Curcumin Prevents Neuroinflammation by Inducing Microglia to Transform into the M2-phenotype via CaMKKβ-dependent Activation of the AMP-Activated Protein Kinase Signal Pathway

2020 ◽  
Vol 17 (8) ◽  
pp. 735-752
Author(s):  
Peifeng Qiao ◽  
Jingxi Ma ◽  
Yangyang Wang ◽  
Zhenting Huang ◽  
Qian Zou ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Kinase ◽  
Ampk Activation ◽  
Ampk Signaling ◽  
M2 Polarization ◽  
Bv2 Cells ◽  
Anti Inflammatory ◽  
Amp Activated Protein Kinase ◽  
The Brain

Background: Neuroinflammation plays an important role in the pathophysiological process of various neurodegenerative diseases. It is well known that curcumin has obvious anti-inflammatory effects in various neuroinflammation models. However, its effect on the modulation of microglial polarization is largely unknown. Objective: This study aimed to investigate whether curcumin changed microglia to an anti-inflammatory M2-phenotype by activating the AMP-activated protein kinase (AMPK) signaling pathway. Methods: LPS treatment was used to establish BV2 cells and primary microglia neuroinflammation models. The neuroinflammation mouse model was established by an intracerebroventricular (ICV) injection of lipopolysaccharide (LPS) in the lateral septal complex region of the brain. TNF-α was measured by ELISA, and cell viability was measured by Cell Counting Kit-8 (CCK-8). The expression of proinflammatory and anti-inflammatory cytokines was examined by Q-PCR and Western blot analysis. Phenotypic polarization of BV2 microglia was detected by immunofluorescence. Results: Curcumin enhanced AMPK activation in BV2 microglial cells in the presence and absence of LPS. Upon LPS stimulation, the addition of curcumin promoted M2 polarization of BV2 cells, as evidenced by suppressed M1 and the elevated M2 signature protein and gene expression. The effects of curcumin were inhibited by an AMPK inhibitor or AMPK knockdown. Calmodulin-dependent protein kinase kinase β (CaMKKβ) and liver kinase B1 (LKB1) are upstream kinases that activate AMPK. Curcumin can activate AMPK in Hela cells, which do not express LKB1. However, both the CaMKKβ inhibitor and siRNA blocked curcumin activation of AMPK in LPS-stimulated BV2 cells. Moreover, the CaMKKβ inhibitor and siRNA weaken the effect of curcumin suppression on M1 and enhancement of M2 protein and gene expression in LPS-stimulated BV2 cells. Finally, curcumin enhanced AMPK activation in the brain area where microglia were over-activated upon LPS stimulation in an in vivo neuroinflammation model. Moreover, curcumin also suppressed M1 and promoted M2 signature protein and gene expression in this in vivo model. Conclusion: Curcumin enhances microglia M2 polarization via the CaMKKβ-dependent AMPK signaling pathway. Additionally, curcumin treatment was found to be neuroprotective and thus might be considered as a novel therapeutic agent to treat the neurodegenerative disease such as Alzheimer‘s disease, Parkinson's disease, etc.

scholarly journals Effects of AMP-Activated Protein Kinase in Cerebral Ischemia

2009 ◽  
Vol 30 (3) ◽  
pp. 480-492 ◽  
Author(s):  
Jun Li ◽  
Louise D McCullough
Keyword(s):  
Protein Kinase ◽  
In Vivo Studies ◽  
Ampk Activation ◽  
Vigorous Exercise ◽  
Nitric Oxide Signaling ◽  
Reductase Inhibitors ◽  
Amp Activated Protein Kinase ◽  
The Brain

AMP-activated protein kinase (AMPK) is a serine threonine kinase that is highly conserved through evolution. AMPK is found in most mammalian tissues including the brain. As a key metabolic and stress sensor/effector, AMPK is activated under conditions of nutrient deprivation, vigorous exercise, or heat shock. However, it is becoming increasingly recognized that changes in AMPK activation not only signal unmet metabolic needs, but also are involved in sensing and responding to ‘cell stress’, including ischemia. The downstream effect of AMPK activation is dependent on many factors, including the severity of the stressor as well as the tissue examined. This review discusses recent in vitro and in vivo studies performed in the brain/neuronal cells and vasculature that have contributed to our understanding of AMPK in stroke. Recent data on the potential role of AMPK in angiogenesis and neurogenesis and the interaction of AMPK with 3-hydroxy-3-methy-glutaryl-CoA reductase inhibitors (statins) agents are highlighted. The interaction between AMPK and nitric oxide signaling is also discussed.

