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Glycolytic overload promotes accumulation of the highly reactive dicarbonyl compounds, resulting in harmful conditions called dicarbonyl stress. Methylglyoxal (MG) is a highly reactive dicarbonyl species and its accumulation plays a crucial pathophysiological role in diabetes and its vascular complications. MG cytotoxicity is mediated by reactive oxygen species (ROS) generation, a key event underlying the intracellular signaling pathways leading to inflammation and apoptosis. The identification of compounds able to inhibit ROS signaling pathways and counteract the MG-induced toxicity is a crucial step for developing new therapeutic strategies in the treatment of diabetic vascular complications. In this study, the effect of genistein, a natural soybean isoflavone, has been evaluated on MG-induced cytotoxicity in human endothelial cells. Our results show that genistein is able to counteract the MG-induced apoptosis by restraining ROS production, thus inhibiting the MAPK signaling pathways and caspase-3 activation. These findings identify a beneficial role for genistein, providing new insights for its potential clinical applications in preserving endothelial function in diabetic vascular complications.
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Apoptosis , Células Endoteliales , Genisteína , Estrés Oxidativo , Piruvaldehído , Especies Reactivas de Oxígeno , Genisteína/farmacología , Piruvaldehído/metabolismo , Humanos , Apoptosis/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Caspasa 3/metabolismo , Transducción de Señal/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/efectos de los fármacosRESUMEN
RET-selective tyrosine kinase inhibitors (TKIs) selpercatinib and pralsetinib have revolutionized the landscape of RET-positive (RET+) advanced non-small cell lung cancer (NSCLC) treatment, thanks to their efficacy and safety profiles. This class of medications currently represents the standard of care for both naïve and patients that have not received selective RET-TKIs in the first-line setting. However, we presently lack a satisfactory understanding of resistance mechanism developing after selective RET-TKIs usage, as well as a specific treatment for patients progressing on selpercatinib or pralsetinib. Chemotherapy ± immunotherapy is considered as a recommended subsequent second-line regimen in these patients. Therefore, it is of paramount importance to better define and understand the resistance mechanisms triggered by RET-TKIs. With this in mind, the present review article has been conceived to provide a comprehensive overview about RET+ advanced NSCLC, both from a therapeutic and molecular point of view. Besides comparing the clinical outcome achieved in RET+ advanced NSCLC patients after multikinase inhibitors (MKIs) and/or RET-selective TKIs' administration, we focused on the molecular mechanisms accountable for their long-term resistance. Finally, a critical perspective on many of today's most debated issues and concerns is provided, with the purpose of shaping the possible pharmacological approaches for tomorrow's therapies.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Mutación , Proteínas Proto-Oncogénicas c-ret/genéticaRESUMEN
Despite the huge efforts in identifying novel risk factors, earlier diagnostic markers and alternative therapeutic approaches, malignant disorders continue to pose the second leading cause of death worldwide [...].
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Recently, we have demonstrated that miR-423-5p modulates the growth and metastases of prostate cancer (PCa) cells both in vitro and in vivo. Here, we have studied the effects of miR-423-5p on the proteomic profile in order to identify its intracellular targets and the affected pathways. Applying a quantitative proteomic approach, we analyzed the effects on the protein expression profile of miR-423-5p-transduced PCa cells. Moreover, a computational analysis of predicted targets of miR-423-5p was carried out by using several target prediction tools. Proteomic analysis showed that 63 proteins were differentially expressed in miR-423-5-p-transfected LNCaP cells if compared to controls. Pathway enrichment analysis revealed that stable overexpression of miR-423-5p in LNCaP PCa cells induced inhibition of glycolysis and the metabolism of several amino acids and a parallel downregulation of proteins involved in transcription and hypoxia, the immune response through Th17-derived cytokines, inflammation via amphorin signaling, and ion transport. Moreover, upregulated proteins were related to the S phase of cell cycle, chromatin modifications, apoptosis, blood coagulation, and calcium transport. We identified seven proteins commonly represented in miR-423-5p targets and differentially expressed proteins (DEPs) and analyzed their expression and influence on the survival of PCa patients from publicly accessible datasets. Overall, our findings suggest that miR-423-5p induces alterations in glucose and amino acid metabolism in PCa cells paralleled by modulation of several tumor-associated processes.
