MARTA ALONSO PEÑA - Academia.edu (original) (raw)

Papers by MARTA ALONSO PEÑA

Research paper thumbnail of ACOX2 deficiency-induced liver fragility (ADILF), a not-so-rare inborn error in bile acid metabolism that responds to ursodeoxycholic acid treatment

Research paper thumbnail of Identificación de un nuevo defecto genético del metabolismo de los ácidos biliares: deficiencia de la enzima ACOX2. Bases moleculares, fisiopatología e implicación en el daño hepatocelular idiopático

[ES] Los ácidos biliares desempeñan un papel determinante en la función digestiva y excretora del... more [ES] Los ácidos biliares desempeñan un papel determinante en la función digestiva y excretora del hígado, pero, además, son importantes moléculas de señalización implicadas en la regulación del metabolismo energético y de los procesos inflamatorios y regenerativos del hígado. Existe una gran variedad de patologías asociadas a fallos en el metabolismo de los ácidos biliares. Se trata, en la mayor parte de los casos, de afecciones muy graves y poco frecuentes, que no sólo afectan al tejido hepático, sino que pueden acompañarse también de trastornos neurológicos, renales y endocrinos debido a la acumulación de metabolitos intermediarios con potencial toxicidad. En esta Tesis Doctoral se describe y estudia el caso de un paciente adolescente con hipertransaminasemia idiopática persistente. Tras descartar las patologías asociadas a daño hepático más comunes, el análisis genético permitió identificar una mutación (c.673C>T) en la región codificante del gen ACOX2, cuyo producto es la variante R225W de la enzima implicada en la síntesis de novo de los ácidos biliares acil-CoA oxidasa 2 (ACOX2). Los estudios funcionales en modelos celulares in vitro revelaron que la mutación causa una reducción de la actividad de esta enzima peroxisomal que acarrea una deficiencia de ácidos biliares maduros y la acumulación de metabolitos intermediarios tóxicos, capaces de inducir estrés oxidativo y de retículo endoplásmico. Los resultados del estudio sugieren que la deficiencia parcial de ACOX2 (APD) podría ser un trastorno más frecuente que las patologías asociadas al metabolismo de los ácidos biliares descritas hasta ahora y estar implicada en la etiología de otros casos de hipertransaminasemia persistente de causa no filiada, así como constituir un factor predisponente a la toxicidad por fármacos. Asimismo, la deficiencia de ACOX2 podría agravar la progresión de enfermedades hepáticas comunes que cursan con inflamación, como la esteatohepatitis no alcohólica. En esta Tesis Doctoral se ha desarrollado un modelo animal “avatar” de la enfermedad, mediante la edición del genoma del ratón con CRISPR/Cas9. Esta valiosa herramienta permitirá el desarrollo de nuevos estudios que ayudarán a caracterizar la fisiopatología de la APD, a evaluar nuevos tratamientos terapéuticos y a determinar el papel de ACOX2 en otras patologías hepáticas

Research paper thumbnail of Pathophysiological Mechanisms in Non-Alcoholic Fatty Liver Disease: From Drivers to Targets

Biomedicines, 2021

Non-alcoholic fatty liver disease (NAFLD) is characterized by the excessive and detrimental accum... more Non-alcoholic fatty liver disease (NAFLD) is characterized by the excessive and detrimental accumulation of liver fat as a result of high-caloric intake and/or cellular and molecular abnormalities. The prevalence of this pathological event is increasing worldwide, and is intimately associated with obesity and type 2 diabetes mellitus, among other comorbidities. To date, only therapeutic strategies based on lifestyle changes have exhibited a beneficial impact on patients with NAFLD, but unfortunately this approach is often difficult to implement, and shows poor long-term adherence. For this reason, great efforts are being made to elucidate and integrate the underlying pathological molecular mechanism, and to identify novel and promising druggable targets for therapy. In this regard, a large number of clinical trials testing different potential compounds have been performed, albeit with no conclusive results yet. Importantly, many other clinical trials are currently underway with resu...

Research paper thumbnail of Immune Assessment of BNT162b2 m-RNA-Spike Based Vaccine Response in Adults

Biomedicines, 2021

Vaccine efficacy is based on clinical data. Currently, the assessment of immune response after SA... more Vaccine efficacy is based on clinical data. Currently, the assessment of immune response after SARS-CoV-2 vaccination is scarce. A total of 52 healthcare workers were immunized with the same lot of BNT162b2 vaccine. The immunological response against the vaccine was tested using a T-specific assay based on the expression of CD25 and CD134 after stimulation with anti-N, -S, and -M specific peptides of SARS-CoV-2. Moreover, IgG anti-S2 and -RBD antibodies were detected using ELISA. Furthermore, the cell subsets involved in the response to the vaccine were measured in peripheral blood by flow cytometry. Humoral-specific responses against the vaccine were detected in 94% and 100% after the first and second doses, respectively. Therefore, anti-S T-specific responses were observed in 57% and 90% of the subjects after the first and second doses of the vaccine, respectively. Thirty days after the second dose, significant increases in T helper 1 memory cells (p < 0.001), peripheral memory...

