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2.
Int J Mol Sci ; 22(6)2021 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-33803747

RESUMEN

Differentiated thyroid cancers (DTC) are commonly and successfully treated with total thyroidectomy plus/minus radioiodine therapy (RAI). Medullary thyroid cancer (MTC) is only treated with surgery but only intrathyroidal tumors are cured. The worst prognosis is for anaplastic (ATC) and poorly differentiated thyroid cancer (PDTC). Whenever a local or metastatic advanced disease is present, other treatments are required, varying from local to systemic therapies. In the last decade, the efficacy of the targeted therapies and, in particular, tyrosine kinase inhibitors (TKIs) has been demonstrated. They can prolong the disease progression-free survival and represent the most important therapeutic option for the treatment of advanced and progressive thyroid cancer. Currently, lenvatinib and sorafenib are the approved drugs for the treatment of RAI-refractory DTC and PDTC while advanced MTC can be treated with either cabozantinib or vandetanib. Dabrafenib plus trametinib is the only approved treatment by FDA for BRAFV600E mutated ATC. A new generation of TKIs, specifically for single altered oncogenes, is under evaluation in phase 2 and 3 clinical trials. The aim of this review was to provide an overview of the current and future treatments of thyroid cancer with regards to the advanced and progressive cases that require systemic therapies that are becoming more and more targeted on the molecular identity of the tumor.


Asunto(s)
Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/cirugía , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Humanos , Terapia Molecular Dirigida , Transducción de Señal , Neoplasias de la Tiroides/tratamiento farmacológico , Microambiente Tumoral/inmunología
3.
Int J Mol Sci ; 22(6)2021 Mar 17.
Artículo en Inglés | MEDLINE | ID: mdl-33802742

RESUMEN

New anti-inflammatory treatments are needed for CF airway disease. Studies have implicated the endoplasmic reticulum stress transducer inositol requiring enzyme 1α (IRE1α) in CF airway inflammation. The activation of IRE1α promotes activation of its cytoplasmic kinase and RNase, resulting in mRNA splicing of X-box binding protein-1 (XBP-1s), a transcription factor required for cytokine production. We tested whether IRE1α kinase and RNase inhibition decreases cytokine production induced by the exposure of primary cultures of homozygous F508del CF human bronchial epithelia (HBE) to supernatant of mucopurulent material (SMM) from CF airways. We evaluated whether IRE1α expression is increased in freshly isolated and native CF HBE, and couples with increased XBP-1s levels. A FRET assay confirmed binding of the IRE1α kinase and RNase inhibitor, KIRA6, to the IRE1α kinase. F508del HBE cultures were exposed to SMM with or without KIRA6, and we evaluated the mRNA levels of XBP-1s, IL-6, and IL-8, and the secretion of IL-6 and IL-8. IRE1α mRNA levels were up-regulated in freshly isolated CF vs. normal HBE and coupled to increased XBP-1s mRNA levels. SMM increased XBP-1s, IL-6, and IL-8 mRNA levels and up-regulated IL-6 and IL-8 secretion, and KIRA6 blunted these responses in a dose-dependent manner. Moreover, a triple combination of CFTR modulators currently used in the clinic had no effect on SMM-increased XBP-1s levels coupled with increased cytokine production in presence or absence of KIRA6. These findings indicate that IRE1α mediates cytokine production in CF airways. Small molecule IRE1α kinase inhibitors that allosterically reduce RNase-dependent XBP-1s may represent a new therapeutic strategy for CF airway inflammation.


