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 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.

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.

scholarly journals Knockdown of MAGEA6 Activates AMP-Activated Protein Kinase (AMPK) Signaling to Inhibit Human Renal Cell Carcinoma Cells

2018 ◽  
Vol 45 (3) ◽  
pp. 1205-1218 ◽  
Author(s):  
Xueting Ye ◽  
Jing Xie ◽  
Hang Huang ◽  
Zhexian Deng
Keyword(s):  
Renal Cell Carcinoma ◽  
Protein Kinase ◽  
Cell Carcinoma ◽  
Cell Apoptosis ◽  
Renal Cell ◽  
Elisa Assay ◽  
Human Renal Cell Carcinoma ◽  
Ampk Signaling ◽  
Amp Activated Protein Kinase

Background/Aims: Melanoma antigen A6 (MAGEA6) is a cancer-specific ubiquitin ligase of AMP-activated protein kinase (AMPK). The current study tested MAGEA6 expression and potential function in renal cell carcinoma (RCC). Methods: MAGEA6 and AMPK expression in human RCC tissues and RCC cells were tested by Western blotting assay and qRT-PCR assay. shRNA method was applied to knockdown MAGEA6 in human RCC cells. Cell survival and proliferation were tested by MTT assay and BrdU ELISA assay, respectively. Cell apoptosis was tested by the TUNEL assay and single strand DNA ELISA assay. The 786-O xenograft in nude mouse model was established to test RCC cell growth in vivo. Results: MAGEA6 is specifically expressed in RCC tissues as well as in the established (786-O and A498) and primary human RCC cells. MAGEA6 expression is correlated with AMPKα1 downregulation in RCC tissues and cells. It is not detected in normal renal tissues nor in the HK-2 renal epithelial cells. MAGEA6 knockdown by targeted-shRNA induced AMPK stabilization and activation, which led to mTOR complex 1 (mTORC1) in-activation and RCC cell death/apoptosis. AMPK inhibition, by AMPKα1 shRNA or the dominant negative AMPKα1 (T172A), almost reversed MAGEA6 knockdown-induced RCC cell apoptosis. Conversely, expression of the constitutive-active AMPKα1 (T172D) mimicked the actions by MAGEA6 shRNA. In vivo, MAGEA6 shRNA-bearing 786-O tumors grew significantly slower in nude mice than the control tumors. AMPKα1 stabilization and activation as well as mTORC1 in-activation were detected in MAGEA6 shRNA tumor tissues. Conclusion: MAGEA6 knockdown inhibits human RCC cells via activating AMPK signaling.

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 Adrenaline is a critical mediator of acute exercise-induced AMP-activated protein kinase activation in adipocytes

2007 ◽  
Vol 403 (3) ◽  
pp. 473-481 ◽  
Author(s):  
Ho-Jin Koh ◽  
Michael F. Hirshman ◽  
Huamei He ◽  
Yangfeng Li ◽  
Yasuko Manabe ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase Activity ◽  
Chronic Exercise ◽  
Rat Adipocytes ◽  
Compound C ◽  
Isolated Adipocytes ◽  
Ampk Activity ◽  
Exercise Induced ◽  
Amp Activated Protein Kinase

Exercise increases AMPK (AMP-activated protein kinase) activity in human and rat adipocytes, but the underlying molecular mechanisms and functional consequences of this activation are not known. Since adrenaline (epinephrine) concentrations increase with exercise, in the present study we hypothesized that adrenaline activates AMPK in adipocytes. We show that a single bout of exercise increases AMPKα1 and α2 activities and ACC (acetyl-CoA carboxylase) Ser79 phosphorylation in rat adipocytes. Similarly to exercise, adrenaline treatment in vivo increased AMPK activities and ACC phosphorylation. Pre-treatment of rats with the β-blocker propranolol fully blocked exercise-induced AMPK activation. Increased AMPK activity with exercise and adrenaline treatment in vivo was accompanied by an increased AMP/ATP ratio. Adrenaline incubation of isolated adipocytes also increased the AMP/ATP ratio and AMPK activities, an effect blocked by propranolol. Adrenaline incubation increased lipolysis in isolated adipocytes, and Compound C, an AMPK inhibitor, attenuated this effect. Finally, a potential role for AMPK in the decreased adiposity associated with chronic exercise was suggested by marked increases in AMPKα1 and α2 activities in adipocytes from rats trained for 6 weeks. In conclusion, both acute and chronic exercise are significant regulators of AMPK activity in rat adipocytes. Our findings suggest that adrenaline plays a critical role in exercise-stimulated AMPKα1 and α2 activities in adipocytes, and that AMPK can function in the regulation of lipolysis.

scholarly journals Myeloid deletion and therapeutic activation of AMP-activated protein kinase (AMPK) do not alter atherosclerosis in male or female mice

2020 ◽  
Author(s):  
Nicholas D. LeBlond ◽  
Peyman Ghorbani ◽  
Conor O’Dwyer ◽  
Nia Ambursley ◽  
Julia R. C. Nunes ◽  
...  
Keyword(s):  
Protein Kinase ◽  
First Generation ◽  
Western Diet ◽  
Daily Injection ◽  
Catalytic Subunits ◽  
Male And Female ◽  
Ampk Signaling ◽  
Female Mice ◽  
Amp Activated Protein Kinase ◽  
Progression Of Atherosclerosis