scholarly journals AMP-activated protein kinase activation ameliorates eicosanoid dysregulation in high-fat-induced kidney disease in mice

2019 ◽  
Vol 60 (5) ◽  
pp. 937-952 ◽  
Author(s):  
Anne-Emilie Declèves ◽  
Anna V. Mathew ◽  
Aaron M. Armando ◽  
Xianlin Han ◽  
Edward A. Dennis ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Kidney Disease ◽  
Ampk Activation ◽  
High Fat ◽  
Kinase Activation ◽  
Venous Circulation ◽  
Protein Kinase Activation ◽  
Anti Inflammatory ◽  
Amp Activated Protein Kinase

High-fat diet (HFD) causes renal lipotoxicity that is ameliorated with AMP-activated protein kinase (AMPK) activation. Although bioactive eicosanoids increase with HFD and are essential in regulation of renal disease, their role in the inflammatory response to HFD-induced kidney disease and their modulation by AMPK activation remain unexplored. In a mouse model, we explored the effects of HFD on eicosanoid synthesis and the role of AMPK activation in ameliorating these changes. We used targeted lipidomic profiling with quantitative MS to determine PUFA and eicosanoid content in kidneys, urine, and renal arterial and venous circulation. HFD increased phospholipase expression as well as the total and free pro-inflammatory arachidonic acid (AA) and anti-inflammatory DHA in kidneys. Consistent with the parent PUFA levels, the AA- and DHA-derived lipoxygenase (LOX), cytochrome P450, and nonenzymatic degradation (NE) metabolites increased in kidneys with HFD, while EPA-derived LOX and NE metabolites decreased. Conversely, treatment with 5-aminoimidazole-4-carboxamide-1-β-D-furanosyl 5′-monophosphate (AICAR), an AMPK activator, reduced the free AA and DHA content and the DHA-derived metabolites in kidney. Interestingly, kidney and circulating AA, AA metabolites, EPA-derived LOX, and NE metabolites are increased with HFD; whereas, DHA metabolites are increased in kidney in contrast to their decreased circulating levels with HFD. Together, these changes showcase HFD-induced pro- and anti-inflammatory eicosanoid dysregulation and highlight the role of AMPK in correcting HFD-induced dysregulated eicosanoid pathways.

scholarly journals A conserved role for AMP-activated protein kinase in NGLY1 deficiency

PLoS Genetics ◽  
2020 ◽  
Vol 16 (12) ◽  
pp. e1009258
Author(s):  
Seung Yeop Han ◽  
Ashutosh Pandey ◽  
Tereza Moore ◽  
Antonio Galeone ◽  
Lita Duraine ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Protein Kinase ◽  
Global Developmental Delay ◽  
Genetic Studies ◽  
Ampk Signaling ◽  
Biochemical Assays ◽  
Severe Reduction ◽  
Amp Activated Protein Kinase ◽  
Impaired Energy Metabolism

Mutations in human N-glycanase 1 (NGLY1) cause the first known congenital disorder of deglycosylation (CDDG). Patients with this rare disease, which is also known as NGLY1 deficiency, exhibit global developmental delay and other phenotypes including neuropathy, movement disorder, and constipation. NGLY1 is known to regulate proteasomal and mitophagy gene expression through activation of a transcription factor called "nuclear factor erythroid 2-like 1" (NFE2L1). Loss of NGLY1 has also been shown to impair energy metabolism, but the molecular basis for this phenotype and its in vivo consequences are not well understood. Using a combination of genetic studies, imaging, and biochemical assays, here we report that loss of NGLY1 in the visceral muscle of the Drosophila larval intestine results in a severe reduction in the level of AMP-activated protein kinase α (AMPKα), leading to energy metabolism defects, impaired gut peristalsis, failure to empty the gut, and animal lethality. Ngly1–/– mouse embryonic fibroblasts and NGLY1 deficiency patient fibroblasts also show reduced AMPKα levels. Moreover, pharmacological activation of AMPK signaling significantly suppressed the energy metabolism defects in these cells. Importantly, the reduced AMPKα level and impaired energy metabolism observed in NGLY1 deficiency models are not caused by the loss of NFE2L1 activity. Taken together, these observations identify reduced AMPK signaling as a conserved mediator of energy metabolism defects in NGLY1 deficiency and suggest AMPK signaling as a therapeutic target in this disease.