Asunto(s)
Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/patología , Endorribonucleasas/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/patología , Pulmón/patología , Terapia Molecular Dirigida , Proteínas Serina-Treonina Quinasas/metabolismo , Células Cultivadas , Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Citocinas/biosíntesis , Endorribonucleasas/genética , Epitelio/efectos de los fármacos , Epitelio/patología , Humanos , Imidazoles/química , Imidazoles/farmacología , Inflamación/genética , Modelos Biológicos , Naftalenos/química , Naftalenos/farmacología , Proteínas Serina-Treonina Quinasas/genética , Pirazinas/química , Pirazinas/farmacología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/genética , Proteína 1 de Unión a la X-Box/metabolismo
4.
Drug Des Devel Ther ; 15: 1345-1356, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33824579

RESUMEN

The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), continues to spread around the world. While prophylactic vaccines against SARS-CoV-2 are making great progress, there is still a need to explore safe and effective therapies with biological products for COVID-19. Currently clinical trial efforts are planned and ongoing using different biological agents for anti-inflammatory therapies, immunomodulation, and therapeutic repair in COVID-19. Targeting inflammatory cytokines with antibodies or inhibitors may be an urgent therapeutic strategy for COVID-19. Importantly, it is critical for an in-depth understanding of these new clinical therapeutic agents in their conditions that are probably involved in both physiological and pathological host responses. In this article, we analyze the potential implications for the current clinical trials of therapeutic biologics and address issues for the development of the COVID-19-related biological therapies.


Asunto(s)
Antiinflamatorios/uso terapéutico , Productos Biológicos/uso terapéutico , Citocinas/antagonistas & inhibidores , Factores Inmunológicos/uso terapéutico , /inmunología , Antiinflamatorios/efectos adversos , Productos Biológicos/efectos adversos , /inmunología , Ensayos Clínicos como Asunto , Citocinas/inmunología , Interacciones Huésped-Patógeno , Humanos , Factores Inmunológicos/efectos adversos , Terapia Molecular Dirigida , Resultado del Tratamiento
5.
Anticancer Res ; 41(4): 1715-1726, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33813375

RESUMEN

Medulloblastoma (MB) is the most frequent malignant brain tumor in children. Treatment of MB is based on histopathological and molecular stratification, and includes surgical intervention, often with craniospinal irradiation and adjuvant chemotherapy. Unfortunately, however, this treatment leads to a high morbidity rate, and it does not cure all patients either, with around 30% succumbing to their disease. With improved cancer genomics and better molecular characterization, MB has been classified into four major subgroups, wingless-activated, sonic hedgehog-activated, Group 3, and Group 4, with each group consisting of additional subtypes. Recently disclosed genetic drivers of MB may in the future help improve treatment, and in this way reduce therapy-related toxicity. In this review, we describe the heterogeneity of the MB subgroups, and potential new options for targeted therapy.


Asunto(s)
Neoplasias Cerebelosas/terapia , Inmunoterapia , Meduloblastoma/terapia , Terapia Molecular Dirigida , Procedimientos Neuroquirúrgicos , Medicina de Precisión , Biomarcadores de Tumor/genética , Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/mortalidad , Neoplasias Cerebelosas/patología , Quimioterapia Adyuvante , Niño , Preescolar , Irradiación Craneana , Femenino , Humanos , Inmunoterapia/efectos adversos , Lactante , Masculino , Meduloblastoma/genética , Meduloblastoma/mortalidad , Meduloblastoma/patología , Terapia Molecular Dirigida/efectos adversos , Procedimientos Neuroquirúrgicos/efectos adversos , Radioterapia Ayuvante , Resultado del Tratamiento
6.
Int J Mol Sci ; 22(6)2021 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-33808629

