scholarly journals AMPK: opposing the metabolic changes in both tumour cells and inflammatory cells?

2013 ◽  
Vol 41 (2) ◽  
pp. 687-693 ◽  
Author(s):  
Madhumita Dandapani ◽  
D. Grahame Hardie
Keyword(s):  
Oxidative Metabolism ◽  
Aerobic Glycolysis ◽  
Inflammatory Cells ◽  
Tumour Cells ◽  
Unicellular Eukaryote ◽  
Energy Status ◽  
Proliferating Cells ◽  
Anti Inflammatory ◽  
Amp Activated Protein Kinase ◽  
Inhibit Cell Proliferation

AMPK (AMP-activated protein kinase) is a sensor of cellular energy status that appears to have arisen during early eukaryotic evolution. In the unicellular eukaryote Saccharomyces cerevisiae, the AMPK orthologue is activated by glucose starvation and is required for the switch from glycolysis (fermentation) to oxidative metabolism when glucose runs low. In mammals, rapidly proliferating cells (including tumour cells) and immune cells involved in inflammation both tend to utilize rapid glucose uptake and glycolysis (termed the Warburg effect or aerobic glycolysis) rather than oxidative metabolism to satisfy their high demand for ATP. Since mammalian AMPK, similar to its yeast orthologue, tends to promote the more energy-efficient oxidative metabolism at the expense of glycolysis, it might be expected that drugs that activate AMPK would inhibit cell proliferation and and hence cancer, as well as exerting anti-inflammatory effects. Evidence supporting this view is discussed, including our findings that AMPK is activated by the classic anti-inflammatory drug salicylate.

scholarly journals AMPKα1 is essential for Glucocorticoid Receptor triggered anti-inflammatory macrophage activation

2020 ◽  
Author(s):  
Giorgio Caratti ◽  
Thibaut Desgeorges ◽  
Gaëtan Juban ◽  
Mascha Koenen ◽  
Bozhena Kozak ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Transcriptional Control ◽  
Inflammatory Cells ◽  
Macrophage Phenotype ◽  
Post Injury ◽  
Inflammatory Phase ◽  
Anti Inflammatory ◽  
Amp Activated Protein Kinase ◽  
Inflammatory Macrophage

SummaryMacrophages are key immune cells which mediate both the acute inflammatory phase and the repair phase after tissue damage. Macrophages switch from pro-inflammatory to anti-inflammatory cells that sustain repair and return to tissue homeostasis. We show that the metabolic sensor, AMP-activated protein kinase (AMPK) is essential for glucocorticoid induction of an anti-inflammatory macrophage phenotype. While canonical gene regulation by glucocorticoids was not affected by loss of AMPK, we identified AMPK-dependent glucocorticoid-regulated genes in macrophages, related to efferocytosis. AMPK-deficient macrophages do not acquire phenotypic and functional anti-inflammatory features upon glucocorticoid exposure. We identified FOXO3 as an AMPK-dependent regulator of glucocorticoid activity in macrophages. Loss of AMPK in macrophages in vivo abrogates glucocorticoid anti-inflammatory actions during post-injury muscle regeneration and endotoxin induced acute lung injury. These data highlight that the glucocorticoid receptor is dependent on AMPK for its immunomodulatory actions in macrophages, linking their metabolic status to transcriptional control in resolving inflammation.

Untangling the Metabolic Reprogramming in Brain Cancer: Discovering Key Molecular Players Using Mass Spectrometry

2019 ◽  
Vol 19 (17) ◽  
pp. 1521-1534 ◽  
Author(s):  
Anatoly Sorokin ◽  
Vsevolod Shurkhay ◽  
Stanislav Pekov ◽  
Evgeny Zhvansky ◽  
Daniil Ivanov ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Brain Cancer ◽  
De Novo ◽  
Aerobic Glycolysis ◽  
Lipid Production ◽  
Dietary Fatty Acids ◽  
Metabolic Reprogramming ◽  
Detection Methods ◽  
Malignant Cells ◽  
Proliferating Cells

