Glycolytic reprogramming controls periodontitis-associated macrophage pyroptosis via AMPK/SIRT1/NF-κB signaling pathway

He, Yani; Wang, Yuting; Jia, Xiangbin; Li, Yingxue; Yang, Yao; Pan, Lifei; Zhao, Rui; Han, Yue; Wang, Rui; Guan, Xiaoyue; Hou, Tiezhou

doi:10.1016/j.intimp.2023.110192

Cited by 16 publications

(6 citation statements)

References 64 publications

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“…In contrast to the control group, TG, CrCl 3 , MnCl 2 , FeCl 3 and ZnSO 4 significantly increased the levels of glucose transporter type 4 (GLUT4), hexokinase 1 (HK1), pyruvate kinase M2 (PKM2) and/or phosphofructokinase, liver type (PFKL) in the cultured mouse ovaries (Figure 4 A). The AMP-activated protein kinase (AMPK) is the main sensor of cellular energy status and its activity is negatively correlated with glycolysis ability 35 , 36 . Compared with the control, 2-DG (the inhibitor of glycolysis) significantly increased p-AMPK levels in the ovaries ( Figure S7 ), suggesting that 2-DG could inhibit glycolysis in the ovaries.…”

Section: Resultsmentioning

confidence: 99%

The metallic compound promotes primordial follicle activation and ameliorates fertility deficits in aged mice

Han¹,

Huang²,

Li³

et al. 2023

Theranostics

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Background: Aged women and premature ovarian insufficiency (POI) patients have residual dormant primordial follicles that are hard to be activated through a physiological process. However, there are no effective and safe drugs to help them. Methods: We used the in vitro culture model of newborn mouse ovaries to identify the drugs that promote primordial follicle activation and study its mechanisms. It was verified by in vivo injection model of newborn mice and in vitro culture model of human ovarian tissue. In addition, we used the aged mice as a low infertility model to verify the effects of primordial follicle activation, and fertility by drugs. Results: Eleven metallic compounds activated mouse primordial follicles, and the five most effective compounds were selected for further study. Thapsigargin (TG), CrCl 3 , MnCl 2 , FeCl 3 and ZnSO 4 increased the levels of the glycolysis-related proteins (glucose transporter type 4, GLUT4; hexokinase 1, HK1; pyruvate kinase M2, PKM2; phosphofructokinase, liver type, PFKL), phosphorylated mammalian target of rapamycin (p-mTOR) in cultured mouse ovaries. The compound-promoted p-mTOR levels could be completely blocked by 2-DG (the inhibitor of glycolysis). The compounds also increased the levels of phosphorylated protein kinase B (p-Akt). TG-, CrCl 3 - and FeCl 3 -promoted p-Akt levels, but not MnCl 2 - and ZnSO 4 - promoted p-Akt levels, could be completely blocked by ISCK03 (the inhibitor of proto-oncogenic receptor tyrosine kinase, KIT). The injection of newborn mice with the compounds also activated primordial follicles and increased the levels of the glycolysis-related proteins, p-mTOR, and p-Akt. The oral administration of the compounds in adolescent and aged mice promoted primordial follicle activation, and had no obvious side effect. Importantly, ZnSO 4 also increased ovulated oocytes, oocyte quality and offspring in aged mice. Furthermore, the compounds promoted human primordial follicle activation and increased the levels of the glycolysis-related proteins, p-mTOR, and p-Akt. Conclusion: The metallic compounds activate primordial follicles through the glycolysis-dependent mTOR pathway and/or the PI3K/Akt pathway, and the oral administration of ZnSO 4 enhances fertility in aged mice. We suggest that these metallic compounds may be oral drugs to ameliorate fertility deficits in aged women and POI patients.

