scholarly journals Deficiency of Myeloid Pfkfb3 Protects Mice From Lung Edema and Cardiac Dysfunction in LPS-Induced Endotoxemia

2021 ◽  
Vol 8 ◽  
Author(s):  
Jiean Xu ◽  
Lina Wang ◽  
Qiuhua Yang ◽  
Qian Ma ◽  
Yaqi Zhou ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cardiac Dysfunction ◽  
Aerobic Glycolysis ◽  
Interleukin 1 ◽  
Critical Role ◽  
Glycolytic Flux ◽  
Lung Edema ◽  
Proinflammatory Gene ◽  
Proinflammatory Gene Expression

Sepsis, a pathology resulting from excessive inflammatory response that leads to multiple organ failure, is a major cause of mortality in intensive care units. Macrophages play an important role in the pathophysiology of sepsis. Accumulating evidence has suggested an upregulated rate of aerobic glycolysis as a key common feature of activated proinflammatory macrophages. Here, we identified a crucial role of myeloid 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (Pfkfb3), a glycolytic activator in lipopolysaccharide (LPS)-induced endotoxemia in mice. Pfkfb3 expression is substantially increased in bone marrow derived macrophages (BMDMs) treated with LPS in vitro and in lung macrophages of mice challenged with LPS in vivo. Myeloid-specific knockout of Pfkfb3 in mice protects against LPS-induced lung edema, cardiac dysfunction and hypotension, which were associated with decreased expression of interleukin 1 beta (Il1b), interleukin 6 (Il6) and nitric oxide synthase 2 (Nos2), as well as reduced infiltration of neutrophils and macrophages in lung tissue. Pfkfb3 ablation in cultured macrophages attenuated LPS-induced glycolytic flux, resulting in a decrease in proinflammatory gene expression. Mechanistically, Pfkfb3 ablation or inhibition with a Pfkfb3 inhibitor AZ26 suppresses LPS-induced proinflammatory gene expression via the NF-κB signaling pathway. In summary, our study reveals the critical role of Pfkfb3 in LPS-induced sepsis via reprogramming macrophage metabolism and regulating proinflammatory gene expression. Therefore, PFKFB3 is a potential target for the prevention and treatment of inflammatory diseases such as sepsis.

scholarly journals Deficiency of the novel high mobility group protein HMGXB4 protects against systemic inflammation-induced endotoxemia in mice

2021 ◽  
Vol 118 (7) ◽  
pp. e2021862118
Author(s):  
Xiangqin He ◽  
Kunzhe Dong ◽  
Jian Shen ◽  
Guoqing Hu ◽  
Jinhua Liu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Critical Role ◽  
Cecal Ligation ◽  
High Mobility ◽  
High Mobility Group ◽  
No Production ◽  
High Mobility Group Protein ◽  
Pulmonary Vascular Permeability ◽  
Proinflammatory Gene

Sepsis is a major cause of mortality in intensive care units, which results from a severely dysregulated inflammatory response that ultimately leads to organ failure. While antibiotics can help in the early stages, effective strategies to curtail inflammation remain limited. The high mobility group (HMG) proteins are chromosomal proteins with important roles in regulating gene transcription. While HMGB1 has been shown to play a role in sepsis, the role of other family members including HMGXB4 remains unknown. We found that expression of HMGXB4 is strongly induced in response to lipopolysaccharide (LPS)-elicited inflammation in murine peritoneal macrophages. Genetic deletion of Hmgxb4 protected against LPS-induced lung injury and lethality and cecal ligation and puncture (CLP)-induced lethality in mice, and attenuated LPS-induced proinflammatory gene expression in cultured macrophages. By integrating genome-wide transcriptome profiling and a publicly available ChIP-seq dataset, we identified HMGXB4 as a transcriptional activator that regulates the expression of the proinflammatory gene, Nos2 (inducible nitric oxide synthase 2) by binding to its promoter region, leading to NOS2 induction and excessive NO production and tissue damage. Similar to Hmgxb4 ablation in mice, administration of a pharmacological inhibitor of NOS2 robustly decreased LPS-induced pulmonary vascular permeability and lethality in mice. Additionally, we identified the cell adhesion molecule, ICAM1, as a target of HMGXB4 in endothelial cells that facilitates inflammation by promoting monocyte attachment. In summary, our study reveals a critical role of HMGXB4 in exacerbating endotoxemia via transcriptional induction of Nos2 and Icam1 gene expression and thus targeting HMGXB4 may be an effective therapeutic strategy for the treatment of sepsis.