Cells metabolism alteration is the new hallmark of cancer, as well as an important method for carcinogenesis investigation. It is well known that the malignant cells switch to aerobic glycolysis pathway occurring also in healthy proliferating cells. Recently, it was shown that in malignant cells de novo synthesis of the intracellular fatty acid replaces dietary fatty acids which change the lipid composition of cancer cells noticeably. These alterations in energy metabolism and structural lipid production explain the high proliferation rate of malignant tissues. However, metabolic reprogramming affects not only lipid metabolism but many of the metabolic pathways in the cell. 2-hydroxyglutarate was considered as cancer cell biomarker and its presence is associated with oxidative stress influencing the mitochondria functions. Among the variety of metabolite detection methods, mass spectrometry stands out as the most effective method for simultaneous identification and quantification of the metabolites. As the metabolic reprogramming is tightly connected with epigenetics and signaling modifications, the evaluation of metabolite alterations in cells is a promising approach to investigate the carcinogenesis which is necessary for improving current diagnostic capabilities and therapeutic capabilities. In this paper, we overview recent studies on metabolic alteration and oncometabolites, especially concerning brain cancer and mass spectrometry approaches which are now in use for the investigation of the metabolic pathway.

scholarly journals Anti-inflammatory genes in PBMCs post-spontaneous intracerebral hemorrhage

2021 ◽  
Vol 12 (1) ◽  
pp. 58-66
Author(s):  
Doan Nguyen ◽  
Vi Tran ◽  
Alireza Shirazian ◽  
Cruz Velasco-Gonzalez ◽  
Ifeanyi Iwuchukwu
Keyword(s):  
Intracerebral Hemorrhage ◽  
Negative Correlation ◽  
Mononuclear Cells ◽  
Inflammatory Cells ◽  
Favorable Outcome ◽  
Hospital Length Of Stay ◽  
Spontaneous Intracerebral Hemorrhage ◽  
Hematoma Volume ◽  
Peripheral Blood Mononuclear ◽  
Anti Inflammatory

Abstract Background Neuroinflammation is important in the pathophysiology of spontaneous intracerebral hemorrhage (ICH) and peripheral inflammatory cells play a role in the clinical evolution and outcome. Methodology Blood samples from ICH patients (n = 20) were collected at admission for 5 consecutive days for peripheral blood mononuclear cells (PBMCs). Frozen PBMCs were used for real-time PCR using Taqman probes (NFKB1, SOD1, PPARG, IL10, NFE2L2, and REL) and normalized to GAPDH. Data on hospital length of stay and modified Rankin score (MRS) were collected with 90-day MRS ≤ 3 as favorable outcome. Statistical analysis of clinical characteristics to temporal gene expression from early to delayed timepoints was compared for MRS groups (favorable vs unfavorable) and hematoma volume. Principle findings and results IL10, SOD1, and REL expression were significantly higher at delayed timepoints in PBMCs of ICH patients with favorable outcome. PPARG and REL increased between timepoints in patients with favorable outcome. NFKB1 expression was not sustained, but significantly decreased from higher levels at early onset in patients with unfavorable outcome. IL10 expression showed a negative correlation in patients with high hematoma volume (>30 mL). Conclusions and significance Anti-inflammatory, pro-survival regulators were highly expressed at delayed time points in ICH patients with a favorable outcome, and IL10 expression showed a negative correlation to high hematoma volume.

scholarly journals BAM15, a Mitochondrial Uncoupling Agent, Attenuates Inflammation in the LPS Injection Mouse Model: An Adjunctive Anti-Inflammation on Macrophages and Hepatocytes

2021 ◽  
pp. 1-17
Author(s):  
Cong Phi Dang ◽  
Jiraphorn Issara-Amphorn ◽  
Awirut Charoensappakit ◽  
Kanyarat Udompornpitak ◽  
Thansita Bhunyakarnjanarat ◽  
...  
Keyword(s):  
Atp Depletion ◽  
Organ Injury ◽  
Flux Analysis ◽  
Energy Status ◽  
Mitochondrial Uncoupling ◽  
Inflammatory Monocytes ◽  
Tnf Α ◽  
Cell Energy ◽  
Anti Inflammatory ◽  
Anti Inflammation

