108 results on '"Cecília M. P. Rodrigues"'
Search Results
2. Lytic cell death in metabolic liver disease
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Gregory J. Gores, Cecília M. P. Rodrigues, and Jérémie Gautheron
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0301 basic medicine ,Programmed cell death ,Cirrhosis ,Necroptosis ,Article ,03 medical and health sciences ,Liver disease ,0302 clinical medicine ,Drug Discovery ,Pyroptosis ,medicine ,Ferroptosis ,Humans ,Regulated Cell Death ,Hepatology ,business.industry ,Liver Diseases ,Liver cell ,Fatty liver ,medicine.disease ,3. Good health ,030104 developmental biology ,Hepatic stellate cell ,Cancer research ,030211 gastroenterology & hepatology ,business - Abstract
Regulated cell death is intrinsically associated with inflammatory liver disease and is pivotal in governing outcomes of metabolic liver disease. Different types of cell death may coexist in the progression of metabolic liver disease to inflammation, fibrosis, and ultimately cirrhosis. In addition to apoptosis, lytic forms of hepatocellular death, such as necroptosis, pyroptosis and ferroptosis elicit strong inflammatory responses due to cell membrane permeabilization and release of cellular components, contributing to the recruitment of immune cells and activation of hepatic stellate cells. Controlling liver cell death, in turn, emerges with fundamental importance and offers novel opportunities for potential therapeutic intervention. This review summarizes the underlying mechanism of distinct lytic cell death modes and their commonalities, discusses its relevance to metabolic liver diseases of different aetiologies, and acknowledges the limitations of current knowledge in the field. We focus on the role of hepatocyte necroptosis, pyroptosis and ferroptosis in non-alcoholic fatty liver disease, alcohol-associated liver disease and other metabolic liver disorders, as well as potential of translation into human disease.
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- 2020
3. Targeted Avenues for Cancer Treatment: The MEK5–ERK5 Signaling Pathway
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Cecília M. P. Rodrigues and Diane M. Pereira
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Proteomics ,0301 basic medicine ,medicine.medical_treatment ,Antineoplastic Agents ,MAP Kinase Kinase 5 ,Targeted therapy ,Metastasis ,Transcriptome ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,Chemosensitization ,Neoplasms ,medicine ,Animals ,Humans ,Protein kinase A ,Molecular Biology ,Mitogen-Activated Protein Kinase 7 ,Activator (genetics) ,Kinase ,business.industry ,medicine.disease ,030104 developmental biology ,Cancer research ,Molecular Medicine ,business ,030217 neurology & neurosurgery ,Signal Transduction - Abstract
Twenty years have passed since extracellular signal-regulated kinase 5 (ERK5) and its upstream activator, mitogen-activated protein kinase 5 (MEK5), first emerged onto the cancer research scene. Although we have come a long way in defining the liaison between dysregulated MEK5-ERK5 signaling and the pathogenesis of epithelial and nonepithelial malignancies, selective targeting of this unique pathway remains elusive. Here, we provide an updated review of the existing evidence for a correlation between aberrant MEK5-ERK5 (phospho)proteomic/transcriptomic profiles, aggressive cancer states, and poor patient outcomes. We then focus on emerging insights from preclinical models regarding the relevance of upregulated ERK5 activity in promoting tumor growth, metastasis, therapy resistance, undifferentiated traits, and immunosuppression, highlighting the opportunities, prospects, and challenges of selectively blocking this cascade for antineoplastic treatment and chemosensitization.
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- 2020
4. Processes exacerbating apoptosis in non-alcoholic steatohepatitis
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Cecília M. P. Rodrigues, Rui E. Castro, and Marta B. Afonso
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0301 basic medicine ,Necroptosis ,Apoptosis ,Context (language use) ,Disease ,Bioinformatics ,Mitochondrial Dynamics ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,Non-alcoholic Fatty Liver Disease ,Fibrosis ,medicine ,Animals ,Humans ,Life Style ,Inflammation ,Liver injury ,business.industry ,Fatty liver ,General Medicine ,Lipid Metabolism ,medicine.disease ,digestive system diseases ,MicroRNAs ,Oxidative Stress ,030104 developmental biology ,030211 gastroenterology & hepatology ,Steatohepatitis ,business - Abstract
Non-alcoholic fatty liver disease (NAFLD) is a significant public health concern, owing to its high prevalence, progressive nature and lack of effective medical therapies. NAFLD is a complex and multifactorial disease involving the progressive and concerted action of factors that contribute to the development of liver inflammation and eventually fibrosis. Here, we summarize fundamental molecular mechanisms underlying the pathogenesis of non-alcoholic steatohepatitis (NASH), how they are interrelated and possible translation to clinical applications. We focus on processes triggering and exacerbating apoptotic signalling in the liver of NAFLD patients and their metabolic and pathological implications. Indeed, liver injury and inflammation are cardinal histopathological features of NASH, a duo in which derailment of apoptosis is of paramount importance. In turn, the liver houses a very high number of mitochondria, crucial metabolic unifiers of both extrinsic and intrinsic signals that converge in apoptosis activation. The role of lifestyle options is also dissected, highlighting the management of modifiable risk factors, such as obesity and harmful alcohol consumption, influencing apoptosis signalling in the liver and ultimately NAFLD progression. Integrating NAFLD-associated pathologic mechanisms in the cell death context could provide clues for a more profound understating of the disease and pave the way for novel rational therapies.
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- 2019
5. Ablation of RIP3 protects from dopaminergic neurodegeneration in experimental Parkinson’s disease
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Cecília M. P. Rodrigues, Joana D. Amaral, Margarida Castro-Caldas, Sara R. Oliveira, Maria Manuela Gaspar, Maria João Gama, and Pedro A. Dionísio
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Cancer Research ,medicine.medical_specialty ,Programmed cell death ,Parkinson's disease ,Necroptosis ,Immunology ,Apoptosis ,Substantia nigra ,Neuroprotection ,Article ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Internal medicine ,medicine ,Glial cell line-derived neurotrophic factor ,Animals ,Humans ,Glial Cell Line-Derived Neurotrophic Factor ,lcsh:QH573-671 ,Pars Compacta ,bcl-2-Associated X Protein ,Mice, Knockout ,biology ,Caspase 3 ,Pars compacta ,lcsh:Cytology ,Dopaminergic Neurons ,MPTP ,Neurodegeneration ,Parkinson Disease ,Chronic inflammation ,Cell Biology ,medicine.disease ,Corpus Striatum ,Endocrinology ,Gene Expression Regulation ,chemistry ,nervous system ,Receptor-Interacting Protein Serine-Threonine Kinases ,Nerve Degeneration ,biology.protein ,Neuroglia - Abstract
Parkinson’s disease (PD) is driven by dopaminergic neurodegeneration in the substantia nigra pars compacta (SN) and striatum. Although apoptosis is considered the main neurodegenerative mechanism, other cell death pathways may be involved. In this regard, necroptosis is a regulated form of cell death dependent on receptor interacting protein 3 (RIP3), a protein also implicated in apoptosis and inflammation independently of its pro-necroptotic activity. Here, we explored the role of RIP3 genetic deletion in in vivo and in vitro PD models. Firstly, wild-type (Wt) and RIP3 knockout (RIP3ko) mice were injected intraperitoneally with MPTP (40 mg/kg, i.p.), and sacrificed after either 6 or 30 days. RIP3ko protected from dopaminergic neurodegeneration in the SN of MPTP-injected mice, but this effect was independent of necroptosis. In keeping with this, necrostatin-1s (10 mg/kg/day, i.p.) did not afford full neuroprotection. Moreover, MPTP led to DNA fragmentation, caspase-3 activation, lipid peroxidation and BAX expression in Wt mice, in the absence of caspase-8 cleavage, suggesting intrinsic apoptosis. This was mimicked in primary cortical neuronal cultures exposed to the active MPTP metabolite. RIP3 deficiency in cultured cells and in mouse brain abrogated all phenotypes. Curiously, astrogliosis was increased in the striatum of MPTP-injected Wt mice and further exacerbated in RIP3ko mice. This was accompanied by absence of microgliosis and reposition of glial cell line-derived neurotrophic factor (GDNF) levels in the striata of MPTP-injected RIP3ko mice when compared to MPTP-injected Wt mice, which in turn showed a massive GDNF decrease. RIP3ko primary mixed glial cultures also presented decreased expression of inflammation-related genes upon inflammatory stimulation. These findings hint at possible undescribed non-necroptotic roles for RIP3 in inflammation and MPTP-driven cell death, which can contribute to PD progression.
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- 2019
6. The role of RIPK3 in liver mitochondria bioenergetics and function
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Cecília M. P. Rodrigues, Tawhidul Islam, and Marta B. Afonso
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Programmed cell death ,Bioenergetics ,Necroptosis ,Clinical Biochemistry ,Mitochondria, Liver ,General Medicine ,Mitochondrion ,Biology ,medicine.disease ,Biochemistry ,Cell biology ,Mitochondrial respiratory chain ,Mitochondrial biogenesis ,Non-alcoholic Fatty Liver Disease ,Receptor-Interacting Protein Serine-Threonine Kinases ,Nonalcoholic fatty liver disease ,medicine ,Animals ,Humans ,Energy Metabolism ,Beta oxidation - Abstract
BACKGROUND Receptor-interacting protein kinase 3 (RIPK3) is a key player of regulated necrosis or necroptosis, an inflammatory form of cell death possibly governing outcomes in chronic liver diseases, such as nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. METHODS This narrative review is based on literature search using PubMed. RESULTS RIPK3 activation depends on post-transcriptional modifications, including phosphorylation, hence coordinating the assembly of macromolecular death complex named 'necrosome', which may also involve diverse mitochondrial components. Curiously, recent studies suggested a potential link between RIPK3 and mitochondrial bioenergetics. RIPK3 can modulate mitochondrial function and quality through the regulation of mitochondrial reactive oxygen species production, sequestration of metabolic enzymes and resident mitochondrial proteins, activity of mitochondrial respiratory chain complexes, mitochondrial biogenesis and fatty acid oxidation. CONCLUSIONS Since mitochondrial dysfunction and RIPK3-mediated necroptosis are intimately involved in chronic liver disease pathogenesis, understanding the role of RIPK3 in mitochondrial bioenergetics and its potential translational application are of great interest.
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- 2021
7. RIPK3 acts as a lipid metabolism regulator contributing to inflammation and carcinogenesis in non-alcoholic fatty liver disease
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Raul Jimenez-Agüero, María Jesús Pareja, Alvaro Santos-Laso, Jérémie Gautheron, Emma Eizaguirre, Jesus M. Banales, André L. Simão, Marta B. Afonso, Enara Arretxe, Cristina Alonso, Vlad Ratziu, Rui E. Castro, Miguel Mateus-Pinheiro, Cecília M. P. Rodrigues, Pedro Rodrigues, Luis Bujanda, Maria Manuela Gaspar, Amine Majdi, Faculdade de Farmácia da Universidade de Lisboa, Universidade de Lisboa = University of Lisbon (ULISBOA), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Universidad del Pais Vasco / Euskal Herriko Unibertsitatea [Espagne] (UPV/EHU), Service d'Hépato-Gastro-Entérologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Gestionnaire, Hal Sorbonne Université, Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP)
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Liver Cirrhosis ,choline-deficient ,Carcinogenesis ,hepatocellular-carcinoma ,molecular carcinogenesis ,Chronic liver disease ,Pathogenesis ,0302 clinical medicine ,Non-alcoholic Fatty Liver Disease ,Fibrosis ,lipid metabolism ,Prospective Studies ,nonalcoholic steatohepatitis ,0303 health sciences ,Liver Neoplasms ,Fatty liver ,hepatocarcinogenesis ,Gastroenterology ,activated receptor-gamma ,3. Good health ,Cell Transformation, Neoplastic ,cell death ,Receptor-Interacting Protein Serine-Threonine Kinases ,Disease Progression ,030211 gastroenterology & hepatology ,protects ,medicine.symptom ,medicine.medical_specialty ,mice ,Necroptosis ,necroptosis ,Inflammation ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,03 medical and health sciences ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Internal medicine ,medicine ,[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Animals ,Humans ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,030304 developmental biology ,Hepatology ,business.industry ,fibrosis ,chronic liver disease ,Lipid metabolism ,[SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology ,cell ,medicine.disease ,gene-expression ,[SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology ,Endocrinology ,Steatohepatitis ,business ,Biomarkers - Abstract
[EN]Objective Receptor-interacting protein kinase 3 (RIPK3) is a key player in necroptosis execution and an emerging metabolic regulator, whose contribution to non-alcoholic fatty liver disease (NAFLD) is controversial. We aimed to clarify the impact of RIPK3 signalling in the pathogenesis of human and experimental NAFLD. Design RIPK3 levels were evaluated in two large independent cohorts of patients with biopsy proven NAFLD diagnosis and correlated with clinical and biochemical parameters. Wild-type (WT) or Ripk3-deficient (Ripk3(-/-)) mice were fed a choline-deficient L-amino acid-defined diet (CDAA) or an isocaloric control diet for 32 and 66 weeks. Results RIPK3 increased in patients with non-alcoholic steatohepatitis (NASH) in both cohorts, correlating with hepatic inflammation and fibrosis. Accordingly, Ripk3 deficiency ameliorated CDAA-induced inflammation and fibrosis in mice at both 32 and 66 weeks. WT mice on the CDAA diet for 66 weeks developed preneoplastic nodules and displayed increased hepatocellular proliferation, which were reduced in Ripk3(-/-) mice. Furthermore, Ripk3 deficiency hampered tumourigenesis. Intriguingly, Ripk3(-/-) mice displayed increased body weight gain, while lipidomics showed that deletion of Ripk3 shifted hepatic lipid profiles. Peroxisome proliferator-activated receptor. (PPAR.) was increased in Ripk3(-/-) mice and negatively correlated with hepatic RIPK3 in patients with NAFLD. Mechanistic studies established a functional link between RIPK3 and PPAR. in controlling fat deposition and fibrosis. Conclusion Hepatic RIPK3 correlates with NAFLD severity in humans and mice, playing a key role in managing liver metabolism, damage, inflammation, fibrosis and carcinogenesis. Targeting RIPK3 and its intricate signalling arises as a novel promising approach to treat NASH and arrest disease progression. Main funding is provided by FEDER funds through the COMPETE programme and by national funds through Fundacao para a Ciencia e a Tecnologia to CMPR (grants SAICTPAC/0019/2015-LISBOA-01-0145--FEDER-016405 and PTDC/MED-FAR/29097/2017 -LISBOA-01-0145-FEDER-029097). Additional funding comes from research grant APEF (Portuguese Association for the Study of Liver)/BAYER 2020 to MBA. JG is funded by the Fondation pour la Recherche Medicale (ARF20170938613), the Institute of Cardiometabolism and Nutrition (PAP17NECJG), the Societe Francophone du Diabete (R19114DD) and the Mairie de Paris (Emergences -R18139DD). MBA, PMR, MMP and ALS were investigators or students funded by Fundacao para a Ciencia e a Tecnologia.
