Vitamin B6 reduces oxidative stress in lungs and liver in experimental sepsis

Giustina, Amanda Della; Danielski, Lucinéia Gainski; Novochadlo, Michele; Joaquim, Larissa; Metzker, Kiuanne Lino Lobo; Carli, Raquel Jaconi De; Denicol, Taís; Cidreira, Thainá; Vieira, Thaynan Cunha; Petronilho, Fabrícia

doi:10.1590/0001-3765201920190434

Cited by 25 publications

(14 citation statements)

References 22 publications

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“…Similar to immune cells, liver cells increase ROS production during sepsis 49,50 . We offer a potential mechanism whereby sepsis leads to significant depletion of redox metabolites within the glutathione pathway ultimately culminating in loss of cellular glutathione levels resulting in ophthalamate accumulation in hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

Dichloroacetate reverses sepsis-induced hepatic metabolic dysfunction

Mainali

Zabalawi

Long

et al. 2020

Preprint

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42Dramatic metabolic reprogramming between an anabolic resistance and catabolic toler-43 ance occurs within the immune system in response to systemic infection with the sepsis 44 syndrome. While metabolic tissues such as the liver are subject to end-organ damage 45 during sepsis and are the primary cause of sepsis death, how their metabolic and energy 46 reprogramming during sepsis state ensures survival is unclear. Employing comprehen-47 sive metabolomic screening, targeted lipidomic screening, and transcriptional profiling in 48 a mouse model of septic shock, we show that hepatocyte lipid metabolism, mitochondrial 49 TCA energetics, and redox balance are significantly reprogramed after cecal ligation and 50 puncture (CLP). We identify increases in TCA cycle metabolites citrate, cis-aconitate, 51 and itaconate with reduced fumarate, elevated triglyceride synthesis, and lipid droplet 52 accumulation in the septic hepatocytes. Transcription analysis of liver tissue supports and 53 extends the hepatocyte findings. Plasma metabolomics show systemic hypoglycemia and 54 increased concentrations of free fatty acids, ketones and corticosterone in parallel with 55 liver reprogramming. Strikingly, the administration of the pyruvate dehydrogenase kinase 56 (PDK) inhibitor dichloroacetate (DCA) reverses dysregulated hepatocyte and systemic 57 metabolism and mitochondrial dysfunction. DCA administered during sepsis arrests ano-58 rexia and weight loss, restores V02 levels as an index of increased carbohydrate oxida-59 tion and promotes physical activity. We suggest that sepsis inflicts an energy demand 60 and supply crisis with distinct shifts in hepatocyte and systemic mitochondrial function.61 Targeting the mitochondrial PDC/PDK energy homeostat rebalances life-threatening en-62 ergy deregulation caused by bacterial sepsis.63 64conserving "hibernation-like" state as a protective mechanism to lower the metabolic de-86 mands of the cell and help with its recovery 6,12,13 . However, staying in this hypometabolic 87 state for a prolonged period can lead to organ dysfunction and failure 12,13 . 88Of particular interest is that, during the hyper-inflammatory anabolic phase of sep-89 sis, an increase in the expression and activity of pyruvate dehydrogenase kinase 1 90 (PDK1) consistently occurs 4 . This enzyme is one of four PDK isoforms that reversibly 91 phosphorylates serine residues on pyruvate dehydrogenase complex (PDC) E1a subunit, 92 inhibiting the conversion of pyruvate to acetyl coenzyme A (acetyl CoA) 14 . Inhibition of 93 this important enzymatic activity that connects glycolysis to tricarboxylic cycle (TCA), ox-94 idative phosphorylation (OXPHOS) and the lipogenic pathway is thought to be one of the 95 main mechanisms that is driving dysfunction of mitochondrial respiration and cell bioen-96 ergetics observed during sepsis 15,16 , suggesting that PDK may be a novel, druggable 97 target for treatment of sepsis.. 98 There a few reports that indicate changes in hepatic metabolism during sepsis but 99 these stud...

