The response of the hepatocyte to ischemia

BACKGROUND: Ischemia-reperfusion (I/R) injury associated with hepatic resections and liver transplantation remains a serious complication in clinical practice, in spite of several attempts to solve the problem. AIMS: To evaluate the response of the hepatocyte to ischemia METHODS: Published data are thus revised. RESULTS: The response of the hepatocyte to ischemia is based on the sensitivity of hepatocytes to different types of ischemia, the kind of cell death of the hepatocyte when it is subjected to ischemia, and on the response of the hepatocyte to the different times and extents of ischemia. Clinical factors including starvation, graft, age, and hepatic steatosis, all of which contribute to enhancing liver susceptibility to ischemia/reperfusion injury. CONCLUSION: Ischemic preconditioning, based on the induction of a brief ischemia to the liver prior to a prolonged ischemia, has been applied in tumor hepatic resections for reducing hepatic I/R injury and recent clinical studies suggest that this surgical strategy could be appropriate for liver transplantation

Impact of Olive Oil Supplement Intake on Dendritic Cell Maturation after Strenuous Physical Exercise: A Preliminary Study

Physical exercise is known to have a dose-dependent effect on the immune system and can result in an inflammatory process in athletes that is proportional to the intensity and duration of exertion. This inflammatory process can be measured by cell markers such as dendritic cells (DCs), which, in humans, consist of the myeloid DC (mDCs) and plasmacytoid DC (pDCs) subpopulations. The aim of this study was to measure DC differentiation to determine the possible anti-inflammatory effects, after intense aerobic effort, of the intake of a 25 mL extra-virgin olive oil supplement. Three healthy sports-trained subjects went through resistance exercise loads on two days separated by a week: on one day after active supplement intake and on the other day after placebo supplement intake. The results show that the highest increase (77%) in the percentage of mDCs as a proportion of pDCs was immediately after testing. Independently of the supplement taken, mature mDCs showed a decreasing trend between the test one hour after and 24 h after testing ended. Nevertheless, measured in terms of the coefficient of variation, only the decrease (46%) for extra-virgin olive oil supplementation was statistically significant (95% CI: 30-62%; p = 0.05). In conclusion, an extra-virgin olive oil supplement could reduce the inflammatory impact of intense aerobic effort and improve recovery at 24 h

Una oportunitat per intercanviar bones pràctiques en l’atenció a la cronicitat a nivell europeu: el projecte JA-CHRODIS

Good practices; Chronic patient; JA-CHRODISBuenas prácticas; Paciente crónico; JA-CHRODISBones pràctiques; Pacient crònic; JA-CHRODISEl nombre de persones que pateixen malalties cròniques ha augmentat considerablement durant les últimes dècades. Aquesta situación ha provocat que el sistema sanitari hagi hagut de reorientar-se i desenvolupar diverses pràctiques que pretenen optimitzar l’atenció als pacients crònics. La Comissió Europea va posar en marxa el 2014 una acció conjunta en la qual han participat 60 institucions que pertanyen a 26 països de la Unió Europea; el projecte JA-CHRODIS. L’objectiu de l’acció ha consistit en identificar les millors experiències que s’estan duent a terme actualment a Europa en atenció a la cronicitat, a partir d’uns criteris d’avaluació unificats i consensuats, per tal de posar-les a disposició tant dels professionals com dels gestors i responsables polítics de serveis d’atenció a la salut a través d’un repositori; es permet així l’intercanvi d’informació sobre aquelles experiències més exitoses i es promou la transferència i la implementació de les millors pràctiques.El número de personas que sufren enfermedades crónicas ha aumentado considerablemente durante las últimas décadas. Esta situación ha provocado que el sistema sanitario haya tenido que reorientarse y desarrollar varias prácticas que pretenden optimizar la atención a los pacientes crónicos. La Comisión Europea puso en marcha el 2014 una acción conjunta en la cual han participado 60 instituciones que pertenecen en 26 países de la Unión Europea; el proyecto JA-CHRODIS. El objetivo de la acción ha consistido en identificar las mejores experiencias que se están llevando a cabo actualmente en Europa en atención a la cronicidad, a partir de unos criterios de evaluación unificados y consensuados, para ponerlas a disposición tanto de los profesionales cómo de los gestores y responsables políticos de servicios de atención a la salud a través de un repositorio; se permite así el intercambio de información sobre aquellas experiencias más exitosas y se promueve la transferencia y la implementación de las mejores prácticas.The number of people are living with a chronic disease has increased considerably during the last decades. This situation has caused a change in the health system. It has to reorient itself and develop several practices that aim to optimize the care of chronic patients. The European Commission launched in 2014 a joint action in which 60 institutions that belong in 26 countries of the European Union have participated; the JA-CHRODIS project. The objective of the action has been to identify the best experiences that is being currently carried out in Europe about attention to chronicity, based on unified and agreed evaluation criteria, to make them available to both professionals and managers and policy makers of health care services through a repository; In this way allows the exchange of information on those most successful experiences and promotes the transfer and implementation of best practices

