Publications by authors named "Jordi Muntané"

126 Publications

Inhibition of the NLRP3 inflammasome prevents ovarian aging.

Sci Adv 2021 Jan 1;7(1). Epub 2021 Jan 1.

Cátedra de Reproducción y Genética Humana del Instituto para el Estudio de la Biología de la Reproducción Humana (INEBIR)-Universidad Europea del Atlántico (UNEATLANTICO)-Fundación Universitaria Iberoamericana (FUNIBER), Seville, Spain.

Inflammation is a hallmark of aging and is negatively affecting female fertility. In this study, we evaluate the role of the NLRP3 inflammasome in ovarian aging and female fertility. Age-dependent increased expression of NLRP3 in the ovary was observed in WT mice during reproductive aging. High expression of NLRP3, caspase-1, and IL-1β was also observed in granulosa cells from patients with ovarian insufficiency. Ablation of NLRP3 improved the survival and pregnancy rates and increased anti-Müllerian hormone levels and autophagy rates in ovaries. Deficiency of NLRP3 also reduced serum FSH and estradiol levels. Consistent with these results, pharmacological inhibition of NLRP3 using a direct NLRP3 inhibitor, MCC950, improved fertility in female mice to levels comparable to those of mice. These results suggest that the NLRP3 inflammasome is implicated in the age-dependent loss of female fertility and position this inflammasome as a potential new therapeutic target for the treatment of infertility.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/sciadv.abc7409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775749PMC
January 2021

Integrated molecular signaling involving mitochondrial dysfunction and alteration of cell metabolism induced by tyrosine kinase inhibitors in cancer.

Redox Biol 2020 09 23;36:101510. Epub 2020 May 23.

Institute of Biomedicine of Seville (IBiS), IBiS/Hospital University "Virgen del Rocío"/CSIC/University of Seville, Seville, Spain; Centro de Investigación Biomédica en red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain; Department of General Surgery, Hospital University "Virgen del Rocío"/IBiS/CSIC/University of Seville, Seville, Spain. Electronic address:

Cancer cells have unlimited replicative potential, insensitivity to growth-inhibitory signals, evasion of apoptosis, cellular stress, and sustained angiogenesis, invasiveness and metastatic potential. Cancer cells adequately adapt cell metabolism and integrate several intracellular and redox signaling to promote cell survival in an inflammatory and hypoxic microenvironment in order to maintain/expand tumor phenotype. The administration of tyrosine kinase inhibitor (TKI) constitutes the recommended therapeutic strategy in different malignancies at advanced stages. There are important interrelationships between cell stress, redox status, mitochondrial function, metabolism and cellular signaling pathways leading to cell survival/death. The induction of apoptosis and cell cycle arrest widely related to the antitumoral properties of TKIs result from tightly controlled events involving different cellular compartments and signaling pathways. The aim of the present review is to update the most relevant studies dealing with the impact of TKI treatment on cell function. The induction of endoplasmic reticulum (ER) stress and Ca disturbances, leading to alteration of mitochondrial function, redox status and phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt)-mammalian target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) signaling pathways that involve cell metabolism reprogramming in cancer cells will be covered. Emphasis will be given to studies that identify key components of the integrated molecular pattern including receptor tyrosine kinase (RTK) downstream signaling, cell death and mitochondria-related events that appear to be involved in the resistance of cancer cells to TKI treatments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.redox.2020.101510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322178PMC
September 2020

Mechanisms of action of metformin in type 2 diabetes: Effects on mitochondria and leukocyte-endothelium interactions.

Redox Biol 2020 07 25;34:101517. Epub 2020 May 25.

CIBERehd (Biomedical Research Networking Centre on Hepatic and Digestive Diseases), Valencia, Spain; Service of Endocrinology and Nutrition. University Hospital Doctor Peset, FISABIO, Valencia, Spain; Department of Physiology, University of Valencia, Valencia, Spain. Electronic address:

Type 2 diabetes (T2D) is a very prevalent, multisystemic, chronic metabolic disorder closely related to atherosclerosis and cardiovascular diseases. It is characterised by mitochondrial dysfunction and the presence of oxidative stress. Metformin is one of the safest and most effective anti-hyperglycaemic agents currently employed as first-line oral therapy for T2D. It has demonstrated additional beneficial effects, unrelated to its hypoglycaemic action, on weight loss and several diseases, such as cancer, cardiovascular disorders and metabolic diseases, including thyroid diseases. Despite the vast clinical experience gained over several decades of use, the mechanism of action of metformin is still not fully understood. This review provides an overview of the existing literature concerning the beneficial mitochondrial and vascular effects of metformin, which it exerts by diminishing oxidative stress and reducing leukocyte-endothelium interactions. Specifically, we describe the molecular mechanisms involved in metformin's effect on gluconeogenesis, its capacity to interfere with major metabolic pathways (AMPK and mTORC1), its action on mitochondria and its antioxidant effects. We also discuss potential targets for therapeutic intervention based on these molecular actions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.redox.2020.101517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7296337PMC
July 2020

Downregulation of thioredoxin-1-dependent CD95 S-nitrosation by Sorafenib reduces liver cancer.

Redox Biol 2020 07 4;34:101528. Epub 2020 Apr 4.

Institute of Biomedicine of Seville (IBiS), Hospital University "Virgen Del Rocío"/CSIC/University of Seville, Seville, Spain; Department of General Surgery, Hospital University "Virgen del Rocío"/IBiS/CSIC/University of Seville, Seville, Spain; Biomedical Research Network Center for Liver and Digestive Diseases (CIBERehd), Madrid, Spain. Electronic address:

Hepatocellular carcinoma (HCC) represents 80% of the primary hepatic neoplasms. It is the sixth most frequent neoplasm, the fourth cause of cancer-related death, and 7% of registered malignancies. Sorafenib is the first line molecular targeted therapy for patients in advanced stage of HCC. The present study shows that Sorafenib exerts free radical scavenging properties associated with the downregulation of nuclear factor E2-related factor 2 (Nrf2)-regulated thioredoxin 1 (Trx1) expression in liver cancer cells. The experimental downregulation and/or overexpression strategies showed that Trx1 induced activation of nitric oxide synthase (NOS) type 3 (NOS3) and S-nitrosation (SNO) of CD95 receptor leading to an increase of caspase-8 activity and cell proliferation, as well as reduction of caspase-3 activity in liver cancer cells. In addition, Sorafenib transiently increased mRNA expression and activity of S-nitrosoglutathione reductase (GSNOR) in HepG2 cells. Different experimental models of hepatocarcinogenesis based on the subcutaneous implantation of HepG2 cells in nude mice, as well as the induction of HCC by diethylnitrosamine (DEN) confirmed the relevance of Trx1 downregulation during the proapoptotic and antiproliferative properties induced by Sorafenib. In conclusion, the induction of apoptosis and antiproliferative properties by Sorafenib were related to Trx1 downregulation that appeared to play a relevant role on SNO of NOS3 and CD95 in HepG2 cells. The transient increase of GSNOR might also participate in the deactivation of CD95-dependent proliferative signaling in liver cancer cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.redox.2020.101528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210585PMC
July 2020

Differential effectiveness of tyrosine kinase inhibitors in 2D/3D culture according to cell differentiation, p53 status and mitochondrial respiration in liver cancer cells.

Cell Death Dis 2020 05 7;11(5):339. Epub 2020 May 7.

Institute of Biomedicine of Seville (IBiS), Hospital University "Virgen del Rocío"/CSIC/University of Seville, Seville, Spain.

Sorafenib and Regorafenib are the recommended first- and second-line therapies in patients with advanced hepatocellular carcinoma (HCC). Lenvatinib and Cabozantinib have shown non-inferior antitumoral activities compared with the corresponding recommended therapies. The clinical trials have established recommended doses for each treatment that lead different blood concentrations in patients for Sorafenib (10 µM), Regorafenib (1 µM), Lenvatinib (0.1 µM), and Cabozantinib (1 µM). However, very low response rates are observed in patients attributed to intrinsic resistances or upregulation of survival signaling. The aim of the study was the comparative dose-response analysis of the drugs (0-100 µM) in well-differentiated (HepG2, Hep3B, and Huh7), moderately (SNU423), and poorly (SNU449) differentiated liver cancer cells in 2D/3D cultures. Cells harbors wild-type p53 (HepG2), non-sense p53 mutation (Hep3B), inframe p53 gene deletion (SNU423), and p53 point mutation (Huh7 and SNU449). The administration of regular used in vitro dose (10 µM) in 3D and 2D cultures, as well as the dose-response analysis in 2D cultures showed Sorafenib and Regorafenib were increasingly effective in reducing cell proliferation, and inducing apoptosis in well-differentiated and expressing wild-type p53 in HCC cells. Lenvatinib and Cabozantinib were particularly effective in moderately to poorly differentiated cells with mutated or lacking p53 that have lower basal oxygen consumption rate (OCR), ATP, and maximal respiration capacity than observed in differentiated HCC cells. Sorafenib and Regorafenib downregulated, and Lenvatinib and Cabozantinib upregulated epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition factor receptor (c-Met) in HepG2 cells. Conclusions: Sorafenib and Regorafenib were especially active in well-differentiated cells, with wild-type p53 and increased mitochondrial respiration. By contrast, Lenvatinib and Cabozantinib appeared more effective in moderately to poorly differentiated cells with mutated p53 and low mitochondrial respiration. The development of strategies that allow us to deliver increased doses in tumors might potentially enhance the effectiveness of the treatments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41419-020-2558-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7206079PMC
May 2020

Molecular Pathways Leading to Induction of Cell Death and Anti-Proliferative Properties by Tacrolimus and mTOR Inhibitors in Liver Cancer Cells.

Cell Physiol Biochem 2020 05;54(3):457-473

Institute of Biomedicine of Seville (IBiS), Hospital University "Virgen del Rocío"/CSIC/University of Seville, Seville, Spain,

Background/aims: Orthotopic liver transplantation (OLT) is the recommended treatment for patients at early stages of hepatocarcinoma (HCC) with portal hypertension and/or increased bilirubinemia, but without vascular-associated diseases. Tumor recurrence, which is the main drawback for the survival of patients submitted to OLT for HCC, has been related to tumor-related variables and the immunosuppressive therapies. We have previously shown that Tacrolimus (FK506) exerts a more potent pro-apoptotic and anti-proliferative effects than the mammalian target of rapamycin (mTOR) inhibitors (Sirolimus and Everolimus) in liver cancer cells. This study identified the role of the immunosuppressant partners such as FK506-binding proteins (FKBPs) in the induction of cell death and arrest of cell proliferation by immunosuppressants in two representative liver cancer cells.

Methods: The regulation of endoplasmic reticulum (ER) stress, apoptosis/autophagy, cell proliferation, and FKBPs expression was determined in Tacrolimus-, Sirolimus- and Everolimus-treated primary human hepatocytes, and hepatoma HepG2 and Huh7 cell lines. The functional repercussion of FKBPs on cell death and proliferation was also addressed using the siRNA technology. The assessed antitumoral properties of the immunosuppressants were associated to microRNAs (miRNAs) pattern.

Results: The enhanced pro-apoptotic and anti-proliferative properties of Tacrolimus versus mTOR inhibitors were associated with increased protein kinase RNA-like endoplasmic reticulum kinase (PERK)-related ER stress, P-p53/p53 ratio and p21 protein expression that may counterbalance the risk of proliferative upregulation caused by enhanced P-Cdk4/Cdk4 activation in liver cancer cells. The inhibition of the mTOR pathway by Sirolimus and Everolimus was related to an induction of autophagy; and at a high dose, these drugs impaired translation likely at a very early step of the elongation phase. Tacrolimus and mTOR inhibitors increased the protein expression of FKBP12 and FKBP51 that appeared to play pro-survival role. Interestingly, the administration of immunosuppressants yields a specific pattern of miRNAs. Tacrolimus and mTOR inhibitors decreased miR-92a-1-5p, miR-197-3p, miR-483-3p and miR-720, and increased miR-22-3p, miR-376a-3p, miR-663b, miR-886-5p, miR-1300 and miR-1303 expressions in HepG2 cells.

Conclusion: The more potent pro-apoptotic and anti-proliferative properties of Tacrolimus versus mTOR inhibitors were associated with an increased activation of PERK and p53 signaling, and p21 protein expression. FKBP12 and FKBP51 appeared to be the most relevant partners of Tacrolimus and mTOR inhibitors exerting a pro-survival effect in HepG2 cells. The observed effects of immunosuppressants were related to a specific miRNA signature in liver cancer cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.33594/000000230DOI Listing
May 2020

Mitochondria and T2D: Role of Autophagy, ER Stress, and Inflammasome.