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Section: Discussionmentioning

confidence: 99%

Dichloroacetate reverses sepsis-induced hepatic metabolic dysfunction

Mainali

Zabalawi

Long

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…In LPS‐induced acute pneumonia, vitamin B6 down‐regulates the inflammatory gene expressions by increasing AMP‐activated protein kinase phosphorylation 15 . In experimental sepsis, vitamin B6 reduces oxidative stress in the lungs and liver 16 . Nevertheless, the exact mechanism of the anti‐inflammatory role of vitamin B6 is still unclear and needs further research.…”

Section: Introductionmentioning

confidence: 99%

Vitamin B6 prevents excessive inflammation by reducing accumulation of sphingosine‐1‐phosphate in a sphingosine‐1‐phosphate lyase–dependent manner

Yang

Zhan

et al. 2020

J Cellular Molecular Medi

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Vitamin B6 is necessary to maintain normal metabolism and immune response, especially the anti‐inflammatory immune response. However, the exact mechanism by which vitamin B6 plays the anti‐inflammatory role is still unclear. Here, we report a novel mechanism of preventing excessive inflammation by vitamin B6 via reduction in the accumulation of sphingosine‐1‐phosphate (S1P) in a S1P lyase (SPL)‐dependent manner in macrophages. Vitamin B6 supplementation decreased the expression of pro‐inflammatory cytokines by suppressing nuclear factor‐κB and mitogen‐activated protein kinases signalling pathways. Furthermore, vitamin B6–reduced accumulation of S1P by promoting SPL activity. The anti‐inflammatory effects of vitamin B6 were inhibited by S1P supplementation or SPL deficiency. Importantly, vitamin B6 supplementation protected mice from lethal endotoxic shock and attenuated experimental autoimmune encephalomyelitis progression. Collectively, these findings revealed a novel anti‐inflammatory mechanism of vitamin B6 and provided guidance on its clinical use.

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“…However, it has been previously demonstrated that the administration of vitamin B-6 (100 mg/kg) considerably ameliorated the chromium-induced oxidative stress in rats [29]. Indeed, the administration of a single dose of vitamin B-6 (600 mg/kg, subcutaneous) immediately into cecal ligation and perforation-induced mid-grade septic rats could remarkably reduce acute oxidative damage in the liver [30]. Since Horowitz et al suggested an impaired transsulfuration pathway in cirrhosis patients [31], we speculated that the antioxidant properties of vitamin B-6 might be deranged or blocked in cirrhosis, even though the plasma PLP levels increased following a large dose of vitamin B-6 supplementation.…”

Section: Discussionmentioning

confidence: 98%

Impact of Glutathione and Vitamin B-6 in Cirrhosis Patients: A Randomized Controlled Trial and Follow-Up Study

et al. 2020

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Vitamin B-6 and glutathione (GSH) are antioxidant nutrients, and inadequate vitamin B-6 may indirectly limit glutathione synthesis and further affect the antioxidant capacities. Since liver cirrhosis is often associated with increased oxidative stress and decreased antioxidant capacities, we conducted a double-blind randomized controlled trial to assess the antioxidative effect of vitamin B-6, GSH, or vitamin B-6/GSH combined supplementation in cirrhotic patients. We followed patients after the end of supplementation to evaluate the association of vitamin B-6 and GSH with disease severity. In total, 61 liver cirrhosis patients were randomly assigned to placebo, vitamin B-6 (50 mg pyridoxine/d), GSH (500 mg/d), or B-6 + GSH groups for 12 weeks. After the end of supplementation, the condition of patient’s disease severity was followed until the end of the study. Neither vitamin B-6 nor GSH supplementation had significant effects on indicators of oxidative stress and antioxidant capacities. The median follow-up time was 984 d, and 21 patients were lost to follow-up. High levels of GSH, a high GSH/oxidized GSH ratio, and high GSH-St activity at baseline (Week 0) had a significant effect on low Child–Turcotte–Pugh scores at Week 0, the end of supplementation (Week 12), and the end of follow-up in all patients after adjusting for potential confounders. Although the decreased GSH and its related enzyme activity were associated with the severity of liver cirrhosis, vitamin B-6 and GSH supplementation had no significant effect on reducing oxidative stress and increasing antioxidant capacities.

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Vitamin B6 reduces oxidative stress in lungs and liver in experimental sepsis

Cited by 25 publications

References 22 publications

Dichloroacetate reverses sepsis-induced hepatic metabolic dysfunction

Dichloroacetate reverses sepsis-induced hepatic metabolic dysfunction

Vitamin B6 prevents excessive inflammation by reducing accumulation of sphingosine‐1‐phosphate in a sphingosine‐1‐phosphate lyase–dependent manner

Impact of Glutathione and Vitamin B-6 in Cirrhosis Patients: A Randomized Controlled Trial and Follow-Up Study

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