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1.
Anticancer Res ; 40(5): 2667-2673, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-32366411

RESUMEN

BACKGROUND/AIM: The therapeutic strategy for patients with non-small-cell lung cancer (NSCLC) harboring the BRAF non-V600E mutation has not been established. LY3009120, a newly discovered pan-RAF inhibitor, has shown strong antitumor effects in cancers with various BRAF genotypes. This study investigated the antitumor effects of LY3009120 in NSCLC cells harboring the BRAF non-V600E mutation. MATERIALS AND METHODS: We examined the antitumor effects of LY3009120 by MTS assay and flow cytometry. We analyzed the expression status of proteins by western blot. The mouse xenograft models were used for the in vivo experiments. RESULTS: LY3009120 suppressed BRAF-related downstream pathway molecules and induced cleavage of poly ADP-ribose polymerase in all examined NSCLC cell lines. LY3009120 also inhibited in vivo tumor growth in NSCLC cells harboring the BRAF non-V600E mutation. CONCLUSION: LY3009120 is a potent therapeutic agent for patients with BRAF non-V600E mutant NSCLC.


Asunto(s)
Antineoplásicos/farmacología , Neoplasias Pulmonares/genética , Mutación/genética , Oncogenes , Compuestos de Fenilurea/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas B-raf/genética , Pirimidinas/farmacología , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Femenino , Humanos , Concentración 50 Inhibidora , Ratones Endogámicos BALB C , Ratones Desnudos , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
2.
J Immunother Cancer ; 8(1)2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32385146

RESUMEN

The pandemic caused by the novel coronavirus SARS-CoV-2 has placed an unprecedented burden on healthcare systems around the world. In patients who experience severe disease, acute respiratory distress is often accompanied by a pathological immune reaction, sometimes referred to as 'cytokine storm'. One hallmark feature of the profound inflammatory state seen in patients with COVID-19 who succumb to pneumonia and hypoxia is marked elevation of serum cytokines, especially interferon gamma, tumor necrosis factor alpha, interleukin 17 (IL-17), interleukin 8 (IL-8) and interleukin 6 (IL-6). Initial experience from the outbreaks in Italy, China and the USA has anecdotally demonstrated improved outcomes for critically ill patients with COVID-19 with the administration of cytokine-modulatory therapies, especially anti-IL-6 agents. Although ongoing trials are investigating anti-IL-6 therapies, access to these therapies is a concern, especially as the numbers of cases worldwide continue to climb. An immunology-informed approach may help identify alternative agents to modulate the pathological inflammation seen in patients with COVID-19. Drawing on extensive experience administering these and other immune-modulating therapies, the Society for Immunotherapy of Cancer offers this perspective on potential alternatives to anti-IL-6 that may also warrant consideration for management of the systemic inflammatory response and pulmonary compromise that can be seen in patients with severe COVID-19.


Asunto(s)
Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/tratamiento farmacológico , Inmunoterapia , Interleucina-6/antagonistas & inhibidores , Interleucina-6/inmunología , Neumonía Viral/complicaciones , Neumonía Viral/tratamiento farmacológico , Síndrome de Dificultad Respiratoria del Adulto/complicaciones , Síndrome de Dificultad Respiratoria del Adulto/tratamiento farmacológico , Sociedades Médicas , Traslado Adoptivo , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/patología , Síndrome de Liberación de Citoquinas/complicaciones , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Liberación de Citoquinas/patología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/antagonistas & inhibidores , Humanos , Inflamación/complicaciones , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Inflamación/patología , Interferón gamma/antagonistas & inhibidores , Interleucina-1/antagonistas & inhibidores , Interleucina-17/antagonistas & inhibidores , Interleucina-23/antagonistas & inhibidores , Interleucina-6/genética , Interleucina-6/metabolismo , Quinasas Janus/antagonistas & inhibidores , Neoplasias/inmunología , Neoplasias/terapia , Pandemias , Neumonía Viral/inmunología , Neumonía Viral/patología , Síndrome de Dificultad Respiratoria del Adulto/inmunología , Síndrome de Dificultad Respiratoria del Adulto/patología , Factores de Transcripción STAT/antagonistas & inhibidores , Síndrome Respiratorio Agudo Grave/patología , Transducción de Señal/efectos de los fármacos , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores
3.
J Exp Clin Cancer Res ; 39(1): 86, 2020 May 12.
Artículo en Inglés | MEDLINE | ID: mdl-32398164