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MicroARNs , Neoplasias de la Próstata , Masculino , Humanos , MicroARNs/metabolismo , Proteómica , Neoplasias de la Próstata/metabolismo , Próstata/patología , Aminoácidos/metabolismo , Proliferación Celular , Regulación Neoplásica de la Expresión GénicaRESUMEN
The high mortality rate together with an ever-growing number of annual cases have defined neoplastic disorders as "the real 21st-century disease". Its dubious distinction also results from conventional therapy failure, which has made cancer an orphan disease. Therefore, innovative and alternative therapeutic strategies are mandatory. The ability to leverage human naturally occurring anti-tumor defenses has always represented a fascinating perspective, and the immuno blockage approval in cancer treatment represents in timeline the latest success. As a multifunctional organ, adipose tissue releases a large amount of adipokines having both carcinogenic and antitumor properties. The negative correlation between serum levels and risk for developing malignancies, as well as the huge number of existing preclinical studies, have identified adiponectin as a potential anticancer adipokine. Nevertheless, its usage in clinical has constantly clashed with the inability to reproduce a mimic synthetic compound. Between 2011 and 2013, two distinct adiponectin receptor agonists were recognized, opening new scenarios even in cancer. Here, we review the first orally active adiponectin receptor agonists AdipoRon, from the discovery to the anticancer evidence. Including our latest findings in osteosarcoma models, we summarize AdipoRon and other existing agonists state-of-art, questioning about the feasibility assessment of this strategy in cancer treatment.
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Neoplasias Óseas/tratamiento farmacológico , Proteínas de Neoplasias/agonistas , Osteosarcoma/tratamiento farmacológico , Piperidinas/uso terapéutico , Receptores de Adiponectina/agonistas , Animales , Neoplasias Óseas/metabolismo , Neoplasias Óseas/patología , Humanos , Proteínas de Neoplasias/metabolismo , Osteosarcoma/metabolismo , Osteosarcoma/patología , Receptores de Adiponectina/metabolismoRESUMEN
Despite the recurring outbreak of resistance mechanisms and adverse reactions, doxorubicin (Doxo) still remains the standard-of-care for several cancers, including osteosarcoma (OS). As an appealing source of phytochemical compounds, naturally occurring molecules have extensively been reported to overcome Doxo limitations in preclinical models. Unlike other dietary polyphenols, only few studies recognize chlorogenic acid (CGA) as a potential partner in combination therapy, while, conversely, its anticancer evidence is steadily growing, ultimately in OS. On this basis, herein we examine the cooperating effects between CGA and Doxo in U2OS and MG-63 human OS cells. With respect to Doxo alone, the concomitant administration of CGA further decreased cell viability and growth, promoting cell death potentially via apoptosis induction. Furthermore, a longer-lasting reduction in clonogenic potential deeply supported the CGA ability to improve Doxo efficacy in those cells. Remarkably, CGA treatment ameliorated Doxo-induced cytotoxicity in H9c2 rat cardiomyocyte cells instead. Although inactivation of p44/42 MAPK was detected in response to CGA plus Doxo, PD98059-mediated p44/42 MAPK impairment enhanced the combination outcome in OS cells. These findings firstly propose CGA as a promising chemosensitizer and cardioprotective agent in OS therapy, suggesting the p44/42 MAPK pathway as relevantly involved in CGA-mediated Doxo susceptibility.
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Neoplasias Óseas/patología , Ácido Clorogénico/farmacología , Doxorrubicina/farmacología , Osteosarcoma/patología , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Cardiotónicos/farmacología , Muerte Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Ácido Clorogénico/administración & dosificación , Doxorrubicina/administración & dosificación , Sinergismo Farmacológico , Humanos , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/fisiología , Osteosarcoma/tratamiento farmacológico , RatasRESUMEN
Osteosarcoma (OS) is a very aggressive metastatic pediatric and adolescent tumor. Due to its recurrent development of chemotherapy resistance, clinical outcome for OS patients remains poor. Therefore, discovering more effective anticancer agents is needed. Chlorogenic acid (CGA) is a phenolic compound contained in plant-related products that modulates many cellular functions and inhibits cell proliferation in several cancer types. However, few evidence is available in OS. Here, we investigate the effects of CGA in U2OS, Saos-2, and MG-63 OS cells. By multiple approaches, we demonstrate that CGA acts as anticancer molecule affecting the cell cycle and provoking cell growth inhibition mainly by apoptosis induction. We also provide evidence that CGA strongly activates extracellular-signal-regulated kinase1/2 (ERK1/2). Strikingly, ERK1/2 inhibitor PD98059 sensitizes the cells to CGA. Altogether, our data enforce the evidence of the anticancer activity mediated by CGA and provide the rationale for the development of innovative therapeutic strategies in OS cure.
