Ischemia-reperfusion injury is an important cause of liver damage occurring during surgical procedures including hepatic resection and liver transplantation, and represents the main underlying cause of graft dysfunction and liver failure post-transplantation. To date, ischemia-reperfusion injury is an unsolved problem in clinical practice. In this context, inflammasome activation, recently described during ischemia-reperfusion injury, might be a potential therapeutic target to mitigate the clinical problems associated with liver transplantation and hepatic resections. The present review aims to summarize the current knowledge in inflammasome-mediated inflammation, describing the experimental models used to understand the molecular mechanisms of inflammasome in liver ischemia-reperfusion injury. In addition, a clear distinction between steatotic and non-steatotic livers and between warm and cold ischemia-reperfusion injury will be discussed. Finally, the most updated therapeutic strategies, as well as some of the scientific controversies in the field will be described. Such information may be useful to guide the design of better experimental models, as well as the effective therapeutic strategies in liver surgery and transplantation that can succeed in achieving its clinical application.

No abstract

Ischemia-reperfusion (I/R) injury is an unresolved problem in liver resection and transplantation. The preexisting nutritional status related to the gut microbial profile might contribute to primary non-function after surgery. Clinical studies evaluating artificial nutrition in liver resection are limited. The optimal nutritional regimen to support regeneration has not yet been exactly defined. However, overnutrition and specific diet factors are crucial for the nonalcoholic or nonalcoholic steatohepatitis liver diseases. Gut-derived microbial products and the activation of innate immunity system and inflammatory response, leading to exacerbation of I/R injury or impaired regeneration after resection. This review summarizes the role of starvation, supplemented nutrition diet, nutritional status, and alterations in microbiota on hepatic I/R and regeneration. We discuss the most updated effects of nutritional interventions, their ability to alter microbiota, some of the controversies, and the suitability of these interventions as potential therapeutic strategies in hepatic resection and transplantation, overall highlighting the relevance of considering the extended criteria liver grafts in the translational liver surgery.

Colocalization of the classic neurotransmitters serotonin (5-HT) and γ-aminobutyric acid (GABA) (or the enzyme that synthesizes the latter, glutamate decarboxylase) has been reported in a few neurons of the rat raphe magnus-obscurus nuclei. However, there are no data on the presence of neurochemically similar neurons in the brain of non-mammalian vertebrates. Lampreys are the oldest extant vertebrates and may provide important data on the phylogeny of neurochemical systems. The colocalization of 5-HT and GABA in neurons of the sea lamprey brain was studied using antibodies directed against 5-HT and GABA and confocal microscopy. Colocalization of the neurotransmitters was observed in the diencephalon and the isthmus. In the diencephalon, about 87% of the serotonergic cells of the rostral tier of the dorsal thalamus (close to the zona limitans) exhibited GABA immunoreactivity. In addition, occasional cells double-labelled for GABA and 5-HT were observed in the hypothalamic tuberal nucleus and the pretectum. Of the three serotonergic isthmic subgroups already recognized in the sea lamprey isthmus (dorsal, medial and ventral), such double-labelled cells were only observed in the ventral subgroup (about 61% of the serotonergic cells in the ventral subgroup exhibited GABA immunoreactivity). An equivalence between these lamprey isthmic cells and the serotonergic/ GABAergic raphe cells of mammals is suggested. Present findings suggest that serotonergic/GABAergic neurons are more extensive in lampreys than in the rat and probably appeared before the separation of agnathans and gnathostomes. Cotransmission by release of 5-HT and GABA by the here-described lamprey brain neurons is proposed.

We examined the effects of VEGFA on damage and regeneration in steatotic and non-steatotic livers of rats submitted to PH under I/R, and characterized the underlying mechanisms involved. Our results indicated that VEGFA levels were decreased in both steatotic and non-steatotic livers after surgery. The administration of VEGFA increased VEGFA levels in non-steatotic livers, reducing the incidence of post-operative complications following surgery through the VEGFR2-Wnt2 pathway, independently of Id1. Unexpectedly, administration of VEGFA notably reduced VEGFA levels in steatotic livers, exacerbating damage and regenerative failure. After exogenous administration of VEGFA in steatotic animals, circulating VEGFA is sequestered by the high circulating levels of sFlt1 released from adipose tissue. Under such conditions, VEGFA cannot reach the steatotic liver to exert its effects. Consequently, the concomitant administration of VEGFA and an antibody against sFlt1 was required to avoid binding of sFlt1 to VEGFA. This was associated with high VEGFA levels in steatotic livers and protection against damage and regenerative failure, plus improvement in the survival rate via up-regulation of PI3K/Akt independently of the Id1-Wnt2 pathway. The current study highlights the different effects and signaling pathways of VEGFA in liver surgery requiring PH and I/R based in the presence of steatosis. Key messages VEGFA administration improves PH+I/R injury only in non-steatotic livers of Ln animals. VEGFA benefits are exerted through the VEGFR2-Wnt2 pathway in non-steatotic livers. In Ob rats, exogenous VEGFA is sequestered by circulating sFlt1, exacerbating liver damage. Therapeutic combination of VEGFA and anti-sFlt1 is required to protect steatotic livers. VEGFA+anti-sFlt1 treatment protects steatotic livers through a VEGFR2-PI3K/Akt pathway. Electronic supplementary material The online version of this article (10.1007/s00109-019-01811-y) contains supplementary material, which is available to authorized users.

No abstract

Recent research has shown that at least two tryptophan hydroxylase (Tph) genes are present in gnathostome vertebrates, but it is not known when the duplication of the ancestral Tph gene took place during evolution. By their position as an out-group of gnathostomes, lampreys (agnathans) are key models to understand molecular evolution in vertebrates. Here, we report the cloning of a Tph cDNA of the sea lamprey and the pattern of Tph mRNA expression in larval and postmetamorphic (young adult) sea lampreys using in situ hybridization. Phylogenetic analysis indicated that the lamprey Tph is an orthologue of Tphs of other vertebrates and suggested that the duplication of the ancestral Tph gene occurred before the separation of agnathans and gnathostomes, although alternative hypothesis are also discussed in the present study. In the sea lamprey brain, the Tph transcript was expressed in perikarya of the pineal organ, the retina, the diencephalic and rhombencephalic nuclei reported previously with serotonin immunohistochemistry and in small cells of the spinal cord, with a pattern similar to that observed with anti-serotonin antibodies. This suggests that expression of this Tph gene is shared by all lamprey serotonergic brain populations, unlike that reported in zebrafish and mammals for their different Tph genes. However, no Tph expression was observed in peripheral serotonergic cells, which, unlike in other vertebrates, are widely distributed in lampreys. Our results suggest that the selection of Tph2 to be expressed in raphe neurons may have occurred along the line leading to gnathostomes.

No abstract