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Bolanle, O. Links between Protein O-GlcNAcylation and Inflammatory Disease. Encyclopedia. Available online: https://encyclopedia.pub/entry/20371 (accessed on 18 July 2025).
Bolanle O. Links between Protein O-GlcNAcylation and Inflammatory Disease. Encyclopedia. Available at: https://encyclopedia.pub/entry/20371. Accessed July 18, 2025.
Bolanle, Olapeju. "Links between Protein O-GlcNAcylation and Inflammatory Disease" Encyclopedia, https://encyclopedia.pub/entry/20371 (accessed July 18, 2025).
Bolanle, O. (2022, March 09). Links between Protein O-GlcNAcylation and Inflammatory Disease. In Encyclopedia. https://encyclopedia.pub/entry/20371
Bolanle, Olapeju. "Links between Protein O-GlcNAcylation and Inflammatory Disease." Encyclopedia. Web. 09 March, 2022.
Links between Protein O-GlcNAcylation and Inflammatory Disease
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This entry is adapted from the peer-reviewed paper 10.3390/cells11040705

Unresolved hyperglycaemia, a hallmark of type 2 diabetes mellitus (T2DM), is a well characterised manifestation of altered fuel homeostasis and our understanding of its role in the pathologic activation of the inflammatory system continues to grow. Metabolic disorders like T2DM trigger changes in the regulation of key cellular processes such as cell trafficking and proliferation, and manifest as chronic inflammatory disorders with severe long-term consequences. Activation of inflammatory pathways has recently emerged as a critical link between T2DM and inflammation. The hexosamine biosynthetic pathway(HBP), a unique nutrient-sensing metabolic pathway, produces the activated amino sugar UDP-GlcNAc which is a critical substrate for protein O-GlcNAcylation, a dynamic, reversible post-translational glycosylation of serine and threonine residues in target proteins. Protein O-GlcNAcylation impacts a range of cellular processes, including inflammation, metabolism, trafficking, and cytoskeletal organisation.

O-GlcNAcylation metabolism diabetes inflammation

1. Introduction

Sustained hyperglycaemia, which is the hallmark of type 2 diabetes mellitus (T2DM), comes with far reaching consequences such as increased risk of cardiovascular diseases (CVD) and kidney failure [1]. While some of the complications associated with hyperglycaemia are the result of acute metabolic derangements e.g., ketoacidosis, a majority of complications are due in part to chronically elevated blood glucose levels e.g., stroke, neuropathy, retinopathy and nephropathy [1]. Metabolic alterations associated with hyperglycaemia have been well characterised [2]. Specifically, the pathogenesis and progression of T2DM have been ascribed to four key mechanisms; increased polyol pathway flux, increased advanced glycation end product (AGE) formation, activation of protein kinase C (PKC) isoforms, and increased hexosamine pathway flux [2][3]. However, until recently, the contribution of increased hexosamine pathway flux to the development of metabolic disorders was unclear [2][4][5][6]. The final product of the hexosamine biosynthetic pathway (HBP) is the activated amino sugar UDP-GlcNAc, a critical substrate for protein glycosylation [6][7][8]. UDP-GlcNAc serves as the sugar donor for O-GlcNAcylation events which is a dynamic, reversible post-translational modification of serine and threonine residues in target proteins within cells [8][9]. This process is controlled by two enzymes: O-linked β-N-acetylglucosamine transferase (OGT) and O-linked β-N-acetylglucosaminidase (OGA) [8][9]. OGT is responsible for catalysing the addition of a O-GlcNAc moiety to either serine or threonine residues in target proteins [10][11]. Conversely, the enzyme OGA reverses this modification by catalysing the hydrolysis of O-GlcNAc from protein targets [10][11]. A large body of evidence has shown that increased hexosamine pathway flux results in increased OGT-mediated O-GlcNAcylation events [6][12][13][14][15]. Importantly, O-GlcNAcylation of inflammatory pathways, and trafficking and proliferation of cells have emerged as a critical link between T2DM and the chronic inflammation observed in pathologies that are a consequence of poor blood glucose control [2][4][5][16]. In recent years, a growing number of findings elucidating the role of O-GlcNAcylation as vital molecular mechanism in the pathogenesis of T2DM and its complications have emerged [2][4][5][12][13][14][15][16].

2. Involvement of O-GlcNAcylation in Inflammation

2.1. Impact of O-GlcNAcylation on Inflammatory Signalling Pathways

Activation of inflammatory signalling pathways by glucose-dependent metabolic stress is a major phenomenon in the pathogenesis and progression of T2DM [2][4] as well as other known pathologies such as cancers, autoimmune disorders and neurological disease [17][18][19][20][21]. Despite the researchers incomplete understanding of the mechanisms responsible for nutrient regulation of inflammation, several studies suggest that O-GlcNAcylation is critical to the pathophysiology of inflammatory derangements [20][22][23][24][25][26]. Importantly, while some studies have indicated that O-GlcNAcylation of target proteins is a pro-inflammatory event in diabetes and is involved in the development of insulin resistance [27][28]. Conversely, others have shown that this dynamic post-translational modification can also confer protection against acute inflammatory stimuli [29][30][31]. These findings [27][28][29][30][31] strongly suggest that diverse forms of insults could result in dynamic changes to O-GlcNAcylation patterns to either promote or inhibit inflammation in response to fluctuations in cellular metabolism. 

