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Mixtures of LiAlH4/FeCl2 and LiBH4/FeCl2 were produced in several conditions of stoichiometry, time, and vial-oscillation frequency at cryogenic conditions (−196 °C) by ball milling. The best production conditions were milling for 30 min at −196 °C and 15 Hz of the oscillation frequency of the vial. Temperature-programmed desorption and differential scanning calorimetry experiments indicated that hydrogen release in LiAlH4/FeCl2 mixtures begins at approximately 60 °C and ends at 160 °C. Meanwhile, the LiBH4/FeCl2 mixtures presented dehydrogenation on-set at 40 °C, finishing at about 300 °C. These materials behave as reactive mixtures, where the LiCl formation is considered the driving force of the decomposition reactions. Cryogenic ball-milling has a good effect on the production of the mixtures and low-temperature dehydrogenation of the studied samples.

We thank Toffa (Language Advisory Service, University of Barcelona, Barcelona, Spain) for revising the English text, Microbiota is defined as the collection of microorganisms within the gastrointestinal ecosystem. These microbes are strongly implicated in the stimulation of immune responses. An unbalanced microbiota, termed dysbiosis, is related to the development of several liver diseases. The bidirectional relationship between the gut, its microbiota and the liver is referred to as the gut–liver axis. The translocation of bacterial products from the intestine to the liver induces inflammation in different cell types such as Kupffer cells, and a fibrotic response in hepatic stellate cells, resulting in deleterious effects on hepatocytes. Moreover, ischemia-reperfusion injury, a consequence of liver surgery, alters the microbiota profile, affecting inflammation, the immune response and even liver regeneration. Microbiota also seems to play an important role in post-operative outcomes (i.e., liver transplantation or liver resection). Nonetheless, studies to determine changes in the gut microbial populations produced during and after surgery, and affecting liver function and regeneration are scarce. In the present review we analyze and discuss the preclinical and clinical studies reported in the literature focused on the evaluation of alterations in microbiota and its products as well as their effects on post-operative outcomes in hepatic surgery., Ministerio de Ciencia, Innovacion y Universidades (MCIU) Madrid, Spain RTI2018-095114-B-I00, European Union (Fondos Feder, "Una manera de hacer Europa"), CERCA Program/Generalitat de Catalunya, Secretaria d'Universitats i Recerca Barcelona, Spain 2017SGR-551, COST action Programs CA17103 CA17126

Hepatocellular carcinoma has become a leading cause of cancer-associated mortality throughout the world, and is of great concern. Currently used chemotherapeutic drugs in the treatment of hepatocellular carcinoma lead to severe side effects, thus underscoring the need for further research to develop novel and safer therapies. Liver resection in cancer patients is routinely performed. After partial resection, liver regeneration is a perfectly calibrated response apparently sensed by the body's required liver function. This process hinges on the effect of several growth factors, among other molecules. However, dysregulation of growth factor signals also leads to growth signaling autonomy and tumor progression, so control of growth factor expression may prevent tumor progression. This review describes the role of some of the main growth factors whose dysregulation promotes liver tumor progression, and are also key in regenerating the remaining liver following resection. We herein summarize and discuss studies focused on partial hepatectomy and liver carcinogenesis, referring to hepatocyte growth factor, insulin-like growth factor, and epidermal growth factor, as well as their suitability as targets in the treatment of hepatocellular carcinoma. Finally, and given that drugs remain one of the mainstay treatment options in liver carcinogenesis, we have reviewed the current pharmacological approaches approved for clinical use or research targeting these factors. Yes