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Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Ácido Clorogénico/farmacología , Osteosarcoma/tratamiento farmacológico , Adolescente , Animales , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Niño , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Flavonoides/farmacología , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Ratones , Persona de Mediana Edad , Proteína Quinasa 3 Activada por Mitógenos/antagonistas & inhibidores , Proteína Quinasa 3 Activada por Mitógenos/genética , Células 3T3 NIH/efectos de los fármacos , Osteosarcoma/genética , Osteosarcoma/patologíaRESUMEN
Chlorogenic acid (CGA) is a very common dietary polyphenolic compound. CGA is becoming very attractive due to its potential use as preventive and therapeutic agent in many diseases, including cancer. Inorganic/organic hybrid materials are gaining considerable attention in the biomedical field. The sol-gel process provides a useful way to obtain functional organic/inorganic hybrids. The aim of this study was to synthesize silica/polyethylene glycol (PEG) hybrids with different percentages of CGA by sol-gel technique and to investigate their impact on the cancer cell proliferation. Synthesized materials have been chemically characterized through the FTIR spectroscopy and their bioactivity evaluated looking by SEM at their ability to produce a hydroxyapatite layer on their surface upon incubation with simulated body fluid (SBF). Finally, their effects on cell proliferation were studied in cell lines by direct cell number counting, MTT, flow cytometry-based cell-cycle and cell death assays, and immunoblotting experiments. Notably, we found that SiO2/PEG/CGA hybrids exhibit clear antiproliferative effects in different tumor, including breast cancer and osteosarcoma, cell lines in a CGA dependent manner, but not in normal cells. Overall, our results increase the evidence of CGA as a possible anticancer agent and illustrate the potential for clinical applications of sol-gel synthesized SiO2/PEG/CGA materials.
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Ácido Clorogénico/química , Polietilenglicoles/química , Dióxido de Silicio/química , Materiales Biocompatibles/síntesis química , Materiales Biocompatibles/química , Técnicas de Química Sintética/métodos , Ácido Clorogénico/síntesis química , Durapatita/química , Humanos , Ensayo de Materiales , Transición de Fase , Polietilenglicoles/síntesis química , Dióxido de Silicio/síntesis químicaRESUMEN
Cancer is a major public health problem and the second leading cause of mortality around the world. Although continuous advances in the science of oncology and cancer research are now leading to improved outcomes for many cancer patients, novel cancer treatment options are strongly demanded. Naturally occurring compounds from a variety of vegetables, fruits, and medicinal plants have been shown to exhibit various anticancer properties in a number of in vitro and in vivo studies and represent an attractive research area for the development of new therapeutic strategies to fight cancer. Forskolin is a diterpene produced by the roots of the Indian plant Coleus forskohlii. The natural compound forskolin has been used for centuries in traditional medicine and its safety has also been documented in conventional modern medicine. Forskolin directly activates the adenylate cyclase enzyme, that generates cAMP from ATP, thus, raising intracellular cAMP levels. Notably, cAMP signaling, through the PKA-dependent and/or -independent pathways, is very relevant to cancer and its targeting has shown a number of antitumor effects, including the induction of mesenchymal-to-epithelial transition, inhibition of cell growth and migration and enhancement of sensitivity to conventional antitumor drugs in cancer cells. Here, we describe some features of cAMP signaling that are relevant to cancer biology and address the state of the art concerning the natural cAMP elevating compound forskolin and its perspectives as an effective anticancer agent. J. Cell. Physiol. 232: 922-927, 2017. © 2016 Wiley Periodicals, Inc.
