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Article: Protective Effect of Protocatechuic Acid on TNBS-Induced Colitis in Mice Is Associated with Modulation of the SphK/S1P Signaling Pathway

Crespo, Irene / Mauriz, Jose L / González-Gallego, Javier

Nutrients, 9(3):288

2017

Abstract: 1) BACKGROUND: The present study aimed to investigate whether beneficial effects of protocatechuic acid (PCA) are associated with inhibition of the SphK/S1P axis and related signaling pathways in a 2,4,6-trinitrobenzenesulfonic acid (TNBS) model of ... ...

Abstract	(1) BACKGROUND: The present study aimed to investigate whether beneficial effects of protocatechuic acid (PCA) are associated with inhibition of the SphK/S1P axis and related signaling pathways in a 2,4,6-trinitrobenzenesulfonic acid (TNBS) model of inflammatory bowel disease; (2) METHODS: Colitis was induced in male Balb/c mice by intracolonic administration of 2 mg of TNBS. PCA (30 or 60 mg/kg body wt) was given intraperitoneally daily for five days; (3) RESULTS: Administration of PCA prevented the macroscopic and microscopic damage to the colonic mucosa, the decrease in body weight gain and the increase in myeloperoxidase activity induced by TNBS. PCA-treated mice exhibited a lower oxidized/reduced glutathione ratio, increased expression of antioxidant enzymes and Nrf2 and reduced expression of proinflammatory cytokines. Following TNBS treatment mRNA levels, protein concentration and immunohistochemical labelling for SphK1 increased significantly. S1P production and expression of S1P receptor 1 and S1P phosphatase 2 were significantly elevated. However, there was a decreased expression of S1P lyase. Furthermore, TNBS-treated mice exhibited increased phosphorylation of AKT and ERK, and a higher expression of pSTAT3 and the NF-κB p65 subunit. PCA administration significantly prevented those changes; (4) CONCLUSIONS: Data obtained suggest a contribution of the SphK/S1P system and related signaling pathways to the anti-inflammatory effect of PCA.
Keywords	SphK/S1P signaling ; colitis ; inflammation ; sphingolipids ; protocatechuic acid
Language	English
Document type	Article
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Article ; Online: Therapeutic approaches in intermediate-stage hepatocellular carcinoma (HCC): a novel insight of adjuvant transarterial chemoembolization (TACE).

Fernández-Palanca, Paula / Mauriz, José L

Chinese clinical oncology

2023 Volume 12, Issue 2, Page(s) 11

MeSH term(s)	Humans ; Carcinoma, Hepatocellular/therapy ; Carcinoma, Hepatocellular/pathology ; Liver Neoplasms/therapy ; Liver Neoplasms/pathology ; Chemoembolization, Therapeutic ; Treatment Outcome ; Vascular Surgical Procedures ; Retrospective Studies
Language	English
Publishing date	2023-03-30
Publishing country	China
Document type	Journal Article
ZDB-ID	2828547-5
ISSN	2304-3873 ; 2304-3873
ISSN (online)	2304-3873
ISSN	2304-3873
DOI	10.21037/cco-23-21
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Article ; Online: Beneficial effects of melatonin on liver fibrosis: A systematic review of current biological evidence.

San-Miguel, Beatriz / Fernández-Palanca, Paula / Mauriz, José L / Tuñón, María J / González-Gallego, Javier

Journal of cellular physiology

2022 Volume 237, Issue 7, Page(s) 2740–2757

Abstract: Hepatic fibrosis is a reversible response to either acute or chronic cellular injury from a wide variety of etiologies, characterized by excessive deposition of extracellular matrix resulting in liver dysfunction and cirrhosis. Melatonin (N-acetyl-5- ... ...