This research was funded by the Ministerio de Ciencia, Innovacion y Universidades (Project Grant RTI2018-095114-B-I00) Madrid, Spain; European Union (Fondos FEDER, "una manera de hacer Europa"); CERCA Program/Generalitat de Catalunya; the Secretaria d' Universitats I Recerca del Departament d' Economia I Coneixement (Project Grant 2017_SGR_551) Barcelona, Spain, by the COST action Programs CA17103 (DARTER), CA17112 (PRO-EURO-DILI-NET), CA17121 (COMULIS) and CA17126 (TUMIEE), and by the Consejo Nacional de Ciencia y Tecnologia (CONACYT), Fondo Sectorial de Investigacion para la Educacion (Project grant 257743), Mexico. Marc Mico-Carnero is the recipient of a fellowship from FCT (Fundacio Catalana de Trasplantament), Spain., Hepatocellular carcinoma has become a leading cause of cancer-associated mortality throughout the world, and is of great concern. Currently used chemotherapeutic drugs in the treatment of hepatocellular carcinoma lead to severe side effects, thus underscoring the need for further research to develop novel and safer therapies. Liver resection in cancer patients is routinely performed. After partial resection, liver regeneration is a perfectly calibrated response apparently sensed by the body’s required liver function. This process hinges on the effect of several growth factors, among other molecules. However, dysregulation of growth factor signals also leads to growth signaling autonomy and tumor progression, so control of growth factor expression may prevent tumor progression. This review describes the role of some of the main growth factors whose dysregulation promotes liver tumor progression, and are also key in regenerating the remaining liver following resection. We herein summarize and discuss studies focused on partial hepatectomy and liver carcinogenesis, referring to hepatocyte growth factor, insulin-like growth factor, and epidermal growth factor, as well as their suitability as targets in the treatment of hepatocellular carcinoma. Finally, and given that drugs remain one of the mainstay treatment options in liver carcinogenesis, we have reviewed the current pharmacological approaches approved for clinical use or research targeting these factors., Ministerio de Ciencia, Innovacion y Universidades Madrid, Spain RTI2018-095114-B-I00, European Union (Fondos FEDER, "una manera de hacer Europa"), General Electric, Secretaria d' Universitats I Recerca del Departament d' Economia I Coneixement Barcelona, Spain 2017_SGR_551, COST action Programs CA17103 CA17112 CA17121 CA17126, Consejo Nacional de Ciencia y Tecnologia (CONACyT), Fondo Sectorial de Investigacion para la Educacion, Mexico 257743, FCT (Fundacio Catalana de Trasplantament), Spain

Herein, we investigate whether: (1) the administration of glucose or a lipid emulsion is useful in liver transplantation (LT) using steatotic (induced genetically or nutritionally) or non-steatotic livers from donors after brain death (DBDs), and (2) any such benefits are due to reductions in intestinal damage and consequently to gut microbiota preservation. In recipients from DBDs, we show increased hepatic damage and failure in the maintenance of ATP, glycogen, phospholipid and growth factor (HGF, IGF1 and VEGFA) levels, compared to recipients from non-DBDs. In recipients of non-steatotic grafts from DBDs, the administration of glucose or lipids did not protect against hepatic damage. This was associated with unchanged ATP, glycogen, phospholipid and growth factor levels. However, the administration of lipids in steatotic grafts from DBDs protected against damage and ATP and glycogen drop and increased phospholipid levels. This was associated with increases in growth factors. In all recipients from DBDs, intestinal inflammation and damage (evaluated by LPS, vascular permeability, mucosal damage, TLR4, TNF, IL1, IL-10, MPO, MDA and edema formation) was not shown. In such cases, potential changes in gut microbiota would not be relevant since neither inflammation nor damage was evidenced in the intestine following LT in any of the groups evaluated. In conclusion, lipid treatment is the preferable nutritional support to protect against hepatic damage in steatotic LT from DBDs, the benefits were independent of alterations in the recipient intestine.

En los últimos años el tema de la migración del norte centroamericano ha ganado presencia en México. La atención se ha centrado principalmente en la migración que transita por el país con el objetivo de llegar a Estados Unidos. En ese entorno, las poblaciones extranjeras inmigrantes aún no han sido materia de gran atención analítica, aunque hay apreciaciones sobre su volumen e incidencia pública. En este texto, con base en cuatro fuentes estadísticas, se caracteriza a nivel sociodemográfico y sociolaboral, el stock de inmigrantes de Guatemala, Honduras y El Salvador, de 1990 a 2015, en un ejercicio comparativo con el resto de las poblaciones latinoamericanas en México. El análisis permite concluir que hay comportamientos similares en indicadores aso- ciados a la estructura familiar, sexo y participación económica, pero profundas diferencias en cuanto a estructura etaria, niveles de escolaridad, lugar de residencia y variables asociadas a la inserción laboral.