2.1.1. Pro-Inflammatory Role of O-GlcNAcylation

Emerging findings have continued to improve the researchers understanding of the pro-inflammatory role of O-GlcNAcylation in the NF-κB signaling pathway. NF-κB is a chief regulator of innate and adaptive immune responses and plays a central role in chronic inflammation responsible for tumour development, rheumatoid arthritis, atherosclerosis, chronic obstructive pulmonary disease, asthma, multiple sclerosis, inflammatory bowel disease, and ulcerative colitis [32][33][34][35][36]. Yang et al. [37] have shown that the p65/RelA NF-κB subunit is O-GlcNAcylated in rat vascular smooth muscle cells. O-GlcNAc modification of NF-κB p65 on Thr352 inhibits the interaction between NF-κB p65 and IκB, thereby promoting translocation of NF-κB heterodimers to the nucleus and increasing transcription of target genes such as the gene for adhesion molecule VCAM-1 under hyperglycaemic conditions [33]. These findings strongly suggest that specific O-GlcNAcylation of p65/RelA on Thr352 may facilitate sustained activation of NF-κB-mediated chronic inflamamtion in response to prolonged hyperglycaemia and development of diabetes [33]. Although the mechanism of how O-GlcNAcylation activates NF-κB signaling is not fully understood, however, O-GlcNAcylation has been shown to increase the phosphorylation and acetylation of NF-κB subunit p65/RelA [34]. O-GlcNAc modification of p65 at Thr305 and Ser319 increased CREB-binding protein (CBP)/p300-dependent activating acetylation of p65 at Lys310, and this contributes to NF-κB transcriptional activation [34]. Also, elevation of O-GlcNAcylation by upregulating the expression of OGT increased the expression of p300, IKKα, and IKKβ and promoted IKK-mediated activating phosphorylation of p65 at Ser536, contributing to NF-κB activation (Figure 1) [34]. Similarly, it has been proposed that O-GlcNAcylation of IKKβ at Ser733 enhances NF-κB activity by increasing IKK activity, IκB phosphorylation and subsequent IκB degradation in both mouse and human fibroblasts [35]. These findings [32][33][35] suggest mechanisms through which O-GlcNAcylation regulates NF-κB signaling through interplay with phosphorylation and acetylation with consequent inflammatory outputs.
Cells 11 00705 g003 550
Figure 1. Schematic of the pro-inflammatory downstream signalling modulation by O-GlcNAcylation. O-GlcNAc (O-linked β-N-acetylglucosamine), OGT (O-linked β-N-acetylglucosamine transferase), NF-κB (nuclear factor kappa light chain enhancer of activated B cells), STAT3 (signal transducer and activator of transcription3), TAK 1 (Transforming growth factor-β activated kinase 1), TAB1 (TAK1-binding protein 1), Nod2 (nucleotide-binding oligomerization domain-containing protein 2), IL-1,6,8, and 12 (Interleukin-1,6,8, and 12), Sp1 (substrate of Keap1), CXCL1 (chemokine ligand 1), VEGF-A (vascular endothelial growth factor), ICAM-1 (intercellular Adhesion Molecule 1), TNF-α (tumor necrosis factor alpha).
Furthermore, Sp1, a zinc finger transcription factor is also O-GlcNAcylated in response to high glucose concentrations and elevated Sp1 activity upon O-GlcNAcylation could play a role in hyperglycaemia-induced pro-fibrotic and pro-inflammatory factors involved in diabetic retinopathy [38][39]. Donovan et al. [38] showed that hyperglycaemia significantly increased Sp1 binding to the gene promoter of the pro-angiogenic mediator vascular endothelial growth factor (VEGF)-A, while shRNA-mediated knockdown of either OGT or Sp1 significantly inhibited glucose-induced increases in VEGF-A levels in ARPE-19 human retinal pigment epithelial cells and TR-iBRB rat retinal microvascular endothelial cells. These observations suggest that hyperglycaemia-induced O-GlcNAcylation of Sp1 drives VEGF-A production in both systems. Zhang et al. [39] have also proposed that hyperglycaemia also stimulates expression of intercellular adhesion molecule (ICAM)-1 by O-GlcNAcylation of Sp1 in both human umbilical vein endothelial cells and rat retinal capillary endothelial cells.
Alternatively, the transcriptional activity of Sp1 can be reduced when O-GlcNAc modified, and this may be due to the resultant distortion in its interaction with its cooperative factors such as Elf-1 [40], NF-Y [41], Ying-Yang 1 [42], and sterol regulatory element binding protein 2 [43]. Thus, O-GlcNAc modification of Sp1 could contribute to negative regulation of placental and embryonic expression of oncofetal protein gene (Pem), a gene which encodes a homeobox protein expressed in reproductive tissues and a wide range of transformed cells [40]. Furthermore, O-GlcNAcylation of Sp1 inhibits hyaluronan synthesis (an important component of the extracellular matrix that plays a crucial role for cumulus cell expansion which occurs during maturation of oocytes [42][43], and lipid synthesis [44]. Intriguingly, Suh et al. [45] demonstrated that O-GlcNAc modification of Sp1 protects primary cultured renal proximal tubule cells against hypoxia-induced dysfunction of Na/glucose cotransporter (SGLT). Similarly, Lee et al. [46] showed that O-GlcNAcylation of Sp1 protects mouse embryonic stem cells against hypoxia-induced apoptosis. A weakened association between Sp1 and its co-operative factors caused by O-GlcNAcylation is one potential mechanism which could explain these phenomena.
As a critical effector of cytokines which activate the Janus kinase (JAK)-STAT pathway, STAT3 function is tightly controlled [47]. However, the researchers understanding of how metabolic changes regulate STAT3 function via specific PTMs that regulate STAT3 function, and their pathophysiological significance remain incomplete. Li et al. [29] demonstrated that there was an increased disease severity in azoxymethane-induced colitis and a colitis-associated cancer model in the bone marrow-derived macrophages isolated from CUL3-deficient mice. Li et al. [29] proposed that this was due to increased O-GlcNAcylation of STAT3. In addition, the expression levels of pro-inflammatory cytokines IL-1 and IL-6, and chemokines CXCL1 and CXCL2 were upregulated by O-GlcNAcylated STAT3 in BMMs from CUL3-deficient mice, thus contributing to azoxymethane-induced colitis and colitis-associated cancer.
Apart from the transcription factors highlighted above, other proteins which control inflammation and immunity e.g., Transforming growth factor-β activated kinase (TAK) 1 are also O-GlcNAcylated. TAK1 is an important serine/threonine protein kinase that mediates signals transduced by multifunctional cytokines such as TGF-β, TNF-α and IL-1 [48]. Emerging data have suggested that O-GlcNAcylation of TAK1-binding protein 1 (TAB1) at Ser395 is needed for TAK1 activation [48]. More so, activated TAK1 is intricate to downstream activation of NF-κB and production of IL-6 and TNF-α in human embryonic kidney (HEK) 293 cells stably expressing the IL-1 receptor and reconstituted Tab1-deficient MEFs upon exposure to IL-1 or hyperosmotic stress [48]. Upon stimulation, O-GlcNAc modification of TAK1 at Ser427 is needed for the phosphorylation of Thr187/Ser192 and full activation of TAK1 in RAW264.7 cells [49]. Thus, O-GlcNAc modification of TAK1 has been shown to trigger downstream activation of JNK and NF-κB signaling pathways, facilitate M1 polarisation of macrophages, and increase production of pro-inflammatory cytokine, resulting in the development of acute inflammatory responses [50]. Also, a cytoplasmic human nucleotide-binding oligomerization domain-containing protein 2 (Nod2)-like receptor that recognises bacterial components, is O-GlcNAcylated and this modification causes it to produce various pro-inflammatory cytokines and chemokines via activation of NF-κB in HEK293T cells (Figure 3) [25].