Retinol binding protein 4 and retinol in steatotic and nonsteatotic rat livers in the setting of partial hepatectomy under ischemia/reperfusion

Steatotic livers show increased hepatic damage and impaired regeneration after partial hepatectomy (PH) under ischemia/reperfusion (I/R), which is commonly applied in clinical practice to reduce bleeding. The known function of retinol-binding protein 4 (RBP4) is to transport retinol in the circulation. We examined whether modulating RBP4 and/or retinol could protect steatotic and nonsteatotic livers in the setting of PH under I/R. Steatotic and nonsteatotic livers from Zucker rats were subjected to PH (70%) with 60 minutes of ischemia. RBP4 and retinol levels were measured and altered pharmacologically, and their effects on hepatic damage and regeneration were studied after reperfusion. Decreased RBP4 levels were observed in both liver types, whereas retinol levels were reduced only in steatotic livers. RBP4 administration exacerbated the negative consequences of liver surgery with respect to damage and liver regeneration in both liver types. RBP4 affected the mobilization of retinol from steatotic livers, and this revealed actions of RBP4 independent of simple retinol transport. The injurious effects of RBP4 were not due to changes in retinol levels. Treatment with retinol was effective only for steatotic livers. Indeed, retinol increased hepatic injury and impaired liver regeneration in nonsteatotic livers. In steatotic livers, retinol reduced damage and improved regeneration after surgery. These benefits of retinol were associated with a reduced accumulation of hepatocellular fat. Thus, strategies based on modulating RBP4 could be ineffective and possibly even harmful in both liver types in the setting of PH under I/R. In terms of clinical applications, a retinol pretreatment might open new avenues for liver surgery that specifically benefit the steatotic liver. Liver Transpl 18:1198-1208, 2012. (c) 2012 AASLD.Spanish Ministry of Science and Innovation [BFU2009-07410]Agency for the Innovation and Internationalization of Catalan Enterprise [VALTEC08-2-0033]Agency for the Support and Evaluation of Graduate Education (Brazilian Ministry of Education)Spanish Society for Liver Transplantation Foundatio

Endoplasmic reticulum stress inhibition protects steatotic and non-steatotic livers in partial hepatectomy under ischemia–reperfusion

During partial hepatectomy, ischemia–reperfusion (I/R) is commonly applied in clinical practice to reduce blood flow. Steatotic livers show impaired regenerative response and reduced tolerance to hepatic injury. We examined the effects of tauroursodeoxycholic acid (TUDCA) and 4-phenyl butyric acid (PBA) in steatotic and non-steatotic livers during partial hepatectomy under I/R (PH+I/R). Their effects on the induction of unfolded protein response (UPR) and endoplasmic reticulum (ER) stress were also evaluated. We report that PBA, and especially TUDCA, reduced inflammation, apoptosis and necrosis, and improved liver regeneration in both liver types. Both compounds, especially TUDCA, protected both liver types against ER damage, as they reduced the activation of two of the three pathways of UPR (namely inositol-requiring enzyme and PKR-like ER kinase) and their target molecules caspase 12, c-Jun N-terminal kinase and C/EBP homologous protein-10. Only TUDCA, possibly mediated by extracellular signal-regulated kinase upregulation, inactivated glycogen synthase kinase-3β. This is turn, inactivated mitochondrial voltage-dependent anion channel, reduced cytochrome c release from the mitochondria and caspase 9 activation and protected both liver types against mitochondrial damage. These findings indicate that chemical chaperones, especially TUDCA, could protect steatotic and non-steatotic livers against injury and regeneration failure after PH+I/R

Levosimendan: a cardiovascular drug to prevent liver ischemia-reperfusion injury?

INTRODUCTION: Temporary occlusion of the hepatoduodenal ligament leads to an ischemic-reperfusion (IR) injury in the liver. Levosimendan is a new positive inotropic drug, which induces preconditioning-like adaptive mechanisms due to opening of mitochondrial KATP channels. The aim of this study was to examine possible protective effects of levosimendan in a rat model of hepatic IR injury. MATERIAL AND METHODS: Levosimendan was administered to male Wistar rats 1 hour (early pretreatment) or 24 hours (late pretreatment) before induction of 60-minute segmental liver ischemia. Microcirculation of the liver was monitored by laser Doppler flowmeter. After 24 hours of reperfusion, liver and blood samples were taken for histology, immuno- and enzyme-histochemistry (TUNEL; PARP; NADH-TR) as well as for laboratory tests. Furthermore, liver antioxidant status was assessed and HSP72 expression was measured. RESULTS: In both groups pretreated with levosimendan, significantly better hepatic microcirculation was observed compared to respective IR control groups. Similarly, histological damage was also reduced after levosimendan administration. This observation was supported by significantly lower activities of serum ALT (pearly = 0.02; plate = 0.005), AST (pearly = 0.02; plate = 0.004) and less DNA damage by TUNEL test (pearly = 0.05; plate = 0.034) and PAR positivity (pearly = 0.02; plate = 0.04). Levosimendan pretreatment resulted in significant improvement of liver redox homeostasis. Further, significantly better mitochondrial function was detected in animals receiving late pretreatment. Finally, HSP72 expression was increased by IR injury, but it was not affected by levosimendan pretreatment. CONCLUSION: Levosimendan pretreatment can be hepatoprotective and it could be useful before extensive liver resection