Research paper thumbnail of Resumen de tesis. Identificación de un nuevo defecto genético del metabolismo de los ácidos biliares: deficiencia de la enzima ACOX2. Bases moleculares, fisiopatología e implicación en el daño hepatocelular idiopático

Los acidos biliares desempenan un papel determinante en la funcion digestiva y excretora del higa... more Los acidos biliares desempenan un papel determinante en la funcion digestiva y excretora del higado, pero, ademas, son importantes moleculas de senalizacion implicadas en la regulacion del metabolismo energetico y de los procesos inflamatorios y regenerativos del higado. Existe una gran variedad de patologias asociadas a fallos en el metabolismo de los acidos biliares. Se trata, en la mayor parte de los casos, de afecciones muy graves y poco frecuentes, que no solo afectan al tejido hepatico, sino que pueden acompanarse tambien de trastornos neurologicos, renales y endocrinos debido a la acumulacion de metabolitos intermediarios con potencial toxicidad. En esta Tesis Doctoral se describe y estudia el caso de un paciente adolescente con hipertransaminasemia idiopatica persistente. Tras descartar las patologias asociadas a dano hepatico mas comunes, el analisis genetico permitio identificar una mutacion (c.673C>T) en la region codificante del gen ACOX2, cuyo producto es la variante...

Research paper thumbnail of Suppression of bile acid-CoA:amino acid N-acyltransferase gene expression by Oncostatin M

36. Jahrestagung der Deutschen Arbeitsgemeinschaft zum Studium der Leber, 2020

Research paper thumbnail of Suppression of bile acid-CoA:amino acid N-acyltransferase gene expression by the interleukin-6-type cytokine Oncostatin M

35. Jahrestagung der Deutschen Arbeitsgemeinschaft zum Studium der Leber, 2019

Research paper thumbnail of Myeloid-derived suppressor cells are increased in frequency but not maximally suppressive in peripheral blood of Type 1 Diabetes Mellitus patients

Clinical Immunology, 2014

Myeloid-derived suppressor cells (MDSCs) have been identified in the majority of patients and exp... more Myeloid-derived suppressor cells (MDSCs) have been identified in the majority of patients and experimental mice with tumors by their suppression of T cell activation. MDSCs have also been reported to be associated with chronic inflammation. In advanced cancer, the T helper (Th) cell balance tends to shift from Th1 to Th2 predominance, and immune function, including cell-mediated immunity, is impaired by cytokines produced by Th2 cells. The present study examined the correlations between MDSC levels and inflammation, immune suppression, malnutrition, and poor prognosis in 155 patients with breast cancer. The levels of MDSCs in preoperative patients and in patients with recurrent breast cancer were significantly higher compared with postoperative patients, patients with recurrent breast cancer who received chemotherapy and healthy volunteers. The MDSC levels of preoperative patients were significantly positively correlated with interleukin (IL)-6 production by peripheral blood mononuclear cells (PBMCs), the neutrophil/lymphocyte ratio and C-reactive protein, and were negatively correlated with the production of interferon-γ and IL-12, serum concentration of rapid turnover protein, and the stimulation index. These patients were divided into two groups based on the levels of MDSCs. In preoperative patients with MDSC levels >1.0% of total PBMCs, the overall survival of patients with stage IV disease was significantly shorter compared with other disease stages, and was also significantly shorter compared with patients with MDSC levels <1.0% of total PBMCs. Thus, the MDSC levels of preoperative patients may function as a good prognostic indicator, particularly in patients with advanced breast cancer.