2.1.2. Anti-Inflammatory Role of O-GlcNAcylation

There is evidence to support O-GlcNAc modification of target proteins in the vasculature as a novel anti-inflammatory and vasoprotective mechanism [30][31]. Xing et al. [30] acutely treated ovariectomized rats with GlcN and PUGNAc before balloon injury of the right carotid artery and found that GlcN and PUGNAc each upregulated protein O-GlcNAcylation and significantly ameliorated acute inflammation [30]. Also, increased levels of proinflammatory HIS48+ granulocytes and ED1+ monocytes in response to injury were significantly reduced by GlcN and PUGNAc treatment through reduced infiltration into injured arteries [30]. The authors were also able to demonstrate that chronic (14 days) treatment with GlcN significantly reduced neointima formation in injured arteries compared with vehicle controls [30]. A protective anti-inflammatory role for O-GlcNAcylation in the vasculature is also supported by Hilgers et al. [31], who demonstrated that acute increases in protein O-GlcNAcylation were associated with reduced TNF-α-induced hypocontractility of rat aortic rings. In this study, iNOS protein expression was increased in TNF-α-treated rings, and this was attenuated by pretreatment with either GlcN or Thiamet-G, suggesting that acute increases in protein O-GlcNAcylation ameliorated TNF-α induced vascular dysfunction at least in part by limiting iNOS expression (Figure 2) [31].
Cells 11 00705 g004 550
Figure 2. Schematic of the anti-inflammatory downstream signaling by O-GlcNAcylation. GlcN (Glucosamine), OGA (O-linked β-N-acetylglucosaminidase), PUGNAc (O-(2-acetamido-2-deoxy-d-glucopyranosyliden)amino-N-phenylcarbamate), iNOS (inducible nitric oxide synthase), IL-6 (interleukin-6), TNF-α (tumor necrosis factor alpha), NF-κB (nuclear factor kappa light chain enhancer of activated B cells), COX2 (cyclooxygenase-2).
Furthermore, Hwang et al. [51] proposed that GlcN could be a novel neuroprotective or anti-inflammatory agent. In this study [51], administration of GlcN was found to reduce infarct volume and ameliorates motor impairment and neurological deficits in a rat middle cerebral artery occlusion model of ischaemic stroke. Also, GlcN suppressed LPS-induced upregulation of pro-inflammatory mediators in BV2 microglial cells and RAW264.7 macrophages [51]. GlcN is a substrate for GFAT, the rate-limiting enzyme in the HBP. Increase in the influx of glucose and glutamine would result in increased UDP-GlcNAc levels and upregulation of O-GlcNAcylation. However, in this case, Hwang et al. [51] suggest that GlcN inhibits the O-GlcNAcylation of NF-κB, probably by disturbing the association between OGT and NF-κB.
In addition, Zou et al. [52] showed that increased O-GlcNAcylation by PUGNAc administration following induction of trauma-haemorrhage (TH) in fasted rats improves recovery of organ perfusion and function. In this study [52], they demonstrated that PUGNAc attenuated the TH-induced increase in plasma IL-6 levels, and suggested that PUGNAc, like GlcN, improves cardiac function and organ perfusion by reducing the level of circulating IL-6 and TNF-α after TH. The same researchers have also shown that treatment of fasted rats with GlcN attenuated TH-induced increases in NF-κB activation and reduced cardiac levels of TNF-α and IL-6 mRNAs, ICAM-1 protein and myeloperoxidase activity (Figure 2) [53]. These results demonstrate that the modulation of O-GlcNAc levels regulates activation of the NF-κB pathway in the heart, which may contribute to the observed GlcN-mediated improvement in cardiac function following haemorrhagic shock.
Also, sepsis leading to multiple organ damage is mainly caused by an uncontrolled systemic inflammatory response. However, the mechanisms responsible for this are unclear and the researchers understanding of its pathogenesis remains incompletely understood [54][55]. As it shares common major blood lineages [56] and strikingly similar immune system architecture with humans, the zebrafish has been proposed as a tractable model to investigate the underlying pathophysiology of infectious diseases as well as immune and inflammatory disorders [56][57][58]. In addition, Hwang et al. [59] have demonstrated that pre-treatment of mice with GlcN upregulated protein O-GlcNAcylation and improved survival in the caecal ligation and puncture (CLP)-induced sepsis, and attenuated LPS-induced septic lung injury and systemic inflammation. In this study [59], they demonstrated that LPS reduced O-GlcNAcylation of nucleocytoplasmic proteins in liver, lung, and spleen. Also, LPS-induced downregulation O-GlcNAcylation in mouse lung was inhibited by GlcN, and the OGA level increased by LPS was suppressed by GlcN [59].
Another study has provided evidence that GlcN stimulates the O-GlcNAcylation of both nuclear and cytosolic forms of c-Rel [60]. Furthermore, this study demonstrated that upon stimulation with LPS, GlcN inhibits the binding of c-Rel to the NF-κB site in the iNOS promoter [60]. Although the mechanism through which GlcN exacts these effects is not fully understood, however, it is suggested that GlcN is impairs the interaction between OGT and c-Rel [60]. It has been observed in N9 microglial cells treated with LPS, the enhanced expression of iNOS, NO and ROS is mediated via the downregulation of OGT and protein O-GlcNAcylation, or via the upregulation of MAPKs phosphorylation and NF-κB translocation [61]. Also, overexpression of OGT inhibits LPS-induced activation of NF-κB and iNOS through modulation of histone acetylation either directly or indirectly [62]. Furthermore, Thiamet G improved clinical outcomes and ameliorated the neurological deficits when used to treat mice either before or after middle cerebral artery occlusion (MCAO) [63]. Additionally, the number of Iba1+ cells in MCAO mice were reduced when treated with Thiamet G [63]. Also, expression of MI markers was decreased by Thiamet G, conversely, the expression of the M2 markers increased in vivo [63]. Also, Thiamet G decreased the expression of iNOS and COX2 mainly by suppressing NF-κB p65 signaling (Figure 2) [63]. These results suggest that Thiamet G exerts a neuroprotective effect which suggest its usefulness as a potential anti-inflammatory agent for ischemic stroke therapy.
Furthermore, the deubiquitinase A20 has been identified as suppressor of NF-κB pathway activation [64]. the researchers understanding of the downstream regulation of the activities of A20 is still unclear. However, it has been shown that GlcN and Thiamet G which significantly increased O-GlcNAc modification of A20 enhanced its binding to TAB1, a key regulator of A20 activity [64]. These studies [64][65] suggest that O-GlcNAcylation is a critical regulatory modulator of the activities of A20, which consequently downregulates NF-κB signaling, including in vascular smooth muscle cells. Furthermore, it has been shown that the activities of Glutathione peroxidase 1 (GPX1) is induced by hyperglycaemia [66]. GPX1 is an anti-oxidant enzyme that is critical for cell survival. Hyperglycaemia enhances the O-GlcNAc modification of GPX1 and subsequently increases the association between non-receptor tyrosine kinase c-Abl and Arg in rat vascular smooth muscle cells [66]. Also, 1,2-dideoxy-2′-propyl-alpha-d-glucopyranoso-[2,1-d]-Delta2′-thiazoline (an OGA inhibitor) was shown to cause the activation of GPX1 in the mouse liver [66]. Furthermore, Hwang et al. [67] after stimulating with LPS, discovered that GlcN relieves the basal transcription activity of RNA polymerase II (RNAPII), a multiprotein complex that catalyzes the transcription of all protein-coding genes and several non-coding RNAs. They suggest that this observation was due to increased O-GlcNAcylation of RNAPII and DNA binding upon treatment with GlcN, which are inhibited by LPS [67].