RESUMEN

Neuropathological lesions in Alzheimer's disease (AD) include amyloid plaques formed by the accumulation of amyloid peptides, neurofibrillary tangles made of hyperphosphorylated tau protein, synaptic and neuronal degenerations, and neuroinflammation. The cause of AD is unknown, but according to the amyloid hypothesis, amyloid oligomers could lead to the activation of kinases such as eukaryotic translation initiation factor 2-alpha kinase 2 (PKR), p38, and receptor-interacting serine/threonine-protein kinase 1 (RIPK1), which all belong to the same stress-activated pathway. Many toxic kinase activations have been described in AD patients and in experimental models. A p38 mitogen-activated protein kinase inhibitor was recently tested in clinical trials but with unsuccessful results. The complex PKR/P38/RIPK1 (PKR/dual specificity mitogen-activated protein kinase kinase 6 (MKK6)/P38/MAP kinase-activated protein kinase 2 (MK2)/RIPK1) is highly activated in AD brains and in the brains of AD transgenic animals. To delineate the implication of this pathway in AD, we carried out a search on PubMed including PKR/MKK6/p38/MK2/RIPK1, Alzheimer, and therapeutics. The involvement of this signaling pathway in the genesis of AD lesions, including Aß accumulations and tau phosphorylation as well as cognitive decline, is demonstrated by the reports described in this review. A future combination strategy with kinase inhibitors should be envisaged to modulate the consequences for neurons and other brain cells linked to the abnormal activation of this pathway.


Asunto(s)
Enfermedad de Alzheimer/metabolismo , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Transducción de Señal , eIF-2 Quinasa/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/etiología , Animales , Biomarcadores , Encéfalo/metabolismo , Encéfalo/patología , Terapia Combinada , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Descubrimiento de Drogas , Humanos , Terapia Molecular Dirigida , Transducción de Señal/efectos de los fármacos
7.
Int J Mol Sci ; 22(6)2021 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-33808647

RESUMEN

Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide. HCC is associated with several etiological factors, including HBV/HCV infections, cirrhosis, and fatty liver diseases. However, the molecular mechanism underlying HCC development remains largely elusive. The advent of high-throughput sequencing has unveiled an unprecedented discovery of a plethora of long noncoding RNAs (lncRNAs). Despite the lack of coding capacity, lncRNAs have key roles in gene regulation through interacting with various biomolecules. It is increasingly evident that the dysregulation of lncRNAs is inextricably linked to HCC cancer phenotypes, suggesting that lncRNAs are potential prognostic markers and therapeutic targets. In light of the emerging research in the study of the regulatory roles of lncRNAs in HCC, we discuss the association of lncRNAs with HCC. We link the biological processes influenced by lncRNAs to cancer hallmarks in HCC and describe the associated functional mechanisms. This review sheds light on future research directions, including the potential therapeutic applications of lncRNAs.


Asunto(s)
Biomarcadores de Tumor , Carcinoma Hepatocelular/genética , Susceptibilidad a Enfermedades , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas/genética , ARN Largo no Codificante , Animales , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/terapia , Transformación Celular Neoplásica/genética , Manejo de la Enfermedad , Genes Supresores de Tumor , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Técnicas de Diagnóstico Molecular , Terapia Molecular Dirigida , Oncogenes , Transducción de Señal/efectos de los fármacos
8.
Int J Mol Sci ; 22(6)2021 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-33809908

RESUMEN

Endoglin (CD105) is a type-1 integral transmembrane glycoprotein and coreceptor for transforming growth factor-ß (TGF-ß) ligands. The endoglin/TGF-ß signaling pathway regulates hemostasis, cell proliferation/migration, extracellular matrix (ECM) synthesis and angiogenesis. Angiogenesis contributes to early progression, invasion, postoperative recurrence, and metastasis in hepatocellular carcinoma (HCC), one of the most widespread malignancies globally. Endoglin is overexpressed in newly formed HCC microvessels. It increases microvessel density in cirrhotic and regenerative HCC nodules. In addition, circulating endoglin is present in HCC patients, suggesting potential for use as a diagnostic or prognostic factor. HCC angiogenesis is dynamic and endoglin expression varies by stage. TRC105 (carotuximab) is an antibody against endoglin, and three of its clinical trials were related to liver diseases. A partial response was achieved when combining TRC105 with sorafenib. Although antiangiogenic therapy still carries some risks, combination therapy with endoglin inhibitors or other targeted therapies holds promise.