Abstract	Hepatic fibrosis is a reversible response to either acute or chronic cellular injury from a wide variety of etiologies, characterized by excessive deposition of extracellular matrix resulting in liver dysfunction and cirrhosis. Melatonin (N-acetyl-5-methoxytryptamine), the main product secreted by the pineal gland, is a multitasking indolamine with important physiological functions such as anti-inflammatory and antioxidant actions, modulation of circadian rhythms, and immune system enhancement. Among the numerous biological activities of melatonin, its antifibrotic effects have received increasingly more attention. In this study, we performed a systematic review of publications of the last 10 years evaluating the mechanisms of action of melatonin against liver fibrosis. The study protocol was registered at PROSPERO (CRD42022304744). Literature research was performed employing PubMed, Scopus, and Web of Science (WOS) databases, and after screening, 29 articles were included. Results from the selected studies provided denoted the useful actions of melatonin on the development, progression, and evolution of liver fibrosis. Melatonin antifibrotic effects in the liver involved the reduction of profibrogenic markers and modulation of several cellular processes and molecular pathways, mainly acting as an antioxidant and anti-inflammatory agent. In addition, the indolamine influenced different molecular processes, such as hepatocyte apoptosis, modulation of autophagy and mitophagy, restoration of circadian rhythms, and modulation of microRNAs, among others. Although some limitations have been found regarding variability in the study design, the findings here summarized display the potential role of melatonin in ameliorating the development of liver fibrosis and its possible progression to liver cirrhosis and hepatocarcinoma.
MeSH term(s)	Anti-Inflammatory Agents/administration & dosage ; Anti-Inflammatory Agents/metabolism ; Anti-Inflammatory Agents/therapeutic use ; Antioxidants/administration & dosage ; Antioxidants/metabolism ; Antioxidants/therapeutic use ; Humans ; Liver Cirrhosis/drug therapy ; Liver Cirrhosis/pathology ; Melatonin/administration & dosage ; Melatonin/metabolism ; Melatonin/therapeutic use
Chemical Substances	Anti-Inflammatory Agents ; Antioxidants ; Melatonin (JL5DK93RCL)
Language	English
Publishing date	2022-04-11
Publishing country	United States
Document type	Journal Article ; Systematic Review ; Research Support, Non-U.S. Gov't
ZDB-ID	3116-1
ISSN	1097-4652 ; 0021-9541
ISSN (online)	1097-4652
ISSN	0021-9541
DOI	10.1002/jcp.30735
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Article ; Online: Neuropilins as potential biomarkers in hepatocellular carcinoma: a systematic review of basic and clinical implications.

Fernández-Palanca, Paula / Payo-Serafín, Tania / Méndez-Blanco, Carolina / San-Miguel, Beatriz / Tuñón, María J / González-Gallego, Javier / Mauriz, José L

Clinical and molecular hepatology

2023 Volume 29, Issue 2, Page(s) 293–319

Abstract: Hepatocellular carcinoma (HCC) is one of the most common and deadly cancers worldwide and is characterized by complex molecular carcinogenesis. Neuropilins (NRPs) NRP1 and NRP2 are the receptors of multiple proteins involved in key signaling pathways ... ...

Abstract	Hepatocellular carcinoma (HCC) is one of the most common and deadly cancers worldwide and is characterized by complex molecular carcinogenesis. Neuropilins (NRPs) NRP1 and NRP2 are the receptors of multiple proteins involved in key signaling pathways associated with tumor progression. We aimed to systematically review all the available findings on their role in HCC. We searched the Scopus, Web of Science (WOS), PubMed, Cochrane and Embase databases for articles evaluating NRPs in preclinical or clinical HCC models. This study was registered in PROSPERO (CRD42022349774) and include 49 studies. Multiple cellular and molecular processes have been associated with one or both NRPs, indicating that they are potential diagnostic and prognostic biomarkers in HCC patients. Mainly NRP1 has been shown to promote tumor cell survival and progression by modulating several signaling pathways. NRPs mainly regulate angiogenesis, invasion and migration and have shown to induce invasion and metastasis. They also regulate the immune response and tumor microenvironment, showing a crucial interplay with the hypoxia response and microRNAs in HCC. Altogether, NRP1 and NRP2 are potential biomarkers and therapeutic targets, providing novel insight into the clinical landscape of HCC patients.
MeSH term(s)	Humans ; Carcinoma, Hepatocellular/diagnosis ; Carcinoma, Hepatocellular/pathology ; Neuropilins/genetics ; Neuropilins/metabolism ; Liver Neoplasms/diagnosis ; Liver Neoplasms/metabolism ; Signal Transduction ; Biomarkers ; Biomarkers, Tumor ; Tumor Microenvironment
Chemical Substances	Neuropilins ; Biomarkers ; Biomarkers, Tumor
Language	English
Publishing date	2023-02-01
Publishing country	Korea (South)
Document type	Systematic Review ; Journal Article ; Review
ZDB-ID	2672560-5
ISSN	2287-285X ; 2287-2728
ISSN (online)	2287-285X
ISSN	2287-2728
DOI	10.3350/cmh.2022.0425
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Article: Prognostic and clinicopathological significance of hypoxia-inducible factors 1α and 2α in hepatocellular carcinoma: a systematic review with meta-analysis.