RESUMEN

BACKGROUND: The very limited time allowed to face the COVID-19 pandemic poses a pressing challenge to find proper therapeutic approaches. However, synthesis and full investigation from preclinical studies to phase III trials of new medications is a time-consuming procedure, and not viable in a global emergency, such as the one we are facing. MAIN BODY: Drug repurposing/repositioning, a strategy effectively employed in cancer treatment, can represent a valid alternative. Most drugs considered for repurposing/repositioning in the therapy of the COVID-19 outbreak are commercially available and their dosage and toxicity in humans is well known, due to years (or even decades) of clinical use. This can allow their fast-track evaluation in phase II-III clinical trials, or even within straightforward compassionate use. Several drugs being re-considered for COVID-19 therapy are or have been used in cancer therapy. Indeed, virus-infected cells are pushed to enhance the synthesis of nucleic acids, protein and lipid synthesis and boost their energy metabolism, in order to comply to the "viral program". Indeed, the same features are seen in cancer cells, making it likely that drugs interfering with specific cancer cell pathways may be effective as well in defeating viral replication. SHORT CONCLUSION: To our knowledge, cancer drugs potentially suitable for facing SARS-CoV-2 infection have not been carefully reviewed. We present here a comprehensive analysis of available information on potential candidate cancer drugs that can be repurposed for the treatment of COIVD-19.


Asunto(s)
Antineoplásicos/farmacología , Infecciones por Coronavirus/tratamiento farmacológico , Reposicionamiento de Medicamentos , Neumonía Viral/tratamiento farmacológico , Antivirales , Betacoronavirus , Humanos , Inmunomodulación , Pandemias , Transducción de Señal/efectos de los fármacos
4.
Med Sci Monit ; 26: e919360, 2020 Apr 03.
Artículo en Inglés | MEDLINE | ID: mdl-32241963

RESUMEN

BACKGROUND This study aimed to undertake a network pharmacology analysis to identify the active compounds of the herbal extract Christina Loosestrife, or Lysimachia Christinae (Jin Qian Cao), in the treatment of nephrolithiasis. MATERIAL AND METHODS The active components of Christina Loosestrife were identified from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database and analysis platform and the online Taiwan TCM database. The potentially active compounds were screened based on their parenteral bioavailability identified from the TCMSP database. The PharmMapper integrated pharmacophore matching platform was used for target identification of active compounds in nephrolithiasis. The identified active compounds were validated by molecular docking using the systemsDock network pharmacology website. Biological functions and pathway outcomes of effective targets were analyzed using the Metascape gene annotation resource. The results were used to construct the pharmacological networks, which were visualized and integrated using Cytoscape software. RESULTS There were 16 active compounds of Christina Loosestrife and 11 nephrolithiasis-associated targets that were obtained. Functional enrichment analysis showed that Christina Loosestrife might exert its therapeutic effects by regulating pathways that included purine salvage, interleukin-4 (IL-4) and IL-13 signaling, and neutrophil degranulation. CONCLUSIONS Network pharmacology analysis of the herbal extract, Christina Loosestrife, identified multiple active compounds, targets, and pathways involved in the effects on nephrolithiasis.


Asunto(s)
Medicamentos Herbarios Chinos/farmacocinética , Cálculos Renales/tratamiento farmacológico , Lythrum/química , Primulaceae/química , Disponibilidad Biológica , Medicamentos Herbarios Chinos/uso terapéutico , Humanos , Medicina China Tradicional/métodos , Simulación del Acoplamiento Molecular , Transducción de Señal/efectos de los fármacos , Resultado del Tratamiento
5.
Med Sci Monit ; 26: e921162, 2020 Apr 04.
Artículo en Inglés | MEDLINE | ID: mdl-32246704

RESUMEN

BACKGROUND This study used network pharmacology method and cell model to assess the effects of Radix Astragali (RA) on cholangiocarcinoma (CCA) and to predict core targets and molecular mechanisms. MATERIAL AND METHODS We performed an in vitro study to assess the effect of RA on CCA using CCK8 assay, the Live-Cell Analysis System, and trypan blue staining. The components and targets of RA were analyzed using the Traditional Chinese Medicine Systems Pharmacology database, and genes associated with CCA were retrieved from the GeneCards and OMIM platforms. Protein-protein interactions were analyzed with the STRING platform. The components-targets-disease network was built by Cytoscape. The TIMER database revealed the expression of core targets with diverse immune infiltration levels. GO and KEGG analyses were performed to identify molecular-biology processes and signaling pathways. The predictions were verified by Western blotting. RESULTS Concentration-dependent antitumor activity was confirmed in the cholangiocarcinoma QBC939 cell line treated with RA. RA contained 16 active compounds, with quercetin and kaempferol as the core compounds. The most important biotargets for RA in CCA were caspase 3, MAPK8, MYC, EGFR, and PARP. The TIMER database revealed that the expression of caspase3 and MYC was related with diverse immune infiltration levels of CCA. The results of Western blotting showed RA significantly influenced the expression of the 5 targets that network pharmacology predicted. CONCLUSIONS RA is an active medicinal material that can be developed into a safe and effective multi-targeted anticancer treatment for CCA.


