scholarly journals Treatment with sodium (S)-2-hydroxyglutarate prevents liver injury in an ischemia-reperfusion model in female Wistar rats

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e12426
Author(s):  
Eduardo Cienfuegos-Pecina ◽  
Diana P. Moreno-Peña ◽  
Liliana Torres-González ◽  
Diana Raquel Rodríguez-Rodríguez ◽  
Diana Garza-Villarreal ◽  
...  
Keyword(s):  
Liver Injury ◽  
Liver Tissue ◽  
Wistar Rats ◽  
Ischemia Reperfusion ◽  
Serum Glucose ◽  
Liver Ischemia ◽  
Total Liver ◽  
Biological Target ◽  
Female Wistar Rats ◽  
Sh Group

Background Ischemia-reperfusion (IR) injury is one of the leading causes of early graft dysfunction in liver transplantation. Techniques such as ischemic preconditioning protect the graft through the activation of the hypoxia-inducible factors (HIF), which are downregulated by the EGLN family of prolyl-4-hydroxylases, a potential biological target for the development of strategies based on pharmacological preconditioning. For that reason, this study aims to evaluate the effect of the EGLN inhibitor sodium (S)-2-hydroxyglutarate [(S)-2HG] on liver IR injury in Wistar rats. Methods Twenty-eight female Wistar rats were divided into the following groups: sham (SH, n = 7), non-toxicity (HGTox, n = 7, 25 mg/kg of (S)-2HG, twice per day for two days), IR (n = 7, total liver ischemia: 20 minutes, reperfusion: 60 minutes), and (S)-2HG+IR (HGIR, n = 7, 25 mg/kg of (S)-2HG, twice per day for two days, total liver ischemia as the IR group). Serum ALT, AST, LDH, ALP, glucose, and total bilirubin were assessed. The concentrations of IL-1β, IL-6, TNF, malondialdehyde, superoxide dismutase, and glutathione peroxidase were measured in liver tissue, as well as the expression of Hmox1, Vegfa, and Pdk1, determined by RT-qPCR. Sections of liver tissue were evaluated histologically, assessing the severity of necrosis, sinusoidal congestion, and cytoplasmatic vacuolization. Results The administration of (S)-2HG did not cause any alteration in the assessed biochemical markers compared to SH. Preconditioning with (S)-2HG significantly ameliorated IR injury in the HGIR group, decreasing the serum activities of ALT, AST, and LDH, and the tissue concentrations of IL-1β and IL-6 compared to the IR group. IR injury decreased serum glucose compared to SH. There were no differences in the other biomarkers assessed. The treatment with (S)-2HG tended to decrease the severity of hepatocyte necrosis and sinusoidal congestion compared to the IR group. The administration of (S)-2HG did not affect the expression of Hmox1 but decreased the expression of both Vegfa and Pdk1 compared to the SH group, suggesting that the HIF-1 pathway is not involved in its mechanism of hepatoprotection. In conclusion, (S)-2HG showed a hepatoprotective effect, decreasing the levels of liver injury and inflammation biomarkers, without evidence of the involvement of the HIF-1 pathway. No hepatotoxic effect was observed at the tested dose.

scholarly journals Effect of sodium (S)-2-hydroxyglutarate in male, and succinic acid in female Wistar rats against renal ischemia-reperfusion injury, suggesting a role of the HIF-1 pathway

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e9438
Author(s):  
Eduardo Cienfuegos-Pecina ◽  
Tannya R. Ibarra-Rivera ◽  
Alma L. Saucedo ◽  
Luis A. Ramírez-Martínez ◽  
Deanna Esquivel-Figueroa ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Succinic Acid ◽  
Wistar Rats ◽  
Ischemia Reperfusion ◽  
The Other ◽  
Oxidative Stress Biomarkers ◽  
Stress Biomarkers ◽  
Female Wistar Rats ◽  
Dose Dependent ◽  
Nephroprotective Effect