Research paper thumbnail of Beneficial effect of ursodeoxycholic acid in patients with acyl‐CoA oxidase 2 (ACOX2) deficiency–associated hypertransaminasemia

Hepatology

BACKGROUND A variant (p.Arg225Trp) of peroxisomal acyl-CoA oxidase 2 (ACOX2), involved in bile ac... more BACKGROUND A variant (p.Arg225Trp) of peroxisomal acyl-CoA oxidase 2 (ACOX2), involved in bile acid (BA) side-chain shortening, has been associated with unexplained persistent hypertransaminasemia and accumulation of C27-BAs, mainly trihydroxycholestanoic acid (THCA). AIMS To investigate the prevalence of ACOX2 deficiency-associated hypertransaminasemia (ADAH), its response to ursodeoxycholic acid (UDCA), elucidate its pathophysiological mechanism and identify other inborn errors that could cause this alteration. METHODS & RESULTS Among 33 patients with unexplained hypertransaminasemia from 11 hospitals, and 13 of their relatives, 7 individuals with abnormally high C27-BA levels (>50% of total BAs) were identified by HPLC-MS/MS. The p.Arg225Trp variant was found in homozygosity (exon amplification/sequencing) in 2 patients and 3 family members. Two additional non-related patients were heterozygous carriers of different alleles: c.673C>T (p.Arg225Trp) and c.456_459del (p.Thr154fs). In ADAH patients, impaired liver expression of ACOX2, but not ACOX3, was found (immunohistochemistry). Treatment with UDCA normalized transaminases levels. Incubation of HuH-7 liver cells with THCA, which was efficiently taken up, but not through BA transporters, increased ROS production (flow cytometry), ER stress biomarkers (GRP78, CHOP and XBP1-S/XBP1-U ratio), and BAXα expression (RT-qPCR and immunoblot), whereas cell viability was decreased (MTT). THCA-induced cell toxicity was higher than that of major C24-BAs and was not prevented by UDCA. Fourteen predicted ACOX2 variants were generated (site-directed mutagenesis) and expressed in HuH-7 cells. Functional tests to determine their ability to metabolize THCA identified six with the potential to cause ADAH. CONCLUSION Dysfunctional ACOX2 has been found in several patients with unexplained hypertransaminasemia. This condition can be accurately identified by a non-invasive diagnostic strategy based on plasma BA profiling and ACOX2 sequencing. Moreover, UDCA treatment can efficiently attenuate liver damage in these patients.

Research paper thumbnail of The absence of OCT1 at the plasma membrane of tumor cells is associated with a worse response of hepatocellular carcinoma to sorafenib

Research paper thumbnail of Innate and Adaptive Immune Assessment at Admission to Predict Clinical Outcome in COVID-19 Patients

Biomedicines

During the COVID-19 pandemic, many studies have been carried out to evaluate different immune sys... more During the COVID-19 pandemic, many studies have been carried out to evaluate different immune system components to search for prognostic biomarkers of the disease. A broad multiparametric antibody panel of cellular and humoral components of the innate and the adaptative immune response in patients with active SARS-CoV-2 infection has been evaluated in this study. A total of 155 patients were studied at admission into our center and were categorized according to the requirement of oxygen therapy as mild or severe (the latter being those with the requirement). The patients with severe disease were older and had high ferritin, D-dimer, C-reactive protein, troponin, interleukin-6 (IL-6) levels, and neutrophilia with lymphopenia at admission. Moreover, the patients with mild symptoms had significantly increased circulating non-classical monocytes, innate lymphoid cells, and regulatory NK cells. In contrast, severe patients had a low frequency of Th1 and regulatory T cells with increased ...

Research paper thumbnail of Innate and Adaptive Immunity Alterations in Metabolic Associated Fatty Liver Disease and Its Implication in COVID-19 Severity

Frontiers in Immunology

The coronavirus infectious disease 2019 (COVID-19) pandemic has hit the world, affecting health, ... more The coronavirus infectious disease 2019 (COVID-19) pandemic has hit the world, affecting health, medical care, economies and our society as a whole. Furthermore, COVID-19 pandemic joins the increasing prevalence of metabolic syndrome in western countries. Patients suffering from obesity, type II diabetes mellitus, cardiac involvement and metabolic associated fatty liver disease (MAFLD) have enhanced risk of suffering severe COVID-19 and mortality. Importantly, up to 25% of the population in western countries is susceptible of suffering from both MAFLD and COVID-19, while none approved treatment is currently available for any of them. Moreover, it is well known that exacerbated innate immune responses are key in the development of the most severe stages of MAFLD and COVID-19. In this review, we focus on the role of the immune system in the establishment and progression of MAFLD and discuss its potential implication in the development of severe COVID-19 in MAFLD patients. As a result,...