A-769662 potentiates the effect of other AMP-activated protein kinase activators on cardiac glucose uptake

2014 ◽  
Vol 306 (12) ◽  
pp. H1619-H1630 ◽  
Author(s):  
Aurélie D. Timmermans ◽  
Magali Balteau ◽  
Roselle Gélinas ◽  
Edith Renguet ◽  
Audrey Ginion ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Glucose Uptake ◽  
Ischemia Reperfusion ◽  
Protective Role ◽  
Ampk Activation ◽  
Perfused Heart ◽  
Ampk Signaling ◽  
Metabolic Outcome ◽  
Amp Activated Protein Kinase ◽  
The Impact

AMP-activated protein kinase (AMPK), a key cellular sensor of energy, regulates metabolic homeostasis and plays a protective role in the ischemic or diabetic heart. Stimulation of cardiac glucose uptake contributes to this AMPK-mediated protection. The small-molecule AMPK activator A-769662, which binds and directly activates AMPK, has recently been characterized. A-769662-dependent AMPK activation protects the heart against an ischemia-reperfusion episode but is unable to stimulate skeletal muscle glucose uptake. Here, we tried to reconcile these conflicting findings by investigating the impact of A-769662 on cardiac AMPK signaling and glucose uptake. We showed that A-769662 promoted AMPK activation, resulting in the phosphorylation of several downstream targets, but was incapable of stimulating glucose uptake in cultured cardiomyocytes and the perfused heart. The lack of glucose uptake stimulation can be explained by A-769662's narrow specificity, since it selectively activates cardiac AMPK heterotrimeric complexes containing α2/β1-subunits, the others being presumably required for this metabolic outcome. However, when combined with classical AMPK activators, such as metformin, phenformin, oligomycin, or hypoxia, which impact AMPK heterotrimers more broadly via elevation of cellular AMP levels, A-769662 induced more profound AMPK phosphorylation and subsequent glucose uptake stimulation. The synergistic effect of A-769662 under such ischemia-mimetic conditions protected cardiomyocytes against ROS production and cell death. In conclusion, despite the fact that A-769662 activates AMPK, it alone does not significantly stimulate glucose uptake. However, strikingly, its ability of potentiating the action on other AMPK activators makes it a potentially useful participant in the protective role of AMPK in the heart.

scholarly journals Smoothened/AMP-Activated Protein Kinase Signaling in Oligodendroglial Cell Maturation

2022 ◽  
Vol 15 ◽  
Author(s):  
Alice Del Giovane ◽  
Mariagiovanna Russo ◽  
Linda Tirou ◽  
Hélène Faure ◽  
Martial Ruat ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Demyelinating Diseases ◽  
Cell Maturation ◽  
Oligodendroglial Cell ◽  
Ampk Signaling ◽  
Shh Pathway ◽  
Canonical Pathways ◽  
The Central Nervous System ◽  
Amp Activated Protein Kinase