Background Ischemia–reperfusion (IR) injury is the main cause of delayed graft function in solid organ transplantation. Hypoxia-inducible factors (HIFs) control the expression of genes related to preconditioning against IR injury. During normoxia, HIF-α subunits are marked for degradation by the egg-laying defective nine homolog (EGLN) family of prolyl-4-hydroxylases. The inhibition of EGLN stabilizes HIFs and protects against IR injury. The aim of this study was to determine whether the EGLN inhibitors sodium (S)-2-hydroxyglutarate [(S)-2HG] and succinic acid (SA) have a nephroprotective effect against renal IR injury in Wistar rats. Methods (S)-2HG was synthesized in a 22.96% yield from commercially available L-glutamic acid in a two-step methodology (diazotization/alkaline hydrolysis), and its structure was confirmed by nuclear magnetic resonance and polarimetry. SA was acquired commercially. (S)-2HG and SA were independently evaluated in male and female Wistar rats respectively after renal IR injury. Rats were divided into the following groups: sham (SH), nontoxicity [(S)-2HG: 12.5 or 25 mg/kg; SA: 12.5, 25, or 50 mg/kg], IR, and compound+IR [(S)-2HG: 12.5 or 25 mg/kg; SA: 12.5, 25, or 50 mg/kg]; independent SH and IR groups were used for each assessed compound. Markers of kidney injury (BUN, creatinine, glucose, and uric acid) and liver function (ALT, AST, ALP, LDH, serum proteins, and albumin), proinflammatory cytokines (IL-1β, IL-6, and TNF-α), oxidative stress biomarkers (malondialdehyde and superoxide dismutase), and histological parameters (tubular necrosis, acidophilic casts, and vascular congestion) were assessed. Tissue HIF-1α was measured by ELISA and Western blot, and the expression of Hmox1 was assessed by RT-qPCR. Results (S)-2HG had a dose-dependent nephroprotective effect, as evidenced by a significant reduction in the changes in the BUN, creatinine, ALP, AST, and LDH levels compared with the IR group. Tissue HIF-1α was only increased in the IR group compared to SH; however, (S)-2HG caused a significant increase in the expression of Hmox1, suggesting an early accumulation of HIF-1α in the (S)-2HG-treated groups. There were no significant effects on the other biomarkers. SA did not show a nephroprotective effect; the only changes were a decrease in creatinine level at 12.5 mg/kg and increased IR injury at 50 mg/kg. There were no effects on the other biochemical, proinflammatory, or oxidative stress biomarkers. Conclusion None of the compounds were hepatotoxic at the tested doses. (S)-2HG showed a dose-dependent nephroprotective effect at the evaluated doses, which involved an increase in the expression of Hmox1, suggesting stabilization of HIF-1α. SA did not show a nephroprotective effect but tended to increase IR injury when given at high doses.

Adenosine Receptor Adora2b Plays a Mechanistic Role in the Protective Effect of the Volatile Anesthetic Sevoflurane during Liver Ischemia/Reperfusion

2016 ◽  
Vol 125 (3) ◽  
pp. 547-560 ◽  
Author(s):  
Tiago F. Granja ◽  
David Köhler ◽  
Jessica Schad ◽  
Claudia Bernardo de Oliveira Franz ◽  
Franziska Konrad ◽  
...  
Keyword(s):  
Adenosine Receptor ◽  
Adenosine Receptors ◽  
Alanine Aminotransferase ◽  
Liver Tissue ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Volatile Anesthetic ◽  
Liver Ischemia ◽  
Cytokine Release ◽  
Wild Type

Abstract Background Liver ischemia/reperfusion (IR) injury is characterized by hepatic tissue damage and an inflammatory response. This is accompanied by the formation and vascular sequestration of platelet–neutrophil conjugates (PNCs). Signaling through Adora2b adenosine receptors can provide liver protection. Volatile anesthetics may interact with adenosine receptors. This study investigates potential antiinflammatory effects of the volatile anesthetic sevoflurane during liver IR. Methods Experiments were performed ex vivo with human blood and in a liver IR model with wild-type, Adora2a−/−, and Adora2b−/− mice. The effect of sevoflurane on platelet activation, PNC formation and sequestration, cytokine release, and liver damage (alanine aminotransferase release) was analyzed using flow cytometry, luminometry, and immunofluorescence. Adenosine receptor expression in liver tissue was analyzed using immunohistochemistry and real-time polymerase chain reaction. Results Ex vivo experiments indicate that sevoflurane inhibits platelet and leukocyte activation (n = 5). During liver IR, sevoflurane (2 Vol%) decreased PNC formation 2.4-fold in wild-type (P < 0.05) but not in Adora2b−/− mice (n ≥ 5). Sevoflurane reduced PNC sequestration 1.9-fold (P < 0.05) and alanine aminotransferase release 3.5-fold (P < 0.05) in wild-type but not in Adora2b−/− mice (n = 5). In Adora2a−/− mice, sevoflurane also inhibited PNC formation and cytokine release. Sevoflurane diminished cytokine release (n ≥ 3) and increased Adora2b transcription and expression in liver tissue of wild-types (n = 4). Conclusions Our experiments highlight antiinflammatory and tissue-protective properties of sevoflurane during liver IR and reveal a mechanistic role of Adora2b in sevoflurane-associated effects. The targeted use of sevoflurane not only as an anesthetic but also to prevent IR damage is a promising approach in the treatment of critically ill patients.

scholarly journals Trisulfate disaccharide protects liver injury secondary to liver ischemia/reperfusion

HPB ◽  
2016 ◽  
Vol 18 ◽  
pp. e299
Author(s):  
E.R. Vasques ◽  
J.E.M. Cunha ◽  
A.M.M. Coelho ◽  
S.N. Sampietre ◽  
R.A. Patzina ◽  
...  
Keyword(s):  
Liver Injury ◽  
Ischemia Reperfusion ◽  
Liver Ischemia

scholarly journals Topical hepatic hypothermia plus ischemic preconditioning: analysis of bile flow and ischemic injuries after initial reperfusion in rats