Research paper thumbnail of Role of transportome in the pharmacogenomics of hepatocellular carcinoma and hepatobiliary cancer

Pharmacogenomics

An important factor determining the pharmacological response to antitumor drugs is their concentr... more An important factor determining the pharmacological response to antitumor drugs is their concentrations in cancer cells, which accounts for the net interaction with their intracellular molecular targets. Accordingly, mechanisms leading to reduced intracellular levels of active agents play a crucial role in cancer chemoresistance. These include impaired drug uptake through solute carrier (SLC) proteins and efficient drug export by ATP-dependent pumps belonging to the ATP-binding cassette (ABC) superfamily of proteins. Since the net movement of drugs in-and-out the cells depends on the overall expression of carrier proteins, defining the so-called transportome, special attention has been devoted to the study of transcriptome regarding these proteins. Nevertheless, genetic variants affecting SLC and ABC genes may markedly affect the bioavailability and, hence, the efficacy of anticancer drugs.

Research paper thumbnail of Pharmacogenetics of hepatocellular carcinoma and cholangiocarcinoma

Cancer Drug Resistance

Primary liver cancers constitute the fourth most deadly group of cancers. Their poor prognosis is... more Primary liver cancers constitute the fourth most deadly group of cancers. Their poor prognosis is due in part to the pre-existence and/or development, often during treatment, of powerful mechanisms accounting for the poor response of cancer cells to antitumor drugs. These include both impaired gene expression and the appearance of spliced variants, polymorphisms and mutations, affecting the function of genes leading to the reduction in intracellular concentrations of active agents, changes in molecular targets and survival pathways, altered tumor microenvironment and phenotypic transition. The present review summarizes available information regarding the role of germline and somatic mutations affecting drug transporters, enzymes involved in drug metabolism, organelles and signaling molecules related to liver cancer chemoresistance. A more complete picture of the actual complexity of this problem is urgently needed for carrying out further pharmacogenomic studies aimed to improve the management of patients suffering from hepatocellular carcinoma or cholangiocarcinoma.

Research paper thumbnail of FRI-422-Genetic and pathophysiological factors leading to deficient acyl-CoA oxidase 2 (ACOX2) activity in hepatocytes, an alteration which causes oxidative and endoplasmic reticulum stress in liver cells

Research paper thumbnail of ACOX2 deficiency: An inborn error of bile acid synthesis identified in an adolescent with persistent hypertransaminasemia

Journal of Hepatology, 2016

Acyl-CoA oxidase (ACOX2) is involved in the shortening of C27 cholesterol derivatives to generate... more Acyl-CoA oxidase (ACOX2) is involved in the shortening of C27 cholesterol derivatives to generate C24 bile acids. Inborn errors affecting the rest of peroxisomal enzymes involved in bile acid biosynthesis have been described. Here we aimed at investigating the case of an adolescent boy with persistent hypertransaminasemia of unknown origin and suspected dysfunction in bile acid metabolism. Serum and urine samples were taken from the patient, his sister and parents and underwent HPLC-MS/MS and HPLC-TOF analyses. Coding exons in genes of interest were amplified by high-fidelity PCR and sequenced. Wild-type or mutated (mutACOX2) variants were overexpressed in human hepatoblastoma HepG2 cells to determine ACOX2 enzymatic activity, expression and subcellular location. The patient&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s serum and urine showed negligible amounts of C24 bile acids, but augmented levels of C27 intermediates, mainly tauroconjugated trihydroxycholestanoic acid (THCA). Genetic analysis of enzymes potentially involved revealed a homozygous missense mutation (c.673C&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;T; R225W) in ACOX2. His only sister was also homozygous for this mutation and exhibited similar alterations in bile acid profiles. Both parents were heterozygous and presented normal C24 and C27 bile acid levels. Immunofluorescence studies showed similar protein size and peroxisomal localization for both normal and mutated variants. THCA biotransformation into cholic acid was enhanced in cells overexpressing ACOX2, but not in those overexpressing mutACOX2. Both cell types showed similar sensitivity to oxidative stress caused by C24 bile acids. In contrast, THCA-induced oxidative stress and cell death were reduced by overexpressing ACOX2, but not mutACOX2. ACOX2 deficiency, a condition characterized by accumulation of toxic C27 bile acid intermediates, is a novel cause of isolated persistent hypertransaminasemia. Elevation of serum transaminases is a biochemical sign of liver damage due to multiplicity of causes (viruses, toxins, autoimmunity, metabolic disorders). In rare cases the origin of this alteration remains unknown. We have identified by the first time in a young patient and his only sister a familiar genetic defect of an enzyme called ACOX2, which participates in the transformation of cholesterol into bile acids as a cause of increased serum transaminases in the absence of any other symptomatology. This treatable condition should be considered in the diagnosis of those patients where the cause of elevated transaminases remains obscure.