The regeneration of myelin is known to restore axonal conduction velocity after a demyelinating event. Remyelination failure in the central nervous system contributes to the severity and progression of demyelinating diseases such as multiple sclerosis. Remyelination is controlled by many signaling pathways, such as the Sonic hedgehog (Shh) pathway, as shown by the canonical activation of its key effector Smoothened (Smo), which increases the proliferation of oligodendrocyte precursor cells via the upregulation of the transcription factor Gli1. On the other hand, the inhibition of Gli1 was also found to promote the recruitment of a subset of adult neural stem cells and their subsequent differentiation into oligodendrocytes. Since Smo is also able to transduce Shh signals via various non-canonical pathways such as the blockade of Gli1, we addressed the potential of non-canonical Smo signaling to contribute to oligodendroglial cell maturation in myelinating cells using the non-canonical Smo agonist GSA-10, which downregulates Gli1. Using the Oli-neuM cell line, we show that GSA-10 promotes Gli2 upregulation, MBP and MAL/OPALIN expression via Smo/AMP-activated Protein Kinase (AMPK) signaling, and efficiently increases the number of axonal contact/ensheathment for each oligodendroglial cell. Moreover, GSA-10 promotes the recruitment and differentiation of oligodendroglial progenitors into the demyelinated corpus callosum in vivo. Altogether, our data indicate that non-canonical signaling involving Smo/AMPK modulation and Gli1 downregulation promotes oligodendroglia maturation until axon engagement. Thus, GSA-10, by activation of this signaling pathway, represents a novel potential remyelinating agent.

scholarly journals Fosl1 Targets AMPK to Inhibit Autophagy-Mediated Anti-Apoptotic and Anti-Inflammatory Effects in Spinal Cord Injury

2020 ◽  
Author(s):  
Lin Zhong ◽  
Sheng Fang ◽  
An-Quan Wang ◽  
Tao Wang ◽  
Wei Huang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Animal Model ◽  
Inflammatory Factor ◽  
Mrna Levels ◽  
Ampk Activation ◽  
Cord Injury ◽  
Anti Inflammatory

Abstract Background: The objective of this study was to delineate the role of Fosl1 in regulating inflammation and apoptosis following spinal cord injury.Methods: GSE45006 datasets from Gene Expression Omnibus (GEO) were explored to analyze Fosl1 gene expression. Next, we established an animal model to assess Fosl1 and AMPK by western blotting, real-time PCR, and immunohistochemical staining and used immunofluorescence staining to check Fosl1 expression in neurons. Fosl1 silencing was used to assess the effect on AMPK, cell viability, autophagy, inflammation and apoptosis. Subsequently, an AMPK activator and inhibitor were added to PC-12 cells with H2O2-induced injury subjected to si-Fosl1 treatment to examine the change in the above indexes and to determine whether the benefits from Fosl1 silencing occurred via AMPK. Moreover, we employed chloroquine (CQ) and rapamycin (RAP) to activate and inhibit autophagy, respectively, and revealed the effects of the upregulation and downregulation of autophagy following AMPK interference. Finally, an animal model was used to identify the effect of si-Fosl1 in vivo.Results: Based on the analysis of the GSE45006 datasets, Fosl1 was found to be highly expressed and was also found to be significantly enhanced in our animal model. Fosl1 knockdown upregulated AMPK at the protein and mRNA levels, promoted autophagic proteins (LC3 II/I, Beclin1) and inhibited inflammatory factors (IL-1β, IL-6, TNF-α) and apoptosis markers (caspase3, Bax). However, Fosl1 decreased the negatively related autophagic protein p62, the anti-inflammatory factor IL-10 and the anti-apoptotic marker Bcl-2. By utilizing compound C (com, an AMPK inhibitor), we learned that AMPK inhibition exhibited unfavorable effects on autophagy but promoted inflammation and apoptosis following Fosl1 silencing. AMPK activation showed contrasting effects. Moreover, we used CQ (an autophagic inhibitor), which indicated that CQ reversed the benefits of AMPK activation on inflammation and apoptosis. The autophagic activator RAP attenuated the negative effects after com treatment. In vivo, si-Fosl1 increased BBB scores at 7 d and 14 d and motor neurons, meanwhile, it decreased the number of apoptotic cells, and inflammatory cytokine expression at 14 d postoperation. Conclusion: Fosl1 can suppress AMPK to promote inflammation and apoptosis through autophagy in SCI.

scholarly journals Preclinical Development of FA5, a Novel AMP-Activated Protein Kinase (AMPK) Activator as an Innovative Drug for the Management of Bowel Inflammation