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Colforsina/uso terapéutico , AMP Cíclico/metabolismo , Neoplasias/tratamiento farmacológico , Animales , Colforsina/química , Colforsina/farmacología , Humanos , Modelos Biológicos , Neoplasias/patología , Transducción de Señal/efectos de los fármacosRESUMEN
INTRODUCTION: Adipokines are known to play a relevant role in a number of cancer related molecular pathways. Adiponectin is a major adipokine with anti-inflammatory and beneficial metabolic actions. Furthermore, it has been shown to exert anti-carcinogenic effects in various tumor models and some clinical studies suggested an inverse relationship between circulating levels of adiponectin and an increased risk for development of malignancies. On the other hand, the cyclic AMP response element binding (CREB) transcription factor has been clearly linked to lung cancer. METHODS: we analyzed cell proliferation, cell cycle of A549 cells treated with adiponectin as well as CREB activation status in human lung adenocarcinoma A549 cells and in non-small cell lung cancer (NSCLC) samples. RESULTS: adiponectin treatment, at concentrations ranging between 5 and 50 µg/ml mimicking human serum levels, has a significant effect on reducing tumor cell proliferation of A549 cells, mainly by altering cell cycle progression. Importantly, we provide evidence that adiponectin clearly inhibits in a dose- and time-dependent manner CREB phosphorylation (activation) and, at least in part, also the level of CREB protein itself, preceding and accompanying the anti-proliferative effects in response to adiponectin. Moreover, in agreement with previous studies demonstrating that CREB over-expression occurs in many tumors, we also show by western-blotting from lung specimen that CREB is significantly up-regulated in NSCLC samples compared to adjacent normal tissues from six patients. CONCLUSIONS: Overall, our results represent the first evidence of CREB inhibition by adiponectin and may provide new insight into therapeutic strategies for lung cancer.
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Adenocarcinoma/metabolismo , Adiponectina/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Neoplasias Pulmonares/metabolismo , Células A549 , Adenocarcinoma del Pulmón , Adiponectina/administración & dosificación , Ciclo Celular , Proliferación Celular , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Regulación hacia Abajo , Humanos , Fosforilación , Factores de TiempoRESUMEN
Osteosarcoma is a very aggressive bone tumor. Its clinical outcome remains discouraging despite intensive surgery, radiotherapy, and chemotherapy. Thus, novel therapeutic approaches are demanded. S-Adenosylmethionine (AdoMet) is a naturally occurring molecule that is synthesized in our body by methionine adenosyltransferase isoenzymes and is also available as a nutritional supplement. AdoMet is the principal methyl donor in numerous methylation reactions and is involved in many biological functions. Interestingly, AdoMet has been shown to exert antiproliferative action in various cancer cells. However, the underlying molecular mechanisms are just starting to be studied. Here, we investigated the effects of AdoMet on the proliferation of osteosarcoma U2OS cells and the underlying mechanisms. We carried out direct cell number counting, MTT and flow cytometry-based assays, and immunoblotting experiments in response to AdoMet treatment. We found that AdoMet strongly inhibits proliferation of U2OS cells by slowing-down cell cycle progression and by inducing apoptosis. We also report that AdoMet consistently causes an increase of p53 and p21 cell-cycle inhibitor, a decrease of cyclin A and cyclin E protein levels, and a marked increase of pro-apoptotic Bax/Bcl-2 ratio, with caspase-3 activation and PARP cleavage. Moreover, the AdoMet-induced antiproliferative effects were dynamically accompanied by profound changes in ERK1/2 and STAT3 protein and phosphorylation levels. Altogether, our data enforce the evidence of AdoMet acting as a biomolecule with antiproliferative action in osteosarcoma cells, capable of down-regulating ERK1/2 and STAT3 pathways leading to cell cycle inhibition and apoptosis, and provide a rationale for the possible use of AdoMet in osteosarcoma therapy.