Asunto(s)
Antineoplásicos Fitogénicos/uso terapéutico , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Colangiocarcinoma/tratamiento farmacológico , Medicamentos Herbarios Chinos/uso terapéutico , Humanos , Medicina China Tradicional/métodos , Transducción de Señal/efectos de los fármacos , Resultado del Tratamiento
6.
Anticancer Res ; 40(4): 1989-1996, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32234888

RESUMEN

BACKGROUND/AIM: The antitumor effect of sustained calcium supply on Src degradation was investigated in the context of hormone-dependent breast cancer, followed by elucidation of the underlying mechanisms. MATERIALS AND METHODS: Hormone-dependent T-47D breast cancer cells were used. Lactate calcium salt (LCS) was used as the source of sustained calcium supply, and the applicable concentration of LCS was determined by the colorimetric MTT assay. LCS-mediated deactivation of downstream signaling via Src degradation was identified by western blot and immunocytochemistry. RESULTS: Calcium-mediated degradation of Src decreased survival signaling via phosphoinositide 3-kinase and protein kinase B and resulted in significant inhibition of the clonogenic ability of hormone-dependent breast cancer cells. Tumor volume was significantly decreased in response to LCS injection in a heterotopic xenograft model, and immuno histochemistry revealed tumor necrosis. CONCLUSION: Sustained supply of calcium inhibited survival signaling via degradation of Src in hormone-dependent breast cancer cells.


Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Neoplasias Hormono-Dependientes/tratamiento farmacológico , Proteolisis/efectos de los fármacos , Familia-src Quinasas/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Calcio/farmacología , Línea Celular Tumoral , Femenino , Humanos , Ácido Láctico/farmacología , Neoplasias Hormono-Dependientes/genética , Neoplasias Hormono-Dependientes/patología , Proteína Oncogénica v-akt/genética , Fosfatidilinositol 3-Quinasas/genética , Transducción de Señal/efectos de los fármacos , Familia-src Quinasas/antagonistas & inhibidores
8.
Basic Res Cardiol ; 115(3): 31, 2020 04 09.
Artículo en Inglés | MEDLINE | ID: mdl-32274570

RESUMEN

From January 2020, coronavirus disease (COVID-19) originated in China has spread around the world. The disease is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The presence of myocarditis, cardiac arrest, and acute heart failure in COVID-19 patients suggests the existence of a relationship between SARS-CoV-2 infection and cardiac disease. The Notch signalling is a major regulator of cardiovascular function and it is also implicated in several biological processes mediating viral infections. In this report we discuss the possibility to target Notch signalling to prevent SARS-CoV-2 infection and interfere with the progression of COVID-19- associated heart and lungs disease.


Asunto(s)
Betacoronavirus/patogenicidad , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/fisiopatología , Cardiopatías/tratamiento farmacológico , Cardiopatías/etiología , Enfermedades Pulmonares/tratamiento farmacológico , Enfermedades Pulmonares/etiología , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/fisiopatología , Receptores Notch/antagonistas & inhibidores , Proteína ADAM17/antagonistas & inhibidores , Betacoronavirus/efectos de los fármacos , China , Infecciones por Coronavirus/patología , Infecciones por Coronavirus/virología , Progresión de la Enfermedad , Furina/metabolismo , Paro Cardíaco/etiología , Paro Cardíaco/patología , Cardiopatías/patología , Cardiopatías/fisiopatología , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/patología , Humanos , Interleucina-6/inmunología , Enfermedades Pulmonares/patología , Enfermedades Pulmonares/fisiopatología , Miocarditis/etiología , Miocarditis/patología , Pandemias , Peptidil-Dipeptidasa A/deficiencia , Peptidil-Dipeptidasa A/metabolismo , Neumonía Viral/patología , Neumonía Viral/virología , Receptores Notch/metabolismo , Transducción de Señal/efectos de los fármacos
9.
Anticancer Res ; 40(4): 1817-1831, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32234870