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- 2021
8. Circulating Inflammatory miRNAs Associated with Parkinson’s Disease Pathophysiology
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Cecília M. P. Rodrigues, Pedro A. Dionísio, Mário M. Rosa, Leonor Correia Guedes, Joana D. Amaral, Sara R. Oliveira, Joaquim J. Ferreira, Miguel Coelho, and Nilza Gonçalves
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0301 basic medicine ,Oncology ,Male ,medicine.medical_specialty ,Parkinson's disease ,lcsh:QR1-502 ,Inflammation ,Disease ,Biochemistry ,Article ,lcsh:Microbiology ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,microRNA ,medicine ,Humans ,Molecular Biology ,Aged ,Receiver operating characteristic ,business.industry ,Neurodegeneration ,Parkinson Disease ,LRRK2 ,medicine.disease ,Pathophysiology ,nervous system diseases ,serum miRNAs ,MicroRNAs ,030104 developmental biology ,Case-Control Studies ,Parkinson’s disease ,Female ,medicine.symptom ,business ,030217 neurology & neurosurgery ,inflammatory miRNAs - Abstract
Parkinson&rsquo, s disease (PD) is the second most common neurodegenerative disease worldwide, being largely characterized by motor features. MicroRNAs (miRNAs) are small non-coding RNAs, whose deregulation has been associated with neurodegeneration in PD. In this study, miRNAs targeting cell death and/or inflammation pathways were selected and their expression compared in the serum of PD patients and healthy controls. We used two independent cohorts (discovery and validation) of 20 idiopathic PD patients (iPD) and 20 healthy controls each. We also analyzed an additional group of 45 patients with a mutation in the leucine-rich repeat kinase 2 (LRRK2) gene (LRRK2-PD). miRNA expression was determined using Taqman qRT-PCR and their performance to discriminate between groups was assessed by receiver operating characteristic (ROC) curve analysis. We found miR-146a, miR-335-3p, and miR-335-5p downregulated in iPD and LRRK2-PD patients versus controls in both cohorts. In addition, miR-155 was upregulated in LRRK2-PD compared to iPD patients showing an appropriate value of area under the ROC curve (AUC 0.80) to discriminate between the two groups. In conclusion, our study identified a panel of inflammatory related miRNAs differentially expressed between PD patients and healthy controls that highlight key pathophysiological processes and may contribute to improve disease diagnosis.
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- 2020
9. Molecular mechanisms of necroptosis and relevance for neurodegenerative diseases
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Pedro A, Dionísio, Joana D, Amaral, and Cecília M P, Rodrigues
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Necroptosis ,Animals ,Humans ,Neurodegenerative Diseases - Abstract
Necroptosis is a regulated cell death pathway morphologically similar to necrosis that depends on the kinase activity of receptor interacting protein 3 (RIP3) and the subsequent activation of the pseudokinase mixed lineage kinase domain-like protein (MLKL), being also generally dependent on RIP1 kinase activity. Necroptosis can be recruited during pathological conditions, usually following the activation of death receptors under specific cellular contexts. In this regard, necroptosis has been implicated in the pathogenesis of multiple disorders, including acute and chronic neurodegenerative diseases, such as Parkinson's and Alzheimer's diseases, and multiple sclerosis. Here, we summarize the molecular mechanisms regulating the induction of necroptosis and downstream effectors of this form of cell death, besides exploring non-necroptotic roles for necroptosis-related proteins that may impact on alternative cell death pathways and inflammatory mechanisms in disease. Finally, we outline the recent evidence implicating necroptosis in neurodegenerative conditions and the emerging therapeutic perspectives targeting necroptosis in these diseases.
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- 2020
10. Current and novel therapeutic opportunities for systemic therapy in biliary cancer
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Giovanni Brandi, Giulia Mentrasti, Vincenzo Cardinale, Jose J.G. Marin, Maite G. Fernandez-Barrena, John Bridgewater, Oreste Segatto, Angela Lamarca, Rocio I.R. Macias, Arndt Vogel, Jesus M. Banales, Patricia Munoz-Garrido, Pilar Acedo, Ana Landa-Magdalena, Cecília M. P. Rodrigues, Juan W. Valle, Marco Marzioni, Chiara Braconi, Adelaida La Casta, Pedro M. Rodrigues, Simona Tavolari, Joachim C. Mertens, Ana Da Silva Ruivo, Maria Giuseppina Prete, Marin J.J.G., Prete M.G., Lamarca A., Tavolari S., Landa-Magdalena A., Brandi G., Segatto O., Vogel A., Macias R.I.R., Rodrigues P.M., Casta A.L., Mertens J., Rodrigues C.M.P., Fernandez-Barrena M.G., Da Silva Ruivo A., Marzioni M., Mentrasti G., Acedo P., Munoz-Garrido P., Cardinale V., Banales J.M., Valle J.W., Bridgewater J., and Braconi C.
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Oncology ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Review Article ,biliary tract cancer, chemotherapy ,Systemic therapy ,Cholangiocarcinoma ,03 medical and health sciences ,0302 clinical medicine ,Stroma ,Internal medicine ,Tumor Microenvironment ,Medicine ,Humans ,Molecular Targeted Therapy ,Precision Medicine ,Chemotherapy ,Clinical Trials as Topic ,Molecular medicine ,business.industry ,Liquid Biopsy ,Correction ,Biliary cancer ,Phenotype ,3. Good health ,Strategies for treating patients ,Biliary Tract Neoplasms ,Liver ,Biliary tract ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Molecular targets ,Biliary tract cancer ,Immunotherapy ,business ,Biliary tract cancers (BTCs) ,Adjuvant ,Aggressive malignancies - Abstract
Biliary tract cancers (BTCs) are a group of rare and aggressive malignancies that arise in the biliary tree within and outside the liver. Beyond surgical resection, which is beneficial for only a small proportion of patients, current strategies for treating patients with BTCs include chemotherapy, as a single agent or combination regimens, in the adjuvant and palliative setting. Increased characterisation of the molecular landscape of these tumours has facilitated the identification of molecular vulnerabilities, such as IDH mutations and FGFR fusions, that can be exploited for the treatment of BTC patients. Beyond targeted therapies, active research avenues explore the development of novel therapeutics that target the crosstalk between cancer and stroma, the cellular pathways involved in the regulation of cell death, the chemoresistance phenotype and the dysregulation of RNA. In this review, we discuss the therapeutic opportunities currently available in the management of BTC patients, and explore the strategies that can support the implementation of precision oncology in BTCs, including novel molecular targets, liquid biopsies and patient-derived predictive tools.
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- 2020
11. Antitumour Potential of Gigartina pistillata Carrageenans against Colorectal Cancer Stem Cell-Enriched Tumourspheres
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Cecília M. P. Rodrigues, Marta B. Afonso, Vanda Marques, João Cotas, and Leonel Pereira
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cancer stem cells ,Colorectal cancer ,Cell Survival ,Pharmaceutical Science ,colorectal cancer ,Antineoplastic Agents ,Carrageenan ,Cellular viability ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,Inhibitory Concentration 50 ,0302 clinical medicine ,Cancer stem cell ,Cell Line, Tumor ,Drug Discovery ,Ic50 values ,medicine ,Humans ,lcsh:QH301-705.5 ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,Gigartina pistillata ,030304 developmental biology ,Gametophyte ,0303 health sciences ,Biological Products ,Chemistry ,medicine.disease ,Seaweed ,Molecular biology ,lcsh:Biology (General) ,030220 oncology & carcinogenesis ,Rhodophyta ,Neoplastic Stem Cells ,Stem cell ,antitumour activity ,Colorectal Neoplasms - Abstract
Gigartina pistillata is a red seaweed common in Figueira da Foz, Portugal. Here, the antitumour potential of G. pistillata carrageenan, with a known variable of the life cycle, the female gametophyte (FG) and tetrasporophyte (T) was evaluated against colorectal cancer stem cell (CSC) -enriched tumourspheres. FTIR-ATR analysis of G. pistillata carrageenan extracts indicated differences between life cycle phases, being FG a &kappa, /&iota, hybrid carrageenan and T a ʎ/&xi, hybrid. Both carrageenan extracts presented IC50 values inferior to 1 &mu, g/mL in HT29-derived CSC-enriched tumourspheres, as well as reduced tumoursphere area. The two extracts were also effective at reducing cellular viability in SW620- and SW480-derived tumourspheres. These results indicate that carrageenans extracted from two G. pistillata life cycle phases have antitumour potential against colorectal cancer stem-like cells, specially the T carrageenan.
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- 2020
12. Impaired cross-talk between the thioredoxin and glutathione systems is related to ASK-1 mediated apoptosis in neuronal cells exposed to mercury
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Jun Lu, Cristina Carvalho, Susana Solá, Cecília M. P. Rodrigues, Vasco Branco, Lucia Coppo, and Arne Holmgren
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0301 basic medicine ,Antioxidant ,animal structures ,medicine.medical_treatment ,Thioredoxin reductase ,Clinical Biochemistry ,Glutaredoxin ,Apoptosis ,MAP Kinase Kinase Kinase 5 ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,Thioredoxins ,Cell Line, Tumor ,medicine ,Animals ,Humans ,ASK1 ,Buthionine sulfoximine ,Thioredoxin ,lcsh:QH301-705.5 ,Cells, Cultured ,Neurons ,lcsh:R5-920 ,Mercury Compounds ,Organic Chemistry ,Glutathione ,Mercury ,3. Good health ,Cell biology ,030104 developmental biology ,chemistry ,lcsh:Biology (General) ,Mercury Poisoning ,ASK- 1 ,lcsh:Medicine (General) ,Signal Transduction ,Research Paper - Abstract
Mercury (Hg) compounds target both cysteine (Cys) and selenocysteine (Sec) residues in peptides and proteins. Thus, the components of the two major cellular antioxidant systems – glutathione (GSH) and thioredoxin (Trx) systems – are likely targets for mercurials. Hg exposure results in GSH depletion and Trx and thioredoxin reductase (TrxR) are prime targets for mercury. These systems have a wide-range of common functions and interaction between their components has been reported. However, toxic effects over both systems are normally treated as isolated events. To study how the interaction between the glutathione and thioredoxin systems is affected by Hg, human neuroblastoma (SH-SY5Y) cells were exposed to 1 and 5 μM of inorganic mercury (Hg2+), methylmercury (MeHg) or ethylmercury (EtHg) and examined for TrxR, GSH and Grx levels and activities, as well as for Trx redox state. Phosphorylation of apoptosis signalling kinase 1 (ASK1), caspase-3 activity and the number of apoptotic cells were evaluated to investigate the induction of Trx-mediated apoptotic cell death. Additionally, primary cerebellar neurons from mice depleted of mitochondrial Grx2 (mGrx2D) were used to examine the link between Grx activity and Trx function. Results showed that Trx was affected at higher exposure levels than TrxR, especially for EtHg. GSH levels were only significantly affected by exposure to a high concentration of EtHg. Depletion of GSH with buthionine sulfoximine (BSO) severely increased Trx oxidation by Hg. Notably, EtHg-induced oxidation of Trx was significantly enhanced in primary neurons of mGrx2D mice. Our results suggest that GSH/Grx acts as backups for TrxR in neuronal cells to maintain Trx turnover during Hg exposure, thus linking different mechanisms of molecular and cellular toxicity. Finally, Trx oxidation by Hg compounds was associated to apoptotic hallmarks, including increased ASK-1 phosphorylation, caspase-3 activation and increased number of apoptotic cells., Graphical abstract fx1, Highlights • Trx is functional even when TrxR is inhibited by Hg compounds. • Depletion of GSH with BSO increases oxidation of Trx by Hg compounds. • Mice neurons lacking mitochondrial Grx2 show increased oxidation of Trx2 by Hg. • GSH/Grx act as a backup for TrxR during Hg exposure. • Oxidation of Trx by Hg leads to activation of ASK-1 and apoptotic cell death.
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- 2017
13. In vitro targeting of colon cancer cells using spiropyrazoline oxindoles
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Joana D. Amaral, Rute C. Nunes, Carlos Ribeiro, Maria M. M. Santos, Ângelo Monteiro, and Cecília M. P. Rodrigues
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Indoles ,Cell Survival ,Colorectal cancer ,Antineoplastic Agents ,Apoptosis ,Pyrazoline ,Pharmacology ,01 natural sciences ,Chemical library ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Drug Discovery ,Tumor Cells, Cultured ,medicine ,Humans ,Spiro Compounds ,Cytotoxicity ,Cell Proliferation ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Organic Chemistry ,Colon cancer cell ,General Medicine ,HCT116 Cells ,medicine.disease ,In vitro ,Oxindoles ,0104 chemical sciences ,Human colon cancer ,chemistry ,Cell culture ,030220 oncology & carcinogenesis ,Pyrazoles ,Drug Screening Assays, Antitumor - Abstract
We report on the synthesis and biological evaluation of a library of twenty-three spiropyrazoline oxindoles. The antiproliferative activity of the chemical library was evaluated in HCT-116 p53 (+/+) human colon cancer cell line with eight derivatives displaying good activities (IC 50 2e with sub-toxic concentrations of the chemotherapeutic agent 5-fluorouracil (5-FU) exerted a synergistic inhibitory effect on HCT-116 colon cancer cell proliferation. Collectively, our results show the potential of spiropyrazoline oxindoles for development of novel anticancer agents.
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- 2017
14. Necrosome Formation and Necroptosis in Experimental Cholestasis
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Marta B, Afonso and Cecília M P, Rodrigues
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Mice ,Necrosis ,Cholestasis ,HEK293 Cells ,Receptor-Interacting Protein Serine-Threonine Kinases ,Animals ,Humans ,Immunoprecipitation ,Apoptosis ,Electrophoresis, Polyacrylamide Gel ,Signal Transduction - Abstract
Necroptosis is emerging as a critical pathogenic mechanism in several liver diseases, including cholestatic disorders. Necroptosis was recently described as a novel cell death subroutine, activated downstream of death receptor stimulation and dependent on receptor-interacting serine/threonine-protein kinase 3 activity and mixed lineage kinase domain-like oligomerization and translocation to cell membrane. Here, we describe a combination of methods to evaluate necroptosis triggering in in vitro and in vivo models of cholestasis. Particularly, we detail alternative protocols to isolate total and soluble/insoluble protein extracts from tissues and cell cultures, as well as in vitro receptor-interacting serine/threonine-protein kinase 3 kinase activity assays, and subsequent Western blot analysis.