scholarly journals A PPARγ agonist reduces proinflammatory cytokine immunoreactivity and infarct size following transient focal ischemia in rats

Stroke ◽  
2001 ◽  
Vol 32 (suppl_1) ◽  
pp. 354-354
Author(s):  
Sophia Sundararajan ◽  
W David Lust ◽  
Gary E Landreth
Keyword(s):  
Gene Expression ◽  
Infarct Size ◽  
Infarct Volume ◽  
Critical Role ◽  
Ischemic Injury ◽  
Nuclear Hormone Receptor ◽  
Markers Of Inflammation ◽  
Pparγ Agonist ◽  
Proinflammatory Gene ◽  
Proinflammatory Gene Expression

P82 Inflammation plays a critical role in the generation of ischemic injury. Ischemic insult results in the activation of microglia and secretion of proinflammatory products including the cytokines interleukin-1β and tumor necrosis factor-α. Both of these cytokines exacerbate ischemic injury. Microglial proinflammatory gene expression is regulated by the transcription factor peroxisome proliferator activated receptor (PPAR). PPARγ is a member of the nuclear hormone receptor family and upon binding of agonist acts to inhibit proinflammatory gene expression. We hypothesized that PPARγ agonists reduce the inflammatory reaction seen following stroke and limit infarction size. We utilized a reversible model of middle cerebral artery occlusion to induce two hours of ischemia in rats to test our hypothesis. Blood pressure, blood gases and temperature were monitored and maintained within normal ranges throughout the procedure. Vehicle (DMSO) or troglitazone, a PPARγ agonist previously approved by the FDA, was administered to rats twenty-four hours before and again at the time of occlusion in doses of 35, 70 or 100 mg/kg in DMSO. Twenty-four hours after occlusion animals were euthanized. Infarct volume was calculated from fixed frozen sections and additional sections were processed for immunocytochemistry. Results show over sixty percent reduction in infarct volume in rats treated with 35 mg/kg and 70 mg/kg troglitazone. These data were statistically significant (n≥5;p<0.05). Interestingly the 100 mg/kg dose of troglitazone did not protect against ischemia. Immunoreactivity against the proinflammatory cytokines Il-1β and TNFα was reduced in the peri-infarct region of troglitazone treated rats. Furthermore, immunoreactivity against other markers of inflammation, intracellular adhesion molecule, major histocompatibility complex antigen I and cyclooxygenase-2 was also reduced in troglitazone treated animals compared with vehicle treated animals. These data indicate that the PPARγ agonist, troglitazone, reduces infarct size following cerebral ischemia likely due to the drug’s anti-inflammatory properties.

scholarly journals Development of cancer metabolism as a therapeutic target: new pathways, patient studies, stratification and combination therapy

2019 ◽  
Vol 122 (1) ◽  
pp. 1-3 ◽  
Author(s):  
Adrian L. Harris
Keyword(s):  
Metabolic Pathways ◽  
Trial Design ◽  
Cancer Metabolism ◽  
Aerobic Glycolysis ◽  
Critical Role ◽  
Therapeutic Approaches ◽  
Preclinical Models ◽  
Wide Range ◽  
Patient Studies

AbstractCancer metabolism has undergone a resurgence in the last decade, 70 years after Warburg described aerobic glycolysis as a feature of cancer cells. A wide range of techniques have elucidated the complexity and heterogeneity in preclinical models and clinical studies. What emerges are the large differences between tissues, tumour types and intratumour heterogeneity. However, synergies with inhibition of metabolic pathways have been found for many drugs and therapeutic approaches, and a critical role of window studies and translational trial design is key to success.

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