Trends Endocrinol Metab 2020 10 4;31(10):725-741. Epub 2020 Apr 4.

Service of Endocrinology, University Hospital Doctor Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), Valencia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain; Department of Physiology, University of Valencia, Valencia, Spain. Electronic address:

Type 2 diabetes (T2D) is one of the main current threats to human health. Both T2D and its numerous clinical complications are related to mitochondrial dysfunction and oxidative stress. Over the past decade, great progress has been made in extending our knowledge about the signaling events regulated by mitochondria. However, the links among mitochondrial impairment, oxidative stress, autophagy, endoplasmic reticulum (ER) stress, and activation of the inflammasome still need to be clarified. In light of this deficit, we aim to provide a review of the existing literature concerning the complicated crosstalk between mitochondrial impairment, autophagy, ER stress, and the inflammasome in the molecular pathogenesis of T2D.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.tem.2020.03.004DOI Listing
October 2020

Assessing Autophagy in Archived Tissue or How to Capture Autophagic Flux from a Tissue Snapshot.

Biology (Basel) 2020 Mar 21;9(3). Epub 2020 Mar 21.

TRANSAUTOPHAGY: European Network for Multidisciplinary Research and Translation of Autophagy Knowledge, COST Action CA15138, 08193 Barcelona, Spain.

Autophagy is a highly conserved degradation mechanism that is essential for maintaining cellular homeostasis. In human disease, autophagy pathways are frequently deregulated and there is immense interest in targeting autophagy for therapeutic approaches. Accordingly, there is a need to determine autophagic activity in human tissues, an endeavor that is hampered by the fact that autophagy is characterized by the flux of substrates whereas histology informs only about amounts and localization of substrates and regulators at a single timepoint. Despite this challenging task, considerable progress in establishing markers of autophagy has been made in recent years. The importance of establishing clear-cut autophagy markers that can be used for tissue analysis cannot be underestimated. In this review, we attempt to summarize known techniques to quantify autophagy in human tissue and their drawbacks. Furthermore, we provide some recommendations that should be taken into consideration to improve the reliability and the interpretation of autophagy biomarkers in human tissue samples.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/biology9030059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7150830PMC
March 2020

Dose-dependent regulation of mitochondrial function and cell death pathway by sorafenib in liver cancer cells.

Biochem Pharmacol 2020 06 7;176:113902. Epub 2020 Mar 7.

Institute of Biomedicine of Seville (IBIS), IBiS/Hospital University "Virgen del Rocío"/CSIC/University of Seville, Seville, Spain; CENTRO DE INVESTIGACIÓN BIOMÉDICA EN RED de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain; COST-European Cooperation in Science & Technology, Mitoeagle Action number: CA15203, Brussels, Belgium; Department of General Surgery, "Virgen del Rocío" University Hospital/IBiS/CSIC/University of Seville, Seville, Spain. Electronic address:

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and the fourth most frequent cause of cancer-related death worldwide. Sorafenib is the first line recommended therapy for patients with locally advanced/metastatic HCC. The low response rate is attributed to intrinsic resistance of HCC cells to Sorafenib. The potential resistance to Sorafenib-induced cell death is multifactorial and involves all hallmarks of cancer. However, the presence of sub-therapeutic dose can negatively influence the antitumoral properties of the drug. In this sense, the present study showed that the sub-optimal Sorafenib concentration (10 nM) was associated with activation of caspase-9, AMP-activated protein kinase (AMPK), sustained autophagy, peroxisome proliferator-activated receptor-coactivator 1α (PGC-1α) and mitochondrial function in HepG2 cells. The increased mitochondrial respiration by Sorafenib (10 nM) was also observed in permeabilized HepG2 cells, but not in isolated rat mitochondria, which suggests the involvement of an upstream component in this regulatory mechanism. The basal glycolysis was dose dependently increased at early time point studied (6 h). Interestingly, Sorafenib increased nitric oxide (NO) generation that played an inhibitory role in mitochondrial respiration in sub-therapeutic dose of Sorafenib. The administration of sustained therapeutic dose of Sorafenib (10 µM, 24 h) induced mitochondrial dysfunction and dropped basal glycolysis derived acidification, as well as increased oxidative stress and apoptosis in HepG2. In conclusion, the accurate control of the administered dose of Sorafenib is relevant for the potential prosurvival or proapoptotic properties induced by the drug in liver cancer cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bcp.2020.113902DOI Listing
June 2020

Thioredoxin Downregulation Enhances Sorafenib Effects in Hepatocarcinoma Cells.

Antioxidants (Basel) 2019 Oct 22;8(10). Epub 2019 Oct 22.

Department of Biochemistry and Molecular Biology, University of Córdoba, 14071 Córdoba, Spain.

Sorafenib is the first-line recommended therapy for patients with advanced hepatocarcinoma (HCC) in de-differentiation stage (presenting epithelial-mesenchymal transition, EMT). We studied the role of the thioredoxin system (Trx1/TrxR1) in the sensitivity or resistance of HCC cells to the treatment with Sorafenib. As a model, we used a set of three established HCC cell lines with different degrees of de-differentiation as occurs in metastasis. By quantitative proteomics, we found that the expression levels of Trx1 and TrxR1 followed the same trend as canonical EMT markers in these cell lines. Treatment with Sorafenib induced thiol redox reductive changes in critical elements of oncogenic pathways in all three cell lines but induced drastic proteome reprograming only in HCC cell lines of intermediate stage. Trx1 downregulation counteracted the thiol reductive effect of Sorafenib on Signal Transducer and Activator of Transcription 3 (STAT3) but not on Mitogen-Activated Protein Kinase (MAPK) or Protein Kinase B (Akt) and transformed advanced HCC cells into Sorafenib-sensitive cells. Ten targets of the combined Sorafenib-siRNATrx1 treatment were identified that showed a gradually changing expression trend in parallel to changes in the expression of canonical EMT markers, likely as a result of the activation of Hippo signaling. These findings support the idea that a combination of Sorafenib with thioredoxin inhibitors should be taken into account in the design of therapies against advanced HCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/antiox8100501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826379PMC
October 2019

NLRP3 Inflammasome Inhibition by MCC950 in Aged Mice Improves Health via Enhanced Autophagy and PPARα Activity.