2.2. Intrinsic Role of OGT and OGA in Inflammatory Pathways

Findings showing the intrinsic involvement of the key modulating enzymes of O-GlcNAcylation in inflammation are beginning to emerge [29][68][69][70]. Mutual and balanced interaction between OGT and OGA is critical for normal O-GlcNAc homeostasis. However, sustained alteration in form of enhancement or inhibition of these key enzymes initiates the development of O-GlcNAcylation mediated pathologies with inflammatory components. Recent findings have demonstrated that OGT promotes inflammatory responses in macrophages [29][32][68][69][71]. NF-κB which is a critical regulator of pro-inflammatory responses in macrophages has been shown to be O-GlcNAc modified [32]. Allison et al. [32] demonstrated that OGT could co-localise to NF-κB–regulated promoters causing the modification of Thr305 residue of the NF-κB subunit RelA. This was shown to promote acetylation on K310 of RelA, and further enhanced NF-κB transcriptional activity after stimulation of tumour necrosis factor (TNF) [32]. Allison et al. [32] further showed that a knockdown of OGT abolishes p300-mediated acetylation of RelA on Lys310, a posttranslational mark required for full NF-κB transcription. Similarly, Ramakrishnan et al. [68] identified Ser350 as the site of modification and activation of NF-κB subunit c-Rel. They also showed that preventing the OGT mediated O-GlcNAc modification of this residue repealed c-Rel–mediated expression of the cytokine-encoding genes IL2, IFNG, and CSF2 in response to TCR activation, whereas increasing the extent of O-GlcNAcylation of cellular proteins promoted the expression of these genes [68].
Microglial cells are the brain resident macrophage [72]. In BV2 microglia cells, c-Rel has been shown to interact with OGT upon lipopolysaccharide (LPS) treatment, which promotes c-Rel O-GlcNAcylation and formation of a c-Rel-p50/p105 heterodimeric complex [60]. More so, this study [71] demonstrated that the S-nitrosylation of OGT inhibits its catalytic activity in resting RAW 264.7 murine macrophage cells [71]. However, stimulation of OGT with LPS results in de-nitrosylation of OGT which then enhanced OGT-mediated O-GlcNAc modification of p65/RelA [71]. Furthermore, attenuation of O-GlcNAcylation negatively modulates p65 nuclear translocation, resulting in diminished production of nitric oxide (NO) and IL-1β [71]. Also, the role of STAT3, a critical transcription factor in promoting inflammation and tissue repair has been well enumerated [73][74]. More so, STAT3 can induce IL-10 production in macrophages to suppress inflammation [75]. It has been previously demonstrated that OGT modulated O-GlcNAc modification of STAT3 at transactivation domain Thr717 competitively downregulates STAT3 phosphorylation which results in reduced production of IL-10 [29]. Furthermore, in macrophages derived from the bone-marrow, OGT expression can be transcriptionally downregulated by myeloid-derived cullin 3 (CUL3), a process dependent on nuclear factor-2 (Nrf2) which binds to the Ogt promoter to increase gene transcription [29][76][77]. Therefore, CUL3 counteracts STAT3 O-GlcNAcylation to elevate STAT3 phosphorylation and inhibit inflammation [29].
In contrast, many studies have demonstrated that increased O-GlcNAcylation correlates with suppression of inflammation in sepsis and ischemia [59][78][79][80][81][82]. Upon GlcN treatment, which bypasses the GFAT rate-limiting step to induce hyper-O-GlcNAcylation [78], the transcriptional activity of c-Rel is inhibited, thereby reducing NF-κB-mediated expression of inducible nitric oxide synthase (iNOS) in LPS stimulated BV2 microglial cells [51][60]. Furthermore, it has recently been shown that receptor-interacting serine/threonine-protein kinase 3 (RIPK3) can be O-GlcNAc modified [79]. RIPK3 is a member of the necrosome complex, a complex consisting of RIP1, RIP3, and Fas-associated protein with death domain causing rapid plasma membrane rupture and induction of an inflammatory response. This is done through the release of damage-associated molecular patterns and cytokines [80][81]. Also, RIPK3 reduces inflammation by diminishing the production of pro-inflammatory cytokines resulting from necroptosis of macrophages [83]. Interestingly, O-GlcNAc modification of RIPK3 at Thr467 is believed to suppress RIPK3-RIPK1 and RIPK3-RIPK3 complex formation, therefore preventing necroptosis of macrophages [79]. Ogtf/f Lyz2-cre conditional knockout mice, in which Ogt is specifically deleted in macrophages, revealed significantly increased activation of RIPK3, elevated production of inflammatory cytokine, and more severe mortality in experimental sepsis when compared with control mice [79]. Furthermore, Yang et al. [70] have shown that OGT prevents macrophage mediated inflammation and metabolic disturbance by suppressing the phosphorylation of S6 kinase beta-1 (S6K1). Phosphorylation of S6K1, a ribosomal protein is critical for macrophage proinflammatory activation [70]. More so, OGT mediated O-GlcNAcylation is downregulated during macrophage proinflammatory activation, and knockout of OGT in high fat-diet induced obese mice enhances macrophage proinflammatory polarization and promotes adipose tissue inflammation [70].
On the other hand, acute upregulation of O-GlcNAcylation by inhibiting OGA have been shown to prevent inflammation-induced vascular dysfunction, hence, confer a protection on the heart and vasculature [31]. Hilgers et al. [31] demonstrated that acute increase in O-GlcNAcylation by inhibiting OGA prevented TNF-α-induced vascular dysfunction. Furthermore, O-GlcNAcylation can possibly modulate the polarisation of M2 macrophages in a pattern that contribute to resolution of inflammation and tissue repair [59][63][82]. This study [59] demonstrated that treatment with GlcN reduced M1 macrophage-specific gene expression profiles in macrophages in an LPS-induced septic lung injury animal model. More so, when Thiamet-G, a selective OGA inhibitor [63] was administered to a mouse model of middle cerebral artery occlusion, there was an increase in the expression M2-specific markers in microglia [63]. Also, there was suppression of NF-κB p65 signaling which resulted in diminished expression of iNOS and cyclooxygenase-2 (COX-2) expression [63]. This strongly suggests that alteration O-GlcNAc homeostasis can vary the differentiation of M2 versus M1 macrophages in tissues.

