Inhibition of GSK3 by lithium, from single molecules to signaling networks

Freland, Laure; Beaulieu, Jean‐Martin

doi:10.3389/fnmol.2012.00014

Cited by 230 publications

(216 citation statements)

References 86 publications

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“…Lithium also decreases the expression of pro-inflammatory cyclooxygenase-2 and inducible nitric oxide synthase. Reports also suggest that LiCl may be inhibiting GSK-3β via phosphorylation of AKT (Freland and Beaulieu, 2012). We have previously reported that AKT phosphorylation is impaired in DCs from aged subjects (Agrawal et al, 2007a).…”

Section: Discussionmentioning

confidence: 99%

Dendritic cells from the elderly display an intrinsic defect in the production of IL-10 in response to Lithium Chloride

Agrawal

Gollapudi

Gupta

et al. 2013

Experimental Gerontology

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Chronic, low grade inflammation is a characteristic of old age. Innate immune system cells such as dendritic cells (DCs) from the elderly display a pro-inflammatory phenotype associated with increased reactivity to self. Lithium is a well-established anti-inflammatory agent used in the treatment of bipolar disorders. It has also been reported to reduce inflammation in DCs. Here, we investigated whether Lithium is effective in reducing the inflammatory responses in DCs from the elderly. The effect of Lithium Chloride (LiCl) was compared on the response of TLR4 agonist, LPS and TLR2 agonist, PAM3CSK4 stimulated aged and young DCs. LiCl enhanced the production of IL-10 in LPS stimulated young DCs. However, it did not affect TNF-α and IL-6 production. In contrast, in aged DCs, LiCl reduced the secretion of TNF-α and IL-6 in LPS stimulated DCs but did not increase IL-10. LiCl had no significant effect on PAM3CSK4 responses in aged and young DCs. LiCl treated DCs also displayed differences at the level of CD4 T cell priming and polarization. LPS-stimulated young DCs reduced IFN-γ secretion and biased the Th cell response towards Th2/Treg while LiCl treated aged DCs only reduced IFN-γ secretion but did not bias the response towards Th2/Treg. In summary, our data suggests that LiCl reduces inflammation in aged and young DCs via different mechanisms. Furthermore, the effect of LiCl is different on LPS and PAM3CSK4 responses.

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Section: Discussionmentioning

confidence: 99%

Dendritic cells from the elderly display an intrinsic defect in the production of IL-10 in response to Lithium Chloride

Agrawal

Gollapudi

Gupta

et al. 2013

Experimental Gerontology

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“…It has been demonstrated that lithium can inhibit GSK activity both directly or indirectly by increasing inhibitory phosphorylation with unclear relativity between these modes of inhibition 24 . However, recent literatures indicated that lithium regulates GSK-3 not only directly but also through more complex network affecting multiple molecular targets at a time 25 , which complicates its effect on GSK-3β even more on top of the bifunctional role of GSK-3β in cell apoptosis 26 . On the other hand, in our study, lithium was given before MIRI, which cancelled the protective effects of myocardial ischemic post-conditioning.…”

Section: ■ Discussionmentioning

confidence: 99%

Myocardial ischemic post-conditioning protects the lung against myocardial ischemia/reperfusion-induced damage by activating GSK-3β

et al. 2017

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Myocardial ischemic post-conditioning protects the lung against myocardial ischemia/reperfusion-induced damage by activating GSK-3β 1 Abstract Purpose: To investigate whether modulating GSK-3β could attenuate myocardial ischemia reperfusion injury (MIRI) induced acute lung injury (ALI) and analyze the underlying mechanism. Methods: Male SD rats were subjected to MIRI with or without myocardial ischemic postconditioning in the presence or absence of GSK-3β inhibitor. GSK-3β inhibitor was injected peritoneally 10min before MIRI. Lung W/D weight ratio, MPO, PMNs, histopathological changes, TUNEL, Bax, Bcl-2, IL-6, IL-8, IL-10, GSK-3β, and caspase-3 were evaluated in the lung tissues of all rats. Results: After MIRI, lung injury was significantly increased manifested as significant morphological changes and increased leukocytes in the interstitial capillaries, Lung W/D ratio, MPO, and PMN in BALF, which was associated with enhanced inflammation evidenced by increased expressions of IL-6, IL-8 and reduced expression of IL-10. MIRI significantly increased cell apoptosis in the lung as increased levels of apoptotosis, Bax, cleaved caspase-3, and reduced expression of Bcl-2 was observed, which was concomitant with reduced p-GSK-3β. All these changes were reversed/prevented by ischemic post-conditioning, while these beneficial effects of ischemic post-conditioning were abolished by GSK-3β inhibition. Conclusion: Myocardial ischemia reperfusion injury induces acute lung injury by induction of inflammation and cell apoptosis. Ischemic post-conditioning protects the lung from ALI following MIRI by increasing p-GSK-3β.