Controlof immune responses through the immunometabolism interference is interesting for sepsis treatment. Then, expression of immunometabolism-associated genes and BAM15, a mitochondrial uncoupling agent, was explored in a proinflammatory model using lipopolysaccharide (LPS) injection. Accordingly, the decreased expression of mitochondrial uncoupling proteins was demonstrated by transcriptomic analysis on metabolism-associated genes in macrophages (RAW246.7) and by polymerase chain reaction in LPS-stimulated RAW246.7 and hepatocytes (Hepa 1–6). Pretreatment with BAM15 at 24 h prior to LPS in macrophages attenuated supernatant inflammatory cytokines (IL-6, TNF-α, and IL-10), downregulated genes of proinflammatory M1 polarization (iNOS and IL-1β), upregulated anti-inflammatory M2 polarization (Arg1 and FIZZ), and decreased cell energy status (extracellular flux analysis and ATP production). Likewise, BAM15 decreased expression of proinflammatory genes (IL-6, TNF-α, IL-10, and iNOS) and reduced cell energy in hepatocytes. In LPS-administered mice, BAM15 attenuated serum cytokines, organ injury (liver enzymes and serum creatinine), and tissue cytokines (livers and kidneys), in part, through the enhanced phosphorylated αAMPK, a sensor of ATP depletion with anti-inflammatory property, in the liver, and reduced inflammatory monocytes/macrophages (Ly6C +ve, CD11b +ve) in the liver as detected by Western blot and flow cytometry, respectively. In conclusion, a proof of concept for inflammation attenuation of BAM15 through metabolic interference-induced anti-inflammation on macrophages and hepatocytes was demonstrated as a new strategy of anti-inflammation in sepsis.

scholarly journals Hyaluronic Acid-Modified and TPCA-1-Loaded Gold Nanocages Alleviate Inflammation

Pharmaceutics ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 143 ◽  
Author(s):  
Jingnan Zhao
Keyword(s):  
Hyaluronic Acid ◽  
Inflammatory Cells ◽  
Oxygen Species ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Nanogold Particles ◽  
Gold Nanocages ◽  
Factor Alpha ◽  
Anti Inflammatory ◽  
Necrosis Factor

Gold nanocages (AuNCs) are biocompatible and porous nanogold particles that have been widely used in biomedical fields. In this study, hyaluronic acid (HA) and peptide- modified gold nanocages (HA-AuNCs/T/P) loaded with 2-[(aminocarbonyl)amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide (TPCA-1) were prepared to investigate their potential for combating inflammation. TPCA-1 was released from AuNCs, intracellularly when HA was hydrolyzed by hyaluronidase. HA-AuNCs/T/P show a much higher intracellular uptake than AuNCs/T/P, and exhibit a much higher efficacy on the suppression of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) than free TPCA-1, suggesting great improvement to the anti-inflammatory efficacy of TPCA-1 through the application of AuNCs. HA-AuNCs/T/P can also reduce the production of reactive oxygen species in inflammatory cells. This study suggests that HA-AuNCs/T/P may be potential agents for anti-inflammatory treatment, and are worthy of further investigation.

scholarly journals Glucose regulates AMP-activated protein kinase activity and gene expression in clonal, hypothalamic neurons expressing proopiomelanocortin: additive effects of leptin or insulin

2007 ◽  
Vol 192 (3) ◽  
pp. 605-614 ◽  
Author(s):  
Fang Cai ◽  
Armen V Gyulkhandanyan ◽  
Michael B Wheeler ◽  
Denise D Belsham
Keyword(s):  
Protein Kinase ◽  
Energy Homeostasis ◽  
Cell Model ◽  
Neuronal Cell ◽  
Cell Types ◽  
Glucose Sensing ◽  
Protein Kinase Activity ◽  
Energy Status ◽  
Ampk Activity ◽  
Amp Activated Protein Kinase

The mammalian hypothalamus comprises an array of phenotypically distinct cell types that interpret peripheral signals of energy status and, in turn, elicits an appropriate response to maintain energy homeostasis. We used a clonal representative hypothalamic cell model expressing proopiomelanocortin (POMC; N-43/5) to study changes in AMP-activated protein kinase (AMPK) activity and glucose responsiveness. We have demonstrated the presence of cellular machinery responsible for glucose sensing in the cell line, including glucokinase, glucose transporters, and appropriate ion channels. ATP-sensitive potassium channels were functional and responded to glucose. The N-43/5 POMC neurons may therefore be an appropriate cell model to study glucose-sensing mechanisms in the hypothalamus. In N-43/5 POMC neurons, increasing glucose concentrations decreased phospho-AMPK activity. As a relevant downstream effect, we found that POMC transcription increased with 2.8 and 16.7 mM glucose. Upon addition of leptin, with either no glucose or with 5 mM glucose, we found that leptin decreased AMPK activity in N-43/5 POMC neurons, but had no significant effect at 25 mM glucose, whereas insulin decreased AMPK activity at only 5 mM glucose. These results demonstrate that individual hypothalamic neuronal cell types, such as the POMC neuron, can have distinct responses to peripheral signals that relay energy status to the brain, and will therefore be activated uniquely to control neuroendocrine function.