J Gerontol A Biol Sci Med Sci 2020 07;75(8):1457-1464

Institute of Nutrition and Food Technology "José Mataix Verdú", Department of Physiology, Biomedical Research Center, University of Granada, Spain.

The NLRP3 inflammasome has emerged as an important regulator of metabolic disorders and age-related diseases in NLRP3-deficient mice. In this article, we determine whether, in old mice C57BL6J, the NLRP3 inflammasome inhibitor MCC950 is able to attenuate age-related metabolic syndrome to providing health benefits. We report that MCC950 attenuates metabolic and hepatic dysfunction in aged mice. In addition, MCC950 inhibited the Pi3K/AKT/mTOR pathway, enhanced autophagy, and activated peroxisome proliferator-activated receptor-α in vivo and in vitro. The data suggest that MCC950 mediates the protective effects by the mammalian target of rapamycin inhibition, thus activating autophagy and peroxisome proliferator-activated receptor-α. In conclusion, pharmacological inhibition of NLRP3 in aged mice has a significant impact on health. Thus, NLRP3 may be a therapeutic target of human age-related metabolic syndrome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/gerona/glz239DOI Listing
July 2020

Nanostructured fibrin agarose hydrogel as a novel haemostatic agent.

J Tissue Eng Regen Med 2019 04 20;13(4):664-673. Epub 2019 Mar 20.

Instituto de Biomedicina de Sevilla, IBIS (HUVR/CSIC/Universidad de Sevilla, Junta de Andalucía), Spain.

Blood loss remains a major concern during surgery and can increase the morbidity of the intervention. The use of topical haemostatic agents to overcome this issue therefore becomes necessary. Fibrin sealants are promising haemostatic agents due to their capacity to promote coagulation, but their effectiveness and applicability need to be improved. We have compared the haemostatic efficacy of a novel nanostructured fibrin-agarose hydrogel patch, with (c-NFAH) or without cells (a-NFAH), against two commercially available haemostatic agents in a rat model of hepatic resection. Hepatic resections were performed by making short or long incisions (mild or severe model, respectively), and haemostatic agents were applied to evaluate time to haemostasis, presence of haematoma, post-operative adhesions to adjacent tissues, and inflammation factors. We found a significantly higher haemostatic success rate (time to haemostasis) with a-NFAH than with other commercial haemostatic agents. Furthermore, other relevant outcomes investigated were also improved in the a-NFAH group, including no presence of haematoma, lower adhesions, and lower grades of haemorrhage, inflammation, and necrosis in histological analysis. Overall, these findings identify a-NFAH as a promising haemostatic agent in liver resection and likely in a range of surgical procedures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/term.2831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594136PMC
April 2019

Differential effects of metformin glycinate and hydrochloride in glucose production, AMPK phosphorylation and insulin sensitivity in hepatocytes from non-diabetic and diabetic mice.

Food Chem Toxicol 2019 Jan 9;123:470-480. Epub 2018 Nov 9.

Instituto de Investigaciones Biomédicas Alberto Sols (IIBm) (CSIC/UAM), C/ Arturo Duperier 4, 28029, Madrid, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERdem), ISCIII, 28029 Madrid, Spain. Electronic address:

The liver is a main target tissue of the biguanide metformin which activates AMP-activated protein kinase (AMPK). We previously reported that administration of metformin glycinate showed a greater decrease of glycated hemoglobin A1c than a placebo in patients with type 2 diabetes mellitus (T2DM). In this study, we compared the effects of metformin hydrochloride, the oral antidiabetic drug of first choice, with those of metformin glycinate in hepatocytes from non-diabetic and diabetic mice and humans. Both formulations were equally potent regard to the reduction of basal and glucagon-induced glucose production and mRNA levels of gluconeogenic enzymes (Pck1 and G6pc) in hepatocytes from C57/Bl6 mice and humans. On the contrary, phosphorylation of AMPK and its substrate acetyl CoA carboxylase (ACC) was faster in hepatocytes treated with metformin glycinate. Likewise, we found stronger reduction in hepatocytes from obese/diabetic db/db mice of glucagon-induced glucose output and more sustained AMPK phosphorylation after treatment with metformin glycinate. Importantly, insulin sensitization regarding phosphorylation of AKT (Ser473) was enhanced in hepatocytes from db/db mice or humans pretreated with metformin glycinate. In conclusion, our data indicate that metformin glycinate may be an alternative therapy against insulin resistance during obesity and/or T2DM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.fct.2018.11.019DOI Listing
January 2019

Serum Metabolites as Diagnostic Biomarkers for Cholangiocarcinoma, Hepatocellular Carcinoma, and Primary Sclerosing Cholangitis.

Hepatology 2019 08 14;70(2):547-562. Epub 2019 Feb 14.

National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), Madrid, Spain.

Early and differential diagnosis of intrahepatic cholangiocarcinoma (iCCA) and hepatocellular carcinoma (HCC) by noninvasive methods represents a current clinical challenge. The analysis of low-molecular-weight metabolites by new high-throughput techniques is a strategy for identifying biomarkers. Here, we have investigated whether serum metabolome can provide useful biomarkers in the diagnosis of iCCA and HCC and could discriminate iCCA from HCC. Because primary sclerosing cholangitis (PSC) is a risk factor for CCA, serum metabolic profiles of PSC and CCA have also been compared. The analysis of the levels of lipids and amino acids in the serum of patients with iCCA, HCC, and PSC and healthy individuals (n = 20/group) showed differential profiles. Several metabolites presented high diagnostic value for iCCA versus control, HCC versus control, and PSC versus control, with areas under the receiver operating characteristic curve (AUC) greater than those found in serum for the nonspecific tumor markers carbohydrate antigen 19-9 (CA 19-9) and alpha-fetoprotein (AFP), commonly used to help in the diagnosis of iCCA and HCC, respectively. The development of an algorithm combining glycine, aspartic acid, SM(42:3), and SM(43:2) permitted to accurately differentiate in the diagnosis of both types of tumors (biopsy-proven). The proposed model yielded 0.890 AUC, 75% sensitivity, and 90% specificity. Another algorithm by combination of PC(34:3) and histidine accurately permitted to differentiate PSC from iCCA, with an AUC of 0.990, 100% sensitivity, and 70% specificity. These results were validated in independent cohorts of 14-15 patients per group and compared with profiles found in patients with nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Conclusion: Specific changes in serum concentrations of certain metabolites are useful to differentiate iCCA from HCC or PSC, and could help in the early diagnosis of these diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hep.30319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6767196PMC
August 2019

Molecular characterization of autophagic and apoptotic signaling induced by sorafenib in liver cancer cells.