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“…6h. Lithium ions dissociated from acetoacetate lithium are biologically active and inhibit the function of GSK-3␣/␤ and other key kinases (COX, Arrestin-2, CaMK1, PHK, CHK2, NEK6, and IKK␥), which play important roles in regulating cell proliferation (71,72). Therefore, we treated C2C12 cells with acetoacetate sodium to rule out the possibility that cell proliferation promoted by acetoacetate lithium was due to the activity of lithium effect rather than acetoacetate itself.…”

Section: Discussionmentioning

confidence: 99%

Acetoacetate Accelerates Muscle Regeneration and Ameliorates Muscular Dystrophy in Mice

Zou

Meng

et al. 2016

Journal of Biological Chemistry

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Acetoacetate (AA) is a ketone body and acts as a fuel to supply energy for cellular activity of various tissues. Here, we uncovered a novel function of AA in promoting muscle cell proliferation. Notably, the functional role of AA in regulating muscle cell function is further evidenced by its capability to accelerate muscle regeneration in normal mice, and it ameliorates muscular dystrophy in mdx mice. Mechanistically, our data from multiparameter analyses consistently support the notion that AA plays a non-metabolic role in regulating muscle cell function. Finally, we show that AA exerts its function through activation of the MEK1-ERK1/2-cyclin D1 pathway, revealing a novel mechanism in which AA serves as a signaling metabolite in mediating muscle cell function. Our findings highlight the profound functions of a small metabolite as signaling molecule in mammalian cells.Satellite cells, which are among the most abundant well defined adult stem cell types in skeletal muscle, play functionally important roles in postnatal growth, repair, and the regeneration of skeletal muscle (1-6). Because of their powerful ability to regenerate in vivo in response to muscle damage and various stimuli, satellite cells represent important targets for the treatment of muscular diseases (7-10). The recent development of stem cell-based regenerative medicine strategies has brought enormous interest in the discovery of regulatory factors capable of controlling satellite cell functions, such as activation, proliferation, differentiation, and self-renewal (11-13). Identification of such factors is expected to not only improve our understanding of the regulatory mechanisms that govern satellite cell functions, but also to facilitate the development of stem cell-based therapies for the treatment of muscular dystrophy or other chronic diseases associated with muscle wasting.Recent studies demonstrating a close correlation between cell proliferation and metabolic alterations in various tumor types have drawn attention to the significance of intrinsic small metabolites as signaling molecules responsible for regulating various cellular activities (14, 15). Although only a very limited number of such metabolites have been identified to date, accumulating evidence suggests that these metabolites can be oncogenic and alter cell signaling through epigenetic regulation. For example, 2-hydroxyglutarate (2-HG), 4 succinate, and fumarate, which are the best characterized small metabolites with oncogenic function, have come to be regarded as oncometabolites (16 -19). In tumor cells, 2-HG is generated by mutant forms of isocitrate dehydrogenase (IDH1 and IDH2) (20 -23), whereas succinate and fumarate accumulate via mutant forms of succinate dehydrogenase and fumarate hydratase, respectively (24 -27). It has been clearly demonstrated that increases in the levels of these oncometabolites play causal roles in tumorigenesis (26 -34). Recent studies of the molecular mechanisms underlying their action have revealed that 2-HG and elevated levels of succinate ...

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Inhibition of GSK3 by lithium, from single molecules to signaling networks

Cited by 230 publications

References 86 publications

Dendritic cells from the elderly display an intrinsic defect in the production of IL-10 in response to Lithium Chloride

Dendritic cells from the elderly display an intrinsic defect in the production of IL-10 in response to Lithium Chloride

Myocardial ischemic post-conditioning protects the lung against myocardial ischemia/reperfusion-induced damage by activating GSK-3β

Acetoacetate Accelerates Muscle Regeneration and Ameliorates Muscular Dystrophy in Mice

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