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- 2019
15. Combining 1,3-Ditriazolylbenzene and Quinoline to Discover a New G-Quadruplex-Interactive Small Molecule Active against Cancer Stem-Like Cells
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João Lavrado, Stephen Neidle, Jorge M. B. Vítor, Eduarda Mendes, Marta B. Afonso, Hugo Brito, Daniel J. V. A. dos Santos, Enrico Cadoni, Filipa Carneiro, Cecília M. P. Rodrigues, and Alexandra Paulo
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Antineoplastic Agents ,G-quadruplex ,01 natural sciences ,Biochemistry ,chemistry.chemical_compound ,Mice ,Cancer stem cell ,Cell Line, Tumor ,Drug Discovery ,medicine ,Cytotoxic T cell ,Animals ,Humans ,General Pharmacology, Toxicology and Pharmaceutics ,Cytotoxicity ,Pharmacology ,Binding Sites ,010405 organic chemistry ,Organic Chemistry ,Quinoline ,Cancer ,DNA ,Triazoles ,medicine.disease ,Small molecule ,0104 chemical sciences ,G-Quadruplexes ,Molecular Docking Simulation ,010404 medicinal & biomolecular chemistry ,chemistry ,Drug Design ,Quinolines ,Molecular Medicine ,Drug Screening Assays, Antitumor - Abstract
Quadruplex nucleic acids are promising targets for cancer therapy. In this study we used a fragment-based approach to create new flexible G-quadruplex (G4) DNA-interactive small molecules with good calculated oral drug-like properties, based on quinoline and triazole heterocycles. G4 melting temperature and polymerase chain reaction (PCR)-stop assays showed that two of these compounds are selective G4 ligands, as they were able to induce and stabilize G4s in a dose- and DNA sequence-dependent manner. Molecular docking studies have suggested plausible quadruplex binding to both the G-quartet and groove, with the quinoline module playing the major role. Compounds were screened for cytotoxicity against four cancer cell lines, where 4,4'-(4,4'-(1,3-phenylene)bis(1H-1,2,3-triazole-4,1-diyl))bis(1-methylquinolin-1-ium) (1 d) showed the greater activity. Importantly, dose-response curves show that 1 d is cytotoxic in the human colon cancer HT-29 cell line enriched in cancer stem-like cells, a subpopulation of cells implicated in chemoresistance. Overall, this study identified a new small molecule as a promising lead for the development of drugs targeting G4 in cancer stem cells.
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- 2019
16. Copper complex nanoformulations featuring highly promising therapeutic potential in murine melanoma models
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Angela Casini, Joana D. Amaral, Cecília M. P. Rodrigues, Graça Soveral, Rui E. Castro, Maria Manuela Gaspar, and Jacinta O. Pinho
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Male ,Cell Survival ,Drug Compounding ,Biomedical Engineering ,Melanoma, Experimental ,Medicine (miscellaneous) ,Bioengineering ,Antineoplastic Agents ,Apoptosis ,02 engineering and technology ,Development ,03 medical and health sciences ,Mice ,In vivo ,Coordination Complexes ,Cell Line, Tumor ,medicine ,Cytotoxic T cell ,Animals ,Humans ,General Materials Science ,030304 developmental biology ,0303 health sciences ,Liposome ,Copper complex ,Chemistry ,Melanoma ,Hydrogen-Ion Concentration ,021001 nanoscience & nanotechnology ,medicine.disease ,In vitro ,Mice, Inbred C57BL ,Drug Liberation ,Tumor progression ,Delayed-Action Preparations ,Liposomes ,Cancer research ,Nanoparticles ,0210 nano-technology ,B16 melanoma ,Copper - Abstract
Aim: Preclinical evaluation of a cytotoxic copper (II) complex formulated in long circulating nanoliposomes for melanoma treatment. Materials & methods: Liposomal nanoformulations of the copper complex were characterized in terms of thermodynamic behavior (differential scanning calorimeter), pH-sensitivity (spectrophotometry) and antiproliferative effects against murine melanoma B16F10 cells in vitro. Preclinical studies were performed in a C57BL/6 syngeneic melanoma model. Results: Nanoformulations were thermodynamically stable, and CHEMS-containing nanoliposomes were pH-sensitive and preserved the antiproliferative properties of the copper compound. These nanoformulations significantly impaired tumor progression in vivo, devoid of toxic side effects, compared with control mice or mice treated with the free metallodrug. Conclusion: Copper complex-containing nanoliposomes demonstrate high anticancer efficacy and safety, constituting a step forward to the development of more effective therapeutic strategies against melanoma.
- Published
- 2019
17. miRNAs as Modulators of EGFR Therapy in Colorectal Cancer
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Diane M, Pereira and Cecília M P, Rodrigues
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ErbB Receptors ,Proto-Oncogene Proteins p21(ras) ,MicroRNAs ,Mutation ,Antibodies, Monoclonal ,Humans ,Antineoplastic Agents ,Colorectal Neoplasms - Abstract
Drug resistance is a serious impediment to the treatment of cancer. The use of anti-epidermal growth factor receptor (EGFR) monoclonal antibody therapies in patients with metastatic colorectal cancer is guided by the presence of activating point mutations in KRAS and NRAS genes in the primary tumour. However, RAS wild-type status is still not sufficient to guarantee response to cetuximab and panitumumab, with response rates limited to 70% for combinations with multidrug chemotherapy. Therefore, additional mechanisms contributing to resistance are currently under investigation, and include genetic alterations and epigenetic mechanisms of resistance. In this regard, deregulation of miRNA expression profiles holds potential to unveil resistance and fuel the development of miRNA-based strategies to overcome EGFR-directed therapy limitations. We discuss current understanding of miRNA impact as modulators of EGFR therapy in patients with metastatic colorectal cancer and the future challenge of miRNAs in circulation as powerful non-invasive tools to monitor anti-EGFR therapy response and predict resistance.
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- 2019
18. Proof-of-Concept Study of Multifunctional Hybrid Nanoparticle System Combined with NIR Laser Irradiation for the Treatment of Melanoma
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Cecília M. P. Rodrigues, David A. Ferreira, Joana Lopes, Hugo Ferreira, Catarina Pinto Reis, Maria Manuela Gaspar, Pedro Faísca, João Coelho, Ana S. Viana, Tânia Ferreira-Gonçalves, Catarina Silva, Isabel Vitória Figueiredo, and Repositório da Universidade de Lisboa
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Male ,Skin erythema ,Skin Neoplasms ,Superficial tumors ,lcsh:QR1-502 ,Metal Nanoparticles ,Context (language use) ,Mice, SCID ,Multifunctional nanoparticles ,Proof of Concept Study ,Biochemistry ,Article ,lcsh:Microbiology ,Targeted therapy ,03 medical and health sciences ,0302 clinical medicine ,In vivo ,Epidermal growth factor ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Gold nanoparticles ,Low-Level Light Therapy ,Melanoma ,Molecular Biology ,030304 developmental biology ,0303 health sciences ,Epidermal Growth Factor ,Chemistry ,Photothermal therapy ,medicine.disease ,Xenograft Model Antitumor Assays ,Colloidal gold ,030220 oncology & carcinogenesis ,Cutaneous melanoma ,Cancer research ,Gold ,Experimental models ,Oleic Acid - Abstract
Supplementary Materials - available online at https://www.mdpi.com/article/10.3390/biom11040511/s1, The global impact of cancer emphasizes the importance of developing innovative, effective and minimally invasive therapies. In the context of superficial cancers, the development of a multifunctional nanoparticle-based system and its in vitro and in vivo safety and efficacy characterization are, herein, proposed as a proof-of-concept. This multifunctional system consists of gold nanoparticles coated with hyaluronic and oleic acids, and functionalized with epidermal growth factor for greater specificity towards cutaneous melanoma cells. This nanoparticle system is activated by a near-infrared laser. The characterization of this nanoparticle system included several phases, with in vitro assays being firstly performed to assess the safety of gold nanoparticles without laser irradiation. Then, hairless immunocompromised mice were selected for a xenograft model upon inoculation of A375 human melanoma cells. Treatment with near-infrared laser irradiation for five minutes combined with in situ administration of the nanoparticles showed a tumor volume reduction of approximately 80% and, in some cases, led to the formation of several necrotic foci, observed histologically. No significant skin erythema at the irradiation zone was verified, nor other harmful effects on the excised organs. In conclusion, these assays suggest that this system is safe and shows promising results for the treatment of superficial melanoma., The authors would like to thank to Fundação para a Ciência e Tecnologia (FCT) for the essential financial support under the project’s references PTDC/BBB-BMC/0611/2012, UIDB/00645/2020, UIDB/04138/2020 and UIDP/04138/2020 as well as for the PhD fellowships SFRH/BD/148044/2019 and SFRH/BD/147306/2019.
- Published
- 2021
19. Tauroursodeoxycholic Acid Protects Against Mitochondrial Dysfunction and Cell Death via Mitophagy in Human Neuroblastoma Cells
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Carla Azevedo, Maria João Nunes, Elsa Rodrigues, Sara Moreira, Cecília M. P. Rodrigues, Margarida Castro-Caldas, Maria João Gama, Gisela Gordino, and Inês T.E. Fonseca
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0301 basic medicine ,Mitochondrial Turnover ,Population ,Neuroscience (miscellaneous) ,Mitochondrial Degradation ,Mitochondrion ,Biology ,Neuroprotection ,Taurochenodeoxycholic Acid ,Neuroblastoma ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Cell Line, Tumor ,Mitophagy ,medicine ,Humans ,education ,education.field_of_study ,Cell Death ,Neurodegeneration ,Tauroursodeoxycholic acid ,medicine.disease ,Mitochondria ,Cell biology ,Neuroprotective Agents ,030104 developmental biology ,Neurology ,chemistry ,Reactive Oxygen Species - Abstract
Mitochondrial dysfunction has been deeply implicated in the pathogenesis of several neurodegenerative diseases. Thus, to keep a healthy mitochondrial population, a balanced mitochondrial turnover must be achieved. Tauroursodeoxycholic acid (TUDCA) is neuroprotective in various neurodegenerative disease models; however, the mechanisms involved are still incompletely characterized. In this study, we investigated the neuroprotective role of TUDCA against mitochondrial damage triggered by the mitochondrial uncoupler carbonyl cyanide m-chlorophelyhydrazone (CCCP). Herein, we show that TUDCA significantly prevents CCCP-induced cell death, ROS generation, and mitochondrial damage. Our results indicate that the neuroprotective role of TUDCA in this cell model is mediated by parkin and depends on mitophagy. The demonstration that pharmacological up-regulation of mitophagy by TUDCA prevents neurodegeneration provides new insights for the use of TUDCA as a modulator of mitochondrial activity and turnover, with implications in neurodegenerative diseases.
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- 2016
20. Nanoformulations of a potent copper-based aquaporin inhibitor with cytotoxic effect against cancer cells
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Maria Manuela Gaspar, Rui E. Castro, Angela Casini, Mariana Nave, Cecília M. P. Rodrigues, and Graça Soveral
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Male ,0301 basic medicine ,Cell Survival ,Biomedical Engineering ,Medicine (miscellaneous) ,Aquaporin ,Antineoplastic Agents ,Bioengineering ,Development ,Biology ,Pharmacology ,Aquaporins ,03 medical and health sciences ,0302 clinical medicine ,Coordination Complexes ,In vivo ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Cytotoxic T cell ,QD ,General Materials Science ,Melanoma ,Cell Proliferation ,Mice, Inbred BALB C ,Liposome ,Cell growth ,medicine.disease ,In vitro ,030104 developmental biology ,030220 oncology & carcinogenesis ,Colonic Neoplasms ,Liposomes ,Cancer cell ,Copper ,Phenanthrolines - Abstract
Aim: Development of liposomal formulations of Cuphen, a potent copper-based aquaporin inhibitor with therapeutic potential against melanoma and colon cancer. Materials & methods: Cuphen was incorporated into liposomes using the dehydration–rehydration method. The ability of Cuphen to induce cancer cell death was evaluated by MTS and ViaCount assays. In vivo toxicity studies were performed in BALB/c mice. Results: In vitro studies illustrated the antiproliferative effects of Cuphen in different cancer cell lines, in free form or after incorporation into liposomes. In vivo studies revealed no toxic effects after parenteral administration of Cuphen liposomes. Conclusions: Cuphen liposomes are highly attractive to be further tested in murine models due to the possibility of stabilizing and specifically deliver this metallodrug to tumor sites.