AMPK involvement in endoplasmic reticulum stress and autophagy modulation after fatty liver graft preservation: a role for melatonin and trimetazidine cocktail

Ischemia/reperfusion injury (IRI) associated with liver transplantation plays an important role in the induction of graft injury. Prolonged cold storage remains a risk factor for liver graft outcome, especially when steatosis is present. Steatotic livers exhibit exacerbated endoplasmic reticulum (ER) stress that occurs in response to cold IRI. In addition, a defective liver autophagy correlates well with liver damage. Here, we evaluated the combined effect of melatonin and trimetazidine as additives to IGL-1 solution in the modulation of ER stress and autophagy in steatotic liver grafts through activation of AMPK. Steatotic livers were preserved for 24 hr (4°C) in UW or IGL-1 solutions with or without MEL + TMZ and subjected to 2-hr reperfusion (37°C). We assessed hepatic injury (ALT and AST) and function (bile production). We evaluated ER stress (GRP78, PERK, and CHOP) and autophagy (beclin-1, ATG7, LC3B, and P62). Steatotic livers preserved in IGL-1 + MEL + TMZ showed lower injury and better function as compared to those preserved in IGL-1 alone. IGL-1 + MEL + TMZ induced a significant decrease in GRP78, pPERK, and CHOP activation after reperfusion. This was consistent with a major activation of autophagic parameters (beclin-1, ATG7, and LC3B) and AMPK phosphorylation. The inhibition of AMPK induced an increase in ER stress and a significant reduction in autophagy. These data confirm the close relationship between AMPK activation and ER stress and autophagy after cold IRI. The addition of melatonin and TMZ to IGL-1 solution improved steatotic liver graft preservation through AMPK activation, which reduces ER stress and increases autophagy

The response of the hepatocyte to ischemia

[Background]: Ischemia-reperfusion (I/R) injury associated with hepatic resections and liver transplantation remains a serious complication in clinical practice, in spite of several attempts to solve the problem. [Aims]: To evaluate the response of the hepatocyte to ischemia: Methods: Published data are thus revised. [Results]: The response of the hepatocyte to ischemia is based on the sensitivity of hepatocytes to different types of ischemia, the kind of cell death of the hepatocyte when it is subjected to ischemia, and on the response of the hepatocyte to the different times and extents of ischemia. Clinical factors including starvation, graft, age, and hepatic steatosis, all of which contribute to enhancing liver susceptibility to ischemia/reperfusion injury. [Conclusion]: Ischemic preconditioning, based on the induction of a brief ischemia to the liver prior to a prolonged ischemia, has been applied in tumor hepatic resections for reducing hepatic I/R injury and recent clinical studies suggest that this surgical strategy could be appropriate for liver transplantation. © 2007 Blackwell Munksgaard.Supported by the Ministerio de Educacióon y Ciencia (project grants SAF 2005-00385, and Ramón y Cajal research contract for Carmen Peralta) Ministerio de Sanidad y Consumo (project grant P1060021) (Madrid, Spain), Generalitat de Catalunya (2005 SGR/00781 project) (Barcelona, Spain) and Ministerio de Asuntos Exteriores (hp2003-0051) (Madrid, Spain).Peer Reviewe

Effect of Almond Supplementation on Non-Esterified Fatty Acid Values and Exercise Performance

Several studies have investigated the effects of fat intake before exercise on subsequent substrate oxidation and exercise performance. While some studies have reported that unsaturated fatty acid supplementation slightly increases fat oxidation, the changes have not been reflected in the maximum oxygen uptake or in other performance and physiological parameters. We selected almonds as a fatty acid (FA) source for acute supplementation and investigated their effect on non-esterified fatty acid (NEFA) values and exercise performance. Five physically active male subjects (age 32.9 ± 12.7 years, height 178.5 ± 3.3 cm, and weight 81.3 ± 9.7 kg) were randomly assigned to take an almond or placebo supplement 2 h before participating in two cycling resistance training sessions separated by an interval of 7-10 days. Their performance was evaluated with a maximal incremental test until exhaustion. Blood samples collected before, during, and after testing were biochemically analysed. The results indicated a NEFA value average increase of 0.09 mg·dL−1 (95% CI: 0.05-0.14; p < 0.001) after active supplement intake and enhanced performance (5389 ± 1795 W vs. placebo 4470 ± 2053 W, p = 0.043) after almond supplementation compared to the placebo. The almond supplementation did not cause gastrointestinal disturbances. Our study suggests that acute almond supplementation 2 h before exercise can improve performance in endurance exercise in trained subjects