RESUMEN

Almost all individuals with neurofibromatosis type 1 (NF1) develop peripheral nerve sheath tumors (PNSTs), mainly benign neurofibromas, however about 10% of PNSTs will undergo transformation to malignant peripheral nerve sheath tumors (MPNSTs). Surgical treatment of PNSTs has traditionally been regarded as a standard approach. The availability of new agents that target specific molecular pathways involved in the pathogenesis of PNST has led to a number of clinical trials, which resulted in increased chances for better survival and quality of life. This review presents the latest evidence and clinical implications for new therapies of PNSTs in patients with NF1 emphasizing the potential benefit from the use of Ras/MAPK pathway inhibitors, immunotherapy, chemotherapy or radiation therapy. We present evaluation of current knowledge on available treatment modalities.


Asunto(s)
Neoplasias/tratamiento farmacológico , Neoplasias de la Vaina del Nervio/tratamiento farmacológico , Neurofibromatosis 1/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/genética , Neoplasias/complicaciones , Neoplasias/genética , Neoplasias/patología , Neoplasias de la Vaina del Nervio/complicaciones , Neoplasias de la Vaina del Nervio/genética , Neoplasias de la Vaina del Nervio/patología , Neurofibromatosis 1/complicaciones , Neurofibromatosis 1/genética , Neurofibromatosis 1/patología , Transducción de Señal/efectos de los fármacos , Tomografía Computarizada por Rayos X , Proteínas ras/antagonistas & inhibidores , Proteínas ras/genética
10.
Anticancer Res ; 40(4): 1867-1874, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32234874

RESUMEN

BACKGROUND/AIM: Molecular targeted agents have been successfully developed against solid tumors and their use is also being investigated for the treatment of malignant pleural mesothelioma (MPM). We have previously reported von Hippel Lindau (VHL) mutations detected by massive parallel sequencing technology in samples of patients with MPM. Here, we conducted an in vitro study to investigate the therapeutic approaches in VHL-mutant MPM. MATERIALS AND METHODS: Three MPM cell lines with or without a VHL mutation were used and the effects of molecular-targeted agents on growth inhibition were evaluated. Based on the characteristics of the molecular targeted agents that exhibited growth inhibitory effect, the effects of knockdown by siRNA were also evaluated. RESULTS: NCI-H28 MPM cells harboring the VHL L89H mutation were sensitive to YC-1, known as an inhibitor of hypoxia inducible factor (HIF)-1α, and YC-1treatment induced massive apoptosis in a dose-and-time-dependent manner. Knockdown of HIF-1α by siRNA partially inhibited the growth of NCI-H28 cells, suggesting that an additional blockade may be required to completely inhibit growth signaling. CONCLUSION: The VHL mutation may predict tumor responses to YC-1, a HIF-1α inhibitor.


Asunto(s)
Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Neoplasias Pulmonares/tratamiento farmacológico , Mesotelioma/tratamiento farmacológico , Neoplasias Pleurales/tratamiento farmacológico , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genética , Apoptosis , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/antagonistas & inhibidores , Indazoles/farmacología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Mesotelioma/genética , Mesotelioma/patología , Mutación/genética , Neoplasias Pleurales/genética , Neoplasias Pleurales/patología , ARN Interferente Pequeño/genética , Transducción de Señal/efectos de los fármacos
11.
Anticancer Res ; 40(4): 1905-1913, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32234879

RESUMEN

BACKGROUND/AIM: Methylsulfonylmethane (MSM) is a natural organic compound that displays anti-inflammatory as well as antioxidant properties. MSM reportedly has potential in inhibition of tumor cells. However, molecular mechanisms underlying the effects of MSM on lung cancer remain unclear. MATERIALS AND METHODS: In this study, the effect of MSM on A549 cells was examined. We focused on the mode of apoptosis induced by MSM and investigated alterations in the integrity of the outer membrane of mitochondria. RESULTS: Our results showed that MSM inhibited viability of A549 cells and changed the shape and permeability of nuclei. In addition, MSM induced G2/M arrest. MSM reduced the mitochondrial membrane potential and contributed to release of cytochrome c from mitochondria to cytoplasm. CONCLUSION: MSM is a potential anticancer agent for the treatment of lung cancer.