Research paper thumbnail of Causes of hOCT 1‐dependent cholangiocarcinoma resistance to sorafenib and sensitization by tumor‐selective gene therapy

Research paper thumbnail of ACOX2 deficiency-induced liver fragility (ADILF), a not-so-rare inborn error in bile acid metabolism that responds to ursodeoxycholic acid treatment

Research paper thumbnail of Identificación de un nuevo defecto genético del metabolismo de los ácidos biliares: deficiencia de la enzima ACOX2. Bases moleculares, fisiopatología e implicación en el daño hepatocelular idiopático

[ES] Los ácidos biliares desempeñan un papel determinante en la función digestiva y excretora del... more [ES] Los ácidos biliares desempeñan un papel determinante en la función digestiva y excretora del hígado, pero, además, son importantes moléculas de señalización implicadas en la regulación del metabolismo energético y de los procesos inflamatorios y regenerativos del hígado. Existe una gran variedad de patologías asociadas a fallos en el metabolismo de los ácidos biliares. Se trata, en la mayor parte de los casos, de afecciones muy graves y poco frecuentes, que no sólo afectan al tejido hepático, sino que pueden acompañarse también de trastornos neurológicos, renales y endocrinos debido a la acumulación de metabolitos intermediarios con potencial toxicidad. En esta Tesis Doctoral se describe y estudia el caso de un paciente adolescente con hipertransaminasemia idiopática persistente. Tras descartar las patologías asociadas a daño hepático más comunes, el análisis genético permitió identificar una mutación (c.673C>T) en la región codificante del gen ACOX2, cuyo producto es la variante R225W de la enzima implicada en la síntesis de novo de los ácidos biliares acil-CoA oxidasa 2 (ACOX2). Los estudios funcionales en modelos celulares in vitro revelaron que la mutación causa una reducción de la actividad de esta enzima peroxisomal que acarrea una deficiencia de ácidos biliares maduros y la acumulación de metabolitos intermediarios tóxicos, capaces de inducir estrés oxidativo y de retículo endoplásmico. Los resultados del estudio sugieren que la deficiencia parcial de ACOX2 (APD) podría ser un trastorno más frecuente que las patologías asociadas al metabolismo de los ácidos biliares descritas hasta ahora y estar implicada en la etiología de otros casos de hipertransaminasemia persistente de causa no filiada, así como constituir un factor predisponente a la toxicidad por fármacos. Asimismo, la deficiencia de ACOX2 podría agravar la progresión de enfermedades hepáticas comunes que cursan con inflamación, como la esteatohepatitis no alcohólica. En esta Tesis Doctoral se ha desarrollado un modelo animal “avatar” de la enfermedad, mediante la edición del genoma del ratón con CRISPR/Cas9. Esta valiosa herramienta permitirá el desarrollo de nuevos estudios que ayudarán a caracterizar la fisiopatología de la APD, a evaluar nuevos tratamientos terapéuticos y a determinar el papel de ACOX2 en otras patologías hepáticas

Research paper thumbnail of Pathophysiological Mechanisms in Non-Alcoholic Fatty Liver Disease: From Drivers to Targets

Biomedicines, 2021

Non-alcoholic fatty liver disease (NAFLD) is characterized by the excessive and detrimental accum... more Non-alcoholic fatty liver disease (NAFLD) is characterized by the excessive and detrimental accumulation of liver fat as a result of high-caloric intake and/or cellular and molecular abnormalities. The prevalence of this pathological event is increasing worldwide, and is intimately associated with obesity and type 2 diabetes mellitus, among other comorbidities. To date, only therapeutic strategies based on lifestyle changes have exhibited a beneficial impact on patients with NAFLD, but unfortunately this approach is often difficult to implement, and shows poor long-term adherence. For this reason, great efforts are being made to elucidate and integrate the underlying pathological molecular mechanism, and to identify novel and promising druggable targets for therapy. In this regard, a large number of clinical trials testing different potential compounds have been performed, albeit with no conclusive results yet. Importantly, many other clinical trials are currently underway with resu...

Research paper thumbnail of Immune Assessment of BNT162b2 m-RNA-Spike Based Vaccine Response in Adults

Biomedicines, 2021

Vaccine efficacy is based on clinical data. Currently, the assessment of immune response after SA... more Vaccine efficacy is based on clinical data. Currently, the assessment of immune response after SARS-CoV-2 vaccination is scarce. A total of 52 healthcare workers were immunized with the same lot of BNT162b2 vaccine. The immunological response against the vaccine was tested using a T-specific assay based on the expression of CD25 and CD134 after stimulation with anti-N, -S, and -M specific peptides of SARS-CoV-2. Moreover, IgG anti-S2 and -RBD antibodies were detected using ELISA. Furthermore, the cell subsets involved in the response to the vaccine were measured in peripheral blood by flow cytometry. Humoral-specific responses against the vaccine were detected in 94% and 100% after the first and second doses, respectively. Therefore, anti-S T-specific responses were observed in 57% and 90% of the subjects after the first and second doses of the vaccine, respectively. Thirty days after the second dose, significant increases in T helper 1 memory cells (p < 0.001), peripheral memory...