Background We evaluated the potential dysfunction caused by changes in growth hormone (GH) levels after brain death (BD), and the effects of modulating GH through exogenous epidermal growth factor (EGF) in steatotic and nonsteatotic grafts. Methods Steatotic and nonsteatotic grafts from non-BD and BD rat donors were cold stored for 6 hours and transplanted to live rats. Administration of GH and EGF and their underlying mechanisms were characterized in recipients of steatotic and nonsteatotic grafts from BD donors maintained normotensive during the 6 hours before donation. Circulating and hepatic GH and EGF levels, hepatic damage, and regeneration parameters were evaluated. Recipient survival was monitored for 14 days. Somatostatin, ghrelin, and GH-releasing hormones that regulate GH secretion from the anterior pituitary were determined. The survival signaling pathway phosphoinositide-3-kinase/protein kinase B that regulates inflammation (suppressors of cytokine signaling, high-mobility group protein B1, oxidative stress, and neutrophil accumulation) was evaluated. Results BD reduced circulating GH and increased GH levels only in steatotic livers. GH administration exacerbated adverse BD-associated effects in both types of graft. Exogenous EGF reduced GH in steatotic livers, thus activating cell proliferation and survival signaling pathways, ultimately reducing injury and inflammation. However, EGF increased GH in nonsteatotic grafts, which exacerbated damage. The benefits of EGF for steatotic grafts were associated with increased levels of somatostatin, a GH inhibitor, whereas the deleterious effect on nonsteatotic grafts was exerted through increased amounts of ghrelin, a GH stimulator. Conclusions GH treatment is not appropriate in rat liver transplant from BD donors, whereas EGF (throughout GH inhibition) protects only in steatotic grafts.

Because of the shortage of liver grafts available for transplantation, the restrictions on graft quality have been relaxed, and marginal grafts, such as steatotic livers, are now accepted. However, this policy change has not solved the problem, because steatotic liver grafts tolerate ischemia-reperfusion (I/R) injury poorly. Adipocytokines differentially modulate steatosis, inflammation, and fibrosis and are broadly present in hepatic resections and transplants. The potential use of adipocytokines as biomarkers of the severity of steatosis and liver damage to aid the identification of high-risk steatotic liver donors and to evaluate hepatic injury in the postoperative period are discussed. The hope of finding new therapeutic strategies aimed specifically at protecting steatotic livers undergoing surgery is a strong impetus for identifying the mechanisms responsible for hepatic failure after major surgical intervention. Hence, the most recently described roles of adipocytokines in steatotic livers subject to I/R injury are discussed, the conflicting results in the literature are summarized, and reasons are offered as to why strategic pharmacologic control of adipocytokines has yet to yield clinical benefits. After this, the next steps needed to transfer basic knowledge about adipocytokines into clinical practice to protect marginal livers subject to I/R injury are presented. Recent strategies based on adipocytokine regulation, which have shown efficacy in various pathologies, and hold promise for hepatic resection and transplantation are also outlined.