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Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Osteosarcoma/tratamiento farmacológico , Osteosarcoma/metabolismo , S-Adenosilmetionina/metabolismo , S-Adenosilmetionina/uso terapéutico , Factor de Transcripción STAT3/metabolismo , Antineoplásicos/uso terapéutico , Neoplasias Óseas/patología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Puntos de Control del Ciclo Celular/fisiología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/fisiología , Humanos , Osteosarcoma/patología , Fosforilación/efectos de los fármacosRESUMEN
Due to its expression profile, triple-negative breast cancer (TNBC) is refractory to the most effective targeted therapies available for breast cancer treatment. Thus, cytotoxic chemotherapy represents the mainstay of treatment for early and metastatic TNBC. Therefore, it would be greatly beneficial to develop therapeutic approaches that cause TNBC cells to increase their sensitivity to cytotoxic drugs. Inorganic phosphate (Pi) is emerging as an important signaling molecule in many cell types. Interestingly, it has been shown that Pi greatly enhances the sensitivity of human osteosarcoma cell line (U2OS) to doxorubicin. We investigated the effects of Pi on the sensitivity of TNBC cells to doxorubicin and the underlying molecular mechanisms, carrying out flow cytometry-based assays of cell-cycle progression and cell death, MTT assays, direct cell number counting and immunoblotting experiments. We report that Pi inhibits the proliferation of triple-negative MDA-MB-231 breast cancer cells mainly by slowing down cell cycle progression. Interestingly, we found that Pi strongly increases doxorubicin-induced cytotoxicity in MDA-MB-231 cells by apoptosis induction, as revealed by a marked increase of sub-G1 population, Bcl-2 downregulation, caspase-3 activation and PARP cleavage. Remarkably, Pi/doxorubicin combination-induced cytotoxicity was dynamically accompanied by profound changes in Erk1/2 and Stat3 protein and phosphorylation levels. Altogether, our data enforce the evidence of Pi acting as a signaling molecule in MDA-MB-231 cells, capable of inhibiting Erk and Stat3 pathways and inducing sensitization to doxorubicin of TNBC cells, and suggest that targeting Pi levels at local sites might represent the rationale for developing effective and inexpensive strategies for improving triple-negative breast cancer therapy.
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Doxorrubicina/farmacología , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Fosfatos/farmacología , Factor de Transcripción STAT3/metabolismo , Neoplasias de la Mama/enzimología , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Transducción de Señal/efectos de los fármacosRESUMEN
Despite the countless therapeutic advances achieved over the years, non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. To this primacy contribute both non-oncogene addicted and advanced NSCLCs, in which conventional therapies are only partially effective. The adiponectin receptor agonist AdipoRon has revealed antiproliferative action in different cancers, including osteosarcoma and pancreatic cancer. Herein, we investigated its potential anticancer role in NSCLC for the first time. We proved that AdipoRon strongly inhibits viability, growth and colony formation in H1299 and A549 NSCLC cells, mainly through a slowdown in cell cycle progression. Along with the biological behaviors, a metabolic switching was observed after AdipoRon administration in NSCLC cells, consisting of higher glucose consumption and lactate accumulation. Remarkably, both 2-Deoxy Glucose and Oxamate glycolytic-interfering agents greatly enhanced AdipoRon's antiproliferative features. As a master regulator of cell metabolism, AMP-activated protein kinase (AMPK) was activated by AdipoRon. Notably, the ablation of AdipoRon-induced AMPK phosphorylation by Compound-C significantly counteracted its effectiveness. However, the engagement of other pathways should be investigated afterwards. With a focus on NSCLC, our findings further support the ability of AdipoRon in acting as an anticancer molecule, driving its endorsement as a future candidate in NSCLC therapy.