scholarly journals Molecular mechanisms of microvascular failure in central nervous system injury—synergistic roles of NKCC1 and SUR1/TRPM4

2010 ◽  
Vol 113 (3) ◽  
pp. 622-629 ◽  
Author(s):  
J. Marc Simard ◽  
Kristopher T. Kahle ◽  
Volodymyr Gerzanich
Keyword(s):  
Endothelial Cells ◽  
Cerebral Edema ◽  
Molecular Mechanisms ◽  
Ischemia Reperfusion ◽  
Extracellular Fluid ◽  
Inflammatory Cells ◽  
Atp Depletion ◽  
Energy Status ◽  
Edema Formation ◽  
Trpm4 Channel

Microvascular failure largely underlies the damaging secondary events that accompany traumatic brain injury (TBI). Changes in capillary permeability result in the extravasation of extracellular fluid, inflammatory cells, and blood, thereby producing cerebral edema, inflammation, and progressive secondary hemorrhage (PSH). Recent work in rat models of TBI and stroke have implicated 2 ion transport proteins expressed in brain endothelial cells as critical mediators of edema formation: the constitutively expressed Na+-K+-2Cl– cotransporter, NKCC1, and the trauma/ischemia-induced SUR1-regulated NCCa-ATP (SUR1/TRPM4) channel. Whereas NKCC1 function requires adenosine 5′-triphosphate (ATP), activation of SUR1/TRPM4 occurs only after ATP depletion. This opposite dependence on intracellular ATP levels implies that one or the other mechanism will activate/deactivate as ATP concentrations rise and fall during periods of ischemia/reperfusion, resulting in continuous edema formation regardless of cellular energy status. Moreover, with critical ATP depletion, sustained opening of SUR1/TRPM4 channels results in the oncotic death of endothelial cells, leading to capillary fragmentation and PSH. Bumetanide and glibenclamide are 2 well-characterized, safe, FDA-approved drugs that inhibit NKCC1 and the SUR1/TRPM4 channel, respectively. When used alone, these drugs have provided documented beneficial effects in animal models of TBI- and ischemiaassociated cerebral edema and PSH. Given the mechanistic and temporal differences by which NKCC1 and the SUR1/TRPM4 channel contribute to the pathophysiological mechanisms of these events, combination therapy with bumetanide and glibenclamide may yield critical synergy in preventing injury-associated capillary failure.

HIF-1α in endurance training: suppression of oxidative metabolism

2007 ◽  
Vol 293 (5) ◽  
pp. R2059-R2069 ◽  
Author(s):  
Steven D. Mason ◽  
Helene Rundqvist ◽  
Ioanna Papandreou ◽  
Roger Duh ◽  
Wayne J. McNulty ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Endurance Training ◽  
Oxidative Metabolism ◽  
Hypoxia Inducible Factor ◽  
Transcriptional Response ◽  
Oxidative Capacity ◽  
Pyruvate Dehydrogenase Kinase ◽  
Amp Activated Protein Kinase ◽  
Training Protocol

During endurance training, exercising skeletal muscle experiences severe and repetitive oxygen stress. The primary transcriptional response factor for acclimation to hypoxic stress is hypoxia-inducible factor-1α (HIF-1α), which upregulates glycolysis and angiogenesis in response to low levels of tissue oxygenation. To examine the role of HIF-1α in endurance training, we have created mice specifically lacking skeletal muscle HIF-1α and subjected them to an endurance training protocol. We found that only wild-type mice improve their oxidative capacity, as measured by the respiratory exchange ratio; surprisingly, we found that HIF-1α null mice have already upregulated this parameter without training. Furthermore, untrained HIF-1α null mice have an increased capillary to fiber ratio and elevated oxidative enzyme activities. These changes correlate with constitutively activated AMP-activated protein kinase in the HIF-1α null muscles. Additionally, HIF-1α null muscles have decreased expression of pyruvate dehydrogenase kinase I, a HIF-1α target that inhibits oxidative metabolism. These data demonstrate that removal of HIF-1α causes an adaptive response in skeletal muscle akin to endurance training and provides evidence for the suppression of mitochondrial biogenesis by HIF-1α in normal tissue.