References

  1. Forbes, J.M.; Cooper, M.E. Mechanisms of diabetic complications. Physiol. Rev. 2013, 93, 137–188.
  2. Hameed, I.; Masoodi, S.R.; Mir, S.A.; Nabi, M.; Ghazanfar, K.; Ganai, B.A. Type 2 diabetes mellitus: From a metabolic disorder to an inflammatory condition. World J. Diabetes 2015, 6, 598–612.
  3. Brownlee, M. Biochemistry and molecular cell biology of diabetic complications. Nature 2001, 414, 813–820.
  4. Pickup, J.C.; Crook, M.A. Is type II diabetes mellitus a disease of the innate immune system? Diabetologia 1998, 41, 1241–1248.
  5. Shoelson, S.E.; Lee, J.; Goldfine, A.B. Inflammation and insulin resistance. J. Clin. Investig. 2006, 116, 1793–1801.
  6. Chang, Y.H.; Weng, C.L.; Lin, K.I. O-GlcNAcylation and its role in the immune system. J. Biomed. Sci. 2020, 27, 57.
  7. Torres, C.R.; Hart, G.W. Topography and polypeptide distribution of terminal N-acetylglucosamine residues on the surfaces of intact lymphocytes. Evidence for O-linked GlcNAc. J. Biol. Chem. 1984, 259, 3308–3317.
  8. Haltiwanger, R.S.; Holt, G.D.; Hart, G.W. Enzymatic addition of O-GlcNAc to nuclear and cytoplasmic proteins. Identification of a uridine diphospho-N-acetylglucosamine:peptide beta-N-acetylglucosaminyltransferase. J. Biol. Chem. 1990, 265, 2563–2568.
  9. Dong, D.L.; Hart, G.W. Purification and characterization of an O-GlcNAc selective N-acetyl-beta-d-glucosaminidase from rat spleen cytosol. J. Biol. Chem. 1994, 269, 19321–19330.
  10. Yang, X.; Qian, K. Protein O-GlcNAcylation: Emerging mechanisms and functions. Nat. Rev. Mol. Cell Biol. 2017, 18, 452–465.
  11. Lazarus, B.D.; Love, D.C.; Hanover, J.A. Recombinant O-heyGlcNAc transferase isoforms: Identification of O-GlcNAcase, yes tyrosine kinase, and tau as isoform-specific substrates. Glycobiology 2006, 16, 415–421.
  12. Wellen, K.E.; Lu, C.; Mancuso, A.; Lemons, J.M.; Ryczko, M.; Dennis, J.W.; Rabinowitz, J.D.; Coller, H.A.; Thompson, C.B. The hexosamine biosynthetic pathway couples growth factor-induced glutamine uptake to glucose metabolism. Genes Dev. 2010, 24, 2784–2799.
  13. Swamy, M.; Pathak, S.; Grzes, K.M.; Damerow, S.; Sinclair, L.V.; van Aalten, D.M.; Cantrell, D.A. Glucose and glutamine fuel protein O-GlcNAcylation to control T cell self-renewal and malignancy. Nat. Immunol. 2016, 17, 712–720.
  14. Taylor, R.P.; Geisler, T.S.; Chambers, J.H.; McClain, D.A. Up-regulation of O-GlcNAc transferase with glucose deprivation in HepG2 cells is mediated by decreased hexosamine pathway flux. J. Biol. Chem. 2009, 284, 3425–3432.
  15. Weigert, C.; Klopfer, K.; Kausch, C.; Brodbeck, K.; Stumvoll, M.; Haring, H.U.; Schleicher, E.D. Palmitate-induced activation of the hexosamine pathway in human myotubes: Increased expression of glutamine:fructose-6-phosphate aminotransferase. Diabetes 2003, 52, 650–656.
  16. Donath, M.Y.; Dalmas, É.; Sauter, N.S.; Böni-Schnetzler, M. Inflammation in obesity and diabetes: Islet dysfunction and therapeutic opportunity. Cell Metab. 2013, 17, 860–872.
  17. Tseng, C.H. The Relationship between Diabetes Mellitus and Gastric Cancer and the Potential Benefits of Metformin: An Extensive Review of the Literature. Biomolecules 2021, 11, 1022.
  18. Tseng, C.H.; Tseng, F.H. Diabetes and gastric cancer: The potential links. World J. Gastroenterol. 2014, 20, 1701–1711.
  19. Subauste, A.; Gianani, R.; Chang, A.M.; Plunkett, C.; Pietropaolo, S.L.; Zhang, Y.J.; Barinas-Mitchell, E.; Kuller, L.H.; Galecki, A.; Halter, J.B.; et al. Islet autoimmunity identifies a unique pattern of impaired pancreatic beta-cell function, markedly reduced pancreatic beta cell mass and insulin resistance in clinically diagnosed type 2 diabetes. PLoS ONE 2014, 9, e106537.
  20. Liu, J.; Ting, J.P.; Al-Azzam, S.; Ding, Y.; Afshar, S. Therapeutic Advances in Diabetes, Autoimmune, and Neurological Diseases. Int. J. Mol. Sci. 2021, 22, 2805.
  21. Schedin-Weiss, S.; Winblad, B.; Tjernberg, L.O. The role of protein glycosylation in Alzheimer disease. FEBS J. 2014, 281, 46–62.
  22. Li, Y.; Xie, M.; Men, L.; Du, J. O-GlcNAcylation in immunity and inflammation: An intricate system (Review). Int. J. Mol. Sci. 2019, 44, 363–374.
  23. Machacek, M.; Slawson, C.; Fields, P.E. O-GlcNAc: A novel regulator of immunometabolism. J. Bioenerg. Biomembr. 2018, 50, 223–229.