Méndez-Blanco, Carolina / Fernández-Palanca, Paula / Fondevila, Flavia / González-Gallego, Javier / Mauriz, José L

Therapeutic advances in medical oncology

2021 Volume 13, Page(s) 1758835920987071

Abstract: Background: Hepatocellular carcinoma (HCC) is a highly recurrent tumor after resection and has been closely related to hypoxia. Hypoxia-inducible factors 1α and 2α (HIF-1α and HIF-2α) have been shown to contribute to tumor progression and therapy ... ...

Abstract	Background: Hepatocellular carcinoma (HCC) is a highly recurrent tumor after resection and has been closely related to hypoxia. Hypoxia-inducible factors 1α and 2α (HIF-1α and HIF-2α) have been shown to contribute to tumor progression and therapy resistance in HCC. We evaluated the prognostic and clinicopathological significance of HIF-1α and HIF-2α in HCC patients. Methods: We systematically searched Embase, Cochrane, PubMed, Scopus and Web of Science (WOS) from inception to 1 June 2020 for studies evaluating HIF-1α and/or HIF-2α expression in HCC. Selected articles evaluate at least one factor by immunohistochemistry (IHC) in HCC patients who underwent surgical resection, and its relationship with prognosis and/or clinicopathological features. Study protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO; CDR42020191977). We meta-analyzed the data extracted or estimated according to the Parmar method employing STATA software. We evaluated the overall effect size for the hazard ratio (HR) and odds ratio (OR) with 95% confidence interval (CI), as well as heterogeneity across studies with the Results: HIF-1α overexpression was correlated with overall survival (OS), disease-free survival (DFS)/recurrence-free survival (RFS) and clinicopathological features including Barcelona Clinic Liver Cancer (BCLC), capsule infiltration, intrahepatic metastasis, lymph node metastasis, tumor-node-metastasis (TNM), tumor differentiation, tumor number, tumor size (3 cm), vascular invasion and vasculogenic mimicry. We also detected a possible correlation of HIF-1α with alpha-fetoprotein (AFP), cirrhosis, histological grade, tumor size (5 cm) and albumin after subgroup analysis. Initially, only DFS/RFS appeared to be associated with HIF-2α overexpression. Subgroup analysis denoted that HIF-2α overexpression was related to OS and capsule infiltration. Conclusions: HIF-1α and HIF-2α overexpression is related to poor OS, DFS/RFS and some clinicopathological features of HCC patients, suggesting that both factors could be useful HCC biomarkers.
Language	English
Publishing date	2021-02-07
Publishing country	England
Document type	Journal Article
ZDB-ID	2503443-1
ISSN	1758-8359 ; 1758-8340
ISSN (online)	1758-8359
ISSN	1758-8340
DOI	10.1177/1758835920987071
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Article ; Online: Hepatocellular carcinoma cells loss lenvatinib efficacy in vitro through autophagy and hypoxia response-derived neuropilin-1 degradation.

Fernández-Palanca, Paula / Payo-Serafín, Tania / San-Miguel, Beatriz / Méndez-Blanco, Carolina / Tuñón, María J / González-Gallego, Javier / Mauriz, José L

Acta pharmacologica Sinica

2022 Volume 44, Issue 5, Page(s) 1066–1082

Abstract: Despite pharmacological advances such as lenvatinib approval, therapeutic failure of hepatocellular carcinoma (HCC) remains a big challenge due to the complexity of its underlying molecular mechanisms. Neuropilin-1 (NRP1) is a co-receptor involved in ... ...