J Cell Physiol 2018 01 21;234(1):692-708. Epub 2018 Aug 21.

Institute of Biomedicine of Seville (IBiS), Hospital University "Virgen del Rocío"/CSIC/University of Seville, Seville, Spain.

Sorafenib is the unique accepted molecular targeted drug for the treatment of patients in advanced stage of hepatocellular carcinoma. The current study evaluated cell signaling regulation of endoplasmic reticulum (ER) stress, c-Jun-N-terminal kinase (JNK), Akt, and 5'AMP-activated protein kinase (AMPK) leading to autophagy and apoptosis induced by sorafenib. Sorafenib induced early (3-12 hr) ER stress characterized by an increase of P-eIF2α/eIF2α, C/EBP homologous protein (CHOP), IRE1α, and sXBP1, but a decrease of activating transcription factor 6 expression, overall temporally associated with the increase of P-JNK1/2/JNK1/2, P-AMPKα, P-Foxo3a, P-AKt/AKt and P-Foxo3a/Foxo3a ratios, and reduction of P-mammalian target of rapamycin (mTOR)/mTOR and protein translation. This pattern was related to a transient increase of tBid, Bim , Beclin-1, Bcl-xL, Bcl-2, autophagy markers, and reduction of myeloid cell leukemia-1 (Mcl-1) expression. The progressive increase of CHOP expression, and reduction of P-AKt/AKt and P-AKt/AKt ratios were associated with the reduction of autophagic flux and an additional upregulation of Bim expression and caspase-3 activity (24 hr). Small interfering-RNA (si-RNA) assays showed that Bim, but not Bak and Bax, was involved in the induction of caspase-3 in sorafenib-treated HepG2 cells. Sorafenib increased autophagic and apoptotic markers in tumor-derived xenograft model. In conclusion, the early sorafenib-induced ER stress and regulation of JNK and AMPK-dependent signaling were related to the induction of survival autophagic process. The sustained drug treatment induced a progressive increase of ER stress and PERK-CHOP-dependent rise of Bim , which was associated with the shift from autophagy to apoptosis. The kinetic of Bim expression profile might also be related to the tight balance between AKt- and AMPK-related signaling leading to Foxo3a-dependent BIM upregulation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jcp.26855DOI Listing
January 2018

Consensus document. Management of non-alcoholic fatty liver disease (NAFLD). Clinical practice guideline.

Gastroenterol Hepatol 2018 May 7;41(5):328-349. Epub 2018 Apr 7.

UGC Aparato Digestivo, CIBERehd, Instituto de Biomedicina de Sevilla. Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Sevilla, España. Electronic address:

Non-alcoholic fatty liver disease (NAFLD) is the main cause of liver diseases in Spain and the incidence is raising due to the outbreak of type 2 diabetes and obesity. This CPG suggests recommendation about diagnosis, mainly non-invasive biomarkers, and clinical management of this entity. Life-style modifications to achieve weight loss is the main target in the management of NAFLD. Low caloric Mediterranean diet and 200 minutes/week of aerobic exercise are encouraged. In non-responders patients with morbid obesity, bariatric surgery or metabolic endoscopy could be indicated. Pharmacological therapy is indicated in patients with NASH and fibrosis and non-responders to weight loss measures. NAFLD could influence liver transplantation, as a growing indication, the impact of steatosis in the graft viability, de novo NAFLD rate after OLT and a raised cardiovascular risk that modify the management of this entity. The current CPG was the result of the First Spanish NAFLD meeting in Seville.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.gastrohep.2017.12.003DOI Listing
May 2018

Simvastatin and metformin inhibit cell growth in hepatitis C virus infected cells via mTOR increasing PTEN and autophagy.

PLoS One 2018 31;13(1):e0191805. Epub 2018 Jan 31.

Department of Digestive Disease, Biomedicine Institute of Seville & CIBERehd, Rocío University Hospital, Seville, Spain.

Hepatitis C virus (HCV) infection has been related to increased risk of development of hepatocellular carcinoma (HCC) while metformin (M) and statins treatment seemed to protect against HCC development. In this work, we aim to identify the mechanisms by which metformin and simvastatin (S) could protect from liver cancer. Huh7.5 cells were infected with HCV particles and treated with M+S. Human primary hepatocytes were treated with M+S. Treatment with both drugs inhibited Huh7.5 cell growth and HCV infection. In non-infected cells S increased translational controlled tumor protein (TCTP) and phosphatase and tensin homolog (PTEN) proteins while M inhibited mammalian target of rapamycin (mTOR) and TCTP. Simvastatin and metformin co-administered down-regulated mTOR and TCTP, while PTEN was increased. In cells infected by HCV, mTOR, TCTP, p62 and light chain 3B II (LC3BII) were increased and PTEN was decreased. S+M treatment increased PTEN, p62 and LC3BII in Huh7.5 cells. In human primary hepatocytes, metformin treatment inhibited mTOR and PTEN, but up-regulated p62, LC3BII and Caspase 3. In conclusion, simvastatin and metformin inhibited cell growth and HCV infection in vitro. In human hepatocytes, metformin increased cell-death markers. These findings suggest that M+S treatment could be useful in therapeutic prevention of HCV-related hepatocellular carcinoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0191805PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5791999PMC
March 2018

Mitochondria, the NLRP3 Inflammasome, and Sirtuins in Type 2 Diabetes: New Therapeutic Targets.

Antioxid Redox Signal 2018 09 30;29(8):749-791. Epub 2018 Jan 30.

1 Service of Endocrinology and Nutrition, University Hospital Doctor Peset , Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), Valencia, Spain .