Asunto(s)
Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Dimetilsulfóxido/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Sulfonas/farmacología , Células A549 , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Mitocondrias/genética , Transducción de Señal/efectos de los fármacos
12.
Curr Opin Ophthalmol ; 31(3): 207-214, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-32205471

RESUMEN

PURPOSE OF REVIEW: The aim of this article is to review and discuss the history, current state, and future implications of promising biomedical offerings in the field of retina. RECENT FINDINGS: The technologies discussed are some of the more recent promising biomedical developments within the field of retina. There is a US Food and Drug Administration-approved gene therapy product and artificial intelligence device for retina, with many other offerings in the pipeline. SUMMARY: Signaling pathway therapies, genetic therapies, mitochondrial therapies, and artificial intelligence have shaped retina care as we know it and are poised to further impact the future of retina care. Retina specialists have the privilege and responsibility of shaping this future for the visual health of current and future generations.


Asunto(s)
Inteligencia Artificial , Terapia Genética , Mitocondrias/efectos de los fármacos , Enfermedades de la Retina/terapia , Transducción de Señal/efectos de los fármacos , Inhibidores de la Angiogénesis/uso terapéutico , Humanos , Oligopéptidos/uso terapéutico , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores
13.
Chem Biol Interact ; 323: 109074, 2020 May 25.
Artículo en Inglés | MEDLINE | ID: mdl-32217108

RESUMEN

Non-small-cell lung cancer (NSCLC) is one of the common malignant tumors, and multidrug resistance (MDR) and tumor metastasis limit the anticancer effect of NSCLC. Therefore, it is necessary to develop new anticancer drug that can inhibit MDR and metastasis of NSCLC. In the present study, we found that 5-(2-chlorophenyl)-4-(4-(3,5-dimethoxyphenyl)piperazine-1-carbonyl)-2H-1,2,3- triazole (MAY) displayed strong cytotoxic effect on A549 and taxol-resistant A549 cells (A549/Taxol cells). We further discovered that MAY led to G2/M phase arrest by inhibiting microtubule polymerization in both cells. Then MAY caused apoptosis by the mitochondrial pathway in A549 cells and through the extrinsic pathway in A549/Taxol cells. Interestingly, MAY was not a substrate for P-glycoprotein (P-gp), which was highly expressed in A549/Taxol cells, and MAY inhibited the expression and efflux function of P-gp. Furthermore, MAY inhibited epithelial-mesenchymal transition (EMT) by targeting Twist1 in A549/Taxol cells. In summary, our results suggest that MAY induces apoptosis in A549 and A549/Taxol cells and inhibits EMT in A549/Taxol cells. These findings suggest that MAY could provide a promising method for the treatment of NSCLC, especially for the treatment of resistant NSCLC.


Asunto(s)
Apoptosis/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Paclitaxel/farmacología , Triazoles/farmacología , Moduladores de Tubulina/farmacología , Células A549 , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Puntos de Control del Ciclo Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Microtúbulos/efectos de los fármacos , Microtúbulos/metabolismo , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Proteínas Nucleares/metabolismo , Paclitaxel/química , Polimerizacion , Transducción de Señal/efectos de los fármacos , Triazoles/química , Moduladores de Tubulina/química , Proteína 1 Relacionada con Twist/metabolismo
14.
Int J Mol Sci ; 21(7)2020 Mar 25.
Artículo en Inglés | MEDLINE | ID: mdl-32218156

RESUMEN

This study examined the biological activities of copaiba essential oil via measurement of its effects on signaling pathways in the SH-SY5Y neuronal cell line. Nanofluidic proteomic technologies were deployed to measure the phosphorylation of biomarker proteins within the signaling cascades. Interestingly, copaiba essential oil upregulated the pI3K/Akt/mTOR, MAPK, and JAK/STAT signaling pathways in neuronal cells. The effects of copaiba essential oil peaked at 30 min post-treatment, with a half-maximal effective concentration (EC50) of approximately 80 ng/mL. Treatment with cannabinoid receptor 2 (CB2) agonist AM1241 or the inverse agonist BML190 abrogated the regulatory effects of copaiba essential oil on the pI3K/Akt/mTOR signaling pathway. Surprisingly, copaiba essential oil also activated the apoptosis signaling pathway and reduced the viability of SH-SY5Y cells with an EC50 of approximately 400 ng/mL. Furthermore, ß-caryophyllene, a principal constituent of copaiba essential oil, downregulated the pI3K/Akt/mTOR signaling pathway. Taken together, the findings indicated that copaiba essential oil upregulated signaling pathways associated with cell metabolism, growth, immunity, and apoptosis. The biological activities of copaiba essential oil were determined to be fast acting, CB2 mediated, and dependent on multiple chemical constituents of the oil. Nanofluidic proteomics provided a powerful means to assess the biological activities of copaiba essential oil.