AbstractObjectiveThe dysregulation of myeloid-derived cell metabolism can drive atherosclerosis. AMP-activated protein kinase (AMPK) controls various aspects of macrophage dynamics and lipid homeostasis, which are important during atherogenesis.Approach and ResultsWe aimed to clarify the role of myeloid-specific AMPK signaling by using LysM-Cre to drive the deletion of both the α1 and α2 catalytic subunits (MacKO), in male and female mice made acutely atherosclerotic by PCSK9-AAV and Western diet-feeding. After 6 weeks of Western diet feeding, half received daily injection of either the AMPK activator, A-769662 or a vehicle control for a further 6 weeks. After 12 weeks, myeloid cell populations were not different between genotype or sex. Similarly, aortic sinus plaque size, lipid staining and necrotic area were not different in male and female MacKO mice compared to their littermate floxed controls. Moreover, therapeutic intervention with A-769662 had no effect. There were no differences in the amount of circulating total cholesterol or triglyceride, and only minor differences in the levels of inflammatory cytokines between groups. Finally, CD68+ area or markers of autophagy showed no effect of either lacking AMPK signaling or systemic AMPK activation.ConclusionsOur data suggest that while defined roles for each catalytic AMPK subunit have been identified, global deletion of myeloid AMPK signaling does not significantly impact atherosclerosis. Moreover, we show that intervention with the first-generation AMPK activator, A-769662, was not able to stem the progression of atherosclerosis.Highlights- The deletion of both catalytic subunits of AMPK in myeloid cells has no significant effect on the progression of atherosclerosis in either male or female mice- Therapeutic delivery of a first-generation AMPK activator (A-769662) for the last 6 weeks of 12-week study had no beneficial effect in either male or female mice- Studying total AMPK deletion may mask specific effects of each isoform and highlights the need for targeted disruption of AMPK phosphorylation sites via knock-in mutations, rather than the traditional “sledgehammer” knockout approach

scholarly journals Reactive Nitrogen Species Is Required for the Activation of the AMP-activated Protein Kinase by Statin in Vivo

2008 ◽  
Vol 283 (29) ◽  
pp. 20186-20197 ◽  
Author(s):  
Hyoung Chul Choi ◽  
Ping Song ◽  
Zhonglin Xie ◽  
Yong Wu ◽  
Jian Xu ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Reactive Nitrogen Species ◽  
Reactive Nitrogen ◽  
Nitrogen Species ◽  
Amp Activated Protein Kinase

scholarly journals Angiotensin AT1 receptor antagonism by losartan stimulates adipocyte browning via induction of apelin

2020 ◽  
Vol 295 (44) ◽  
pp. 14878-14892
Author(s):  
Dong Young Kim ◽  
Mi Jin Choi ◽  
Tae Kyung Ko ◽  
Na Hyun Lee ◽  
Ok-Hee Kim ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Protein Kinase ◽  
Metabolic Disorders ◽  
Angiotensin Ii Receptor ◽  
Adeno Associated Virus ◽  
Receptor Antagonism ◽  
White Adipocytes ◽  
Treatment Of Obesity ◽  
Amp Activated Protein Kinase

Adipocyte browning appears to be a potential therapeutic strategy to combat obesity and related metabolic disorders. Recent studies have shown that apelin, an adipokine, stimulates adipocyte browning and has negative cross-talk with angiotensin II receptor type 1 (AT1 receptor) signaling. Here, we report that losartan, a selective AT1 receptor antagonist, induces browning, as evidenced by an increase in browning marker expression, mitochondrial biogenesis, and oxygen consumption in murine adipocytes. In parallel, losartan up-regulated apelin expression, concomitant with increased phosphorylation of protein kinase B and AMP-activated protein kinase. However, the siRNA-mediated knockdown of apelin expression attenuated losartan-induced browning. Angiotensin II cotreatment also inhibited losartan-induced browning, suggesting that AT1 receptor antagonism-induced activation of apelin signaling may be responsible for adipocyte browning induced by losartan. The in vivo browning effects of losartan were confirmed using both C57BL/6J and ob/ob mice. Furthermore, in vivo apelin knockdown by adeno-associated virus carrying–apelin shRNA significantly inhibited losartan-induced adipocyte browning. In summary, these data suggested that AT1 receptor antagonism by losartan promotes the browning of white adipocytes via the induction of apelin expression. Therefore, apelin modulation may be an effective strategy for the treatment of obesity and its related metabolic disorders.

scholarly journals Withdrawal: Reactive nitrogen species is required for the activation of the AMP-activated protein kinase by statin in vivo.

2019 ◽  
Vol 294 (27) ◽  
pp. 10742-10742
Author(s):  
Hyoung Chul Choi ◽  
Ping Son ◽  
Zhonglin Xie ◽  
Yong Wu ◽  
Jian Xu ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Reactive Nitrogen Species ◽  
Reactive Nitrogen ◽  
Nitrogen Species ◽  
Amp Activated Protein Kinase
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