Abstract	Despite pharmacological advances such as lenvatinib approval, therapeutic failure of hepatocellular carcinoma (HCC) remains a big challenge due to the complexity of its underlying molecular mechanisms. Neuropilin-1 (NRP1) is a co-receptor involved in several cellular processes associated to chemoresistance development. Since both the double-edged process of autophagy and hypoxia-derived response play crucial roles in the loss of therapeutic effectiveness, herein we investigated the interplay among NRP1, autophagy and hypoxia in development of lenvatinib resistance in HCC cell lines. We first analyzed NRP1 expression levels in human HCC samples from public databases, found significantly increased NRP1 expression in human HCC samples as well as its correlation with advanced tumor and metastasis stages. Among 3 HCC cell lines (HepG2, Huh-7 and Hep3B), Hep3B and Huh-7 cells showed significantly increased NRP1 expression levels and cell migration ability together with higher susceptibility to lenvatinib. We demonstrated that NRP1 gene silencing significantly enhanced the anticancer effects of lenvatinib on Hep3B and Huh-7 cells. Furthermore, lenvatinib suppressed NRP1 expression through promoting autophagy in Hep3B and Huh-7 cells; co-treatment with bafilomycin A1 attenuated the antitumor effects of lenvatinib, and NRP1 silencing prevented this loss of in vitro effectiveness of lenvatinib even in the presence of bafilomycin A1. In addition, exposure to a hypoxic microenvironment significantly decreased NRP1 expression through autophagy in Hep3B and Huh-7 cells. Under hypoxia, HIF-1α directly modulated NRP1 expression; HIF-1α silencing not only enhanced the anticancer effects of combined lenvatinib and hypoxia, but also prevented the loss of effectiveness caused by bafilomycin A1, highlighting the potential role of HIF-1α-derived hypoxia response in the adaptive cellular response to lenvatinib and promoting resistance acquisition by autophagy modulation. Overall, NRP1 may constitute a potential therapeutic target to prevent lenvatinib failure derived from a hypoxia-associated modulation of autophagy in advanced HCC.
MeSH term(s)	Humans ; Autophagy ; Carcinoma, Hepatocellular/drug therapy ; Carcinoma, Hepatocellular/metabolism ; Cell Line, Tumor ; Drug Resistance, Neoplasm/genetics ; Gene Expression Regulation, Neoplastic ; Hypoxia ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Liver Neoplasms/drug therapy ; Liver Neoplasms/metabolism ; Neuropilin-1/genetics ; Neuropilin-1/metabolism
Chemical Substances	bafilomycin A1 (88899-55-2) ; Hypoxia-Inducible Factor 1, alpha Subunit ; lenvatinib (EE083865G2) ; Neuropilin-1 (144713-63-3)
Language	English
Publishing date	2022-11-14
Publishing country	United States
Document type	Journal Article
ZDB-ID	1360774-1
ISSN	1745-7254 ; 0253-9756 ; 1671-4083
ISSN (online)	1745-7254
ISSN	0253-9756 ; 1671-4083
DOI	10.1038/s41401-022-01021-2
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Article ; Online: Impact of Aberrant β-Catenin Pathway on Cholangiocarcinoma Heterogeneity.

Lozano, Elisa / Sanchon-Sanchez, Paula / Morente-Carrasco, Ana / Chinchilla-Tábora, Luis Miguel / Mauriz, José L / Fernández-Palanca, Paula / Marin, Jose J G / Macias, Rocio I R

Cells

2023 Volume 12, Issue 8

Abstract: The poor prognosis of most cases of advanced cholangiocarcinoma (CCA) constitutes a severe problem in modern oncology, which is aggravated by the fact that the incidence of this liver cancer is increasing worldwide and is often diagnosed late, when ... ...

Abstract	The poor prognosis of most cases of advanced cholangiocarcinoma (CCA) constitutes a severe problem in modern oncology, which is aggravated by the fact that the incidence of this liver cancer is increasing worldwide and is often diagnosed late, when surgical removal is not feasible. The difficulty of dealing with this deadly tumor is augmented by the heterogeneity of CCA subtypes and the complexity of mechanisms involved in enhanced proliferation, apoptosis avoidance, chemoresistance, invasiveness, and metastasis that characterize CCA. Among the regulatory processes implicated in developing these malignant traits, the Wnt/β-catenin pathway plays a pivotal role. Alteration of β-catenin expression and subcellular localization has been associated with worse outcomes in some CCA subtypes. This heterogeneity, which also affects cellular and in vivo models commonly used to study CCA biology and anticancer drug development, must be taken into account for CCA investigation to more accurately extrapolate basic laboratory research to the clinical situation. A better understanding of the altered Wnt/β-catenin pathway in relationship with the heterogeneous forms of CCA is mandatory for developing novel diagnostic tools and therapeutic strategies for patients suffering from this lethal disease.
MeSH term(s)	Humans ; beta Catenin/metabolism ; Bile Duct Neoplasms/pathology ; Cholangiocarcinoma/pathology ; Wnt Signaling Pathway ; Bile Ducts, Intrahepatic/pathology
Chemical Substances	beta Catenin
Language	English
Publishing date	2023-04-12
Publishing country	Switzerland
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells12081141
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Article: Correction: Méndez-Blanco et al. Stabilization of Hypoxia-Inducible Factors and BNIP3 Promoter Methylation Contribute to Acquired Sorafenib Resistance in Human Hepatocarcinoma Cells.