Asunto(s)
Fabaceae/química , Neuroblastoma/metabolismo , Aceites Volátiles/farmacología , Aceites Vegetales/farmacología , Transducción de Señal/efectos de los fármacos , Línea Celular Tumoral , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Humanos , Neuroblastoma/patología , Fosfatidilinositol 3-Quinasas/metabolismo , Serina-Treonina Quinasas TOR/metabolismo
15.
Mol Pharmacol ; 97(5): 304-313, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32132133

RESUMEN

Free-fatty acid receptor-4 (FFA4), previously termed GPR120, is a G protein-coupled receptor (GPCR) for medium and long-chained fatty acids, agonism of which can regulate a myriad of metabolic, sensory, inflammatory, and proliferatory signals. Two alternative splice isoforms of FFA4 exist that differ by the presence of an additional 16 amino acids in the longer (FFA4-L) transcript, which has been suggested to be an intrinsically ß-arrestin-biased GPCR. Although the shorter isoform (FFA4-S) has been studied more extensively, very little is known about mechanisms of regulation or signaling of the longer isoform. Because ß-arrestin recruitment is dependent on receptor phosphorylation, in the current study, we used the endogenous agonist docosahexaenoic acid (DHA) to examine the mechanisms of FFA4-L phosphorylation, as well as DHA-dependent ß-arrestin recruitment and DHA-dependent extracellular-signal regulated kinase-1/2 (ERK1/2) signaling in human embryonic kidney 293 cells. Our results reveal differences in basal phosphorylation of the two FFA4 isoforms, and we show that DHA-mediated phosphorylation of FFA4-L is primarily regulated by G protein-coupled receptor kinase 6, whereas protein kinase-C can also contribute to agonist-induced and heterologous phosphorylation. Moreover, our data demonstrate that FFA4-L phosphorylation occurs on the distal C terminus and is directly responsible for recruitment and interactions with ß-arrestin-2. Finally, using CRISPR/Cas9 genome-edited cells, our data reveal that unlike FFA4-S, the longer isoform is unable to facilitate phosphorylation of ERK1/2 in cells that are devoid of ß-arrestin-1/2. Together, these results are the first to demonstrate phosphoregulation of FFA4-L as well as the effects of loss of phosphorylation sites on ß-arrestin recruitment and ERK1/2 activation. SIGNIFICANCE STATEMENT: Free-fatty acid receptor-4 (FFA4) is a cell-surface G protein-coupled receptor for medium and long-chained fatty acids that can be expressed as distinct short (FFA4-S) or long (FFA4-L) isoforms. Although much is known about FFA4-S, the longer isoform remains virtually unstudied. Here, we reveal the mechanisms of docosahexaenoic acid-induced phosphorylation of FFA4-L and subsequent ß-arrestin-2 recruitment and extracellular-signal regulated kinase-1/2 activity.


Asunto(s)
Empalme Alternativo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Sistema de Señalización de MAP Quinasas , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/metabolismo , Arrestina beta 2/metabolismo , Empalme Alternativo/efectos de los fármacos , Secuencia de Aminoácidos , Ácidos Docosahexaenoicos/farmacología , Quinasas de Receptores Acoplados a Proteína-G/metabolismo , Subunidades alfa de la Proteína de Unión al GTP Gq-G11/metabolismo , Células HEK293 , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Fosforilación/efectos de los fármacos , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteína Quinasa C/metabolismo , Receptores Acoplados a Proteínas G/genética , Transducción de Señal/efectos de los fármacos
16.
Chemosphere ; 249: 126554, 2020 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-32213394