Research paper thumbnail of Resumen de tesis. Identificación de un nuevo defecto genético del metabolismo de los ácidos biliares: deficiencia de la enzima ACOX2. Bases moleculares, fisiopatología e implicación en el daño hepatocelular idiopático

Los acidos biliares desempenan un papel determinante en la funcion digestiva y excretora del higa... more Los acidos biliares desempenan un papel determinante en la funcion digestiva y excretora del higado, pero, ademas, son importantes moleculas de senalizacion implicadas en la regulacion del metabolismo energetico y de los procesos inflamatorios y regenerativos del higado. Existe una gran variedad de patologias asociadas a fallos en el metabolismo de los acidos biliares. Se trata, en la mayor parte de los casos, de afecciones muy graves y poco frecuentes, que no solo afectan al tejido hepatico, sino que pueden acompanarse tambien de trastornos neurologicos, renales y endocrinos debido a la acumulacion de metabolitos intermediarios con potencial toxicidad. En esta Tesis Doctoral se describe y estudia el caso de un paciente adolescente con hipertransaminasemia idiopatica persistente. Tras descartar las patologias asociadas a dano hepatico mas comunes, el analisis genetico permitio identificar una mutacion (c.673C>T) en la region codificante del gen ACOX2, cuyo producto es la variante...

Research paper thumbnail of Suppression of bile acid-CoA:amino acid N-acyltransferase gene expression by Oncostatin M

36. Jahrestagung der Deutschen Arbeitsgemeinschaft zum Studium der Leber, 2020

Research paper thumbnail of Suppression of bile acid-CoA:amino acid N-acyltransferase gene expression by the interleukin-6-type cytokine Oncostatin M

35. Jahrestagung der Deutschen Arbeitsgemeinschaft zum Studium der Leber, 2019

Research paper thumbnail of Myeloid-derived suppressor cells are increased in frequency but not maximally suppressive in peripheral blood of Type 1 Diabetes Mellitus patients

Clinical Immunology, 2014

Myeloid-derived suppressor cells (MDSCs) have been identified in the majority of patients and exp... more Myeloid-derived suppressor cells (MDSCs) have been identified in the majority of patients and experimental mice with tumors by their suppression of T cell activation. MDSCs have also been reported to be associated with chronic inflammation. In advanced cancer, the T helper (Th) cell balance tends to shift from Th1 to Th2 predominance, and immune function, including cell-mediated immunity, is impaired by cytokines produced by Th2 cells. The present study examined the correlations between MDSC levels and inflammation, immune suppression, malnutrition, and poor prognosis in 155 patients with breast cancer. The levels of MDSCs in preoperative patients and in patients with recurrent breast cancer were significantly higher compared with postoperative patients, patients with recurrent breast cancer who received chemotherapy and healthy volunteers. The MDSC levels of preoperative patients were significantly positively correlated with interleukin (IL)-6 production by peripheral blood mononuclear cells (PBMCs), the neutrophil/lymphocyte ratio and C-reactive protein, and were negatively correlated with the production of interferon-γ and IL-12, serum concentration of rapid turnover protein, and the stimulation index. These patients were divided into two groups based on the levels of MDSCs. In preoperative patients with MDSC levels >1.0% of total PBMCs, the overall survival of patients with stage IV disease was significantly shorter compared with other disease stages, and was also significantly shorter compared with patients with MDSC levels <1.0% of total PBMCs. Thus, the MDSC levels of preoperative patients may function as a good prognostic indicator, particularly in patients with advanced breast cancer.