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BACKGROUND: For compensated advanced chronic liver disease (cACLD) patients, the first decompensation represents a dramatically worsening prognostic event. Based on the first decompensation event (DE), the transition to decompensated advanced chronic liver disease (dACLD) can occur through two modalities referred to as acute decompensation (AD) and non-AD (NAD), respectively. Clinically Significant Portal Hypertension (CSPH) is considered the strongest predictor of decompensation in these patients. However, due to its invasiveness and costs, CSPH is almost never evaluated in clinical practice. Therefore, recognizing non-invasively predicting tools still have more appeal across healthcare systems. The red cell distribution width to platelet ratio (RPR) has been reported to be an indicator of hepatic fibrosis in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). However, its predictive role for the decompensation has never been explored. AIM: In this observational study, we investigated the clinical usage of RPR in predicting DEs in MASLD-related cACLD patients. METHODS: Fourty controls and 150 MASLD-cACLD patients were consecutively enrolled and followed up (FUP) semiannually for 3 years. At baseline, biochemical, clinical, and Liver Stiffness Measurement (LSM), Child-Pugh (CP), Model for End-Stage Liver Disease (MELD), aspartate aminotransferase/platelet count ratio index (APRI), Fibrosis-4 (FIB-4), Albumin-Bilirubin (ALBI), ALBI-FIB-4, and RPR were collected. During FUP, DEs (timing and modaities) were recorded. CSPH was assessed at the baseline and on DE occurrence according to the available Clinical Practice Guidelines. RESULTS: Of 150 MASLD-related cACLD patients, 43 (28.6%) progressed to dACLD at a median time of 28.9 months (29 NAD and 14 AD). Baseline RPR values were significantly higher in cACLD in comparison to controls, as well as MELD, CP, APRI, FIB-4, ALBI, ALBI-FIB-4, and LSM in dACLD-progressing compared to cACLD individuals [all P < 0.0001, except for FIB-4 (P: 0.007) and ALBI (P: 0.011)]. Receiving operator curve analysis revealed RPR > 0.472 and > 0.894 as the best cut-offs in the prediction respectively of 3-year first DE, as well as its superiority compared to the other non-invasive tools examined. RPR (P: 0.02) and the presence of baseline-CSPH (P: 0.04) were significantly and independently associated with the DE. Patients presenting baseline-CSPH and RPR > 0.472 showed higher risk of decompensation (P: 0.0023). CONCLUSION: Altogether these findings suggest the RPR as a valid and potentially applicable non-invasive tool in the prediction of timing and modalities of decompensation in MASLD-related cACLD patients.
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Enfermedad Hepática en Estado Terminal , Hígado Graso , Hipertensión Portal , Enfermedades Metabólicas , Humanos , Índices de Eritrocitos , Enfermedad Hepática en Estado Terminal/complicaciones , Enfermedad Hepática en Estado Terminal/diagnóstico , NAD , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Cirrosis Hepática/complicaciones , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/epidemiología , Fibrosis , Hipertensión Portal/complicaciones , Hígado Graso/complicaciones , Hígado Graso/diagnósticoRESUMEN
Non-Small-Cell Lung Cancer (NSCLC) is considered one of the most frequently diagnosed cancers and the leading cause of cancer-related deaths worldwide. Despite the undoubted therapeutic advances that have occurred in clinical practice over time, due to its high degree in both heterogeneity and resistance, NSCLC remains largely incurable. As a natural cAMP elevating agent, Forskolin has shown anti-cancer properties in different tumor types, thus supposing its possible usage in treating malignancies. In this study, we investigated the Forskolin outcome in H1299 and A549 NSCLC cell lines, either alone or in combination with Paclitaxel. We proved that Forskolin impairs cell growth and migration ability of these cells, concurrently. Albeit with a different extent between H1299 and A549, changes in cell-cycle progression and epithelial-mesenchymal markers were observed in response to Forskolin administration. Interestingly, comparable cell growth impairment was also obtained with the cAMP phosphodiesterase inhibitor IBMX, while the employment of adenylyl cyclase inhibitor SQ22536 counteracted, at least in part, the Forskolin-mediated anticancer effects. Besides as a single agent, we also demonstrated that Forskolin strongly enhances Paclitaxel-induced cytotoxicity, affecting cell death mainly via apoptosis induction. Notably, H89-mediated protein kinase A (PKA) inhibition further deteriorated the combination outcome. Altogether, our data designate Forskolin as a possible anticancer molecule in NSCLC, and recognize the adenylyl cyclase/cAMP axis as one of the pathways involved in. Although achieved at preclinical stage, our findings encourage the design of future studies aimed at further exploring the Forskolin employment in NSCLC treatment.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Adenilil Ciclasas/metabolismo , AMP Cíclico/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Colforsina/farmacología , Paclitaxel/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Proliferación Celular , Línea CelularRESUMEN
Taking into account the huge epidemiologic impact of lung cancer (in 2020, lung cancer accounted for 2,206,771 of the cases and for 1,796,144 of the cancer-related deaths, representing the second most common cancer in female patients, the most common cancer in male patients, and the second most common cancer in male and female patients) and the current lack of recommendations in terms of prognostic factors for patients selection and management, this article aims to provide an overview of the current landscape in terms of currently available immunotherapy treatments and the most promising assessed prognostic biomarkers, highlighting the current state-of-the-art and hinting at future challenges.