Very high dilutions of dexamethasone inhibit its pharmacological effects in vivo

2001 ◽  
Vol 90 (04) ◽  
pp. 198-203 ◽  
Author(s):  
LV Bonamin ◽  
KS Martinho ◽  
AL Nina ◽  
F Caviglia ◽  
RGW Do Rio
Keyword(s):  
Inflammatory Cells ◽  
Experimental Models ◽  
Tumour Cells ◽  
Pharmacological Effects ◽  
Trypan Blue Exclusion ◽  
Male Adult ◽  
Trypan Blue Exclusion Method ◽  
High Dilutions ◽  
Ascitic Tumour

AbstractWe evaluated the interaction of dexamethasone 10−17 and 10−33 M (equivalent to 7cH and 15cH) with dexamethasone in pharmacological concentrations, using as experimental models: acute inflammation induced by carrageenan, Ehrlich ascitic tumour, and migration of tumour infiltrating leukocytes (TIL). Male adult BALB/c mice (n=7 per group) were used in all experiments. Carrageenan (1%) was injected into the footpad for oedema evaluation and into the peritoneal cavity (i.p.), for differential counting of inflammatory cells. Ehrlich ascitic tumour cells (107 viable cells/ml) were injected i.p. and tumour cells were counted after 6 days, by the Trypan blue exclusion method. The differential TIL was counted using smears stained by hematoxylin–eosin. Treatments were made immediately after carrageenan inoculation or once a day, during Ehrlich tumour development, until the animals were killed. Animals were treated with the following preparations: (1) phosphate buffer saline (PBS) solution; (2) dexamethasone (0.5 mg/kg for inflammation model or 4 mg/kg for tumour model) mixed with dexamethasone 7cH or 15cH; (3) dexamethasone (same doses) mixed in PBS. Homeopathic dexamethasone partially blocked the anti-inflammatory effect of pharmacological dexamethasone with regard to paw oedema (two-way ANOVA, P≤0.0008) and polymorphonuclear cell migration (χ2, P=0.0001). No important differences were observed between experimental and control groups, in relation to Ehrlich tumour cells viability or count, or bodyweight, but potentised dexamethasone restored control levels of TIL viability, compared to mice treated with pharmacological doses of dexamethasone (χ2, P≤0.001). The results demonstrate that a potentised substance may change its own pharmacological effects and suggest that ultradilutions effects act mostly on host response.

scholarly journals A concise review on advances in development of small molecule anti-inflammatory therapeutics emphasising AMPK: An emerging target

2016 ◽  
Vol 29 (4) ◽  
pp. 562-571 ◽  
Author(s):  
Chethan Gejjalagere Honnappa ◽  
Unnikrishnan Mazhuvancherry Kesavan
Keyword(s):  
Drug Targets ◽  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Cyclooxygenase Inhibitors ◽  
Evolutionarily Conserved ◽  
Inflammatory Drugs ◽  
Anti Inflammatory ◽  
Acid Pathway ◽  
Clinical Trial Results ◽  
Amp Activated Protein Kinase

Inflammatory diseases are complex, multi-factorial outcomes of evolutionarily conserved tissue repair processes. For decades, non-steroidal anti-inflammatory drugs and cyclooxygenase inhibitors, the primary drugs of choice for the management of inflammatory diseases, addressed individual targets in the arachidonic acid pathway. Unsatisfactory safety and efficacy profiles of the above have necessitated the development of multi-target agents to treat complex inflammatory diseases. Current anti-inflammatory therapies still fall short of clinical needs and the clinical trial results of multi-target therapeutics are anticipated. Additionally, new drug targets are emerging with improved understanding of molecular mechanisms controlling the pathophysiology of inflammation. This review presents an outline of small molecules and drug targets in anti-inflammatory therapeutics with a summary of a newly identified target AMP-activated protein kinase, which constitutes a novel therapeutic pathway in inflammatory pathology.

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