) that result in the absence or severe reduction of the cytoskeletal protein dystrophin. In addition to the primary dystrophin defect, secondary processes such as inflammation, calcium influx, dysregulated autophagy and fibrosis exacerbate dystrophic pathology and thus increase disease progression. While therapies to restore dystrophin deficiency are being developed, strategies which target these secondary processes could be of benefit to patients. Benfotiamine is a lipid soluble precursor to thiamine that can reduce secondary processes such as inflammation and oxidative stress in diabetic patients. As such we tested it in the mdx mouse model of DMD and found that benfotiamine reduced multiple markers of dystrophic pathology and improved grip strength. In addition, members of the utrophin and dystrophin glycoprotein complexes were significantly increased at the sarcolemma which could improve cell adhesion. We also demonstrated that benfotiamine treatment lowered the expression of macrophage markers and pro-inflammatory cytokines suggesting that benfotiamine is reducing dystrophic pathology by acting on inflammatory processes.

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