This research was supported by the "Ministerio de Ciencia, Innovacion y Universidades (MCIU)" (RTI2018-095114-B-I00) Madrid, Spain, by the European Union (Fondos Feder, "Una manera de hacer Europa"), by "CERCA Program/Generalitat de Catalunya", and by the "Secretaria d'Universitats i Recerca" (2017SGR-551) Barcelona, Spain, and by the COST action Programs CA17103 (DARTER), CA17121 (COMULIS), CA17112 (PROEURO-DILI-NETWORK) and CA17126 (TUMIEE). Marc Mico-Carnero is a recipient of a fellowship from "Fundacio Catalana de trasplantament" (FCT)., The pro-tumorigenic activity of fibroblast growth factor (FGF) 19 (FGF15 in its rodent orthologue) in hepatocellular carcinoma (HCC), as well as the unsolved problem that ischemia-reperfusion (IR) injury supposes in liver surgeries, are well known. However, it has been shown that FGF15 administration protects against liver damage and regenerative failure in liver transplantation (LT) from brain-dead donors without tumor signals, providing a benefit in avoiding IR injury. The protection provided by FGF15/19 is due to its anti-apoptotic and pro-regenerative properties, which make this molecule a potentially beneficial or harmful factor, depending on the disease. In the present review, we describe the preclinical models currently available to understand the signaling pathways responsible for the apparent controversial effects of FGF15/19 in the liver (to repair a damaged liver or to promote tumorigenesis). As well, we study the potential pharmacological use that has the activation or inhibition of FGF15/19 pathways depending on the disease to be treated. We also discuss whether FGF15/19 non-pro-tumorigenic variants, which have been developed for the treatment of liver diseases, might be promising approaches in the surgery of hepatic resections and LT using healthy livers and livers from extended-criteria donors., "Ministerio de Ciencia, Innovacion y Universidades (MCIU)", Madrid, Spain RTI2018-095114-B-I00, European Union (Fondos Feder, "Una manera de hacer Europa"), CERCA Program/Generalitat de Catalunya, "Secretaria d'Universitats i Recerca", Barcelona, Spain 2017SGR-551, European Cooperation in Science and Technology (COST) CA17103 CA17121 CA17112 CA17126, "Fundacio Catalana de trasplantament" (FCT)

Visceral obesity is an important component of metabolic syndrome, a cluster of diseases that also includes diabetes and insulin resistance. A combination of these metabolic disorders damages liver function, which manifests as non-alcoholic fatty liver disease (NAFLD). NAFLD is a common cause of abnormal liver function, and numerous studies have established the enormously deleterious role of hepatic steatosis in ischemia-reperfusion (I/R) injury that inevitably occurs in both liver resection and transplantation. Thus, steatotic livers exhibit a higher frequency of post-surgical complications after hepatectomy, and using liver grafts from donors with NAFLD is associated with an increased risk of post-surgical morbidity and mortality in the recipient. Diabetes, another MetS-related metabolic disorder, also worsens hepatic I/R injury, and similar to NAFLD, diabetes is associated with a poor prognosis after liver surgery. Due to the large increase in the prevalence of MetS, NAFLD, and diabetes, their association is frequent in the population and therefore, in patients requiring liver resection and in potential liver graft donors. This scenario requires advancement in therapies to improve postoperative results in patients suffering from metabolic diseases and undergoing liver surgery; and in this sense, the bases for designing therapeutic strategies are in-depth knowledge about the molecular signaling pathways underlying the effects of MetS-related diseases and I/R injury on liver tissue. A common denominator in all these diseases is autophagy. In fact, in the context of obesity, autophagy is profoundly diminished in hepatocytes and alters mitochondrial functions in the liver. In insulin resistance conditions, there is a suppression of autophagy in the liver, which is associated with the accumulation of lipids, being this is a risk factor for NAFLD. Also, oxidative stress occurring in hepatic I/R injury promotes autophagy. The present review aims to shed some light on the role of autophagy in livers undergoing surgery and also suffering from metabolic diseases, which may lead to the discovery of effective therapeutic targets that could be translated from laboratory to clinical practice, to improve postoperative results of liver surgeries when performed in the presence of one or more metabolic diseases. Yes

Microbiota is defined as the collection of microorganisms within the gastrointestinal ecosystem. These microbes are strongly implicated in the stimulation of immune responses. An unbalanced microbiota, termed dysbiosis, is related to the development of several liver diseases. The bidirectional relationship between the gut, its microbiota and the liver is referred to as the gut-liver axis. The translocation of bacterial products from the intestine to the liver induces inflammation in different cell types such as Kupffer cells, and a fibrotic response in hepatic stellate cells, resulting in deleterious effects on hepatocytes. Moreover, ischemia-reperfusion injury, a consequence of liver surgery, alters the microbiota profile, affecting inflammation, the immune response and even liver regeneration. Microbiota also seems to play an important role in post-operative outcomes (i.e., liver transplantation or liver resection). Nonetheless, studies to determine changes in the gut microbial populations produced during and after surgery, and affecting liver function and regeneration are scarce. In the present review we analyze and discuss the preclinical and clinical studies reported in the literature focused on the evaluation of alterations in microbiota and its products as well as their effects on post-operative outcomes in hepatic surgery. Yes