  24. Woo, C.M.; Lund, P.J.; Huang, A.C.; Davis, M.M.; Bertozzi, C.R.; Pitteri, S.J. Mapping and quantification of over 2000 O-linked glycopeptides in activated human T cells with isotope-targeted glycoproteomics (IsoTaG). Mol. Cell. Proteom. 2018, 17, 764–775.
  25. Hou, C.W.; Mohanan, V.; Zachara, N.E.; Grimes, C.L. Identification and biological consequences of the O-GlcNAc modification of the human innate immune receptor, Nod2. Glycobiology 2016, 26, 13–18.
  26. Zhang, D.; Cai, Y.; Chen, M.; Gao, L.; Shen, Y.; Huang, Z. OGT-mediated O-GlcNAcylation promotes NF-κB activation and inflammation in acute pancreatitis. Inflamm. Res. 2015, 64, 943–952.
  27. Li, Y.; Liu, H.; Xu, Q.S.; Du, Y.G.; Xu, J. Chitosan oligosaccharides block LPS-induced O-GlcNAcylation of NF-κB and endothelial inflammatory response. Carbohydr. Polym. 2014, 99, 568–578.
  28. James, L.R.; Tang, D.; Ingram, A.; Ly, H.; Thai, K.; Cai, L.; Scholey, J.W. Flux through the hexosamine pathway is a determinant of nuclear factor κB- dependent promoter activation. Diabetes 2002, 51, 1146–1156.
  29. Li, X.; Zhang, Z.; Li, L.; Gong, W.; Lazenby, A.J.; Swanson, B.J.; Herring, L.E.; Asara, J.M.; Singer, J.D.; Wen, H. Myeloid-derived cullin 3 promotes STAT3 phosphorylation by inhibiting OGT expression and protects against intestinal inflammation. J. Exp. Med. 2017, 214, 1093–1109.
  30. Xing, D.; Feng, W.; Not, L.G.; Miller, A.P.; Zhang, Y.; Chen, Y.F.; Majid-Hassan, E.; Chatham, J.C.; Oparil, S. Increased protein O-GlcNAc modification inhibits inflammatory and neointimal responses to acute endoluminal arterial injury. Am. J. Physiol. Heart Circ. Physiol. 2008, 295, H335–H342.
  31. Hilgers, R.H.; Xing, D.; Gong, K.; Chen, Y.F.; Chatham, J.C.; Oparil, S. Acute O-GlcNAcylation prevents inflammation-induced vascular dysfunction. Am. J. Physiol. Heart Circ. Physiol. 2012, 303, H513–H522.
  32. Allison, D.F.; Wamsley, J.J.; Kumar, M.; Li, D.; Gray, L.G.; Hart, G.W.; Jones, D.R.; Mayo, M.W. Modification of RelA by O-linked N-acetylglucosamine links glucose metabolism to NF-κB acetylation and transcription. Proc. Natl. Acad. Sci. USA 2012, 109, 16888–16893.
  33. Yang, W.H.; Park, S.Y.; Nam, H.W.; Kim, D.H.; Kang, J.G.; Kang, E.S.; Kim, Y.S.; Lee, H.C.; Kim, K.S.; Cho, J.W. NFkappaB activation is associated with its O-GlcNAcylation state under hyperglycemic conditions. Proc. Natl. Acad. Sci. USA 2008, 105, 17345–17350.
  34. Ma, Z.; Chalkley, R.J.; Vosseller, K. Hyper-O-GlcNAcylation activates nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) signaling through interplay with phosphorylation and acetylation. J. Biol. Chem. 2017, 292, 9150–9163.
  35. Kawauchi, K.; Araki, K.; Tobiume, K.; Tanaka, N. Loss of p53 enhances catalytic activity of IKKbeta through O-linked beta-N-acetyl glucosamine modification. Proc. Natl. Acad. Sci. USA 2009, 106, 3431–3436.
  36. Tak, P.P.; Firestein, G.S. NF-kappaB: A key role in inflammatory diseases. J. Clin. Investig. 2001, 107, 7–11.
  37. Pantarelli, C.; Welch, H.C.E. Rac-GTPases and Rac-GEFs in neutrophil adhesion, migration and recruitment. Eur. J. Clin. Investig. 2018, 48 (Suppl. 2), e12939.
  38. Donovan, K.; Alekseev, O.; Qi, X.; Cho, W.; Azizkhan-Clifford, J. O-GlcNAc modification of transcription factor Sp1 mediates hyperglycemia-induced VEGF-A upregulation in retinal cells. Investig. Ophthalmol. Vis. Sci. 2014, 55, 7862–7873.
  39. Zhang, Y.; Qu, Y.; Niu, T.; Wang, H.; Liu, K. O-GlcNAc modification of Sp1 mediates hyperglycaemia-induced ICAM-1 up-regulation in endothelial cells. Biochem. Biophys. Res. Commun. 2017, 484, 79–84.
  40. Lim, K.; Chang, H.I. O-GlcNAc inhibits interaction between Sp1 and Elf-1 transcription factors. Biochem. Biophys. Res. Commun. 2009, 380, 569–574.
  41. Lim, K.; Chang, H.I. O-GlcNAcylation of Sp1 interrupts Sp1 interaction with NF-Y. Biochem. Biophys. Res. Commun. 2009, 382, 593–597.
  42. Jokela, T.A.; Makkonen, K.M.; Oikari, S.; Kärnä, R.; Koli, E.; Hart, G.W.; Tammi, R.H.; Carlberg, C.; Tammi, M.I. Cellular content of UDP-N-acetylhexosamines controls hyaluronan synthase 2 expression and correlates with O-linked N-acetylglucosamine modification of transcription factors YY1 and SP1. J. Biol. Chem. 2011, 286, 33632–33640.
  43. Marei, W.F.; Ghafari, F.; Fouladi-Nashta, A.A. Role of hyaluronic acid in maturation and further early embryo development of bovine oocytes. Theriogenology 2012, 78, 670–677.