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- 2016
21. MEK5/ERK5 signaling inhibition increases colon cancer cell sensitivity to 5-fluorouracil through a p53-dependent mechanism
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Cecília M. P. Rodrigues, Diane M. Pereira, Pedro M. Borralho, André E. S. Simões, Rui E. Castro, Sofia E. Gomes, and Tânia Carvalho
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p53 ,0301 basic medicine ,Colorectal cancer ,medicine.medical_treatment ,Apoptosis ,Mice, SCID ,MAP Kinase Kinase 5 ,medicine.disease_cause ,Metastasis ,Mice ,Puma ,Cytotoxic T cell ,5-fluorouracil ,Caspase 7 ,Benzodiazepinones ,Mice, Inbred BALB C ,biology ,Caspase 3 ,chemosensitization ,3. Good health ,Oncology ,Fluorouracil ,Colonic Neoplasms ,KRAS ,Research Paper ,medicine.drug ,Antimetabolites, Antineoplastic ,MAP Kinase Signaling System ,MEK5/ERK5 ,Proto-Oncogene Proteins p21(ras) ,03 medical and health sciences ,Cell Line, Tumor ,Proto-Oncogene Proteins ,medicine ,Animals ,Humans ,Mitogen-Activated Protein Kinase 7 ,Cell Proliferation ,Chemotherapy ,business.industry ,HCT116 Cells ,medicine.disease ,biology.organism_classification ,Xenograft Model Antitumor Assays ,Enzyme Activation ,030104 developmental biology ,Immunology ,Cancer research ,Tumor Suppressor Protein p53 ,Apoptosis Regulatory Proteins ,business - Abstract
// Diane M. Pereira 1 , Andre E. S. Simoes 1 , Sofia E. Gomes 1 , Rui E. Castro 1 , Tânia Carvalho 2 , Cecilia M. P. Rodrigues 1, * , Pedro M. Borralho 1, * 1 Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal 2 Histology and Comparative Pathology Laboratory, Instituto de Medicina Molecular, Lisbon, Portugal * These authors have contributed equally and share senior authorship Correspondence to: Cecilia M. P. Rodrigues, email: cmprodrigues@ff.ulisboa.pt Pedro M. Borralho, email: borralho@ff.ulisboa.pt Keywords: MEK5/ERK5, p53, 5-fluorouracil, apoptosis, chemosensitization Received: November 16, 2015 Accepted: March 31, 2016 Published: April 29, 2016 ABSTRACT The MEK5/ERK5 signaling pathway is emerging as an important contributor to colon cancer onset, progression and metastasis; however, its relevance to chemotherapy resistance remains unknown. Here, we evaluated the impact of the MEK5/ERK5 cascade in colon cancer cell sensitivity to 5-fluorouracil (5-FU). Increased ERK5 expression was correlated with poor overall survival in colon cancer patients. In colon cancer cells, 5-FU exposure impaired endogenous KRAS/MEK5/ERK5 expression and/or activation. In turn, MEK5 constitutive activation reduced 5-FU-induced cytotoxicity. Using genetic and pharmacological approaches, we showed that ERK5 inhibition increased caspase-3/7 activity and apoptosis following 5-FU exposure. Mechanistically, this was further associated with increased p53 transcriptional activation of p21 and PUMA . In addition, ERK5 inhibition increased the response of HCT116 p53 +/+ cells to 5-FU, but failed to sensitize HCT116 p53 −/− cells to the cytotoxic effects of this chemotherapeutic agent, suggesting a p53-dependent axis mediating 5-FU sensitization. Finally, ERK5 inhibition using XMD8-92 was shown to increase the antitumor effects of 5-FU in a murine subcutaneous xenograft model, enhancing apoptosis while markedly reducing tumor growth. Collectively, our results suggest that ERK5-targeted inhibition provides a promising therapeutic approach to overcome resistance to 5-FU-based chemotherapy and improve colon cancer treatment.
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- 2016
22. Imidazoline Receptors Agonists for Managing Hypertension May Hold Promise for Treatment of Intracerebral Hemorrhage
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Afshin A. Divani, M. Di Napoli, Cecília M. P. Rodrigues, Eric M. Bershad, Simona Lattanzi, Alireza Majdi, and Javad Mahmoudi
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Excitotoxicity ,Imidazoline receptor ,Blood Pressure ,Inflammation ,030204 cardiovascular system & hematology ,Pharmacology ,medicine.disease_cause ,Biochemistry ,Neuroprotection ,03 medical and health sciences ,0302 clinical medicine ,Animals ,Humans ,Medicine ,cardiovascular diseases ,Risk factor ,Molecular Biology ,Stroke ,Antihypertensive Agents ,Cerebral Hemorrhage ,Intracerebral hemorrhage ,business.industry ,General Medicine ,medicine.disease ,nervous system diseases ,Blood pressure ,Hypertension ,Molecular Medicine ,Imidazoline Receptors ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
Intracerebral hemorrhage (ICH), which accounts for 10% of all strokes, leads to higher morbidity and mortality compared with other stroke subtypes. Hypertension has been recognized as a major risk factor for ICH. Current antihypertensive options have not been fully effective for either prevention of ICH or ameliorating its complications. Therefore, attempts should be made to use novel antihypertensive medications for more effective management of blood pressure (BP) in the acute phase of ICH. Imidazoline receptor (IR) agonists can potentially be effective agents for BP control with the adjunctive ability to attenuate post-ICH brain injury. IR agonists render neuroprotective effects including inhibition of inflammatory reactions, apoptotic cell death, excitotoxicity, and brain edema. Given these properties, the present review aims to focus on the application of IR agonists for managing BP in ICH patients.
- Published
- 2018
23. In Silico HCT116 Human Colon Cancer Cell-Based Models En Route to the Discovery of Lead-Like Anticancer Drugs
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Sofia E. Gomes, Susana P. Gaudêncio, Pedro M. Borralho, Sara Cruz, Florbela Pereira, Cecília M. P. Rodrigues, LAQV@REQUIMTE, DQ - Departamento de Química, UCIBIO - Applied Molecular Biosciences Unit, and DCV - Departamento de Ciências da Vida
- Subjects
Models, Molecular ,0301 basic medicine ,HCT116 Cell ,Magnetic Resonance Spectroscopy ,Support Vector Machine ,lcsh:QR1-502 ,Quantitative Structure-Activity Relationship ,01 natural sciences ,Biochemistry ,Anticancer activity ,lcsh:Microbiology ,Drug Discovery ,Marine natural products (MNPs) ,marine-derived actinobacteria ,Chemistry ,quantitative structure–activity relationship (QSAR) ,HCT116 cell line ,Machine learning (ML) ,chEMBL ,3. Good health ,Actinobacteria ,anticancer activity ,Quantitative structure-Activity relationship (QSAR) ,Colonic Neoplasms ,biological phenomena, cell phenomena, and immunity ,Human colon ,Quantitative structure–activity relationship ,Cell Survival ,marine natural products (MNPs) ,In silico ,Marine-derived actinobacteria ,Antineoplastic Agents ,Computational biology ,Article ,Molecular descriptors ,Inhibitory Concentration 50 ,03 medical and health sciences ,molecular descriptors ,SDG 3 - Good Health and Well-being ,Molecular descriptor ,Humans ,Computer Simulation ,SDG 14 - Life Below Water ,Molecular Biology ,neoplasms ,Cell Proliferation ,Biological Products ,010405 organic chemistry ,machine learning (ML) ,HCT116 Cells ,NMR descriptors ,digestive system diseases ,0104 chemical sciences ,Human colon cancer ,030104 developmental biology ,Drug Screening Assays, Antitumor ,Databases, Chemical ,Cell based - Abstract
To discover new inhibitors against the human colon carcinoma HCT116 cell line, two quantitative structure&ndash, activity relationship (QSAR) studies using molecular and nuclear magnetic resonance (NMR) descriptors were developed through exploration of machine learning techniques and using the value of half maximal inhibitory concentration (IC50). In the first approach, A, regression models were developed using a total of 7339 molecules that were extracted from the ChEMBL and ZINC databases and recent literature. The performance of the regression models was successfully evaluated by internal and external validations, the best model achieved R2 of 0.75 and 0.73 and root mean square error (RMSE) of 0.66 and 0.69 for the training and test sets, respectively. With the inherent time-consuming efforts of working with natural products (NPs), we conceived a new NP drug hit discovery strategy that consists in frontloading samples with 1D NMR descriptors to predict compounds with anticancer activity prior to bioactivity screening for NPs discovery, approach B. The NMR QSAR classification models were built using 1D NMR data (1H and 13C) as descriptors, from 50 crude extracts, 55 fractions and five pure compounds obtained from actinobacteria isolated from marine sediments collected off the Madeira Archipelago. The overall predictability accuracies of the best model exceeded 63% for both training and test sets.
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- 2018
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24. Mechanism and disease implications of necroptosis and neuronal inflammation
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Sara R. Oliveira, Joana D. Amaral, and Cecília M. P. Rodrigues
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0301 basic medicine ,Inflammation ,Neurons ,Cancer Research ,Mechanism (biology) ,lcsh:Cytology ,Necroptosis ,Immunology ,Comment ,Apoptosis ,Cell Biology ,Disease ,Biology ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Necrosis ,030104 developmental biology ,medicine ,Humans ,Microglia ,medicine.symptom ,lcsh:QH573-671 ,Neuroscience ,Signal Transduction - Published
- 2018
25. Acquired resistance to aromatase inhibitors: where we stand!
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Georgina Correia-da-Silva, Cristina Amaral, Tiago V. Augusto, Natércia Teixeira, and Cecília M. P. Rodrigues
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0301 basic medicine ,Cancer Research ,medicine.drug_class ,Endocrinology, Diabetes and Metabolism ,Anastrozole ,Breast Neoplasms ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Endocrinology ,Breast cancer ,Exemestane ,Medicine ,Humans ,Aromatase ,PI3K/AKT/mTOR pathway ,biology ,business.industry ,Aromatase Inhibitors ,Letrozole ,medicine.disease ,Androgen receptor ,030104 developmental biology ,Oncology ,chemistry ,Estrogen ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Female ,business ,medicine.drug - Abstract
Aromatase inhibitors (AIs) are one of the principal therapeutic approaches for estrogen receptor-positive (ER+) breast cancer in postmenopausal women. They block estrogen biosynthesis through aromatase inhibition, thus preventing tumour progression. Besides the therapeutic success of the third-generation AIs, acquired resistance may develop, leading to tumour relapse. This resistance is thought to be the result of a change in the behaviour of ER in these breast cancer cells, presumably by PI3K/AKT pathway enhancement along with alterations in other signalling pathways. Nevertheless, biological mechanisms, such as apoptosis, autophagy, cell cycle modulation and activation of androgen receptor (AR), are also implicated in acquired resistance. Moreover, clinical evidence demonstrated that there is a lack of cross-resistance among AIs, although the reason is not fully understood. Thus, there is a demand to understand the mechanisms involved in endocrine resistance to each AI, since the search for new strategies to surpass breast cancer acquired resistance is of major concern.
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- 2018
26. Monoterpene indole alkaloid hydrazone derivatives with apoptosis inducing activity in human HCT116 colon and HepG2 liver carcinoma cells
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Cecília M. P. Rodrigues, Maria-José U. Ferreira, Sofia E. Gomes, Silva Mulhovo, Angela Paterna, and Pedro M. Borralho
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Colon ,Tabernaemontana ,Clinical Biochemistry ,Pharmaceutical Science ,Apoptosis ,Plant Roots ,Biochemistry ,Indole Alkaloids ,Flow cytometry ,chemistry.chemical_compound ,Hydroxylamine ,Drug Discovery ,medicine ,Humans ,Cytotoxicity ,Molecular Biology ,Indole test ,medicine.diagnostic_test ,Indole alkaloid ,biology ,Liver Neoplasms ,Organic Chemistry ,Hydrazones ,Tabernaemontana elegans ,Hep G2 Cells ,HCT116 Cells ,biology.organism_classification ,Antineoplastic Agents, Phytogenic ,Liver ,chemistry ,Cell culture ,Colonic Neoplasms ,Molecular Medicine - Abstract
The derivatization of dregamine (1) and tabernaemontanine (2), two epimeric monoterpene indole alkaloids isolated from the methanol extract of the roots of Tabernaemontana elegans, with several hydrazines and hydroxylamine gave rise to ten new derivatives (3-12). Their structures were assigned by spectroscopic methods, including 2D NMR experiments. The compounds were tested for their ability to induce apoptosis in HCT116 colon and HepG2 liver cancer cells. Firstly, the cytotoxicity of all compounds (1-12) was evaluated in both cell lines by the MTS assay. The most active compounds (6, 9, 10) along with 1 and 2 were further investigated for their apoptosis induction capability by Guava ViaCount flow cytometry assays, nuclear morphology evaluation by Hoechst staining, and caspase-3/7 activity assays. Compounds 9 and 10 showed promising apoptosis induction profile, displaying higher activities than 5-fluorouracil, the mainstay in colon cancer treatment.
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- 2015
27. Distinct kinetics and pathways of apoptosis in influenza A and B virus infection
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Susana Solá, Luis A Santos, Cecília M. P. Rodrigues, and Helena Rebelo-de-Andrade
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Cancer Research ,Host (biology) ,Strain (biology) ,NF-kappa B ,Defence mechanisms ,Apoptosis ,Influenza a ,Biology ,Virus Replication ,Virology ,Virus ,Microbiology ,Influenza B virus ,Kinetics ,Infectious Diseases ,Viral replication ,Influenza A virus ,Influenza, Human ,Humans ,PI3K/AKT/mTOR pathway ,Signal Transduction - Abstract
Annual influenza epidemics are associated with high incidence and mortality rates, and are an important cause of work absenteeism and productivity losses. For successful replication, influenza viruses have evolved as to counteract and/or take a part on host defense mechanisms. Manipulation of apoptosis is one of such mechanisms that have been subject of attention, particularly in relation to influenza type A viruses over the past years. However, this knowledge has not been extended to include influenza type B viruses. In this study, MDCK-SIAT1 cells were infected with influenza A and B strains and the kinetics and pathways of apoptosis post infection were studied, through LDH measurements, Hoechst dye staining, caspase activity assays and protein expression analysis. The resulting data points to a difference in induction of apoptosis profiles between influenza A and B strains. While influenza A strain induced apoptosis later in the course of infection and mainly by the intrinsic pathway, influenza B strain induced apoptosis early in infection by both intrinsic and extrinsic pathways. Also, data revealed the IκB/NF-κB pathway as the major contributor for the observed differences. The study of the virus–host interactions, particularly those that could have an impact on viral replication, are essential in both influenza A and B viruses, as they will allow the identification of viral/host targets common to both influenza types, which could affect viral replication. This information may prove useful for vaccine and antiviral research.
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- 2015
28. Cyclopentadienyl–Ruthenium(II) and Iron(II) Organometallic Compounds with Carbohydrate Derivative Ligands as Good Colorectal Anticancer Agents
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Pedro Florindo, M. F. M. Piedade, Cecília M. P. Rodrigues, Pedro M. Borralho, Diane M. Pereira, and Ana C. Fernandes
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Cell Survival ,Stereochemistry ,Carbohydrates ,chemistry.chemical_element ,Antineoplastic Agents ,Chemistry Techniques, Synthetic ,Crystal structure ,Crystallography, X-Ray ,Ligands ,Ruthenium ,Metal ,Inhibitory Concentration 50 ,Cyclopentadienyl complex ,Drug Discovery ,Organometallic Compounds ,medicine ,Humans ,Ferrous Compounds ,Viability assay ,Group 2 organometallic chemistry ,Dose-Response Relationship, Drug ,Molecular Structure ,HCT116 Cells ,Oxaliplatin ,chemistry ,visual_art ,visual_art.visual_art_medium ,Molecular Medicine ,Drug Screening Assays, Antitumor ,Colorectal Neoplasms ,Linker ,medicine.drug - Abstract
New ruthenium(II) and iron(II) organometallic compounds of general formula [(η(5)-C5H5)M(PP)Lc][PF6], bearing carbohydrate derivative ligands (Lc), were prepared and fully characterized and the crystal structures of five of those compounds were determined by X-ray diffraction studies. Cell viability of colon cancer HCT116 cell line was determined for a total of 23 organometallic compounds and SAR's data analysis within this library showed an interesting dependency of the cytotoxic activity on the carbohydrate moiety, linker, phosphane coligands, and metal center. More importantly, two compounds, 14Ru and 18Ru, matched oxaliplatin IC50 (0.45 μM), the standard metallodrug used in CC chemotherapeutics, and our leading compound 14Ru was shown to be significantly more cytotoxic than oxaliplatin to HCT116 cells, triggering higher levels of caspase-3 and -7 activity and apoptosis in a dose-dependent manner.