RESUMEN

Polybrominated diphenyl ethers (PBDEs) are more frequently suspected with the induction of toxicity via signal transduction pathway of cytosolic aryl hydrocarbon receptor (AhR), the initial binding to which is assumed to be an essential prerequisite during the ligand-dependent activation. However, the AhR binding property and associated toxicity of PBDEs is yet to be clearly known for lacking insights into the structural requirements at molecular level. To understand the AhR binding property of PBDEs, the ligand binding domain (LBD) of AhR was simulatively developed on homologous protein after basic validation of geometrical rationality and the binding interaction profile was visually described using molecular docking approach. For AhR binding, the offset or edge-on π-π stackings with aromatic motifs including Phe289, Phe345 and His285 were shown to be structurally required whereas the electrostatic attraction validated for AhR binding to dioxins might be less effective for 2,2',3,4,4'-pentabromodiphenyl ether (BDE-85). Besides the demands of less steric hindrance from alanines and weak formulation of hydrogen bonds, the dispersion force through large contact and polarization of S-π electrons seemed to be impactful when BDE-85 were closer to Cys327, Met334 or Met342. With theoretical computation of AhR binding energies, the more significant correlativity with bioassays was derived especially for the lowly/moderately brominated congeners, and could be used to predict the AhR binding affinity on certain degree. The informative results would thus not only help well understand the molecular basis of AhR-mediated toxicity but give an approach for accelerative evaluation of AhR binding and toxicity of PBDEs.


Asunto(s)
Contaminantes Ambientales/toxicidad , Éteres Difenilos Halogenados/toxicidad , Receptores de Hidrocarburo de Aril/metabolismo , Bioensayo , Éteres Difenilos Halogenados/metabolismo , Humanos , Enlace de Hidrógeno , Ligandos , Simulación del Acoplamiento Molecular , Bifenilos Polibrominados/farmacología , Unión Proteica , Transducción de Señal/efectos de los fármacos
17.
Science ; 367(6484): 1362-1366, 2020 03 20.
Artículo en Inglés | MEDLINE | ID: mdl-32193325

RESUMEN

Stimulants such as methylphenidate are increasingly used for cognitive enhancement but precise mechanisms are unknown. We found that methylphenidate boosts willingness to expend cognitive effort by altering the benefit-to-cost ratio of cognitive work. Willingness to expend effort was greater for participants with higher striatal dopamine synthesis capacity, whereas methylphenidate and sulpiride, a selective D2 receptor antagonist, increased cognitive motivation more for participants with lower synthesis capacity. A sequential sampling model informed by momentary gaze revealed that decisions to expend effort are related to amplification of benefit-versus-cost information attended early in the decision process, whereas the effect of benefits is strengthened with higher synthesis capacity and by methylphenidate. These findings demonstrate that methylphenidate boosts the perceived benefits versus costs of cognitive effort by modulating striatal dopamine signaling.


Asunto(s)
Cognición/efectos de los fármacos , Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Metilfenidato/farmacología , Motivación/efectos de los fármacos , Sulpirida/farmacología , Adolescente , Núcleo Caudado/metabolismo , Conducta de Elección , Toma de Decisiones , Dopamina/biosíntesis , Antagonistas de los Receptores de Dopamina D2/farmacología , Inhibidores de Captación de Dopamina/farmacología , Femenino , Fijación Ocular , Humanos , Masculino , Memoria , Recompensa , Movimientos Sacádicos , Transducción de Señal/efectos de los fármacos , Adulto Joven
18.
Toxicol Lett ; 326: 78-82, 2020 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-32173488

RESUMEN

Mustard vesicants, including sulfur mustard (2,2'-dichlorodiethyl sulfide, SM) and nitrogen mustard (bis(2-chloroethyl)methylamine, HN2) are cytotoxic blistering agents synthesized for chemical warfare. Because they contain highly reactive electrophilic chloroethyl side chains, they readily react with cellular macromolecules like DNA forming monofunctional and bifunctional adducts. By targeting DNA, mustards can compromise genomic integrity, disrupt the cell cycle, and cause mutations and cytotoxicity. To protect against genotoxicity following exposure to mustards, cells initiate a DNA damage response (DDR). This involves activation of signaling cascades including ATM (ataxia telangiectasia mutated), ATR (ataxia telangiectasia and Rad3-related) and DNA-PKcs (DNA-dependent protein kinase, catalytic unit). Signaling induced by the DDR leads to the recruitment and activation of repair related proteins such as phospho H2AX and phospho p53 to sites of DNA lesions. Excessive DNA modifications by mustards can overwhelm DNA repair leading to single and double strand DNA breaks, cytotoxicity and tissue damage, sometimes leading to cancer. Herein we summarize DDR signaling pathways induced by SM, HN2 and the half mustard, 2-chloroethyl ethyl sulfide (CEES). At the present time, little is known about how mustard-induced DNA damage leads to the activation of DDR signaling. A better understanding of mechanisms by which mustard vesicants induce the DDR may lead to the development of countermeasures effective in mitigating tissue injury.