Asunto(s)
Carcinoma Hepatocelular/etiología , Carcinoma Hepatocelular/metabolismo , Susceptibilidad a Enfermedades , Endoglina/genética , Endoglina/metabolismo , Neoplasias Hepáticas/etiología , Neoplasias Hepáticas/metabolismo , Animales , Biomarcadores de Tumor , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/terapia , Endoglina/sangre , Endoglina/química , Células Endoteliales/metabolismo , Regulación Neoplásica de la Expresión Génica , Hepacivirus/fisiología , Hepatitis C/metabolismo , Hepatitis C/virología , Humanos , Neoplasias Hepáticas/patología , Técnicas de Diagnóstico Molecular , Terapia Molecular Dirigida , Neovascularización Patológica/genética , Neovascularización Patológica/metabolismo , Transducción de Señal , Relación Estructura-Actividad , Proteínas del Núcleo Viral/metabolismo
9.
Int J Mol Sci ; 22(6)2021 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-33809961

RESUMEN

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative neuromuscular disease. Although genome-wide association studies (GWAS) have successfully identified many variants significantly associated with ALS, it is still difficult to characterize the underlying biological mechanisms inducing ALS. In this study, we performed a transcriptome-wide association study (TWAS) to identify disease-specific genes in ALS. Using the largest ALS GWAS summary statistic (n = 80,610), we identified seven novel genes using 19 tissue reference panels. We conducted a conditional analysis to verify the genes' independence and to confirm that they are driven by genetically regulated expressions. Furthermore, we performed a TWAS-based enrichment analysis to highlight the association of important biological pathways, one in each of the four tissue reference panels. Finally, utilizing a connectivity map, a database of human cell expression profiles cultured with bioactive small molecules, we discovered functional associations between genes and drugs to identify 15 bioactive small molecules as potential drug candidates for ALS. We believe that, by integrating the largest ALS GWAS summary statistic with gene expression to identify new risk loci and causal genes, our study provides strong candidates for molecular basis experiments in ALS.


Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Transcriptoma , Esclerosis Amiotrófica Lateral/diagnóstico , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Biomarcadores , Biología Computacional/métodos , Desarrollo de Medicamentos , Reposicionamiento de Medicamentos , Perfilación de la Expresión Génica , Humanos , Anotación de Secuencia Molecular , Terapia Molecular Dirigida , Medición de Riesgo , Factores de Riesgo , Flujo de Trabajo
10.
Int J Mol Sci ; 22(6)2021 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-33810078

RESUMEN

Metastatic melanoma remains the deadliest form of skin cancer. Immune checkpoint inhibition (ICI) immunotherapy has defined a new age in melanoma treatment, but responses remain inconsistent and some patients develop treatment resistance. The myriad of newly developed small molecular (SM) inhibitors of specific effector targets now affords a plethora of opportunities to increase therapeutic responses, even in resistant melanoma. In this review, we will discuss the multitude of SM classes currently under investigation, current and prospective clinical combinations of ICI and SM therapies, and their potential for synergism in melanoma eradication based on established mechanisms of immunotherapy resistance.


Asunto(s)
Antineoplásicos/farmacología , Descubrimiento de Drogas , /farmacología , Inhibidores de la Angiogénesis/farmacología , Animales , Antineoplásicos/química , Biomarcadores de Tumor , Línea Celular Tumoral , Descubrimiento de Drogas/métodos , Sinergismo Farmacológico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , /metabolismo , Inmunomodulación/efectos de los fármacos , Melanoma/tratamiento farmacológico , Melanoma/etiología , Melanoma/metabolismo , Terapia Molecular Dirigida , Inhibidores de Proteínas Quinasas/farmacología
11.
Eur Rev Med Pharmacol Sci ; 25(7): 3122-3131, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33877681