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- 2015
29. Essential versus accessory aspects of cell death: recommendations of the NCCD 2015
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Lorenzo Galluzzi, Thomas Rudel, Hans-Uwe Simon, Vishva M. Dixit, Erwin F. Wagner, Marie-Lise Gougeon, Andreas Linkermann, J M Bravo-San Pedro, Rosario Rizzuto, Cecília M. P. Rodrigues, Gian Maria Fimia, Hidenori Ichijo, Mathieu J.M. Bertrand, Kodi S. Ravichandran, Francis Ka-Ming Chan, Stephen W.G. Tait, Jochen H. M. Prehn, Richard A. Lockshin, Valina L. Dawson, Andreas Villunger, Sharad Kumar, Emily H. Cheng, Carlos López-Otín, Theocharis Panaretakis, Lucia Altucci, Gabriel A. Rabinovich, Michelangelo Campanella, Peter Vandenabeele, Marcus E. Peter, Francesco Cecconi, Noboru Mizushima, Ilio Vitale, Frank Madeo, Mikhail V. Blagosklonny, Zahra Zakeri, Stuart A. Aaronson, Gabriel Núñez, Eric H. Baehrecke, Nektarios Tavernarakis, Gyorgy Szabadkai, Eleonora Candi, Brent R. Stockwell, Dale E. Bredesen, Seamus J. Martin, Thomas Kaufmann, Sonia Melino, Dieter Adam, John M. Abrams, Katiuscia Bianchi, Yufang Shi, Emad S. Alnemri, Klas Blomgren, Pascal Meier, Catherine Brenner, Michael O. Hengartner, Philipp J. Jost, J M Hardwick, Eileen White, T Vanden Berghe, N. Di Daniele, Nicolas G. Bazan, H. L. Tang, Mauro Piacentini, V De Laurenzi, Beth Levine, Margherita Annicchiarico-Petruzzelli, Josef M. Penninger, Walter Malorni, Ted M. Dawson, Carmen Garrido, David W. Andrews, Douglas R. Green, György Hajnóczky, Jerry E. Chipuk, Wafik S. El-Deiry, Christoph Borner, Stuart A. Lipton, John A. Cidlowski, Klaus-Michael Debatin, Junying Yuan, Jan Paul Medema, Bertrand Joseph, Aaron Ciechanover, Ute M. Moll, Hinrich Gronemeyer, Paolo Pinton, Gerry Melino, Daniel J. Klionsky, Simone Fulda, John J. Lemasters, Cristina Muñoz-Pinedo, Hamsa Puthalakath, Navdeep S. Chandel, R De Maria, Jean-Christophe Marine, Richard A. Flavell, Brian David Dynlacht, W. G. Wood, Henning Walczak, David C. Rubinsztein, Guido Kroemer, Oliver Kepp, Richard A. Knight, Andrew Oberst, Enrico Lugli, J-C Martinou, Boris Zhivotovsky, Yoshihide Tsujimoto, Galluzi, L, Bravo-San, Pedro JM, Vitale, I, Aaaronson, SA, Kumar, S, Kroemer, Guido, Galluzzi, L, Bravo San Pedro, J. M, Aaronson, S. A, Abrams, J. M, Adam, D, Alnemri, E. S, Altucci, L, Andrews, D, Annicchiarico Petruzzelli, M, Baehrecke, E. H, Bazan, N. G, Bertrand, M. J, Bianchi, K, Blagosklonny, M. V, Blomgren, K, Borner, C, Bredesen, D. E, Brenner, C, Campanella, M, Candi, E, Cecconi, F, Chan, F. K, Chandel, N. S, Cheng, E. H, Chipuk, J. E, Cidlowski, J. A, Ciechanover, A, Dawson, T. M, Dawson, V. L, De Laurenzi, V, De Maria, R, Debatin, K. M, Di Daniele, N, Dixit, V. M, Dynlacht, B. D, El Deiry, W. S, Fimia, Gian Maria, Flavell, R. A, Fulda, S, Garrido, C, Gougeon, M. L, Green, D. R, Gronemeyer, H, Hajnoczky, G, Hardwick, J. M, Hengartner, M. O, Ichijo, H, Joseph, B, Jost, P. J, Kaufmann, T, Kepp, O, Klionsky, D. J, Knight, R. A, Lemasters, J. J, Levine, B, Linkermann, A, Lipton, S. A, Lockshin, R. A, López Otín, C, Lugli, E, Madeo, F, Malorni, W, Marine, J. C, Martin, S. J, Martinou, J. C, Medema, J. P, Meier, P, Melino, S, Mizushima, N, Moll, U, Muñoz Pinedo, C, Nuñez, G, Oberst, A, Panaretakis, T, Penninger, J. M, Peter, M. E, Piacentini, M, Pinton, P, Prehn, J. H, Puthalakath, H, Rabinovich, G. A, Ravichandran, K. S, Rizzuto, R, Rodrigues, C. M, Rubinsztein, D. C, Rudel, T, Shi, Y, Simon, H. U, Stockwell, B. R, Szabadkai, G, Tait, S. W, Tang, H. L, Tavernarakis, N, Tsujimoto, Y, Vanden Berghe, T, Vandenabeele, P, Villunger, A, Wagner, E. F, Walczak, H, White, E, Wood, W. G, Yuan, J, Zakeri, Z, Zhivotovsky, B, Melino, G, Kroemer, G., Bravo San Pedro, Jm, Aaronson, Sa, Abrams, Jm, Alnemri, E, Altucci, Lucia, Baehrecke, Eh, Bazan, Ng, Bertrand, Mj, Blagosklonny, Mv, Bredesen, De, Chan, Fk, Chandel, N, Cheng, Eh, Chipuk, Je, Cidlowski, Ja, Dawson, Tm, Dawson, Vl, Debatin, Km, Dixit, Vm, Dynlacht, Bd, El Deiry, W, Fimia, Gm, Flavell, Ra, Gougeon, Ml, Green, Dr, Hardwick, Jm, Hengartner, Mo, Jost, Pj, Klionsky, Dj, Knight, Ra, Lemasters, Jj, Lipton, Sa, Lockshin, Ra, Marine, Jc, Martin, Sj, Martinou, Jc, Medema, Jp, Penninger, Jm, Peter, Me, Prehn, Jh, Rabinovich, Ga, Ravichandran, K, Rodrigues, Cm, Rubinsztein, Dc, Simon, Hu, Stockwell, Br, Tait, Sw, Tang, Hl, Wagner, Ef, and Wood, Wg
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Biochemical Manifestations of Cell Death ,ISCHEMIA-REPERFUSION INJURY ,Apoptosis ,Review ,Transduction (genetics) ,0302 clinical medicine ,CASPASE INHIBITION SWITCHES ,Animals ,Humans ,Terminology as Topic ,Signal Transduction ,610 Medicine & health ,Caspase ,TUMOR-NECROSIS-FACTOR ,0303 health sciences ,Settore BIO/17 ,biology ,Settore BIO/11 ,Neurodegeneration ,Settore BIO/13 ,APOPTOSIS ,3. Good health ,Medicina Básica ,cell death ,030220 oncology & carcinogenesis ,Morphologic Aspects of Cell Death ,Signal transduction ,DOMAIN-LIKE PROTEIN ,Intracellular ,Human ,Necroptosi ,CYTOCHROME-C RELEASE ,OUTER-MEMBRANE PERMEABILIZATION ,Programmed cell death ,CIENCIAS MÉDICAS Y DE LA SALUD ,Settore BIO/06 ,Inmunología ,CELL DEATH ,NO ,Q-VD-OPH ,03 medical and health sciences ,Settore MED/04 - PATOLOGIA GENERALE ,ddc:570 ,APOPTOSIS-INDUCING FACTOR ,MIXED LINEAGE KINASE ,medicine ,Molecular Biology ,Cell Biology ,Settore BIO/10 ,030304 developmental biology ,Animal ,Cell growth ,Apoptosi ,Biology and Life Sciences ,medicine.disease ,MITOCHONDRIAL PERMEABILITY TRANSITION ,Immunology ,biology.protein ,Neuroscience - Abstract
Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as ?accidental cell death' (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. "Regulated cell death" (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death Fil: Rabinovich, Gabriel Adrian. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina Fil: Nomenclature Committee on Cell Death. Equipe 11 Apoptose, Cancer et Immunité. Centre de Recherche des Cordeliers; Francia
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- 2015
30. miRNA-21 ablation protects against liver injury and necroptosis in cholestasis
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Rui E. Castro, André L. Simão, Tânia Carvalho, Maria Manuela Gaspar, Marta B. Afonso, Jesus M. Banales, Cecília M. P. Rodrigues, Pedro M. Rodrigues, and Paula Borralho
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0301 basic medicine ,Cell death ,Male ,Programmed cell death ,Necrosis ,medicine.drug_class ,Necroptosis ,Apoptosis ,medicine.disease_cause ,digestive system ,Article ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Cholestasis ,Fibrosis ,medicine ,Animals ,Humans ,Immune response ,Molecular Biology ,Liver injury ,Mice, Knockout ,Bile acid ,business.industry ,Cell Biology ,medicine.disease ,Gastrointestinal disease ,digestive system diseases ,Disease Models, Animal ,MicroRNAs ,Oxidative Stress ,030104 developmental biology ,Liver ,030220 oncology & carcinogenesis ,Cancer research ,Female ,medicine.symptom ,business ,Oxidative stress ,Gene Deletion - Abstract
Inhibition of microRNA-21 (miR-21) prevents necroptosis in the mouse pancreas. Necroptosis contributes to hepatic necro-inflammation in the common bile duct ligation (BDL) murine model. We aimed to evaluate the role of miR-21 in mediating deleterious processes associated with cholestasis. Mechanistic studies established a functional link between miR-21 and necroptosis through cyclin-dependent kinase 2-associated protein 1 (CDK2AP1). miR-21 expression increased in the liver of primary biliary cholangitis (PBC) patients and BDL wild-type (WT) mice at both 3 and 14 days. Notably, under BDL, miR-21 (−/−) mice displayed decreased liver injury markers in serum compared with WT mice, accompanied by reduced hepatocellular degeneration, oxidative stress and fibrosis. Hallmarks of necroptosis were decreased in the liver of BDL miR-21 (−/−) mice, via relieved repression of CDK2AP1. Further, miR-21 (−/−) mice displayed improved adaptive response of bile acid homeostasis. In conclusion, miR-21 ablation ameliorates liver damage and necroptosis in BDL mice. Inhibition of miR-21 should arise as a promising approach to treat cholestasis.
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- 2017
31. Spirotriazoline oxindoles: A novel chemical scaffold with in vitro anticancer properties
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Rui Moreira, Cecília M. P. Rodrigues, Maria M. M. Santos, Rute C. Nunes, Joana D. Amaral, Carlos Ribeiro, and Lídia Gonçalves
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Programmed cell death ,Cell cycle checkpoint ,Indoles ,Proton Magnetic Resonance Spectroscopy ,Antineoplastic Agents ,Pharmacology ,010402 general chemistry ,01 natural sciences ,Cell Line, Tumor ,Drug Discovery ,Cytotoxic T cell ,Humans ,Carbon-13 Magnetic Resonance Spectroscopy ,Cytotoxicity ,Cell Proliferation ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,General Medicine ,In vitro ,0104 chemical sciences ,HEK293 Cells ,Apoptosis ,Cell culture ,Drug Design ,Cancer cell ,Cancer research - Abstract
The design and synthesis of a library of twenty-six spirotriazoline oxindoles and their in vitro evaluation as potential anticancer agents is reported. The antiproliferative activity of the synthesized compounds was assessed against four different cancer cell lines (HCT-116 p53 (+/+) , HCT-116 p53 (−/−) , MCF-7, and MDA-MB-231). Four spirotriazoline oxindoles showed selectivity against the four cancer cell lines tested over the non-cancer derived HEK 293T cell line. To characterize the molecular mechanisms involved in compound antitumoral activity, two spirotriazoline oxindoles were selected for further studies. Both compounds were able to induce apoptosis and cell cycle arrest at G0/G1 phase and upregulated p53 steady-state levels, while decreasing its main inhibitor MDM2, in HCT-116 cells. Importantly, cytotoxic effects induced by spirotriazoline oxindoles occurred in cancer cells without eliciting cell death in non-malignant CCD-18Co human colon fibroblasts. In addition, four spirotriazoline oxindoles showed selectivity against the triple-negative breast cancer cell line MDA-MB-231 with IC 50 values of 3.5–6.7 μM. These results highlight the anticancer potential of spirotriazoline oxindoles, especially when dealing with aggressive and challenging triple-negative breast cancer.