Asunto(s)
Supervivencia Celular/efectos de los fármacos , Daño del ADN/efectos de los fármacos , Mecloretamina/toxicidad , Gas Mostaza/toxicidad , Transducción de Señal/efectos de los fármacos , Humanos , Planta de la Mostaza/química
19.
Mol Biol (Mosk) ; 54(1): 128-136, 2020.
Artículo en Ruso | MEDLINE | ID: mdl-32163396

RESUMEN

Neuroinflammation plays a key role in the pathogenesis of neurodegenerative diseases. Microglial cells are the main immune cells of the central nervous system. On exposure to lipopolysaccharides (LPS, components of the cell wall of Gram-negative enterobacteria), microglia is activated to produce reactive oxygen species (ROS), cytokines, and inflammatory mediators, which may cause neuron death. Exogenous recombinant human heat shock protein 70 (HSP70) was tested for effect on the activation of human microglial and neuroblastoma cells in response to LPS from Escherichia coli. Experiments included cell cultivation separately and transferring the conditioned medium from A-172 microglial cells to SK-N-SH neuroblastoma cells to simulate the effect of microglia treated with LPS and/or HSP70. The levels of ROS, TNFα, and apoptosis in LPS-treated cells were estimated in the presence or absence of HSP70. HSP70 was found to reduce the LPS-induced ROS generation, TNFα production, apoptosis, and necrosis, in both separate cell cultures and neuroblastoma cells grown in the conditioned medium from microglial cells. Signaling pathways involving protein kinases p38MAPK, JNK, and PI3K were demonstrated to play an important role in HSP70-mediated protection of microglial and neuroblastoma cells from LPS-induced apoptosis and ROS production.


Asunto(s)
Medios de Cultivo Condicionados/química , Proteínas HSP70 de Choque Térmico/farmacología , Lipopolisacáridos/toxicidad , Neuroblastoma/tratamiento farmacológico , Neuroprotección/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Transducción de Señal/efectos de los fármacos , Apoptosis/efectos de los fármacos , Medios de Cultivo Condicionados/farmacología , Humanos , Lipopolisacáridos/inmunología , Microglía/efectos de los fármacos , Microglía/inmunología , Microglía/metabolismo , Neuroblastoma/metabolismo , Neuroblastoma/patología , Especies Reactivas de Oxígeno/metabolismo
20.
Toxicol Lett ; 326: 61-69, 2020 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-32169443

RESUMEN

Notch-1 intervenes in the reparative processes of mucosa by controlling cell proliferation, differentiation and stem cell maintenance. Cigarette smoke alters airway epithelial homeostasis. The present study explored whether: Smokers showed altered Notch-1 expression; and whether in bronchial epithelial cells (16HBE): a) cigarette smoke extracts (CSE) altered the expression of Notch-1, of its ligand Jagged-1 (Jag-1) and the nuclear translocation of Notch-1; b) Notch-1 signaling activation as well as CSE modified Ki67, PCNA, p21, IL-33 expression, cell proliferation and repair processes. Notch-1 expression was assessed in the epithelium from large airway surgical samples from non-smoker and smoker subjects by immunohistochemistry.16HBE were cultured with/without CSE and Jag-1. A Notch-1 inhibitor (DAPT) was used as control. The expression of Notch-1, Jag-1, Ki67, PCNA, p21, IL-33 and cell proliferation (by CFSE) were all assessed by flow cytometry. Notch-1 nuclear expression was evaluated by immunofluorescence and western blot analysis. Repair processes were assessed by wound assay. Smokers had cytoplasmic but not nuclear Notch-1 expression. Although CSE increased Notch-1 expression, it counteracted Notch-1 signaling activation since it reduced Jag-1 expression and Notch-1 nuclear translocation. Notch-1 signaling activation by Jag-1 increased Ki67, PCNA and repair processes but reduced intracellular IL-33 and p21 expression without affecting cell proliferation. DAPT counteracted the effects of Notch-1 activation on PCNA and IL-33. CSE increased Ki67, PCNA, p21 and IL-33 expression but reduced cell proliferation and repair processes. In conclusion, cigarette smoke exposure, limiting Notch-1 signaling activation and hindering repair processes, amplifies injury processes in bronchial epithelial cells.


Asunto(s)
Apoptosis/efectos de los fármacos , Bronquios/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Receptores Notch/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Contaminación por Humo de Tabaco/efectos adversos , Humanos
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