RESUMEN

OBJECTIVE: Transcriptome data related to severe acute respiratory syndrome-related coronavirus 2 (a novel coronavirus discovered in 2019, SARS-CoV-2) in GEO database were downloaded. Based on the data, influence of SARS-CoV-2 on human cells was analyzed and potential therapeutic compounds against the SARS-CoV-2 were screened. MATERIALS AND METHODS: R package "DESeq2" was used for differential gene analysis on the data of cells infected or non-infected with SARS-CoV-2. The "ClusterProfiler" package was used for GO functional annotation and KEGG pathway enrichment analysis of the differentially expressed genes (DEGs). A protein-protein interaction (PPI) network of the DEGs was constructed through STRING website, and the key subset in the PPI network was identified after visualization by Cytoscape software. Connectivity Map (CMap) database was used to screen known compounds that caused genomic change reverse to that caused by SARS-CoV-2. RESULTS: By intersecting DEGs in two datasets, a total of 145 DEGs were screened out, among which 136 genes were upregulated and 9 genes were downregulated in SARS-CoV-2-infected cells. Functional enrichment analyses revealed that these genes were mainly associated with the pathways involved in viral infection, inflammatory response, and immunity. The CMap research found that there were three compounds with a median_tau_score less than -90, namely triptolide, tivozanib and daunorubicin. CONCLUSIONS: SARS-CoV-2 can cause abnormal changes in a large number of molecules and related signaling pathways in human cells, among which IL-17 and TNF signaling pathways may play a key role in pathogenic process of SARS-CoV-2. Here, three compounds that may be effective for the treatment of SARS-CoV-2 were screened, which would provide new options for improving treatment of patients infected with SARS-CoV-2.


Asunto(s)
/tratamiento farmacológico , Descubrimiento de Drogas , Perfilación de la Expresión Génica , Bases de Datos Genéticas , Bases de Datos Farmacéuticas , Daunorrubicina , Diterpenos , Regulación hacia Abajo , Compuestos Epoxi , Ontología de Genes , Redes Reguladoras de Genes , Humanos , Terapia Molecular Dirigida , Fenantrenos , Compuestos de Fenilurea , Mapas de Interacción de Proteínas , Quinolinas , Transducción de Señal/genética , Regulación hacia Arriba
12.
Anticancer Res ; 41(3): 1485-1496, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33788741

RESUMEN

BACKGROUND: As the prognosis of biliary tract cancer (BTC) is extremely poor and treatment options are limited, new treatment modalities are urgently needed. We designed a phase II clinical trial to investigate the immune responses and clinical benefits of OCV-C01, an HLA-A*24:02-restricted three-peptide cancer vaccine targeting VEGFR1, VEGFR2, and KIF20A. PATIENTS AND METHODS: Participants were patients with advanced BTC who had unresectable tumours and were refractory to standard chemotherapy. OCV-C01 was injected weekly until the discontinuance criteria were met. RESULTS: Six participants, including four patients positive for HLA-A*24:02, were enrolled in this study for assessment of efficacy. Four out of six patients exhibited vaccine-specific T-cell responses to one or more of three antigens. Log-rank tests revealed that vaccine-specific T cell responses contributed significantly to overall survival. CONCLUSION: The cancer vaccine had positive effects on survival, indicating that this approach warrants further clinical studies.


Asunto(s)
Neoplasias del Sistema Biliar/tratamiento farmacológico , Vacunas contra el Cáncer/administración & dosificación , Cinesina/antagonistas & inhibidores , Vacunas de Subunidad/administración & dosificación , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Anciano , Anciano de 80 o más Años , Neoplasias del Sistema Biliar/inmunología , Neoplasias del Sistema Biliar/metabolismo , Vacunas contra el Cáncer/efectos adversos , Vacunas contra el Cáncer/inmunología , Supervivencia sin Enfermedad , Femenino , Fiebre/inducido químicamente , Cefalea/inducido químicamente , Humanos , Cinesina/inmunología , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida/métodos , Pronóstico , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/metabolismo , Vacunas de Subunidad/efectos adversos , Vacunas de Subunidad/inmunología , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Factor A de Crecimiento Endotelial Vascular/inmunología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/inmunología
13.
Int J Mol Sci ; 22(4)2021 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-33669775