In the present study, we examined the effects of cortisol on steatotic and non-steatotic liver grafts from brain-dead donors and characterized the underlying mechanisms involved. Non-steatotic liver grafts showed reduced cortisol and increased cortisone levels in association with up-regulation of enzymes that inactivate cortisol. Conversely, steatotic liver grafts exhibited increased cortisol and reduced cortisone levels. The enzymes involved in cortisol generation were overexpressed, and those involved in cortisol inactivation or clearance were down-regulated in steatotic liver grafts. Exogenous administration of cortisol negatively affected hepatic damage and survival rate in non-steatotic liver transplantation (LT); however, cortisol treatment up-regulated the phosphoinositide 3-kinase (PI3K)–protein kinase C (PKC) pathway, resulting in protection against the deleterious effects of brain-dead donors on damage and inflammatory response in steatotic LT as well as in increased survival of recipients. The present study highlights the differences in the role of cortisol and hepatic mechanisms that regulate cortisol levels based on the type of liver. Our findings suggest that cortisol treatment is a feasible and highly protective strategy to reduce the adverse effects of brain-dead donor livers in order to ultimately improve liver graft quality in the presence of steatosis, whereas cortisol treatment would not be recommended for non-steatotic liver grafts. * 11β-HSD1, : 11 β-hydroxysteroid dehydrogenase type 1; 11β-HSD2, : 11 β-hydroxysteroid dehydrogenase type 2; 5αR1, : 5α-reductase 1 enzyme; 5αR2, : 5α-reductase 2 enzyme; 5βR, : 5β-reductase enzyme; ACTH, : adrenocorticotropin hormone; Akt, : protein kinase B; ALT, : alanine aminotransferase; AST, : aspartate aminotransferase; BD, : brain dead; CRH, : corticotropin-releasing hormone; HPA, : hypothalamus–pituitary–adrenal axis; i.p., : intraperitoneal; I/R, : ischemia-reperfusion; i.v., : intravenous; Ln, : lean; LT, : liver transplantation; MDA, : malondialdehyde; MPO, : myeloperoxidase; Ob, : obese; PI3K, : phosphoinositide 3-kinase; PKC, : protein kinase C; UW, : University of Wisconsin

We elucidate the relevance of fibroblast growth factor 15 (FGF15) in liver transplantation (LT) using rats with both steatotic and non-steatotic organs from donors after cardiocirculatory death (DCD). Compared to LT from non-DCDs, the induction of cardiocirculatory death (CD) increases hepatic damage, proliferation, and intestinal and circulatory FGF15. This is associated with high levels of FGF15, bilirubin and bile acids (BAs), and overexpression of the enzyme involved in the alternative BA synthesis pathway, CYP27A1, in non-steatotic livers. Furthermore, CD activates the proliferative pathway, Hippo/YAP, in these types of liver. Blocking FGF15 action in LT from DCDs does not affect CYP27A1 but causes an overexpression of CYP7A, an enzyme from the classic BA synthesis pathway, and this is related to further accumulation of BAs and exacerbated damage. FGF15 inhibition also impairs proliferation without changing Hippo/YAP. In spite of worse damage, steatosis prevents a proliferative response in livers from DCDs. In steatotic grafts, CD does not modify CYP7A1, CYP27A1, BA, or the Hippo/YAP pathway, and FGF15 is not involved in damage or proliferation. Thus, endogenous FGF15 protects against BA accumulation and damage and promotes regeneration independently of the Hippo/YAP pathway, in non-steatotic LT from DCDs. Herein we show a minor role of FGF15 in steatotic LT from DCDs.