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- 2017
32. Ursodeoxycholic acid: Effects on hepatic unfolded protein response, apoptosis and oxidative stress in morbidly obese patients
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Cecília M. P. Rodrigues, Anders Thorell, Merima Herac, Rui E. Castro, Michaela Mueller, Michael Trauner, Hanns-Ulrich Marschall, and Nicole Auer
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0301 basic medicine ,miR‐34a ,medicine.medical_specialty ,medicine.drug_class ,microRNA signalling ,Apoptosis ,CHOP ,medicine.disease_cause ,Endoplasmic Reticulum ,03 medical and health sciences ,Fibrosis ,Non-alcoholic Fatty Liver Disease ,Internal medicine ,medicine ,Humans ,Endoplasmic Reticulum Chaperone BiP ,Sweden ,Hepatology ,Bile acid ,business.industry ,Fatty liver ,Ursodeoxycholic Acid ,NASH ,medicine.disease ,Endoplasmic Reticulum Stress ,Ursodeoxycholic acid ,Obesity, Morbid ,MicroRNAs ,Oxidative Stress ,030104 developmental biology ,Endocrinology ,Genetic and Metabolic Liver Disease ,Liver ,Unfolded protein response ,Unfolded Protein Response ,Steatosis ,business ,ER stress ,Oxidative stress ,Transcription Factor CHOP ,medicine.drug - Abstract
Background and Aims Ursodeoxycholic acid (UDCA) is a secondary hydrophilic bile acid (BA) used as therapy for a range of hepatobiliary diseases. Its efficacy in non-alcoholic fatty liver disease (NAFLD) is still under debate. Here we aimed to decipher molecular mechanisms of UDCA in regulating endoplasmic reticulum (ER) homeostasis, apoptosis and oxidative stress in morbidly obese patients. Methods In this randomized controlled pharmacodynamic study, liver and serum samples from 40 well-matched morbidly obese NAFLD-patients were analyzed. Patients received UDCA (20 mg/kg/day) or no treatment three weeks before samples were obtained during bariatric surgery. Results Patients treated with UDCA displayed higher scoring of steatosis (S), activity (A) and fibrosis (F), the so called SAF-scoring. UDCA partially disrupted ER homeostasis by inducing the expression of the ER stress markers CHOP and GRP78. However, ERDJ4 and sXBP1 levels were unaffected. Enhanced CHOP expression, a suggested pro-apoptotic trigger, failed to induce apoptosis via BAK and BAX in the UDCA treated group. Potentially pro-apoptotic miR-34a was reduced in the vesicle-free fraction in serum but not in liver after UDCA treatment. Thiobarbituric acid reactive substances, 4-hydroxynonenal and mRNA levels of several oxidative stress indicators remained unchanged after UDCA treatment. Conclusion Our data suggest that UDCA treatment has ambivalent effects in NAFLD patients. While increased SAF-scores and elevated CHOP levels may be disadvantageous in the UDCA treated cohort, UDCA's cytoprotective properties potentially changed the apoptotic threshold as reflected by absent induction of pro-apoptotic triggers. UDCA treatment failed to improve the oxidative stress status in NAFLD patients. This article is protected by copyright. All rights reserved.
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- 2017
33. Synthesis and evaluation of spiroisoxazoline oxindoles as anticancer agents
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Cecília M. P. Rodrigues, Rui Moreira, Carlos Ribeiro, Joana D. Amaral, and Maria M. M. Santos
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Programmed cell death ,Indoles ,Clinical Biochemistry ,Pharmaceutical Science ,Antineoplastic Agents ,Apoptosis ,Biochemistry ,Protein–protein interaction ,Bimolecular fluorescence complementation ,Drug Discovery ,medicine ,Humans ,Spiro Compounds ,neoplasms ,Molecular Biology ,Cell Proliferation ,biology ,Chemistry ,Cell growth ,Organic Chemistry ,Cancer ,medicine.disease ,Oxindoles ,biology.protein ,Molecular Medicine ,Mdm2 - Abstract
Restoring p53 levels through disruption of p53-MDM2 interaction has been proved to be a valuable approach in fighting cancer. We herein report the synthesis and evaluation of eighteen spiroisoxazoline oxindoles derivatives as p53-MDM2 interaction inhibitors. Seven compounds showed an antiproliferative profile superior to the p53-MDM2 interaction inhibitor nutlin-3, and induced cell death by apoptosis. Moreover, proof-of-concept was demonstrated by inhibition of the interaction between p53 and MDM2 in a live-cell bimolecular fluorescence complementation assay.
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- 2014
34. Apoptosis inducing activity of benzophenanthridine-type alkaloids and 2-arylbenzofuran neolignans in HCT116 colon carcinoma cells
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Silva Mulhovo, Tayyab A. Mansoor, Maria-José U. Ferreira, Pedro M. Borralho, Cecília M. P. Rodrigues, and X Luo
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Zanthoxylum ,Pharmaceutical Science ,Apoptosis ,Dioxoles ,Zanthoxylum capense ,Lignans ,Indole Alkaloids ,chemistry.chemical_compound ,Drug Discovery ,Humans ,Cytotoxic T cell ,Viability assay ,Fragmentation (cell biology) ,Cytotoxicity ,Benzophenanthridines ,Pharmacology ,Lignan ,Plants, Medicinal ,biology ,HCT116 Cells ,biology.organism_classification ,Antineoplastic Agents, Phytogenic ,digestive system diseases ,Staining ,Complementary and alternative medicine ,Biochemistry ,chemistry ,Quinazolines ,Quinolines ,Molecular Medicine ,Drug Screening Assays, Antitumor - Abstract
Thirteen compounds belonging to different classes of alkaloids (1-9) and lignans (10-13), isolated from the methanol extract of roots of the African medicinal plant Zanthoxylum capense, were assayed for their ability as apoptosis inducers in HCT116 colon carcinoma cells. The cytotoxicity of these compounds was evaluated in HCT116 colon carcinoma cells by the MTS assay. Out of the tested compounds, three benzophenanthridine alkaloids (1, 4, and 7), a dibenzyl butyrolactone lignan (10), and two 2-arylbenzofuran neolignans (12 and 13) displayed significant cytotoxicity to HCT116 cells, confirmed by the Guava ViaCount viability assay. The selected compounds (1, 4, 7, 10, 12, and 13) were further tested for apoptosis induction activity in HCT116 cells, by evaluation of nuclear morphology following Hoechst staining, and by caspase-3 like activity assays. Morphologic evaluation of HCT116 nuclei following Hoechst staining and fluorescence microscopy revealed that compounds 1, 4, 7, 10, 12, and 13 induced apoptosis in HCT116 colon carcinoma cells, producing similar, or higher, apoptosis levels when compared with 5-fluorouracil (5-FU), the cornerstone cytotoxic used in colon cancer treatment for several decades. In fact, HCT116 cells developed morphological changes characteristic of apoptosis, including chromatin condensation, nuclear fragmentation and formation of apoptotic bodies. Importantly, compounds 4 and 13 at 20 μM were the most promising in this study, inducing respectively ∼11- and 7-fold increases in apoptotic cells as compared to vehicle control, whereas 5-FU increased apoptosis by ∼2-fold. Apoptosis induction for compounds 4 and 13 was further confirmed by caspase-3-like activity assays, which showed respectively ∼2- and 1.5-fold increases in caspase-3-like activity compared to vehicle control. These results suggested that specific benzophenanthridine alkaloids and 2-arylbenzofuran neolignans isolated from Zanthoxylum capense show strong anticancer activity in HCT116 colon carcinoma cells.
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- 2013
35. Vobasinyl-Iboga Alkaloids from Tabernaemontana elegans: Cell Cycle Arrest and Apoptosis-Inducing Activity in HCT116 Colon Cancer Cells
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Silva Mulhovo, Pedro M. Borralho, Angela Paterna, Maria-José U. Ferreira, Sofia E. Gomes, and Cecília M. P. Rodrigues
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Cell cycle checkpoint ,Stereochemistry ,Tabernaemontana ,Molecular Conformation ,Pharmaceutical Science ,Apoptosis ,Biology ,Crystallography, X-Ray ,01 natural sciences ,Plant Roots ,Analytical Chemistry ,Indole Alkaloids ,chemistry.chemical_compound ,Lactate dehydrogenase ,Drug Discovery ,Cytotoxic T cell ,Humans ,Cytotoxicity ,Nuclear Magnetic Resonance, Biomolecular ,Mozambique ,Pharmacology ,Plants, Medicinal ,L-Lactate Dehydrogenase ,Molecular Structure ,010405 organic chemistry ,Caspase 3 ,Organic Chemistry ,Cell Cycle ,Tabernaemontana elegans ,Metabolism ,Cell Cycle Checkpoints ,Hep G2 Cells ,biology.organism_classification ,HCT116 Cells ,Molecular biology ,Antineoplastic Agents, Phytogenic ,digestive system diseases ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Complementary and alternative medicine ,chemistry ,Ibogaine ,Cancer cell ,Africa ,Colonic Neoplasms ,Molecular Medicine ,Drug Screening Assays, Antitumor - Abstract
Phytochemical investigation of the roots of the African medicinal plant Tabernaemontana elegans led to the isolation of three new (1–3) and two known (4 and 5) bisindole alkaloids of the vobasinyl–iboga type. The structures of 1–3 were assigned by spectroscopic methods, mainly using 1D and 2D NMR experiments. All of the isolated compounds were evaluated for their cytotoxicity against HCT116 colon and HepG2 liver carcinoma cells by the MTS metabolism assay. Compounds 1–3 and 5 were found to be cytotoxic to HCT116 colon cancer cells, displaying IC50 values in the range 8.4 to >10 μM. However, the compounds did not display significant cytotoxicity against HepG2 cancer cells. The cytotoxicity of compounds 1–3 and 5 was corroborated using a lactate dehydrogenase assay. Hoechst staining and nuclear morphology assessment and caspase-3/7 activity assays were also performed for investigating the activity of compounds 1–3 and 5 as apoptosis inducers. The induced inhibition of proliferation of HCT116 cells by compou...
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- 2016
36. New [(η(5)-C5H5)Ru(N-N)(PPh3)][PF6] compounds: colon anticancer activity and GLUT-mediated cellular uptake of carbohydrate-appended complexes
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Pedro Florindo, Pedro M. Borralho, Diane M. Pereira, Ana C. Fernandes, M. F. M. Piedade, Cecília M. P. Rodrigues, and Paulo J. Costa
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Models, Molecular ,Monosaccharide Transport Proteins ,Glycoconjugate ,Stereochemistry ,Carbohydrates ,chemistry.chemical_element ,Antineoplastic Agents ,010402 general chemistry ,01 natural sciences ,Inorganic Chemistry ,Coordination Complexes ,medicine ,Humans ,Cytotoxicity ,IC50 ,chemistry.chemical_classification ,010405 organic chemistry ,Glucose transporter ,Cancer ,Biological Transport ,Carbohydrate ,medicine.disease ,HCT116 Cells ,0104 chemical sciences ,Ruthenium ,Human colon cancer ,chemistry ,Biochemistry ,Colonic Neoplasms ,Ruthenium Compounds - Abstract
Eight ruthenium(ii) compounds of the general formula [(η(5)-C5H5)Ru(N-N)(PPh3)][PF6] were rationally designed, exhibiting high cytotoxicity against HCT116 human colon cancer cells, with IC50 between 14.56 and 1.56 μM; importantly, compounds 5Ru and 6Ru are the first reported ruthenium glycoconjugates exploiting glucose transporters, widely overexpressed in cancer, for cellular uptake.
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- 2016
37. (3'R)-hydroxytabernaelegantine C: A bisindole alkaloid with potent apoptosis inducing activity in colon (HCT116, SW620) and liver (HepG2) cancer cells
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Sofia E. Gomes, Pedro M. Borralho, Silva Mulhovo, Maria-José U. Ferreira, Cecília M. P. Rodrigues, and Angela Paterna
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Magnetic Resonance Spectroscopy ,Apoptosis ,Pharmacology ,01 natural sciences ,Mass Spectrometry ,Indole Alkaloids ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Lactate dehydrogenase ,Cell Line, Tumor ,Drug Discovery ,Spectroscopy, Fourier Transform Infrared ,Cytotoxic T cell ,Humans ,Viability assay ,Caspase 7 ,biology ,Caspase 3 ,Tabernaemontana elegans ,biology.organism_classification ,Molecular biology ,Antineoplastic Agents, Phytogenic ,0104 chemical sciences ,XIAP ,Apocynaceae ,010404 medicinal & biomolecular chemistry ,chemistry ,Cell culture ,030220 oncology & carcinogenesis ,Cancer cell - Abstract
Ethnopharmacological relevance Tabernaemontana elegans Stapf. (Apocynaceae) is a medicinal plant traditionally used in African countries to treat cancer. Aims of the study To discover new apoptosis inducing lead compounds from T. elegans and provide scientific validation of the ethnopharmacological use of this plant. Materials and methods Through fractionation, (3′R)-hydroxytaberanelegantine C (1), a vobasinyl-iboga bisindole alkaloid, was isolated from a cytotoxic alkaloid fraction of the methanol extract of T. elegans roots. Its structure was identified by spectroscopic methods, mainly 1D and 2D NMR experiments. Compound 1 was evaluated for its ability to induce apoptosis in HCT116 and SW620 colon and HepG2 liver carcinoma cells. The cell viability of compound 1 was evaluated by the MTS and lactate dehydrogenase (LDH) assays. Induction of apoptosis was analyzed through Guava ViaCount assay, by flow cytometry, caspase-3/7 activity assays and evaluation of nuclear morphology by Hoechst staining. To determine the molecular pathways elicited by 1 exposure, immunoblot analysis was also performed. Results (3′R)-hydroxytaberanelegantine C (1) displayed strong apoptosis induction activity as compared to 5-fluorouracil (5-FU), the most used anticancer agent in colorectal cancer treatment. In the MTS assay, compound 1 exhibited IC50 values similar or lower than 5-FU in the three cell lines tested. The IC50 value of 1 was also calculated in CCD18co normal human colon fibroblasts. The lactate dehydrogenase assay showed increased LDH release by compound 1, and the Guava ViaCount assay revealed that 1 significantly increased the incidence of apoptosis to a further extent than 5-FU. Moreover, the induction of apoptosis was corroborated by evaluation of nuclear morphology by Hoechst staining and caspase-3/7 activity assays of 1 treated cells. As expected, in immunoblot analysis, compound 1 treatment led to poly(ADP-ribose) polymerase cleavage. This was accompanied by decreased anti-apoptotic proteins Bcl-2 and XIAP steady state levels in all three cancer cell lines tested. Conclusions Compound 1 showed remarkable induction of apoptosis in HCT116, SW620 and HepG2 cells. Together, the results suggest that compound 1 is a promising lead structure for inducing apoptosis.
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- 2016
38. Application of Tauroursodeoxycholic Acid for Treatment of Neurological and Non-neurological Diseases: Is There a Potential for Treating Traumatic Brain Injury?