Significance: Type 2 diabetes mellitus and hyperglycemia can lead to the development of comorbidities such as atherosclerosis and microvascular/macrovascular complications. Both type 2 diabetes and its complications are related to mitochondrial dysfunction and oxidative stress. Type 2 diabetes is also a chronic inflammatory condition that leads to inflammasome activation and the release of proinflammatory mediators, including interleukins (ILs) IL-1β and IL-18. Moreover, sirtuins are energetic sensors that respond to metabolic load, which highlights their relevance in metabolic diseases, such as type 2 diabetes. Recent Advances: Over the past decade, great progress has been made in clarifying the signaling events regulated by mitochondria, inflammasomes, and sirtuins. Nod-like receptor family pyrin domain containing 3 (NLRP3) is the best characterized inflammasome, and the generation of oxidant species seems to be critical for its activation. NLRP3 inflammasome activation and altered sirtuin levels have been observed in type 2 diabetes. Critical Issue: Despite increasing evidence of the relationship between the NLRP3 inflammasome, mitochondrial dysfunction, and oxidative stress and of their participation in type 2 diabetes physiopathology, therapeutic strategies to combat type 2 diabetes that target NLRP3 inflammasome and sirtuins are yet to be consolidated.

Future Directions: In this review article, we attempt to provide an overview of the existing literature concerning the crosstalk between mitochondrial impairment and the inflammasome, with particular attention to cellular and mitochondrial redox metabolism and the potential role of the NLRP3 inflammasome and sirtuins in the pathogenesis of type 2 diabetes. In addition, we discuss potential targets for therapeutic intervention based on these molecular interactions. Antioxid. Redox Signal. 29, 749-791.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/ars.2017.7313DOI Listing
September 2018

NLRP3-inflammasome inhibition prevents high fat and high sugar diets-induced heart damage through autophagy induction.

Oncotarget 2017 Nov 8;8(59):99740-99756. Epub 2017 Sep 8.

Institute of Nutrition and Food Technology "José Mataix Verdú", Department of Physiology, Biomedical Research Center, University of Granada, Granada, Spain.

The NLRP3-inflammasome complex has emerged as an important component of inflammatory processes in metabolic dysfunction induced by high-caloric diets. In this study, we investigate the molecular mechanisms by which NLRP3 inhibition may attenuate diet-induced cardiac injury. Here we show the cardiac damage induced by high sugar diet (HSD), high fat diet (HFD) or high sugar/fat diet (HSFD) over 15 weeks. Genetic ablation of NLRP3 protected against this damage by autophagy induction and apoptotic control. Furthermore, NLRP3 inhibition by the selective small molecule MCC950 resulted in similar autophagy induction and apoptotic control in hearts after diets. These data were reproduced in THP-1 cells treated with MCC950 and cultured in media supplemented with serum from mice dosed with MCC950 and fed with diets. NLRP3 inhibition exerted beneficial metabolic, and autophagic adaptations in hearts from obesogenic diets. The inhibition of NLRP3 activation may hold promise in the treatment of metabolic and cardiovascular diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.20763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5725128PMC
November 2017

SIRT1 Controls Acetaminophen Hepatotoxicity by Modulating Inflammation and Oxidative Stress.

Antioxid Redox Signal 2018 05 11;28(13):1187-1208. Epub 2017 Dec 11.

1 Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM) , Madrid, Spain .

Aims: Sirtuin 1 (SIRT1) is a key player in liver physiology and a therapeutic target against hepatic inflammation. We evaluated the role of SIRT1 in the proinflammatory context and oxidative stress during acetaminophen (APAP)-mediated hepatotoxicity.

Results: SIRT1 protein levels decreased in human and mouse livers following APAP overdose. SIRT1-Tg mice maintained higher levels of SIRT1 on APAP injection than wild-type mice and were protected against hepatotoxicity by modulation of antioxidant systems and restrained inflammatory responses, with decreased oxidative stress, proinflammatory cytokine messenger RNA levels, nuclear factor kappa B (NFκB) signaling, and cell death. Mouse hepatocytes stimulated with conditioned medium of APAP-treated macrophages (APAP-CM) showed decreased SIRT1 levels; an effect mimicked by interleukin (IL)1β, an activator of NFκB. This negative modulation was abolished by neutralizing IL1β in APAP-CM or silencing p65-NFκB in hepatocytes. APAP-CM of macrophages from SIRT1-Tg mice failed to downregulate SIRT1 protein levels in hepatocytes. In vivo administration of the NFκB inhibitor BAY 11-7082 preserved SIRT1 levels and protected from APAP-mediated hepatotoxicity.

Innovation: Our work evidenced the unique role of SIRT1 in APAP hepatoprotection by targeting oxidative stress and inflammation.

Conclusion: SIRT1 protein levels are downregulated by IL1β/NFκB signaling in APAP hepatotoxicity, resulting in inflammation and oxidative stress. Thus, maintenance of SIRT1 during APAP overdose by inhibiting NFκB might be clinically relevant. Rebound Track: This work was rejected during standard peer review and rescued by Rebound Peer Review (Antioxid Redox Signal 16:293-296, 2012) with the following serving as open reviewers: Rafael de Cabo, Joaquim Ros, Kalervo Hiltunen, and Neil Kaplowitz. Antioxid. Redox Signal. 28, 1187-1208.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/ars.2017.7373DOI Listing
May 2018

Regulation of Cell Survival, Apoptosis, and Epithelial-to-Mesenchymal Transition by Nitric Oxide-Dependent Post-Translational Modifications.

Antioxid Redox Signal 2018 11 22;29(13):1312-1332. Epub 2017 Sep 22.

3 Department of General Surgery, "Virgen del Rocío" University Hospital/IBiS/CSIC/University of Seville , Seville, Spain .

Significance: Nitric oxide (NO) is a physiopathological messenger generating different reactive nitrogen species (RNS) according to hypoxic, acidic and redox conditions. Recent Advances: RNS and reactive oxygen species (ROS) promote relevant post-translational modifications, such as nitrosation, nitration, and oxidation, in critical components of cell proliferation and death, epithelial-to-mesenchymal transition, and metastasis.

Critical Issues: The pro- or antitumoral properties of NO are dependent on local concentration, redox state, cellular status, duration of exposure, and compartmentalization of NO generation. The increased expression of NO synthase has been associated with cancer progression. However, the experimental strategies leading to high intratumoral NO generation have been shown to exert antitumoral properties. The effect of NO and ROS on cell signaling is critically altered by factors modulating tumor progression such as oxygen content, metabolism, and inflammatory response. The review describes the alteration of key components involved in cell survival and death, metabolism, and metastasis induced by RNS- and ROS-related post-translational modifications.