Research paper thumbnail of Beneficial effect of ursodeoxycholic acid in patients with acyl‐CoA oxidase 2 (ACOX2) deficiency–associated hypertransaminasemia

Hepatology

BACKGROUND A variant (p.Arg225Trp) of peroxisomal acyl-CoA oxidase 2 (ACOX2), involved in bile ac... more BACKGROUND A variant (p.Arg225Trp) of peroxisomal acyl-CoA oxidase 2 (ACOX2), involved in bile acid (BA) side-chain shortening, has been associated with unexplained persistent hypertransaminasemia and accumulation of C27-BAs, mainly trihydroxycholestanoic acid (THCA). AIMS To investigate the prevalence of ACOX2 deficiency-associated hypertransaminasemia (ADAH), its response to ursodeoxycholic acid (UDCA), elucidate its pathophysiological mechanism and identify other inborn errors that could cause this alteration. METHODS & RESULTS Among 33 patients with unexplained hypertransaminasemia from 11 hospitals, and 13 of their relatives, 7 individuals with abnormally high C27-BA levels (>50% of total BAs) were identified by HPLC-MS/MS. The p.Arg225Trp variant was found in homozygosity (exon amplification/sequencing) in 2 patients and 3 family members. Two additional non-related patients were heterozygous carriers of different alleles: c.673C>T (p.Arg225Trp) and c.456_459del (p.Thr154fs). In ADAH patients, impaired liver expression of ACOX2, but not ACOX3, was found (immunohistochemistry). Treatment with UDCA normalized transaminases levels. Incubation of HuH-7 liver cells with THCA, which was efficiently taken up, but not through BA transporters, increased ROS production (flow cytometry), ER stress biomarkers (GRP78, CHOP and XBP1-S/XBP1-U ratio), and BAXα expression (RT-qPCR and immunoblot), whereas cell viability was decreased (MTT). THCA-induced cell toxicity was higher than that of major C24-BAs and was not prevented by UDCA. Fourteen predicted ACOX2 variants were generated (site-directed mutagenesis) and expressed in HuH-7 cells. Functional tests to determine their ability to metabolize THCA identified six with the potential to cause ADAH. CONCLUSION Dysfunctional ACOX2 has been found in several patients with unexplained hypertransaminasemia. This condition can be accurately identified by a non-invasive diagnostic strategy based on plasma BA profiling and ACOX2 sequencing. Moreover, UDCA treatment can efficiently attenuate liver damage in these patients.

Research paper thumbnail of The absence of OCT1 at the plasma membrane of tumor cells is associated with a worse response of hepatocellular carcinoma to sorafenib

Research paper thumbnail of Innate and Adaptive Immune Assessment at Admission to Predict Clinical Outcome in COVID-19 Patients

Biomedicines

During the COVID-19 pandemic, many studies have been carried out to evaluate different immune sys... more During the COVID-19 pandemic, many studies have been carried out to evaluate different immune system components to search for prognostic biomarkers of the disease. A broad multiparametric antibody panel of cellular and humoral components of the innate and the adaptative immune response in patients with active SARS-CoV-2 infection has been evaluated in this study. A total of 155 patients were studied at admission into our center and were categorized according to the requirement of oxygen therapy as mild or severe (the latter being those with the requirement). The patients with severe disease were older and had high ferritin, D-dimer, C-reactive protein, troponin, interleukin-6 (IL-6) levels, and neutrophilia with lymphopenia at admission. Moreover, the patients with mild symptoms had significantly increased circulating non-classical monocytes, innate lymphoid cells, and regulatory NK cells. In contrast, severe patients had a low frequency of Th1 and regulatory T cells with increased ...

Research paper thumbnail of Innate and Adaptive Immunity Alterations in Metabolic Associated Fatty Liver Disease and Its Implication in COVID-19 Severity

Frontiers in Immunology

The coronavirus infectious disease 2019 (COVID-19) pandemic has hit the world, affecting health, ... more The coronavirus infectious disease 2019 (COVID-19) pandemic has hit the world, affecting health, medical care, economies and our society as a whole. Furthermore, COVID-19 pandemic joins the increasing prevalence of metabolic syndrome in western countries. Patients suffering from obesity, type II diabetes mellitus, cardiac involvement and metabolic associated fatty liver disease (MAFLD) have enhanced risk of suffering severe COVID-19 and mortality. Importantly, up to 25% of the population in western countries is susceptible of suffering from both MAFLD and COVID-19, while none approved treatment is currently available for any of them. Moreover, it is well known that exacerbated innate immune responses are key in the development of the most severe stages of MAFLD and COVID-19. In this review, we focus on the role of the immune system in the establishment and progression of MAFLD and discuss its potential implication in the development of severe COVID-19 in MAFLD patients. As a result,...

