PFKFB3 promotes endotoxemia-induced myocardial dysfunction through inflammatory signaling and apoptotic induction

Tian, Wen; Guo, Hongsheng; Li, Chongyao; Cao, Wei; Mo, Dan; Hao, Xiao-Wei; Feng, Yixuan; Sun, Yang; Fan, Lei; Zhang, Hui-Nan; Zhao, Ming; Li, Xiaoqiang

doi:10.1016/j.taap.2019.02.007

Cited by 13 publications

(10 citation statements)

References 51 publications

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“…Therefore, in the first part of this study, we explored the temporal pattern of PFKFB3 after t-SCI. Additionally, similar to a previous study reporting an upregulated level of PFKFB3 after endotoxemia-induced myocardial injury 54 , we observed significant activation of PFKFB3, evidenced by increased PFKFB3 expression and upregulated levels of its substrate F2,6BP, after t-SCI. We then further investigated the effect of PFKFB3 under t-SCI conditions.…”

Section: Discussionsupporting

confidence: 91%

6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase Suppresses Neuronal Apoptosis by Increasing Glycolysis and “cyclin-dependent kinase 1-Mediated Phosphorylation of p27 After Traumatic Spinal Cord Injury in Rats

et al. 2020

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Apoptosis is a vital pathological factor that accounts for the poor prognosis of traumatic spinal cord injury (t-SCI). The 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3) is a critical regulator for energy metabolism and proven to have antiapoptotic effects. This study aimed to investigate the neuroprotective role of PFKFB3 in t-SCI. A compressive clip was introduced to establish the t-SCI model. Herein, we identified that PFKFB3 was extensively distributed in neurons, and PFKFB3 levels significantly increased and peaked 24 h after t-SCI. Additionally, knockdown of PFKFB3 inhibited glycolysis, accompanied by aggravated neuronal apoptosis and white matter injury, while pharmacological activation of PFKFB3 with meclizine significantly enhanced glycolysis, attenuated t-SCI-induced spinal cord injury, and alleviated neurological impairment. The PFKFB3 agonist, meclizine, activated cyclin-dependent kinase 1 (CDK1) and promoted the phosphorylation of p27, ultimately suppressing neuronal apoptosis. However, the neuroprotective effects of meclizine against t-SCI were abolished by the CDK1 antagonist, RO3306. In summary, our data demonstrated that PFKFB3 contributes robust neuroprotection against t-SCI by enhancing glycolysis and modulating CDK1-related antiapoptotic signals. Moreover, targeting PFKFB3 may be a novel and promising therapeutic strategy for t-SCI.

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Section: Discussionsupporting

confidence: 91%

6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase Suppresses Neuronal Apoptosis by Increasing Glycolysis and “cyclin-dependent kinase 1-Mediated Phosphorylation of p27 After Traumatic Spinal Cord Injury in Rats

et al. 2020

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“…C57BL/6J mice were randomly divided into five groups: (1) sham group, (2) CLP group, (3) sham-3PO (50 mg/kg) group, (4) CLP+3PO (50 mg/kg) group, and (5) CLP+Gsdmd -/group. The dose of 3PO was selected based on a previous experimental study [13]. The mice were euthanized 24 hours after the sham operation or CLP surgery for subsequent experiments.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of PFKFB Preserves Intestinal Barrier Function in Sepsis by Inhibiting NLRP3/GSDMD

Zhang

Liu

Xie

et al. 2022

Oxidative Medicine and Cellular Longevity

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Intestinal barrier dysfunction is associated with the occurrence and development of sepsis. Further, aerobic glycolysis plays an essential role in inflammation and cell death. This study is aimed at investigating the protective effect and mechanism of PFKFB3 inhibition on intestinal barrier dysfunction in sepsis mice. Sepsis mouse models were established by cecal ligation and puncture (CLP) in wild-type mice and Gsdmd-/- mice. The results showed that the expression of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) in the small intestines was significantly upregulated in sepsis. 3-(3-Pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO), the specific inhibitor of PFKFB3, and Gsdmd gene knockout significantly inhibited the inflammatory response and cell death caused by sepsis, thus alleviating intestinal damage and barrier dysfunction. 3PO was also shown to significantly inhibit oxidative stress and NLRP3/caspase-1/GSDMD-dependent cell pyroptosis in the small intestines. The in vitro studies revealed that 3PO reduced NLRP3/caspase-1/GSDMD-dependent cell pyroptosis by inhibiting ROS. Taken together, our results suggest that PFKFB3 is involved in inflammation, oxidative stress, and pyroptosis during sepsis and enhances intestinal damage, which may provide important clues about the potential targets to be exploited in this highly lethal disease.

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“…In mice models of endotoxemia and polymicrobial sepsis, circulating exosomes showed the carriage of hydrogen peroxide transferable to cardiac endothelial cells both in vitro and in vivo where it induced the formation of podosome clusters, fragmentation of the tight junction protein, zonula occludens-1 (ZO-1), and consequently endothelial hyperpermeability [ 107 ]. Cardiac and endothelial dysfunction are associated with increased glycolysis in sepsis [ 21 , 85 , 86 , 108 ]. Again, increased glycolysis and ROS production induce apoptosis of alveolar epithelial cells in septic mice [ 109 ].…”

Section: Exosome Involvement In Sepsis-induced Metabolic Changesmentioning

confidence: 99%

Cellular and Exosomal Regulations of Sepsis-Induced Metabolic Alterations

Appiah

Park

Akama

et al. 2021

IJMS

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Sepsis is a sustained systemic inflammatory condition involving multiple organ failures caused by dysregulated immune response to infections. Sepsis induces substantial changes in energy demands at the cellular level leading to metabolic reprogramming in immune cells and stromal cells. Although sepsis-associated organ dysfunction and mortality have been partly attributed to the initial acute hyperinflammation and immunosuppression precipitated by a dysfunction in innate and adaptive immune responses, the late mortality due to metabolic dysfunction and immune paralysis currently represent the major problem in clinics. It is becoming increasingly recognized that intertissue and/or intercellular metabolic crosstalk via endocrine factors modulates maintenance of homeostasis, and pathological events in sepsis and other inflammatory diseases. Exosomes have emerged as a novel means of intercellular communication in the regulation of cellular metabolism, owing to their capacity to transfer bioactive payloads such as proteins, lipids, and nucleic acids to their target cells. Recent evidence demonstrates transfer of intact metabolic intermediates from cancer-associated fibroblasts via exosomes to modify metabolic signaling in recipient cells and promote cancer progression. Here, we review the metabolic regulation of endothelial cells and immune cells in sepsis and highlight the role of exosomes as mediators of cellular metabolic signaling in sepsis.

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PFKFB3 promotes endotoxemia-induced myocardial dysfunction through inflammatory signaling and apoptotic induction

Cited by 13 publications

References 51 publications

6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase Suppresses Neuronal Apoptosis by Increasing Glycolysis and “cyclin-dependent kinase 1-Mediated Phosphorylation of p27 After Traumatic Spinal Cord Injury in Rats

6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase Suppresses Neuronal Apoptosis by Increasing Glycolysis and “cyclin-dependent kinase 1-Mediated Phosphorylation of p27 After Traumatic Spinal Cord Injury in Rats

Inhibition of PFKFB Preserves Intestinal Barrier Function in Sepsis by Inhibiting NLRP3/GSDMD

Cellular and Exosomal Regulations of Sepsis-Induced Metabolic Alterations

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