  44. Lim, K.; Chang, H.I. O-GlcNAc inhibits interaction between Sp1 and sterol regulatory element binding protein 2. Biochem. Biophys. Res. Commun. 2010, 393, 314–318.
  45. Suh, H.N.; Lee, Y.J.; Kim, M.O.; Ryu, J.M.; Han, H.J. Glucosamine- induced Sp1 O-GlcNAcylation ameliorates hypoxia-induced SGLT dysfunction in primary cultured renal proximal tubule cells. J. Cell. Physiol. 2014, 229, 1557–1568.
  46. Lee, H.J.; Ryu, J.M.; Jung, Y.H.; Lee, K.H.; Kim, D.I.; Han, H.J. Glycerol-3-phosphate acyltransferase-1 upregulation by O-GlcNAcylation of Sp1 protects against hypoxia-induced mouse embryonic stem cell apoptosis via mTOR activation. Cell Death Dis. 2016, 7, e2158.
  47. O’Shea, J.J.; Plenge, R. JAK and STAT signaling molecules in immunoregulation and immune-mediated disease. Immunity 2012, 36, 542–550.
  48. Pathak, S.; Borodkin, V.S.; Albarbarawi, O.; Campbell, D.G.; Ibrahim, A.; van Aalten, D.M. O-GlcNAcylation of TAB1 modulates TAK1-mediated cytokine release. EMBO J. 2012, 31, 1394–1404.
  49. Hirata, Y.; Takahashi, M.; Morishita, T.; Noguchi, T.; Matsuzawa, A. Post-translational modifications of the TAK1-TAB complex. Int. J. Mol. Sci. 2017, 18, 205.
  50. Zhang, D.; Xu, Z.; Tao, T.; Liu, X.; Sun, X.; Ji, Y.; Han, L.; Qiu, H.; Zhu, G.; Shen, Y.; et al. Modification of TAK1 by O-linked N-acetylglucosamine facilitates TAK1 activation and promotes M1 macrophage polarization. Cell. Signal. 2016, 28, 1742–1752.
  51. Hwang, S.Y.; Shin, J.H.; Hwang, J.S.; Kim, S.Y.; Shin, J.A.; Oh, E.S.; Oh, S.; Kim, J.B.; Lee, J.K.; Han, I.O. Glucosamine exerts a neuroprotective effect via suppression of inflammation in rat brain ischemia/reperfusion injury. Glia 2010, 58, 1881–1892.
  52. Zou, L.; Yang, S.; Hu, S.; Chaudry, I.H.; Marchase, R.B.; Chatham, J.C. The protective effects of PUGNAc on cardiac function after trauma-hemorrhage are mediated via increased protein O-GlcNAc levels. Shock 2007, 27, 402–408.
  53. Zou, L.; Yang, S.; Champattanachai, V.; Hu, S.; Chaudry, I.H.; Marchase, R.B.; Chatham, J.C. Glucosamine improves cardiac function following trauma-hemorrhage by increased protein O-GlcNAcylation and attenuation of NF-B signaling. Am. J. Physiol. Heart Circ. Physiol. 2009, 296, H515–H523.
  54. Fleischmann, C.; Scherag, A.; Adhikari, N.K.; Hartog, C.S.; Tsaganos, T.; Schlattmann, P.; Angus, D.C.; Reinhart, K.; International Forum of Acute Care Trialists. Assessment of global incidence and mortality of hospital-treated sepsis: Current estimates and limitations. Am. J. Respir. Crit. Care Med. 2016, 193, 259–272.
  55. Sunyer, J.O. Fishing for mammalian paradigms in the teleost immune system. Nat. Immunol. 2013, 14, 320–326.
  56. Stachura, D.L.; Svoboda, O.; Campbell, C.A.; Espín-Palazon, R.; Lau, R.P.; Zon, L.I.; Bartunek, P.; Traver, D. The zebrafish granulocyte colony-stimulating factors (Gcsfs): 2 paralogous cytokines and their roles in hematopoietic development and maintenance. Blood 2013, 122, 3918–3928.
  57. Lieschke, G.J.; Trede, N.S. Fish immunology. Curr. Biol. 2009, 19, R678–R682.
  58. Trede, N.S.; Langenau, D.M.; Traver, D.; Look, A.T.; Zon, L.I. The use of zebrafish to understand immunity. Immunity 2004, 20, 367–379.
  59. Hwang, J.S.; Kim, K.H.; Park, J.; Kim, S.M.; Cho, H.; Lee, Y.; Han, I.J. Glucosamine improves survival in a mouse model of sepsis and attenuates sepsis-induced lung injury and inflammation. J. Biol. Chem. 2019, 294, 608–622.
  60. Hwang, S.Y.; Hwang, J.S.; Kim, S.Y.; Han, I.O. O-GlcNAcylation and p50/p105 binding of c-Rel are dynamically regulated by LPS and glucosamine in BV2 microglia cells. Br. J. Pharmacol. 2013, 169, 1551–1560.
  61. Zheng, G.M.; Yu, C.; Yang, Z. Puerarin suppresses production of nitric oxide and inducible nitric oxide synthase in lipopolysac-charide-induced N9 microglial cells through regulating MAPK phosphorylation, O-GlcNAcylation and NF-κB translocation. Int. J. Oncol. 2012, 40, 1610–1618.
  62. Hwang, S.Y.; Hwang, J.S.; Kim, S.Y.; Han, I.O. O-GlcNAc transferase inhibits LPS-mediated expression of inducible nitric oxide synthase through an increased interaction with mSin3A in RAW264.7 cells. Am. J. Physiol. Cell Physiol. 2013, 305, C601–C608.
  63. He, Y.; Ma, X.; Li, D.; Hao, J. Thiamet G mediates neuroprotection in experimental stroke by modulating microglia/macrophage polarization and inhibiting NF-κB p65 signaling. J. Cereb. Blood Flow Metab. 2017, 37, 2938–2951.
