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 21 publications

(8 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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

View full text Add to dashboard Cite

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...

show abstract

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

show abstract

“…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

View full text Add to dashboard Cite

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.

show abstract

“…In cardiomyocytes, co-administration with fenofibrate inhibits the hypertrophic response induced by endothelin-1 by reducing cardiomyocyte surface area and decreasing protein synthesis (11). Fenofibrate also reduces the expression of transforming growth factor (TGF-β1), macrophage infiltration and collagen deposition induced by AngII during the process of myocardial inflammation (12,13).…”

Section: Introductionmentioning

confidence: 99%

The effect of fenofibrate, a peroxisome proliferator-activated receptor α agonist, on cardiac damage from sepsis in BALB/c mice

Xie

Long

2022

Cell Mol Biol (Noisy-le-grand)

View full text Add to dashboard Cite

Cardiac dysfunction can be a fatal consequence of sepsis and lead to increased inflammatory responses or reduced fatty acid oxidation and final ATP depletion. Fenofibrate, which is an agonist of peroxisome proliferator-activated receptor α, has been used primarily in hypercholesterolemia and mixed dyslipidemia. Recent studies found that fenofibrate could alleviate energy metabolism and inflammation caused by cardiac damage during sepsis, and thus it had been paid great attention. This study was to investigate the possible protective roles of fenofibrate against cardiac damage in septic BALB/c mice. Methods: Forty male BALB/c mice aged 8 weeks old were divided randomly into four groups: control group; fenofibrate group; cecal ligation and puncture (CLP) group; and fenofibrate + CLP group. After administering fenofibrate or saline for 2 weeks, CLP was performed. Cardiac tissue and plasma were obtained 48 hours later. Plasma Troponin-T (Tnt), ATP, ADP and reactive oxygen species (ROS) levels were determined. PPARα and 53 protein levels were detected using western blotting. IL-6 and tumor necrosis factor-α (TNFα) were also assayed. We found that fenofibrate decreased plasma cTnT, ROS and increased the ratio of ATP/ADP. The elevations of IL-6, TNFα and P53 induced by sepsis were significantly suppressed by fenofibrate. Our results suggest that fenofibrate can regulate energy metabolism efficiently, which makes it a possible agent for treating sepsis-induced cardiac damage.

show abstract

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

Cited by 21 publications

References 22 publications

Dichloroacetate reverses sepsis-induced hepatic metabolic dysfunction

Dichloroacetate reverses sepsis-induced hepatic metabolic dysfunction

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

The effect of fenofibrate, a peroxisome proliferator-activated receptor α agonist, on cardiac damage from sepsis in BALB/c mice

Contact Info

Product

Resources

About