2021 ◽  
Vol 22 (12) ◽  
pp. 6325
Author(s):  
Luca Antonioli ◽  
Carolina Pellegrini ◽  
Matteo Fornai ◽  
Laura Benvenuti ◽  
Vanessa D’Antongiovanni ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Experimental Model ◽  
Spleen Weight ◽  
Preclinical Development ◽  
Innovative Drug ◽  
Inflammatory Parameters ◽  
Anti Inflammatory ◽  
Amp Activated Protein Kinase

Acadesine (ACA), a pharmacological activator of AMP-activated protein kinase (AMPK), showed a promising beneficial effect in a mouse model of colitis, indicating this drug as an alternative tool to manage IBDs. However, ACA displays some pharmacodynamic limitations precluding its therapeutical applications. Our study was aimed at evaluating the in vitro and in vivo effects of FA-5 (a novel direct AMPK activator synthesized in our laboratories) in an experimental model of colitis in rats. A set of experiments evaluated the ability of FA5 to activate AMPK and to compare the efficacy of FA5 with ACA in an experimental model of colitis. The effects of FA-5, ACA, or dexamethasone were tested in rats with 2,4-dinitrobenzenesulfonic acid (DNBS)-induced colitis to assess systemic and tissue inflammatory parameters. In in vitro experiments, FA5 induced phosphorylation, and thus the activation, of AMPK, contextually to the activation of SIRT-1. In vivo, FA5 counteracted the increase in spleen weight, improved the colon length, ameliorated macroscopic damage score, and reduced TNF and MDA tissue levels in DNBS-treated rats. Of note, FA-5 displayed an increased anti-inflammatory efficacy as compared with ACA. The novel AMPK activator FA-5 displays an improved anti-inflammatory efficacy representing a promising pharmacological tool against bowel inflammation.

scholarly journals Anti-inflammatory Role of GM1 and Other Gangliosides on Microglia

2021 ◽  
Author(s):  
Simonetta Sipione ◽  
Danny Galleguillos ◽  
Qian Wang ◽  
Noam Steinberg ◽  
Asifa Zaidi ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Sialic Acid Residue ◽  
Microglia Activation ◽  
Neuroprotective Effects ◽  
Bv2 Cells ◽  
Inflammatory Stimuli ◽  
Anti Inflammatory ◽  
The Brain

Abstract BackgroundGangliosides are glycosphingolipids highly enriched in the brain, with important roles in cell signaling, cell-to-cell communication, and immunomodulation. Genetic defects in the ganglioside biosynthetic pathway result in severe neurodegenerative diseases, while a partial decrease in the levels of specific gangliosides was reported in Parkinson’s disease and Huntington’s disease. In models of both diseases and other conditions, administration of GM1 - one of the most abundant gangliosides in the brain – provides neuroprotection. Most studies have focused on the direct neuroprotective effects of gangliosides on neurons, but their role in other brain cells, in particular microglia, is not known. In this study we investigated the effects of exogenous ganglioside administration and modulation of endogenous ganglioside levels on the response of microglia to inflammatory stimuli, which often contributes to initiation or exacerbation of neurodegeneration.MethodsIn vitro studies were performed using BV2 cells, mouse, rat, and human primary microglia cultures. Modulation of microglial ganglioside levels was achieved by administration of exogenous gangliosides, or by treatment with GENZ-123346 and L-t-PDMP, an inhibitor and activator of glycolipid biosynthesis, respectively. Response of microglia to inflammatory stimuli (LPS, IL-1b, phagocytosis of latex beads) was measured by analysis of gene expression and/or secretion of pro-inflammatory cytokines. The effects of GM1 administration on microglia activation were also assessed in vivo in C57Bl/6 mice, following intraperitoneal injection of LPS.ResultsGM1 decreased inflammatory microglia responses in vitro and in vivo, even when administered after microglia activation. These anti-inflammatory effects depended on the presence of the sialic acid residue in the GM1 glycan headgroup and the presence of a lipid tail. Other gangliosides shared similar anti-inflammatory effects in in vitro models, including GD3, GD1a, GD1b, and GT1b. Conversely, GM3 and GQ1b displayed pro-inflammatory activity. The anti-inflammatory effects of GM1 and other gangliosides were partially reproduced by increasing endogenous ganglioside levels with L-t-PDMP, whereas inhibition of glycolipid biosynthesis exacerbated microglial activation in response to LPS stimulation.ConclusionsOur data suggest that gangliosides are important modulators of microglia inflammatory responses and reveal that administration of GM1 and other complex gangliosides exerts anti-inflammatory effects on microglia that could be exploited therapeutically.