  64. Coornaert, B.; Carpentier, I.; Beyaert, R. A20: Central gatekeeper in inflammation and immunity. J. Biol. Chem. 2009, 284, 8217–8221.
  65. Yao, D.; Xu, L.; Xu, O.; Li, R.; Chen, M.; Shen, H.; Zhu, H.; Zhang, F.; Yao, D.; Chen, Y.F.; et al. O-Linked β-N-acetylglucosamine modification of A20 enhances the inhibition of NF-κB (nuclear factor-κB) activation and elicits vascular protection after acute endoluminal arterial injury. Arterioscler. Thromb. Vasc. Biol. 2018, 38, 1309–1320.
  66. Yang, W.H.; Park, S.Y.; Ji, S.; Kang, J.G.; Kim, J.E.; Song, H.; Mook-Jung, I.; Choe, K.M.; Cho, J.W. O-GlcNAcylation regulates hyperglycemia-induced GPX1 activation. Biochem. Biophys. Res. Commun. 2010, 391, 756–761.
  67. Hwang, J.S.; Hwang, S.Y.; Han, I.O. Basal transcription is regulated by lipopolysaccharide and glucosamine via the regulation of DNA binding of RNA polymerase II in RAW264.7 cells. Life Sci. 2014, 110, 93–98.
  68. Ramakrishnan, P.; Clark, P.M.; Mason, D.E.; Peters, E.C.; Hsieh-Wilson, L.C.; Baltimore, D. Activation of the transcriptional function of the NF-κB protein c-Rel by O-GlcNAc glycosylation. Sci. Signal. 2013, 6, ra75.
  69. Li, T.; Li, X.; Attri, K.S.; Liu, C.; Li, L.; Herring, L.E.; Asara, J.M.; Lei, Y.L.; Singh, P.K.; Gao, C.; et al. O-GlcNAc transferase links glucose metabolism to MAVS-mediated antiviral innate immunity. Cell Host Microbe 2018, 24, 791–803.
  70. Yang, Y.; Li, X.; Luan, H.H.; Zhang, B.; Zhang, K.; Nam, J.H.; Li, Z.; Fu, M.; Munk, A.; Zhang, D.; et al. OGT suppresses S6K1-mediated macrophage inflammation and metabolic disturbance. Proc. Natl. Acad. Sci. USA 2020, 117, 16616–16625.
  71. Ryu, I.H.; Do, S.I. Denitrosylation of S-nitrosylated OGT is triggered in LPS-stimulated innate immune response. Biochem. Biophys. Res. Commun. 2011, 408, 52–57.
  72. Sierra, A.; de Castro, F.; Del Rio-Hortega, J.; Rafael Iglesias-Rozas, J.; Garrosa, M.; Kettenmann, H. The “big-bang” for modern glial biology: Translation and comments on Pio del Rio-Hortega 1919 series of papers on microglia. Glia 2016, 64, 1801–1840.
  73. Yu, H.; Pardoll, D.; Jove, R. STATs in cancer inflammation and immunity: A leading role for STAT3. Nat. Rev. Cancer 2009, 9, 798–809.
  74. Huynh, J.; Chand, A.; Gough, D.; Ernst, M. Therapeutically exploiting STAT3 activity in cancer—Using tissue repair as a road map. Nat. Rev. Cancer 2019, 19, 82–96.
  75. Staples, K.J.; Smallie, T.; Williams, L.M.; Foey, A.; Burke, B.; Foxwell, B.M.; Ziegler-Heitbrock, L. IL-10 induces IL-10 in primary human monocyte-derived macrophages via the transcription factor Stat3. J. Immunol. 2007, 178, 4779–4785.
  76. Kobayashi, A.; Kang, M.I.; Okawa, H.; Ohtsuji, M.; Zenke, Y.; Chiba, T.; Igarashi, K.; Yamamoto, M. Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2. Mol. Cell. Biol. 2004, 24, 7130–7139.
  77. Cullinan, S.B.; Gordan, J.D.; Jin, J.; Harper, J.W.; Diehl, J.A. The Keap1-BTB protein is an adaptor that bridges Nrf2 to a Cul3-based E3 ligase: Oxidative stress sensing by a Cul3-Keap1 ligase. Mol. Cell. Biol. 2004, 24, 8477–8486.
  78. Marshall, S.; Nadeau, O.; Yamasaki, K. Dynamic actions of glucose and glucosamine on hexosamine biosynthesis in isolated adipocytes: Differential effects on glucosamine 6-phosphate, UDP-N-acetylglucosamine, and ATP levels. J. Biol. Chem. 2004, 279, 35313–35319.
  79. Li, X.; Gong, W.; Wang, H.; Li, T.; Attri, K.S.; Lewis, R.E.; Kalil, A.C.; Bhinderwala, F.; Powers, R.; Yin, G.; et al. O-GlcNAc transferase suppresses inflammation and necroptosis by targeting receptor-interacting serine/threonine-protein kinase 3. Immunity 2019, 50, 576–590.
  80. Newton, K.; Manning, G. Necroptosis and inflammation. Annu. Rev. Biochem. 2016, 85, 743–763.
  81. Seifert, L.; Miller, G. Molecular Pathways: The Necrosome—A Target for Cancer Therapy. Clin. Cancer Res. 2017, 23, 1132–1136.
  82. Shapouri-Moghaddam, A.; Mohammadian, S.; Vazini, H.; Taghadosi, M.; Esmaeili, S.A.; Mardani, F.; Seifi, B.; Mohammadi, A.; Afshari, J.T.; Sahebkar, A. Macrophage plasticity, polarization, and function in health and disease. J. Cell. Physiol. 2018, 233, 6425–6440.
  83. Hart, G.W.; Slawson, C.; Ramirez-Correa, G.; Lagerlof, O. Cross talk between O-GlcNAcylation and phosphorylation: Roles in signaling, transcription, and chronic disease. Annu. Rev. Biochem. 2011, 80, 825–858.
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