Future Directions: The identification of the molecular targets affected by nitrosation, nitration, and oxidation, as well as their interactions with other post-translational modifications, will improve the understanding on the complex signaling and cell fate decision in cancer. The therapeutic NO-based strategies have to address the complex crosstalk among NO and ROS with regard to critical components affecting tumor cell survival, metabolism, and metastasis in the progression of cancer, as well as close interaction with ionizing radiation and chemotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/ars.2017.7072DOI Listing
November 2018

The search for novel diagnostic and prognostic biomarkers in cholangiocarcinoma.

Biochim Biophys Acta Mol Basis Dis 2018 04 4;1864(4 Pt B):1468-1477. Epub 2017 Aug 4.

Experimental Hepatology and Drug Targeting (HEVEFARM), University of Salamanca, IBSAL, Salamanca, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain.

The poor prognosis of cholangiocarcinoma (CCA) is in part due to late diagnosis, which is currently achieved by a combination of clinical, radiological and histological approaches. Available biomarkers determined in serum and biopsy samples to assist in CCA diagnosis are not sufficiently sensitive and specific. Therefore, the identification of new biomarkers, preferably those obtained by minimally invasive methods, such as liquid biopsy, is important. The development of innovative technologies has permitted to identify a significant number of genetic, epigenetic, proteomic and metabolomic CCA features with potential clinical usefulness in early diagnosis, prognosis or prediction of treatment response. Potential new candidates must be rigorously evaluated prior to entering routine clinical application. Unfortunately, to date, no such biomarker has achieved validation for these purposes. This review is an up-to-date of currently used biomarkers and the candidates with promising characteristics that could be included in the clinical practice in the next future. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbadis.2017.08.002DOI Listing
April 2018

Role of p63 and p73 isoforms on the cell death in patients with hepatocellular carcinoma submitted to orthotopic liver transplantation.

PLoS One 2017 28;12(3):e0174326. Epub 2017 Mar 28.

Department of General Surgery, Hospital University "Virgen del Rocío"/IBiS/CSIC/University of Seville, Seville, Spain.

Background & Aims: Patients with hepatocellular carcinoma (HCC) submitted to orthotopic liver transplantation (OLT) have a variable 5-year survival rate limited mostly by tumor recurrence. The etiology, age, sex, alcohol, Child-Pugh, and the immunesuppressor have been associated with tumour recurrence. The expression of ΔNp73 is related to the reduced survival of patients with HCC. The study evaluated the expression of p63 and p73 isoforms and cell death receptors, and their relation to tumour recurrence and survival. The results were in vitro validated in HCC cell lines.

Methods: HCC sections from patients submitted to OLT were used. The in vitro study was done in differentiated hepatitis B virus (HBV)-expressing Hep3B and control HepG2 cells. The expression of cell death receptors and cFLIPS/L, caspase-8 and -3 activities, and cell proliferation were determined in control and p63 and p73 overexpressing HCC cells.

Results: The reduced tumor expression of cell death receptors and TAp63 and TAp73, and increased ΔNp63 and ΔNp73 expression were associated with tumor recurrence and reduced survival. The in vitro study demonstrated that HBV-expressing Hep3B vs HepG2 cells showed reduced expression of p63 and p73, cell death receptors and caspase activation, and increased cFLIPL/cFLIPS ratio. The overexpression of TAp63 and TAp73 exerted a more potent pro-apoptotic and anti-proliferative effects in Hep3B than HepG2-transfected cells which was related to cFLIPL upregulation.

Conclusions: The reduction of TAp63 and TAp73 isoforms, rather than alteration of ΔN isoform expression, exerted a significant functional repercussion on cell death and proliferation in HBV-expressing HepB cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0174326PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5369777PMC
September 2017

Amitriptyline induces mitophagy that precedes apoptosis in human HepG2 cells.

Genes Cancer 2016 Jul;7(7-8):260-277

Centro Andaluz de Biología de Desarrollo (CABD), Universidad Pablo de Olavide/CSIC/, Sevilla, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain.

Systemic treatments for hepatocellular carcinoma (HCC) have been largely unsuccessful. This study investigated the antitumoral activity of Amitriptyline, a tricyclic antidepressant, in hepatoma cells. Amitriptyline-induced toxicity involved early mitophagy activation that subsequently switched to apoptosis. Amitriptyline induced mitochondria dysfunction and oxidative stress in HepG2 cells. Amitriptyline specifically inhibited mitochondrial complex III activity that is associated with decreased mitochondrial membrane potential (∆Ψm) and increased reactive oxygen species (ROS) production. Transmission electron microscopy (TEM) studies revealed structurally abnormal mitochondria that were engulfed by double-membrane structures resembling autophagosomes. Consistent with mitophagy activation, fluorescence microscopy analysis showed mitochondrial Parkin recruitment and colocalization of mitochondria with autophagosome protein markers. Pharmacological or genetic inhibition of autophagy exacerbated the deleterious effects of Amitriptyline on hepatoma cells and led to increased apoptosis. These results suggest that mitophagy acts as an initial adaptive mechanism of cell survival. However persistent mitochondrial damage induced extensive and lethal mitophagy, autophagy stress and autophagolysome permeabilization leading eventually to cell death by apoptosis. Amitriptyline also induced cell death in hepatoma cells lines with mutated p53 and non-sense p53 mutation. Our results support the hypothesis that Amitriptyline-induced mitochondrial dysfunction can be a useful therapeutic strategy for HCC treatment, especially in tumors showing p53 mutations and/or resistant to genotoxic treatments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/genesandcancer.114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5059116PMC
July 2016

Differential Antitumoral Properties and Renal-Associated Tissue Damage Induced by Tacrolimus and Mammalian Target of Rapamycin Inhibitors in Hepatocarcinoma: In Vitro and In Vivo Studies.

PLoS One 2016 12;11(8):e0160979. Epub 2016 Aug 12.

Department of General Surgery, "Virgen del Rocío"-"Virgen Macarena" University Hospital/CSIC/University of Seville/IBIS/CSIC/University of Seville, Seville, Spain.