scholarly journals Chronic activation of AMP-activated protein kinase leads to early onset polycystic kidney phenotype

2021 ◽  
Author(s):  
Laura Wilson ◽  
Alice Pollard ◽  
Lucy Penfold ◽  
Phillip Muckett ◽  
Chad Whilding ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Kidney Function ◽  
Early Onset ◽  
Ampk Activation ◽  
Polycystic Kidney ◽  
Cystic Kidneys ◽  
Gene And Protein Expression ◽  
Kidney Morphology ◽  
Amp Activated Protein Kinase

AMP-activated protein kinase (AMPK) plays a key role in the cellular response to low energy stress and has emerged as an attractive therapeutic target for tackling metabolic diseases. Whilst significant progress has been made regarding the physiological role of AMPK, its function in the kidney remains only partially understood. We use a mouse model expressing a constitutively active mutant of AMPK to investigate the effect of AMPK activation on kidney function in vivo. Kidney morphology and changes in gene and protein expression were monitored and serum and urine markers were measured to assess kidney function in vivo. Global AMPK activation resulted in an early onset polycystic kidney phenotype, featuring collecting duct cysts and compromised renal function in adult mice. Mechanistically, the cystic kidneys had increased cAMP levels and ERK activation, increased hexokinase I expression, glycogen accumulation and altered expression of proteins associated with autophagy. Kidney tubule-specific activation of AMPK also resulted in a polycystic phenotype, demonstrating that renal tubular AMPK activation caused the cystogenesis. Importantly, human ADPKD kidney sections revealed similar protein localisation patterns to that observed in the murine cystic kidneys. Our findings show that early onset chronic AMPK activation leads to a polycystic kidney phenotype, suggesting dysregulated AMPK signalling is a contributing factor in cystogenesis.

scholarly journals Stimulation of Wnt/β-Catenin Signaling to Improve Bone Development by Naringin via Interacting with AMPK and Akt

2015 ◽  
Vol 36 (4) ◽  
pp. 1563-1576 ◽  
Author(s):  
Dawei Wang ◽  
Wenpu Ma ◽  
Fu Wang ◽  
Jinlei Dong ◽  
Dan Wang ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Bone Development ◽  
Akt Inhibitor ◽  
Ampk Signaling ◽  
T Cell Factor ◽  
Protein Expressions ◽  
Amp Activated Protein Kinase ◽  
Umr 106

Background/Aims: Naringin is a naturally existing compound in citrus fruits and has been elucidated to promote bone development and maintenance. Methods: The biological roles of naringin were investigated in vitro using osteoblast-like UMR-106 cells, and in vivo through performing ovariectomy to mimic osteoporosis in female mice. Since Wnt/β-catenin signaling is involved in osteoblastogenesis, the effect of naringin on Wnt/β-catenin signaling was studied. Results: Naringin promoted the mRNA and protein expressions of β-catenin, and improved Ser552 phosphorylation on β-catenin in UMR-106 cells, which leads to the activation of lymphoid enhancer factor (LEF)/ T-cell factor (TCF) transcription factors. The recruitments of protein kinase B (Akt) inhibitor (Akti-1/2) and AMP-activated protein kinase (AMPK) inhibitor (Dorsomorphin) reduced the influence of naringin on β-catenin phosphorylation, suggesting naringin activates β-catenin via regulating Akt and AMPK. In ovariectomized (OVX) mice naringin treatment improved the bone strength while AMPK and Akt inhibitors partly reversed the effect, which further proved the involvements of Akt and AMPK in the action of naringin in vivo. Conclusion: Our study points to a novel finding on the mechanism of naringin in facilitating bone formation via Akt and AMPK signaling.

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