RESUMEN

Liver metastasis is the primary contributor to the death of patients with colorectal cancer. Despite the overall success of current treatments including targeted therapy, chemotherapy, and immunotherapy combinations in colorectal cancer patients, the prognosis of patients with liver metastasis remains poor. Recent studies have highlighted the importance of the tumour microenvironment and the crosstalk within that determines the fate of circulating tumour cells in distant organs. Understanding the interactions between liver resident cells and tumour cells colonising the liver opens new therapeutic windows for the successful treatment of metastatic colorectal cancer. Here we discuss critical cellular interactions within the tumour microenvironment in primary tumours and in liver metastases that highlight potential therapeutic targets. We also discuss recent therapeutic advances for the treatment of metastatic colorectal cancer.


Asunto(s)
Neoplasias Colorrectales/patología , Terapia Molecular Dirigida , Microambiente Tumoral , Animales , Humanos , Hígado/patología , Metástasis de la Neoplasia , Pronóstico
14.
Int J Mol Sci ; 22(4)2021 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-33669845

RESUMEN

Pancreatic ductal adenocarcinoma (PDA) is the most common cancer of the exocrine pancreas and probably the tumor that has benefited the least from clinical progress in the last three decades. A consensus has been reached regarding the histologic classification of the ductal preneoplastic lesions (pancreatic intra-epithelial neoplasia-PanIN) and the molecular alterations associated with them. Mutations in KRAS and inactivation of CDKN2A, SMAD4 and TP53 are among the most prevalent alterations. Next generation sequencing studies are providing a broad picture of the enormous heterogeneity in this tumor type, describing new mutations less prevalent. These studies have also allowed the characterization of different subtypes with prognostic value. However, all this knowledge has not been translated into a clinical progress. Effective preventive and early diagnostic strategies are essential to improve the survival rates. The main challenge is, indeed, to identify new effective drugs. Despite many years of research and its limited success, gemcitabine is still the first line treatment of PDA. New drug combinations and new concepts to improve drug delivery into the tumor, as well as the development of preclinical predictive assays, are being explored and provide optimism and prospects for better therapies.


Asunto(s)
Neoplasias Pancreáticas/genética , Investigación en Medicina Traslacional , Epigénesis Genética , Heterogeneidad Genética , Predisposición Genética a la Enfermedad , Humanos , Terapia Molecular Dirigida , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología
16.
Cell ; 184(6): 1604-1620, 2021 03 18.
Artículo en Inglés | MEDLINE | ID: mdl-33740455

RESUMEN

Historically, emerging viruses appear constantly and have cost millions of human lives. Currently, climate change and intense globalization have created favorable conditions for viral transmission. Therefore, effective antivirals, especially those targeting the conserved protein in multiple unrelated viruses, such as the compounds targeting RNA-dependent RNA polymerase, are urgently needed to combat more emerging and re-emerging viruses in the future. Here we reviewed the development of antivirals with common targets, including those against the same protein across viruses, or the same viral function, to provide clues for development of antivirals for future epidemics.


Asunto(s)
Antivirales/uso terapéutico , Enfermedades Transmisibles Emergentes/tratamiento farmacológico , Enfermedades Transmisibles Emergentes/epidemiología , Terapia Molecular Dirigida/métodos , Pandemias , Virosis/tratamiento farmacológico , Virosis/epidemiología , Virus/enzimología , Animales , Antivirales/farmacología , Enfermedades Transmisibles Emergentes/virología , Humanos , Proteínas del Envoltorio Viral/antagonistas & inhibidores , Virosis/virología , Internalización del Virus/efectos de los fármacos
17.
Int J Mol Sci ; 22(5)2021 Feb 25.
Artículo en Inglés | MEDLINE | ID: mdl-33668976