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The latest scientific knowledge has provided additional insights accountable for the worst prognosis for pancreatic ductal adenocarcinoma (PDAC). Among the causative factors, the aptitude to develop resistance towards approved medications denotes the master key for understanding the lack of improvement in PDAC survival over the years. Even though several compounds have achieved encouraging results at preclinical stage, no new adjuvant agents have reached the bedside of PDAC patients lately. The adiponectin receptor agonist AdipoRon is emerging as a promising anticancer drug in different cancer models, particularly in PDAC. Building on the existing findings, we recently reinforced its candidacy in PDAC cells, proposing AdipoRon either as a suitable partner in gemcitabine-based treatment or as an effective drug in resistant cells. Crossing the current state-of-the-art, herein we provide a critical perspective on AdipoRon to figure out whether this receptor agonist can potentially be considered a future therapeutic choice in overcoming chemotherapy-induced resistance, expressly in PDAC.
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Pancreatic ductal adenocarcinoma (PDAC) accounts for 90% of all pancreatic cancers. Albeit its incidence does not score among the highest in cancer, PDAC prognosis is tremendously fatal. As a result of either aggressiveness or metastatic stage at diagnosis, chemotherapy constitutes the only marginally effective therapeutic approach. As gemcitabine (Gem) is still the cornerstone for PDAC management, the low response rate and the onset of resistant mechanisms claim for additional therapeutic strategies. The first synthetic orally active adiponectin receptor agonist AdipoRon (AdipoR) has recently been proposed as an anticancer agent in several tumors, including PDAC. To further address the AdipoR therapeutic potential, herein we investigated its pharmacodynamic interaction with Gem in human PDAC cell lines. Surprisingly, their simultaneous administration revealed a more effective action in contrasting PDAC cell growth and limiting clonogenic potential than single ones. Moreover, the combination AdipoR plus Gem persisted in being effective even in Gem-resistant MIA PaCa-2 cells. While a different ability in braking cell cycle progression between AdipoR and Gem supported their cooperating features in PDAC, mechanistically, PD98059-mediated p44/42 MAPK ablation hindered combination effectiveness. Taken together, our findings propose AdipoR as a suitable partner in Gem-based therapy and recognize the p44/42 MAPK pathway as potentially involved in combination outcomes.
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Actively involved in tumor maintenance, cAMP-dependent protein kinase A (PKA) has been proposed as a putative biomarker in cancer. Recently, an active PKA form has been identified in human sera and PKA autoantibodies have been detected in cancer patients. However, their serum functions, as well as diagnostic significance, remain largely unknown. Although several PKA detection assays have been developed, none refer to a laboratory diagnostic procedure. Among these, ELISA and Western blotting (WB) assays have been employed in PKA detection. Since, to the best of our knowledge, there are no data showing its presence in human urine samples, herein, we explore the possibility of PKA's existence in this biological specimen. Interestingly, among the 30 screened urines by quantitative sandwich ELISA, we recognized detectable PKA levels in 5 different samples, and of those two exhibited a considerable high concentration. To corroborate these results, we also evaluated PKA's presence in both positive and negative ELISA urines by WB. Remarkably, immunoblotting analysis confirmed PKA's existence in certain, but not in all, human urine specimens. Despite being quite preliminary, these findings firstly identify PKA in urine samples and provide evidence for its potential clinic usage as a diagnostic analyte in laboratory medicine.
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Inflammation is a major risk factor for pancreatic ductal adenocarcinoma (PDAC). When occurring in the context of pancreatitis, KRAS mutations accelerate tumor development in mouse models. We report that long after its complete resolution, a transient inflammatory event primes pancreatic epithelial cells to subsequent transformation by oncogenic KRAS. Upon recovery from acute inflammation, pancreatic epithelial cells display an enduring adaptive response associated with sustained transcriptional and epigenetic reprogramming. Such adaptation enables the reactivation of acinar-to-ductal metaplasia (ADM) upon subsequent inflammatory events, thereby limiting tissue damage through a rapid decrease of zymogen production. We propose that because activating mutations of KRAS maintain an irreversible ADM, they may be beneficial and under strong positive selection in the context of recurrent pancreatitis.