Research paper thumbnail of Role of transportome in the pharmacogenomics of hepatocellular carcinoma and hepatobiliary cancer

Pharmacogenomics

An important factor determining the pharmacological response to antitumor drugs is their concentr... more An important factor determining the pharmacological response to antitumor drugs is their concentrations in cancer cells, which accounts for the net interaction with their intracellular molecular targets. Accordingly, mechanisms leading to reduced intracellular levels of active agents play a crucial role in cancer chemoresistance. These include impaired drug uptake through solute carrier (SLC) proteins and efficient drug export by ATP-dependent pumps belonging to the ATP-binding cassette (ABC) superfamily of proteins. Since the net movement of drugs in-and-out the cells depends on the overall expression of carrier proteins, defining the so-called transportome, special attention has been devoted to the study of transcriptome regarding these proteins. Nevertheless, genetic variants affecting SLC and ABC genes may markedly affect the bioavailability and, hence, the efficacy of anticancer drugs.

Research paper thumbnail of Pharmacogenetics of hepatocellular carcinoma and cholangiocarcinoma

Cancer Drug Resistance

Primary liver cancers constitute the fourth most deadly group of cancers. Their poor prognosis is... more Primary liver cancers constitute the fourth most deadly group of cancers. Their poor prognosis is due in part to the pre-existence and/or development, often during treatment, of powerful mechanisms accounting for the poor response of cancer cells to antitumor drugs. These include both impaired gene expression and the appearance of spliced variants, polymorphisms and mutations, affecting the function of genes leading to the reduction in intracellular concentrations of active agents, changes in molecular targets and survival pathways, altered tumor microenvironment and phenotypic transition. The present review summarizes available information regarding the role of germline and somatic mutations affecting drug transporters, enzymes involved in drug metabolism, organelles and signaling molecules related to liver cancer chemoresistance. A more complete picture of the actual complexity of this problem is urgently needed for carrying out further pharmacogenomic studies aimed to improve the management of patients suffering from hepatocellular carcinoma or cholangiocarcinoma.

Research paper thumbnail of FRI-422-Genetic and pathophysiological factors leading to deficient acyl-CoA oxidase 2 (ACOX2) activity in hepatocytes, an alteration which causes oxidative and endoplasmic reticulum stress in liver cells

Research paper thumbnail of ACOX2 deficiency: An inborn error of bile acid synthesis identified in an adolescent with persistent hypertransaminasemia

Journal of Hepatology, 2016

Acyl-CoA oxidase (ACOX2) is involved in the shortening of C27 cholesterol derivatives to generate... more Acyl-CoA oxidase (ACOX2) is involved in the shortening of C27 cholesterol derivatives to generate C24 bile acids. Inborn errors affecting the rest of peroxisomal enzymes involved in bile acid biosynthesis have been described. Here we aimed at investigating the case of an adolescent boy with persistent hypertransaminasemia of unknown origin and suspected dysfunction in bile acid metabolism. Serum and urine samples were taken from the patient, his sister and parents and underwent HPLC-MS/MS and HPLC-TOF analyses. Coding exons in genes of interest were amplified by high-fidelity PCR and sequenced. Wild-type or mutated (mutACOX2) variants were overexpressed in human hepatoblastoma HepG2 cells to determine ACOX2 enzymatic activity, expression and subcellular location. The patient&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s serum and urine showed negligible amounts of C24 bile acids, but augmented levels of C27 intermediates, mainly tauroconjugated trihydroxycholestanoic acid (THCA). Genetic analysis of enzymes potentially involved revealed a homozygous missense mutation (c.673C&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;T; R225W) in ACOX2. His only sister was also homozygous for this mutation and exhibited similar alterations in bile acid profiles. Both parents were heterozygous and presented normal C24 and C27 bile acid levels. Immunofluorescence studies showed similar protein size and peroxisomal localization for both normal and mutated variants. THCA biotransformation into cholic acid was enhanced in cells overexpressing ACOX2, but not in those overexpressing mutACOX2. Both cell types showed similar sensitivity to oxidative stress caused by C24 bile acids. In contrast, THCA-induced oxidative stress and cell death were reduced by overexpressing ACOX2, but not mutACOX2. ACOX2 deficiency, a condition characterized by accumulation of toxic C27 bile acid intermediates, is a novel cause of isolated persistent hypertransaminasemia. Elevation of serum transaminases is a biochemical sign of liver damage due to multiplicity of causes (viruses, toxins, autoimmunity, metabolic disorders). In rare cases the origin of this alteration remains unknown. We have identified by the first time in a young patient and his only sister a familiar genetic defect of an enzyme called ACOX2, which participates in the transformation of cholesterol into bile acids as a cause of increased serum transaminases in the absence of any other symptomatology. This treatable condition should be considered in the diagnosis of those patients where the cause of elevated transaminases remains obscure.

Research paper thumbnail of Causes of hOCT 1‐dependent cholangiocarcinoma resistance to sorafenib and sensitization by tumor‐selective gene therapy