RESUMEN

Alzheimer's disease (AD), the most common cause of dementia, is a progressive neurodegenerative disease. The number of AD cases has been rapidly growing worldwide. Several the related etiological hypotheses include atypical amyloid ß (Aß) deposition, neurofibrillary tangles of tau proteins inside neurons, disturbed neurotransmission, inflammation, and oxidative stress. During AD progression, aberrations in neurotransmission cause cognitive decline-the main symptom of AD. Here, we review the aberrant neurotransmission systems, including cholinergic, adrenergic, and glutamatergic network, and the interactions among these systems as they pertain to AD. We also discuss the key role of N-methyl-d-aspartate receptor (NMDAR) dysfunction in AD-associated cognitive impairment. Furthermore, we summarize the results of recent studies indicating that increasing glutamatergic neurotransmission through the alteration of NMDARs shows potential for treating cognitive decline in mild cognitive impairment or early stage AD. Future studies on the long-term efficiency of NMDA-enhancing strategies in the treatment of AD are warranted.


Asunto(s)
Adrenérgicos/metabolismo , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/fisiopatología , Colinérgicos/metabolismo , Disfunción Cognitiva/complicaciones , Glutamatos/metabolismo , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/tratamiento farmacológico , Animales , Humanos , Terapia Molecular Dirigida
18.
Int J Mol Sci ; 22(4)2021 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-33670021

RESUMEN

The World Health Organization has estimated that approximately 3 million deaths are attributable to alcohol consumption each year. Alcohol consumption is notably associated with the development and/or progression of many non-communicable inflammatory diseases-particularly in the liver. Although these alcoholic liver diseases were initially thought to be caused by the toxicity of ethanol on hepatocytes, the latest research indicates Kupffer cells (the liver macrophages) are at the heart of this "inflammatory shift". Purinergic signaling (notably through P2X7 receptors and the NLRP3 inflammasome) by Kupffer cells appears to be a decisive factor in the pathophysiology of alcoholic liver disease. Hence, the modulation of purinergic signaling might represent a new means of treating alcoholic liver disease. Here, we review current knowledge on the pathophysiology of alcoholic liver diseases and therapeutic perspectives for targeting these inflammatory pathways.


Asunto(s)
Inflamasomas/metabolismo , Hepatopatías Alcohólicas/tratamiento farmacológico , Hepatopatías Alcohólicas/metabolismo , Terapia Molecular Dirigida , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Receptores Purinérgicos P2X7/metabolismo , Animales , Humanos , Transducción de Señal
19.
Int J Mol Sci ; 22(4)2021 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-33670032

RESUMEN

Pulmonary arterial hypertension (PAH) is a progressive and fatal disease without a cure. The exact pathogenic mechanisms of PAH are complex and poorly understood, yet a number of abnormally expressed genes and regulatory pathways contribute to sustained vasoconstriction and vascular remodeling of the distal pulmonary arteries. Mammalian target of rapamycin (mTOR) is one of the major signaling pathways implicated in regulating cell proliferation, migration, differentiation, and protein synthesis. Here we will describe the canonical mTOR pathway, structural and functional differences between mTOR complexes 1 and 2, as well as the crosstalk with other important signaling cascades in the development of PAH. The pathogenic role of mTOR in pulmonary vascular remodeling and sustained vasoconstriction due to its contribution to proliferation, migration, phenotypic transition, and gene regulation in pulmonary artery smooth muscle and endothelial cells will be discussed. Despite the progress in our elucidation of the etiology and pathogenesis of PAH over the two last decades, there is a lack of effective therapeutic agents to treat PAH patients representing a significant unmet clinical need. In this review, we will explore the possibility and therapeutic potential to use inhibitors of mTOR signaling cascade to treat PAH.


Asunto(s)
Terapia Molecular Dirigida , Hipertensión Arterial Pulmonar/metabolismo , Hipertensión Arterial Pulmonar/patología , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Enfermedades Vasculares/metabolismo , Animales , Ensayos Clínicos como Asunto , Humanos , Serina-Treonina Quinasas TOR/química
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