2011 ◽  
Vol 26 (3) ◽  
pp. 194-201 ◽  
Author(s):  
Tomaz de Jesus Maria Grezzana Filho ◽  
Tais Burmann de Mendonça ◽  
Gémerson Gabiatti ◽  
Graziella Rodrigues ◽  
Norma Anair Possa Marroni ◽  
...  
Keyword(s):  
Body Temperature ◽  
Ischemic Preconditioning ◽  
Bile Flow ◽  
Wistar Rats ◽  
Ischemia Reperfusion ◽  
Hepatic Function ◽  
The Other ◽  
Antioxidant Defenses ◽  
Liver Ischemia ◽  
Early Recovery

PURPOSE: To evaluate the effects of the topical liver hypothermia and IPC combination against I/R injury after initial reperfusion. METHODS: In 32 Wistar rats, partial liver ischemia was induced for 90 minutes in normothermia (IN), ischemic preconditioning (IPC), 26ºC topical hypothermia (H) and 26ºC topical hypothermia plus IPC (H+IPC). MAP, body temperature and bile flow were recorded each 15 minutes. Plasmatic injury markers and tissue antioxidant defenses were assessed after 120 minutes of reperfusion. RESULTS: MAP and body temperature remained constant during all experiment. Bile flow returned to levels similar to controls after 45 minutes of reperfusion in the H and H+IPC groups and increased significantly in comparison to the NI and IPC groups after 105 and 120 minutes. AST and ALT increased significantly in the normothermic groups in comparison to controls. TBARS levels decreased significantly in the H+IPC group in comparison to the other groups whereas Catalase levels increased significantly in the IPC group. SOD levels were significantly higher in the H group in comparison to all groups. CONCLUSION: The induction of 26ºC topical hypothermia associated or not to IPC protected the ischemic liver against ischemia/reperfusion injuries and allowed an early recovery of the hepatic function.

scholarly journals Trisulfate Disaccharide Decreases Calcium Overload and Protects Liver Injury Secondary to Liver Ischemia/Reperfusion

PLoS ONE ◽  
2016 ◽  
Vol 11 (2) ◽  
pp. e0149630 ◽  
Author(s):  
Enio Rodrigues Vasques ◽  
Jose Eduardo Monteiro Cunha ◽  
Ana Maria Mendonca Coelho ◽  
Sandra N. Sampietre ◽  
Rosely Antunes Patzina ◽  
...  
Keyword(s):  
Liver Injury ◽  
Ischemia Reperfusion ◽  
Calcium Overload ◽  
Liver Ischemia

scholarly journals Mo1794 Heparin Fragments Effects in Liver Injury Secondary to Liver Ischemia/Reperfusion (I/R)

2014 ◽  
Vol 146 (5) ◽  
pp. S-1072
Author(s):  
Ênio R. Vasques ◽  
José Eduardo M. Cunha ◽  
Ana Maria M. Coelho ◽  
Emílio E. Abdo ◽  
Sandra N. Sampietre ◽  
...  
Keyword(s):  
Liver Injury ◽  
Ischemia Reperfusion ◽  
Liver Ischemia

scholarly journals Maresin 1, a Proresolving Lipid Mediator, Ameliorates Liver Ischemia-Reperfusion Injury and Stimulates Hepatocyte Proliferation in Sprague-Dawley Rats

2020 ◽  
Vol 21 (2) ◽  
pp. 540 ◽  
Author(s):  
Gonzalo Soto ◽  
María José Rodríguez ◽  
Roberto Fuentealba ◽  
Adriana V. Treuer ◽  
Iván Castillo ◽  
...  
Keyword(s):  
Cell Division ◽  
Liver Injury ◽  
Mitotic Activity ◽  
Activity Index ◽  
Ischemia Reperfusion ◽  
Hepatocyte Proliferation ◽  
Liver Ischemia ◽  
Tnf Α ◽  
Mitotic Activity Index ◽  
Maresin 1

Maresin-1 (MaR1) is a specialized pro-resolving mediator, derived from omega-3 fatty acids, whose functions are to decrease the pro-inflammatory and oxidative mediators, and also to stimulate cell division. We investigated the hepatoprotective actions of MaR1 in a rat model of liver ischemia-reperfusion (IR) injury. MaR1 (4 ng/gr body weight) was administered prior to ischemia (1 h) and reperfusion (3 h), and controls received isovolumetric vehicle solution. To analyze liver function, transaminases levels and tissue architecture were assayed, and serum cytokines TNF-α, IL-6, and IL-10, mitotic activity index, and differential levels of NF-κB and Nrf-2 transcription factors, were analyzed. Transaminase, TNF-α levels, and cytoarchitecture were normalized with the administration of MaR1 and associated with changes in NF-κB. IL-6, mitotic activity index, and nuclear translocation of Nrf-2 increased in the MaR1-IR group, which would be associated with hepatoprotection and cell proliferation. Taken together, these results suggest that MaR1 alleviated IR liver injury, facilitated by the activation of hepatocyte cell division, increased IL-6 cytokine levels, and the nuclear localization of Nrf-2, with a decrease of NF-κB activity. All of them were related to an improvement of liver injury parameters. These results open the possibility of MaR1 as a potential therapeutic tool in IR and other hepatic pathologies.

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