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Section: Resultsmentioning

confidence: 99%

The metallic compound promotes primordial follicle activation and ameliorates fertility deficits in aged mice

Han¹,

Huang²,

Li³

et al. 2023

Theranostics

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“…THP-1 cells were primed with 100 ng/mL phorbol 12-mysistate 12-acetate (PMA, Sigma-Aldrich, St. Louis, MO, USA) for 24 h to differentiate into Mφ (dTHP-1) [30]. Amounts of 100 ng/mL P. gingivalis lipopolysaccharide (Pg.LPS, Sigma-Aldrich, St. Louis, MO, USA) and 40 ng/mL interferon-γ (IFN-γ, Santa Clara, CA, USA) were then added into dTHP-1 to mimic the inflammatory conditions in the infected periapical region [31,32].…”

Section: Cell Culture and Treatmentsmentioning

confidence: 99%

The Role of Macrophage Efferocytosis in the Pathogenesis of Apical Periodontitis

Guan,

Wang,

et al. 2024

IJMS

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Macrophages (Mφs) play a crucial role in the homeostasis of the periapical immune micro-environment caused by bacterial infection. Mφ efferocytosis has been demonstrated to promote the resolution of multiple infected diseases via accelerating Mφ polarization into M2 type. However, the Mφ efferocytosis–apical periodontitis (AP) relationship has not been elucidated yet. This study aimed to explore the role of Mφ efferocytosis in the pathogenesis of AP. Clinical specimens were collected to determine the involvement of Mφ efferocytosis in the periapical region via immunohistochemical and immunofluorescence staining. For a further understanding of the moderator effect of Mφ efferocytosis in the pathogenesis of AP, both an in vitro AP model and in vivo AP model were treated with ARA290, a Mφ efferocytosis agonist. Histological staining, micro-ct, flow cytometry, RT-PCR and Western blot analysis were performed to detect the inflammatory status, alveolar bone loss and related markers in AP models. The data showed that Mφ efferocytosis is observed in the periapical tissues and enhancing the Mφ efferocytosis ability could effectively promote AP resolution via facilitating M2 Mφ polarization. Collectively, our study demonstrates the functional importance of Mφ efferocytosis in AP pathology and highlights that accelerating Mφ efferocytosis via ARA290 could serve as an adjuvant therapeutic strategy for AP.

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“…When pathogenic microbes invade periodontal tissues, a vast array of immune cells, such as macrophages, T cells, B cells, and dendritic cells, are recruited [ 14 ]. Macrophages play a crucial role in the destruction of periodontal tissues, where their heightened aggregation and activation lead to tissue lesion [ 15 , 16 , 17 , 18 ]. The buildup of inflammatory agents originating from macrophages in gingival tissues and crevicular fluid is linked to the intensity and advancement of periodontitis, while blocking their release is associated with improved bone resorption and the infiltration of inflammatory cells [ 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

Copper Chelation Therapy Attenuates Periodontitis Inflammation through the Cuproptosis/Autophagy/Lysosome Axis

Zhang,

Tsai,

et al. 2024

IJMS

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Periodontitis development arises from the intricate interplay between bacterial biofilms and the host’s immune response, where macrophages serve pivotal roles in defense and tissue homeostasis. Here, we uncover the mitigative effect of copper chelator Tetrathiomolybdate (TTM) on periodontitis through inhibiting cuproptosis, a newly identified form of cell death which is dependent on copper. Our study reveals concurrent cuproptosis and a macrophage marker within murine models. In response to lipopolysaccharide (LPS) stimulation, macrophages exhibit elevated cuproptosis-associated markers, which are mitigated by the administration of TTM. TTM treatment enhances autophagosome expression and mitophagy-related gene expression, countering the LPS-induced inhibition of autophagy flux. TTM also attenuates the LPS-induced fusion of autophagosomes and lysosomes, the degradation of lysosomal acidic environments, lysosomal membrane permeability increase, and cathepsin B secretion. In mice with periodontitis, TTM reduces cuproptosis, enhances autophagy flux, and decreases Ctsb levels. Our findings underscore the crucial role of copper-chelating agent TTM in regulating the cuproptosis/mitophagy/lysosome pathway during periodontitis inflammation, suggesting TTM as a promising approach to alleviate macrophage dysfunction. Modulating cuproptosis through TTM treatment holds potential for periodontitis intervention.

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Glycolytic reprogramming controls periodontitis-associated macrophage pyroptosis via AMPK/SIRT1/NF-κB signaling pathway

Cited by 16 publications

References 64 publications

The metallic compound promotes primordial follicle activation and ameliorates fertility deficits in aged mice

The metallic compound promotes primordial follicle activation and ameliorates fertility deficits in aged mice

The Role of Macrophage Efferocytosis in the Pathogenesis of Apical Periodontitis

Copper Chelation Therapy Attenuates Periodontitis Inflammation through the Cuproptosis/Autophagy/Lysosome Axis

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