Orthotopic liver transplantation (OLT) is the recommended treatment for patients at early stages of hepatocarcinoma (HCC) with potential portal hypertension and/or bilirubinemia, but without vascular-associated diseases. The patients are receiving immunosuppressive therapy to reduce graft rejection, but differential side effects have been related to calcineurin and mTOR inhibitor administration regarding tumor recurrence and nephrotoxicity. The in vitro studies showed that Tacrolimus exerted a more potent pro-apoptotic effect than Everolimus (Huh 7>Hep 3B>HepG2), being sirolimus only active in Hep3B cell line. Tacrolimus and Everolimus exerted potent antiproliferative properties in Huh 7 and Hep3B in which cells Sirolimus was inactive. Interestingly, Tacrolimus- and Everolimus-dependent G0/G1 cell accumulation occurred as a consequence of drastic reduction in S, as well as in S and G2+M phases, respectively. The in vivo studies support data on the more effective antitumoral properties of Everolimus, eventual risk of pro-angiogenic tumoral properties and nephrotoxicity of Tacrolimus, and pro-proliferative properties of Sirolimus in tumors developed in nude mice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0160979PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4982663PMC
August 2017

Modulation of Autophagy by Sorafenib: Effects on Treatment Response.

Front Pharmacol 2016 8;7:151. Epub 2016 Jun 8.

Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)León, Spain; Institute of Biomedicine (IBIOMED), University of LeónLeón, Spain.

The multikinase inhibitor sorafenib is, at present, the only drug approved for the treatment of hepatocellular carcinoma (HCC), one of the most lethal types of cancer worldwide. However, the increase in the number of sorafenib tumor resistant cells reduces efficiency. A better knowledge of the intracellular mechanism of the drug leading to reduced cell survival could help to improve the benefits of sorafenib therapy. Autophagy is a bulk cellular degradation process activated in a broad range of stress situations, which allows cells to degrade misfolded proteins or dysfunctional organelles. This cellular route can induce survival or death, depending on cell status and media signals. Sorafenib, alone or in combination with other drugs is able to induce autophagy, but cell response to the drug depends on the complex integrative crosstalk of different intracellular signals. In cancerous cells, autophagy can be regulated by different cellular pathways (Akt-related mammalian target of rapamycin (mTOR) inhibition, 5' AMP-activated protein kinase (AMPK) induction, dissociation of B-cell lymphoma 2 (Bcl-2) family proteins from Beclin-1), or effects of some miRNAs. Inhibition of mTOR signaling by sorafenib and diminished interaction between Beclin-1 and myeloid cell leukemia 1 (Mcl-1) have been related to induction of autophagy in HCC. Furthermore, changes in some miRNAs, such as miR-30α, are able to modulate autophagy and modify sensitivity in sorafenib-resistant cells. However, although AMPK phosphorylation by sorafenib seems to play a role in the antiproliferative action of the drug, it does not relate with modulation of autophagy. In this review, we present an updated overview of the effects of sorafenib on autophagy and its related activation pathways, analyzing in detail the involvement of autophagy on sorafenib sensitivity and resistance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2016.00151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4896953PMC
July 2016

Oxidative stress influence on renal dysfunction in patients with obstructive jaundice: A case and control prospective study.

Redox Biol 2016 08 29;8:160-4. Epub 2015 Dec 29.

Department of General Surgery, Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla, Sevilla, Spain.

Background: Obstructive Jaundice (OJ) is associated with a significant risk of developing acute renal failure (ARF). The involvement of oxidative stress in the development of cholestasis has been demonstrated in different experimental models. However, its role in the morbidity of human cholestasis is far to be elucidated. The aim of the study was the evaluation of oxidative stress markers in blood from patients with OJ and its relation to complications and benign/malignant evolution of cholestasis.

Methods: A prospective cross-sectional study of 105 patients with OJ and 34 control subjects were included. Several markers of liver function and oxidative stress, such as lipoperoxides (LPO), as well as reduced glutathione (GSH), catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities were assessed.

Results: The patients with OJ showed a marked increase in plasma levels of LPO, SOD and GSH, while GSH-Px levels were decreased. The increase in lipid peroxidation products and the depletion of SOD activity in blood were also related to renal dysfunction. The highest level of LPO was associated with malignant etiology of the disease. The logistic regression analysis showed that the age of the patient and the levels of LPO in blood were predictors of renal dysfunction in OJ patients.

Conclusions: This study demonstrates a correlation between oxidative stress and renal dysfunction patients with OJ.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.redox.2015.12.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4731952PMC
August 2016

Antitumoral Activity of Sorafenib in Hepatocellular Carcinoma: Effects on Cell Survival and Death Pathways, Cell Metabolism Reprogramming, and Nitrosative and Oxidative Stress.

Crit Rev Oncog 2016 ;21(5-6):413-432

Department of General Surgery, Virgen del Rocio University Hospital/IBiS/CSIC/University of Seville, Seville, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.

Sorafenib is an oral multikinase inhibitor approved for the treatment of hepatocellular carcinoma (HCC). Its antitumor activity is attributed to inhibition of tyrosine kinase receptors (VEGFR, PDGFR, c-kit) and intracellular serine/threonine kinases (Raf), which alter gene expression to promote apoptosis and downregulate survival and angiogenesis pathways. The beneficial properties of sorafenib have also been related to a reduction in liver fibrosis trough regulation of TGF-βR-related STAT3 signaling. Sorafenib plays a role in the regulation of mitochondrial function, ATP, and autophagy, a process leading to either survival or apoptotic cell death depending on its intensity and duration, by altering several cellular pathways such as mTOR, AMPK, activating endoplasmic reticulum stress responses, and deregulating miRNAs that modulate autophagy. Sorafenib reduces S-nitrosation of cell death receptors and caspase-3, triggering a switch to caspase-3 from caspase-8. In this paper, we review the antitumor effects of sorafenib by interaction with cell survival and apoptosis pathways, metabolic reprogramming, and effect on oxidative and nitrosative stress, along with different mechanisms that might be involved in resistance to the drug.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1615/CritRevOncog.2017021302DOI Listing
January 2016

Special collection: Nitric oxide in cancer.

Redox Biol 2015 Dec 25;6:505-506. Epub 2015 Sep 25.

Department of Microbiology, Immunology, and Molecular Genetics David Geffen School of Medicine Jonsson Comprehensive Cancer Center University of California, Los Angeles, CA 90095, USA. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.redox.2015.09.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4600854PMC
December 2015