Méndez-Blanco, Carolina / Fondevila, Flavia / Fernández-Palanca, Paula / García-Palomo, Andrés / van Pelt, Jos / Verslype, Chris / González-Gallego, Javier / Mauriz, José L

Cancers

2023 Volume 15, Issue 23

Abstract: In the original publication [ ... ]. ...

Abstract	In the original publication [...].
Language	English
Publishing date	2023-11-30
Publishing country	Switzerland
Document type	Published Erratum
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers15235668
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Article: Melatonin as an Antitumor Agent against Liver Cancer: An Updated Systematic Review.

Fernández-Palanca, Paula / Méndez-Blanco, Carolina / Fondevila, Flavia / Tuñón, María J / Reiter, Russel J / Mauriz, José L / González-Gallego, Javier

Antioxidants (Basel, Switzerland)

2021 Volume 10, Issue 1

Abstract: Melatonin ( ...

Abstract	Melatonin (
Language	English
Publishing date	2021-01-12
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2704216-9
ISSN	2076-3921
ISSN	2076-3921
DOI	10.3390/antiox10010103
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Article ; Online: Anti-tumoral activity of single and combined regorafenib treatments in preclinical models of liver and gastrointestinal cancers.

Fondevila, Flavia / Méndez-Blanco, Carolina / Fernández-Palanca, Paula / González-Gallego, Javier / Mauriz, José L

Experimental & molecular medicine

2019 Volume 51, Issue 9, Page(s) 1–15

Abstract: Regorafenib is a sorafenib-derived chemotherapy drug belonging to the multikinase inhibitor family. This agent effectively targets a wide range of tyrosine kinases involved in cancer biology, such as those implicated in oncogenesis, angiogenesis, and ... ...

Abstract	Regorafenib is a sorafenib-derived chemotherapy drug belonging to the multikinase inhibitor family. This agent effectively targets a wide range of tyrosine kinases involved in cancer biology, such as those implicated in oncogenesis, angiogenesis, and tumor microenvironment control. The beneficial effects of regorafenib in clinical trials of patients who suffer from advanced hepatocellular carcinoma (HCC), colorectal cancer (CRC) or gastrointestinal stromal tumors (GISTs) refractory to standard treatments led to regorafenib monotherapy approval as a second-line treatment for advanced HCC and as a third-line treatment for advanced CRC and GISTs. Multiple in vitro and in vivo studies have been performed over the last decade to reveal the molecular mechanisms of the favorable actions exerted by regorafenib in patients. Given the hypothetical loss of sensitivity to regorafenib in tumor cells, preclinical research is also searching for novel therapeutic approaches consisting of co-administration of this drug plus other agents as a strategy to improve regorafenib effectiveness. This review summarizes the anti-tumor effects of regorafenib in single or combined treatment in preclinical models of HCC, CRC and GISTs and discusses both the global and molecular effects that account for its anti-cancer properties in the clinical setting.
MeSH term(s)	Antineoplastic Agents/therapeutic use ; Carcinoma, Hepatocellular/drug therapy ; Carcinoma, Hepatocellular/pathology ; Combined Modality Therapy ; Gastrointestinal Neoplasms/drug therapy ; Gastrointestinal Neoplasms/pathology ; Humans ; Liver/drug effects ; Liver/pathology ; Liver Neoplasms/drug therapy ; Liver Neoplasms/pathology ; Phenylurea Compounds/therapeutic use ; Protein Kinase Inhibitors/therapeutic use ; Pyridines/therapeutic use ; Sorafenib/therapeutic use ; Tumor Microenvironment/drug effects
Chemical Substances	Antineoplastic Agents ; Phenylurea Compounds ; Protein Kinase Inhibitors ; Pyridines ; regorafenib (24T2A1DOYB) ; Sorafenib (9ZOQ3TZI87)
Language	English
Publishing date	2019-09-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1328915-9
ISSN	2092-6413 ; 1226-3613 ; 0378-8512
ISSN (online)	2092-6413
ISSN	1226-3613 ; 0378-8512
DOI	10.1038/s12276-019-0308-1
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