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Cecília M. P. Rodrigues, Eric M. Bershad, Afshin A. Divani, Salam P. Bachour, Javad Mahmoudi, Kyle R. Gronbeck, and Geoffrey S.F. Ling
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0301 basic medicine ,medicine.medical_specialty ,Neurology ,Traumatic brain injury ,Anti-Inflammatory Agents ,Inflammation ,Apoptosis ,Disease ,Critical Care and Intensive Care Medicine ,Bioinformatics ,Neuroprotection ,Taurochenodeoxycholic Acid ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Brain Injuries, Traumatic ,Medicine ,Animals ,Humans ,Neuroinflammation ,business.industry ,Neurointensive care ,Tauroursodeoxycholic acid ,medicine.disease ,030104 developmental biology ,Neuroprotective Agents ,chemistry ,Neurology (clinical) ,medicine.symptom ,business ,Neuroscience ,030217 neurology & neurosurgery - Abstract
The objective of this review was to evaluate the potential of tauroursodeoxycholic acid (TUDCA) for neuroprotection in traumatic brain injury (TBI) patients in the neurocritical care setting. Specifically, we surveyed preclinical studies describing the neuroprotective and systemic effects of TUDCA, and the potential therapeutic application of TUDCA. Preclinical studies have provided promising data supporting its use in neurological disease characterized by apoptosis-induced neuronal loss. TUDCA inhibits multiple proteins involved in apoptosis and upregulates cell survival pathways. In addition, TUDCA exhibits anti-inflammatory effects in models of neuroinflammation and attenuates neuronal loss in chronic neurodegenerative diseases. This may be applicable to TBI, which also triggers inflammatory and apoptotic processes. Additionally, preliminary data support the use of pharmacological therapies that reduce apoptosis and inflammation associated with TBI. The anti-apoptotic and anti-inflammatory mechanisms of TUDCA could prove promising in the treatment of TBI. Currently, there are no published data supporting improvement in clinical outcomes of TBI by treatment with TUDCA, but future studies should be considered.
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- 2016
39. Activation of necroptosis in human and experimental cholestasis
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Tânia Carvalho, Maria Manuela Gaspar, Joana D. Amaral, Junying Yuan, André L. Simão, Dimitry Ofengeim, Marta B. Afonso, Cecília M. P. Rodrigues, Helena Cortez-Pinto, Rui E. Castro, Pedro M. Rodrigues, and Repositório da Universidade de Lisboa
- Subjects
Liver Cirrhosis ,0301 basic medicine ,Cancer Research ,Pathology ,Necrosis ,Apoptosis ,ComputingMilieux_LEGALASPECTSOFCOMPUTING ,Fibrosis ,Liver injury ,Cholestasis ,Bile acid ,3. Good health ,Liver ,Receptor-Interacting Protein Serine-Threonine Kinases ,Acute Disease ,Female ,Original Article ,medicine.symptom ,Programmed cell death ,medicine.medical_specialty ,medicine.drug_class ,Iron ,Necroptosis ,Immunology ,Inflammation ,Biology ,digestive system ,Bile Acids and Salts ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,medicine ,Animals ,Humans ,Ligation ,Cell Biology ,medicine.disease ,digestive system diseases ,Enzyme Activation ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,Data_GENERAL ,Chronic Disease ,Hepatocytes ,Cancer research ,Bile Ducts ,Heme Oxygenase-1 - Abstract
© The Author(s) 2016. Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/, Cholestasis encompasses liver injury and inflammation. Necroptosis, a necrotic cell death pathway regulated by receptor-interacting protein (RIP) 3, may mediate cell death and inflammation in the liver. We aimed to investigate the role of necroptosis in mediating deleterious processes associated with cholestatic liver disease. Hallmarks of necroptosis were evaluated in liver biopsies of primary biliary cholangitis (PBC) patients and in wild-type and RIP3-deficient (RIP3-/-) mice subjected to common bile duct ligation (BDL). The functional link between RIP3, heme oxygenase-1 (HO-1) and antioxidant response was investigated in vivo after BDL and in vitro. We demonstrate increased RIP3 expression and mixed lineage kinase domain-like protein (MLKL) phosphorylation in liver samples of human PBC patients, coincident with thioflavin T labeling, suggesting activation of necroptosis. BDL resulted in evident hallmarks of necroptosis, concomitant with progressive bile duct hyperplasia, multifocal necrosis, fibrosis and inflammation. MLKL phosphorylation was increased and insoluble aggregates of RIP3, MLKL and RIP1 formed in BLD liver tissue samples. Furthermore, RIP3 deficiency blocked BDL-induced necroinflammation at 3 and 14 days post-BDL. Serum hepatic enzymes, fibrogenic liver gene expression and oxidative stress decreased in RIP3-/- mice at 3 days after BDL. However, at 14 days, cholestasis aggravated and fibrosis was not halted. RIP3 deficiency further associated with increased hepatic expression of HO-1 and accumulation of iron in BDL mice. The functional link between HO-1 activity and bile acid toxicity was established in RIP3-deficient primary hepatocytes. Necroptosis is triggered in PBC patients and mediates hepatic necroinflammation in BDL-induced acute cholestasis. Targeting necroptosis may represent a therapeutic strategy for acute cholestasis, although complementary approaches may be required to control progression of chronic cholestatic liver disease., The study was supported in part by Fundação para a Ciência e a Tecnologia through grant HMSP-ICT/0018/2011 and fellowships SFRH/BD/91119/2012 (MBA), SFRH/BD/ 88212/2012 (PMR), and SFRH/BD/104160/201 (ALS) as well as through UID/DTP/ 04138/2013.
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- 2016
40. Endoplasmic Reticulum Enrollment in Alzheimer’s Disease
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Cecília M. P. Rodrigues, Ricardo J.S. Viana, and Ana Nunes
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Programmed cell death ,biology ,Effector ,Endoplasmic reticulum ,Neuroscience (miscellaneous) ,Disease ,Mitochondrion ,Endoplasmic Reticulum ,Endoplasmic Reticulum Stress ,Models, Biological ,Cell biology ,Cellular and Molecular Neuroscience ,Neurology ,Alzheimer Disease ,biology.protein ,Unfolded protein response ,Animals ,Humans ,Protein folding ,Caspase - Abstract
Alzheimer's disease (AD) poses a huge challenge for society and health care worldwide as molecular pathogenesis of the disease is poorly understood and curative treatment does not exist. The mechanisms leading to accelerated neuronal cell death in AD are still largely unknown, but accumulation of misfolded disease-specific proteins has been identified as potentially involved. In the present review, we describe the essential role of endoplasmic reticulum (ER) in AD. Despite the function that mitochondria may play as the central major player in the apoptotic process, accumulating evidence highlights ER as a critical organelle in AD. Stress that impairs ER physiology leads to accumulation of unfolded or misfolded proteins, such as amyloid β (Aβ) peptide, the major component of amyloid plaques. In an attempt to ameliorate the accumulation of unfolded proteins, ER stress triggers a protective cellular mechanism, which includes the unfolded protein response (UPR). However, when activation of the UPR is severe or prolonged enough, the final cellular outcome is pathologic apoptotic cell death. Distinct pathways can be activated in this process, involving stress sensors such as the JNK pathway or ER chaperones such as Bip/GRP94, stress modulators such as Bcl-2 family proteins, or even stress effectors such as caspase-12. Here, we detail the involvement of the ER and associated stress pathways in AD and discuss potential therapeutic strategies targeting ER stress.
- Published
- 2012
41. TUDCA, a Bile Acid, Attenuates Amyloid Precursor Protein Processing and Amyloid-β Deposition in APP/PS1 Mice
- Author
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Cecília M. P. Rodrigues, Adrian C. Lo, Ana Nunes, Joana D. Amaral, Zsuzsanna Callaerts-Vegh, Ricardo J.S. Viana, Rudi D'Hooge, and Maria B. Fonseca
- Subjects
medicine.medical_specialty ,Synucleins ,Neuroscience (miscellaneous) ,Taurochenodeoxycholic acid ,Hippocampus ,Mice, Transgenic ,Nerve Tissue Proteins ,Neuroprotection ,Presenilin ,Bile Acids and Salts ,Taurochenodeoxycholic Acid ,Amyloid beta-Protein Precursor ,Mice ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Alzheimer Disease ,Internal medicine ,mental disorders ,Presenilin-1 ,medicine ,Amyloid precursor protein ,Animals ,Humans ,Gamma secretase ,Neurons ,Amyloid beta-Peptides ,biology ,Brain ,Nuclear Proteins ,Tauroursodeoxycholic acid ,Lipid Metabolism ,medicine.disease ,DNA-Binding Proteins ,Endocrinology ,Neurology ,chemistry ,Biochemistry ,Astrocytes ,biology.protein ,Microglia ,Alzheimer's disease ,Cognition Disorders ,Protein Processing, Post-Translational - Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by accumulation of amyloid-β (Aβ) peptide in the hippocampus and frontal cortex of the brain, leading to progressive cognitive decline. The endogenous bile acid tauroursodeoxycholic acid (TUDCA) is a strong neuroprotective agent in several experimental models of disease, including neuronal exposure to Aβ. Nevertheless, the therapeutic role of TUDCA in AD pathology has not yet been ascertained. Here we report that feeding APP/PS1 double-transgenic mice with diet containing 0.4 % TUDCA for 6 months reduced accumulation of Aβ deposits in the brain, markedly ameliorating memory deficits. This was accompanied by reduced glial activation and neuronal integrity loss in TUDCA-fed APP/PS1 mice compared to untreated APP/PS1 mice. Furthermore, TUDCA regulated lipid-metabolism mediators involved in Aβ production and accumulation in the brains of transgenic mice. Overall amyloidogenic APP processing was reduced with TUDCA treatment, in association with, but not limited to, modulation of γ-secretase activity. Consequently, a significant decrease in Aβ(1-40) and Aβ(1-42) levels was observed in both hippocampus and frontal cortex of TUDCA-treated APP/PS1 mice, suggesting that chronic feeding of TUDCA interferes with Aβ production, possibly through the regulation of lipid-metabolism mediators associated with APP processing. These results highlight TUDCA as a potential therapeutic strategy for the prevention and treatment of AD.
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- 2012
42. microRNAs in Mitochondria: An Unexplored Niche
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Pedro M, Borralho, Cecília M P, Rodrigues, and Clifford J, Steer
- Subjects
MicroRNAs ,Gene Expression Regulation ,Transcription, Genetic ,Animals ,Humans ,Mitochondria - Abstract
Mitochondria are pivotal organelles involved in the regulation of a myriad of crucial biological processes, including cell survival and cell death, rendering mitochondrial dysfunction a relevant step in numerous pathophysiological processes. MicroRNAs (miRNAs) are endogenous small noncoding RNAs that add a new layer of complexity to the control of gene expression. miRNAs function as master regulators and fine-tuners of gene expression, primarily via posttranscriptional mechanisms, and are increasingly demonstrated as a paramount class of endogenous molecules with relevant diagnostic, prognostic, and therapeutic applications. miRNAs and other RNA interference have recently been reported to be present in mitochondria from several species, and we are now beginning to unveil mitochondrial miRNA transport mechanisms, biological function and targets to ascertain their role in this unexplored niche. Here, we describe miRNA biogenesis and present key findings regarding miRNA localization to mitochondria, origin, putative biological function, and implications for human disease.
- Published
- 2015
43. Apoptosis and insulin resistance in liver and peripheral tissues of morbidly obese patients is associated with different stages of non-alcoholic fatty liver disease
- Author
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F. Carepa, T. Evangelista, Rui E. Castro, Mariana V. Machado, D.M.S. Ferreira, Cecília M. P. Rodrigues, Helena Cortez-Pinto, Ana Rita Silvestre, Adília Costa, and J. Coutinho
- Subjects
Adult ,Male ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Immunoblotting ,Adipose tissue ,Apoptosis ,Intra-Abdominal Fat ,Insulin resistance ,Non-alcoholic Fatty Liver Disease ,Internal medicine ,Insulin receptor substrate ,Internal Medicine ,medicine ,Humans ,Immunoprecipitation ,Obesity ,Muscle, Skeletal ,biology ,Insulin ,Fatty liver ,Middle Aged ,medicine.disease ,Fatty Liver ,Insulin receptor ,Endocrinology ,Liver ,biology.protein ,Female ,Insulin Resistance ,Steatosis ,Steatohepatitis - Abstract
Non-alcoholic fatty liver disease (NAFLD) is associated with insulin resistance and characterised by different degrees of hepatic lesion. Its pathogenesis and correlation with apoptosis and insulin resistance in insulin target tissues remains incompletely understood. We investigated how insulin signalling, caspase activation and apoptosis correlate with different NAFLD stages in liver, muscle and visceral adipose tissues. Liver, muscle and adipose tissue biopsies from 26 morbidly obese patients undergoing bariatric surgery were grouped according to the Kleiner–Brunt scoring system into simple steatosis, and less severe and more severe non-alcoholic steatohepatitis (NASH). Apoptosis was assessed by DNA fragmentation, and caspase-2 and -3 activation. Insulin signalling and c-Jun NH2-terminal kinase (JNK) proteins were evaluated by western blot. Caspase-3 and -2 activation, and DNA fragmentation were markedly increased in the liver of patients with severe NASH vs in that of those with simple steatosis (p
- Published
- 2011
44. Organelle Stress Sensors and Cell Death Mechanisms in Neurodegenerative Diseases
- Author
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Cecília M. P. Rodrigues, Ana Nunes, Maria B. Fonseca, Rita M. Ramalho, and Ricardo J.S. Viana
- Subjects
Neurons ,Organelles ,Pharmacology ,Programmed cell death ,Cell signaling ,Cell Death ,General Neuroscience ,Neurodegeneration ,Apoptosis ,Neurodegenerative Diseases ,Mitochondrion ,Biology ,medicine.disease ,Neuroprotection ,Cell biology ,Crosstalk (biology) ,Stress, Physiological ,Drug Discovery ,medicine ,Humans ,Cytoskeleton ,Intracellular ,Signal Transduction - Abstract
Neurodegenerative diseases trigger neuronal cell death by a variety of endogenous suicide pathways. Although cell death may occur through highly heterogeneous processes, specific cell organelles and stress sensors have shown promise as potential therapeutic targets. The plasma membrane senses stress through residing receptors, which can directly or indirectly activate apoptosis. Importantly, several events involved in neuronal death also affect mitochondria homeostasis, leading to calcium uptake, opening of the permeability transition pore, and release of apoptogenic factors. In addition, nuclear DNA damage triggers cell death, where p53 is activated to modulate the expression of selected apoptosis target genes. Signaling proteins implicated in apoptosis pathways are enriched at the Golgi complex, including death receptors and the phosphoinositide 3-kinase. Finally, neurodegenerative diseases progress with accumulation of misfolded proteins, deficiently removed by intracellular proteases or chaperones, and transport abnormalities due to disturbance of cytoskeletal organization in degenerating neurons. The challenge is to decode the complex signaling network of inter-organellar crosstalk leading to cell death and identify therapeutic approaches for delaying or preventing neurodegenerative diseases.
