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http://dx.doi.org/10.14348/molcells.2020.0198

Allithiamine Exerts Therapeutic Effects on Sepsis by Modulating Metabolic Flux during Dendritic Cell Activation  

Choi, Eun Jung (Department of Biomedical Science, School of Medicine, Kyungpook National University)
Jeon, Chang Hyun (Department of Biomedical Science, School of Medicine, Kyungpook National University)
Park, Dong Ho (Department of Ophthalmology, Kyungpook National University Hospital, School of Medicine, Kyungpook National University)
Kwon, Tae-Hwan (Department of Biomedical Science, School of Medicine, Kyungpook National University)
Publication Information
Molecules and Cells / v.43, no.11, 2020 , pp. 964-973 More about this Journal
Abstract
Recent studies have highlighted that early enhancement of the glycolytic pathway is a mode of maintaining the proinflammatory status of immune cells. Thiamine, a wellknown co-activator of pyruvate dehydrogenase complex, a gatekeeping enzyme, shifts energy utilization of glucose from glycolysis to oxidative phosphorylation. Thus, we hypothesized that thiamine may modulate inflammation by alleviating metabolic shifts during immune cell activation. First, using allithiamine, which showed the most potent anti-inflammatory capacity among thiamine derivatives, we confirmed the inhibitory effects of allithiamine on the lipopolysaccharide (LPS)-induced pro-inflammatory cytokine production and maturation process in dendritic cells. We applied the LPS-induced sepsis model to examine whether allithiamine has a protective role in hyper-inflammatory status. We observed that allithiamine attenuated tissue damage and organ dysfunction during endotoxemia, even when the treatment was given after the early cytokine release. We assessed the changes in glucose metabolites during LPS-induced dendritic cell activation and found that allithiamine significantly inhibited glucose-driven citrate accumulation. We then examined the clinical implication of regulating metabolites during sepsis by performing a tail bleeding assay upon allithiamine treatment, which expands its capacity to hamper the coagulation process. Finally, we confirmed that the role of allithiamine in metabolic regulation is critical in exerting anti-inflammatory action by demonstrating its inhibitory effect upon mitochondrial citrate transporter activity. In conclusion, thiamine could be used as an alternative approach for controlling the immune response in patients with sepsis.
Keywords
allithiamine; citrate accumulation; lipid droplet formation; lipopolysaccharides; metabolic flux;
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