- Published
- 2010
45. Targeting the p53 Pathway of Apoptosis
- Author
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Joana D. Amaral, Cecília M. P. Rodrigues, Joana M. Xavier, and Clifford J. Steer
- Subjects
Pharmacology ,Cholagogues and Choleretics ,Programmed cell death ,Tumor suppressor gene ,Angiogenesis ,Drug discovery ,Liver Diseases ,Ursodeoxycholic Acid ,Neurodegeneration ,Cancer ,Apoptosis ,Proto-Oncogene Proteins c-mdm2 ,Disease ,Biology ,medicine.disease ,Ursodeoxycholic acid ,Drug Design ,Drug Discovery ,Immunology ,Cancer research ,medicine ,Animals ,Humans ,Tumor Suppressor Protein p53 ,medicine.drug - Abstract
The tumor suppressor protein, p53 is regarded as a key player in tumor suppression, as it promotes growth arrest, apoptosis and cellular senescence, while also blocking angiogenesis. The plethora of mechanisms underlying the p53 efficient death response involves transcriptional activation or repression of target genes, as well as the recently identified microRNAs, and transcription-independent functions. Pathological conditions such as cancer, neurodegeneration, ischemia, cholestasis or atherosclerosis are all strongly associated with deregulated levels of apoptosis in which p53 dysfunction has a prominent role. The effect of targeting cell death signaling proteins has been established in preclinical models of human diseases. In this regard, therapeutic strategies aimed at reactivation of p53 in tumors emerge as a promising approach for the treatment of cancer patients, as well as chemical inhibitors of p53 that may prove effective in suppressing disorders associated with widespread p53 activation. This review highlights recent developments of p53-induced apoptosis in human diseases. In addition, we will discuss controversies arising from the double-edge sword of targeting p53 in disease. Finally, ursodeoxycholic acid (UDCA), an endogenous bile acid used to treat cholestatic liver diseases, was recently described as a fine modulator of the complex control of p53 by Mdm-2. We will also review recent therapeutic strategies and clinical applications of targeted agents, and their progress in drug lead discovery, with particular emphasis on the potential use of UDCA.
- Published
- 2010
46. No evidence of direct binding between ursodeoxycholic acid and the p53 DNA-binding domain
- Author
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Cláudio M. Gomes, Ana R. Correia, Joana D. Amaral, Clifford J. Steer, Cecília M. P. Rodrigues, iMed.UL, Faculty of Pharmacy, and Universidade de Lisboa (ULISBOA)
- Subjects
Cholagogues and Choleretics ,Protein Denaturation ,Programmed cell death ,medicine.drug_class ,Biophysics ,Inhibitor of apoptosis ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Molecular Biology ,Transcription factor ,030304 developmental biology ,0303 health sciences ,biology ,Bile acid ,Ursodeoxycholic Acid ,Life Sciences ,Cell Biology ,DNA-binding domain ,Ursodeoxycholic acid ,Protein Structure, Tertiary ,3. Good health ,030220 oncology & carcinogenesis ,biology.protein ,Mdm2 ,Tumor Suppressor Protein p53 ,Protein Binding ,Transforming growth factor ,medicine.drug - Abstract
UDCA (ursodeoxycholic acid) is used increasingly for the treatment of cholestatic liver diseases. Among other cytoprotective effects, this endogenous bile acid is a potent inhibitor of apoptosis, interfering with both intrinsic and extrinsic apoptotic pathways. In previous studies, we have demonstrated that the transforming growth factor β1-induced E2F-1/Mdm2 (murine double minute 2)/p53 apoptotic pathway was an upstream molecular target of UDCA. In agreement with this, we have recently established p53 as a key molecular target in UDCA prevention of cell death. The tumour suppressor p53 is a well-described transcription factor that induces the expression of multiple different pro-apoptotic gene products. Its regulation involves a variety of signalling proteins and small molecules, and occurs at multiple levels, including transcription, translation and post-translation levels. In the present study, by using different biophysical techniques, we have investigated the possibility of a direct interaction between the p53 core domain, also referred to as the DNA-binding domain, and UDCA. Our in vitro analysis did not provide any evidence for direct binding between the bile acid UDCA and the p53 core domain.
- Published
- 2010
47. Convergence of miR-143 overexpression, oxidative stress and cell death in HCT116 human colon cancer cells
- Author
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Cecília M. P. Rodrigues, Diane M. Pereira, Sofia E. Gomes, Alexandra R. Fernandes, Catarina Roma-Rodrigues, and Pedro M. Borralho
- Subjects
0301 basic medicine ,Colorectal cancer ,medicine.medical_treatment ,Protein Expression ,lcsh:Medicine ,Gene Expression ,Apoptosis ,medicine.disease_cause ,Biochemistry ,Antioxidants ,Targeted therapy ,Superoxide Dismutase-1 ,Medicine and Health Sciences ,lcsh:Science ,Multidisciplinary ,Cell Death ,Enzymes ,Nucleic acids ,Dismutases ,Oncology ,Cell Processes ,Colonic Neoplasms ,Research Article ,Programmed cell death ,Biology ,Research and Analysis Methods ,03 medical and health sciences ,microRNA ,Genetics ,Gene Expression and Vector Techniques ,medicine ,Humans ,Non-coding RNA ,Molecular Biology Techniques ,Molecular Biology ,Cell Proliferation ,Colorectal Cancer ,Molecular Biology Assays and Analysis Techniques ,Superoxide Dismutase ,Cell growth ,lcsh:R ,Biology and Life Sciences ,Cancers and Neoplasms ,Proteins ,Cancer ,Cell Biology ,HCT116 Cells ,medicine.disease ,Gene regulation ,Health Care ,MicroRNAs ,Oxidative Stress ,030104 developmental biology ,Enzymology ,Cancer research ,RNA ,lcsh:Q ,Carcinogenesis ,Oxidative stress - Abstract
MicroRNAs (miRNAs) regulate a wide variety of biological processes, including tumourigenesis. Altered miRNA expression is associated with deregulation of signalling pathways, which in turn cause abnormal cell growth and de-differentiation, contributing to cancer. miR-143 and miR-145 are anti-tumourigenic and influence the sensitivity of tumour cells to chemotherapy and targeted therapy. Comparative proteomic analysis was performed in HCT116 human colon cancer cells stably transduced with miR-143 or miR-145. Immunoblotting analysis validated the proteomic data in stable and transient miRNA overexpression conditions in human colon cancer cells. We show that approximately 100 proteins are differentially expressed in HCT116 human colon cancer cells stably transduced with miR-143 or miR-145 compared to Empty control cells. Further, Gene Ontology and pathway enrichment analysis indicated that proteins involved in specific cell signalling pathways such as cell death, response to oxidative stress, and protein folding might be modulated by these miRNAs. In particular, antioxidant enzyme superoxide dismutase 1 (SOD1) was downregulated by stable expression of either miR-143 or miR-145. Further, SOD1 gain-of-function experiments rescued cells from miR-143-induced oxidative stress. Moreover, miR-143 overexpression increased oxaliplatin-induced apoptosis associated with reactive oxygen species generation, which was abrogated by genetic and pharmacological inhibition of oxidative stress. Overall, miR-143 might circumvent resistance of colon cancer cells to oxaliplatin via increased oxidative stress in HCT116 human colon cancer cells.
- Published
- 2018
48. Safety, Tolerability, and Cerebrospinal Fluid Penetration of Ursodeoxycholic Acid in Patients With Amyotrophic Lateral Sclerosis
- Author
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Sarah J. Hilbert, Cecília M. P. Rodrigues, Walter C. Low, Praful Kelkar, Clifford J. Steer, Márcia M. Aranha, Gareth Parry, and Cynthia S Davey
- Subjects
Adult ,Male ,Cholagogues and Choleretics ,medicine.medical_specialty ,Pathology ,Time Factors ,medicine.drug_class ,Gastroenterology ,Bile Acids and Salts ,Cerebrospinal fluid ,Double-Blind Method ,Oral administration ,Internal medicine ,medicine ,Humans ,Pharmacology (medical) ,Amyotrophic lateral sclerosis ,Stroke ,Aged ,Pharmacology ,Analysis of Variance ,Dose-Response Relationship, Drug ,Bile acid ,business.industry ,Amyotrophic Lateral Sclerosis ,Ursodeoxycholic Acid ,Drug Tolerance ,Middle Aged ,medicine.disease ,Ursodeoxycholic acid ,Treatment Outcome ,Tolerability ,Blood-Brain Barrier ,Cerebrospinal fluid penetration ,Female ,Neurology (clinical) ,business ,medicine.drug - Abstract
Objective Amyotrophic lateral sclerosis is a progressive degenerative disease, which typically leads to death in 3 to 5 years. Neuronal cell death offers a potential target for therapeutic intervention. Ursodeoxycholic acid is a cytoprotective, endogenous bile acid that has been shown to be neuroprotective in experimental Huntington and Alzheimer diseases, retinal degeneration, and ischemic and hemorrhagic stroke. The objective of this research was to study the safety and the tolerability of ursodeoxycholic acid in amyotrophic lateral sclerosis and document effective and dose-dependent cerebrospinal fluid penetration. Methods Eighteen patients were randomly assigned to receive ursodeoxycholic acid at doses of 15, 30, and 50 mg/kg of body weight per day. Serum and cerebrospinal fluid were obtained for analysis after 4 weeks of treatment. Treatment-emergent clinical and laboratory events were monitored weekly. Results Our data indicated that ursodeoxycholic acid is well tolerated by all subjects at all doses. We also showed that ursodeoxycholic acid is well absorbed after oral administration and crosses the blood-brain barrier in a dose-dependent manner. Conclusions These results show excellent safety and tolerability of ursodeoxycholic acid. The drug penetrates the cerebrospinal fluid in a dose-dependent manner. A large, placebo-controlled clinical trial is needed to assess the efficacy of ursodeoxycholic acid in treating amyotrophic lateral sclerosis.
- Published
- 2010
49. p53 and the regulation of hepatocyte apoptosis: implications for disease pathogenesis
- Author
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Clifford J. Steer, Joana D. Amaral, Rui E. Castro, and Cecília M. P. Rodrigues
- Subjects
Bile acid ,medicine.drug_class ,Liver cell ,Ursodeoxycholic Acid ,Neurodegeneration ,Cancer ,Apoptosis ,Endogeny ,Biology ,medicine.disease ,Ursodeoxycholic acid ,Cell biology ,Hepatocytes ,medicine ,Cancer research ,biology.protein ,Humans ,Molecular Medicine ,Mdm2 ,Tumor Suppressor Protein p53 ,Molecular Biology ,medicine.drug - Abstract
The interplay between p53 and apoptosis in diseases such as cancer, neurodegeneration, ischemia and atherosclerosis underscores the need to understand the complexity of p53 networks. Here, we highlight recent studies of p53-induced apoptosis in human diseases, with a focus on the modulation of liver cell apoptosis. In addition, recent work has provided new insights into mechanisms underlying the antiapoptotic functions of the endogenous bile acid ursodeoxycholic acid (UDCA), suggesting that the finely tuned, complex control of p53 by Mdm2 is a key step in the UDCA modulation of deregulated, p53-triggered apoptosis. The effect of targeting cell death signaling proteins has been established in preclinical models of human diseases. Finally, we review recent therapeutic strategies and clinical applications of targeted agents, with a particular emphasis on the potential use of UDCA.
- Published
- 2009
50. Role of Nuclear Steroid Receptors in Apoptosis
- Author
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Susana Solá, Joana D. Amaral, Clifford J. Steer, Cecília M. P. Rodrigues, and Repositório da Universidade de Lisboa
- Subjects
Biochemistry & Molecular Biology ,Receptors, Steroid ,Programmed cell death ,Cell type ,Receptors, Cytoplasmic and Nuclear ,Chemistry, Medicinal ,Apoptosis ,Cell fate determination ,Biology ,Models, Biological ,Biochemistry ,Glucocorticoid receptor ,Drug Discovery ,medicine ,Humans ,Pharmacology & Pharmacy ,Receptor ,Transcription factor ,Pharmacology ,Organic Chemistry ,Cell biology ,Cell nucleus ,medicine.anatomical_structure ,Nuclear receptor ,Molecular Medicine - Abstract
Nuclear steroid receptors (NSR) are ligand-activated transcription factors that play a key role in a variety of vital physiological phenomena including developmental or endocrine signaling, reproduction, and homeostasis. In addition, they are implicated in other important biological processes, such as apoptosis. Modulation of apoptosis by NSR is mostly associated with control of pro-apoptotic versus anti-apoptotic gene expression, and includes both induction and prevention of apoptosis depending on cell type. However, it is unclear how NSR can affect opposing expression of the same gene in different cells. Of note, recently described nongenomic mechanisms of NSR, in particular glucocorticoid receptor translocation to mitochondria, were suggested to be crucial steps for triggering apoptosis. NSR often act solely as nuclear transporters of other regulatory molecules, thus indirectly regulating several apoptosis-related genes. Curiously, NSR are thought to cooperate with the anti-apoptotic endogenous bile acid, ursodeoxycholic acid (UDCA), to prevent programmed cell death. In fact, as cholesterol-derived molecules and due to their chemical and structural similarities to steroid hormones, bile acids also modulate NSR activation. Although the precise link between NSR and UDCA remains unclear, we have demonstrated that the bile acid requires NSR for translocation to the cell nucleus as part of a ligand-receptor complex, using a mechanism similar to that of steroid hormones. Interestingly, other studies revealed that UDCA interacts with the glucocorticoid receptor as a novel and selective NSR modifier. The huge diversity of natural ligands and xenobiotics that bind to NSR and regulate their function represents one of the most exciting drug targets for potential therapeutic intervention. The next decade will almost certainly unveil the remarkable role of NSR in modulating cell fate in human health and disease.. - Fundacao para a Ciencia e a Tecnologia, Lisbon, Portugal [PTDC/SAU-FCF/67912/2006, PTDC/BIA-BCM/67922/2006, BPD/47376/2008]. - Supported, in part, by grants PTDC/SAU-FCF/67912/ 2006 and PTDC/BIA-BCM/67922/2006 (to C.M.P.R) and postdoctoral fellowship BPD/47376/2008 (to J.D.A.) from Fundacao para a Ciencia e a Tecnologia, Lisbon, Portugal. The authors thank all members of the laboratory for their help during the course of these studies.
- Published
- 2009
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