Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 4.082
Filtrar
3.
BMC Bioinformatics ; 22(1): 418, 2021 Sep 03.
Artículo en Inglés | MEDLINE | ID: mdl-34479477

RESUMEN

BACKGROUND: Prediction of the drug-target interaction (DTI) is a critical step in the drug repurposing process, which can effectively reduce the following workload for experimental verification of potential drugs' properties. In recent studies, many machine-learning-based methods have been proposed to discover unknown interactions between drugs and protein targets. A recent trend is to use graph-based machine learning, e.g., graph embedding to extract features from drug-target networks and then predict new drug-target interactions. However, most of the graph embedding methods are not specifically designed for DTI predictions; thus, it is difficult for these methods to fully utilize the heterogeneous information of drugs and targets (e.g., the respective vertex features of drugs and targets and path-based interactive features between drugs and targets). RESULTS: We propose a DTI prediction method DTI-HeNE (DTI based on Heterogeneous Network Embedding), which is specifically designed to cope with the bipartite DTI relations for generating high-quality embeddings of drug-target pairs. This method splits a heterogeneous DTI network into a bipartite DTI network, multiple drug homogeneous networks and target homogeneous networks, and extracts features from these sub-networks separately to better utilize the characteristics of bipartite DTI relations as well as the auxiliary similarity information related to drugs and targets. The features extracted from each sub-network are integrated using pathway information between these sub-networks to acquire new features, i.e., embedding vectors of drug-target pairs. Finally, these features are fed into a random forest (RF) model to predict novel DTIs. CONCLUSIONS: Our experimental results show that, the proposed DTI network embedding method can learn higher-quality features of heterogeneous drug-target interaction networks for novel DTIs discovery.


Asunto(s)
Desarrollo de Medicamentos , Preparaciones Farmacéuticas , Interacciones Farmacológicas , Reposicionamiento de Medicamentos , Aprendizaje Automático
4.
Biomed Res Int ; 2021: 5533946, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34471638

RESUMEN

Weibing Formula 1, a classic traditional formula, has been widely used clinically to treat gastritis in recent years. However, the potential pharmacological mechanism of Weibing Formula 1 is still unclear to date. A network pharmacology-based strategy was performed to uncover the underlying mechanisms of Weibing Formula 1 against gastritis. Furthermore, we structured the drug-active ingredients-genes-disease network and PPI network of shared targets, and function enrichment analysis of these targets was carried out. Ultimately, Gene Expression Omnibus (GEO) datasets and real-time quantitative PCR were used to verify the related genes. We found 251 potential targets corresponding to 135 bioactive components of Weibing Formula 1. Then, 327 gastritis-related targets were known gastritis-related targets. Among which, 60 common targets were shared between potential targets of Weibing Formula 1 and known gastritis-related targets. The results of pathway enrichment analysis displayed that 60 common targets mostly participated in various pathways related to Toll-like receptor signaling pathway, MAPK signaling pathway, cytokine-cytokine receptor interaction pathway, chemokine signaling pathway, and apoptosis. Based on the GSE60427 dataset, 15 common genes were shared between differentially expressed genes and 60 candidate targets. The verification results of the GSE5081 dataset showed that except for DUOX2 and VCAM1, the other 13 genes were significantly upregulated in gastritis, which was consistent with the results in the GSE60427 dataset. More importantly, real-time quantitative PCR results showed that the expressions of PTGS2, MMP9, CXCL2, and CXCL8 were significantly upregulated and NOS2, EGFR, and IL-10 were downregulated in gastritis patients, while the expressions of PTGS2, MMP9, CXCL2, and CXCL8 were significantly downregulated and NOS2, EGFR, and IL-10 were upregulated after the treatment of Weibing Formula 1. PTGS2, NOS2, EGFR, MMP9, CXCL2, CXCL8, and IL-10 may be the important direct targets of Weibing Formula 1 in gastritis treatment. Our study revealed the mechanism of Weibing Formula 1 in gastritis from an overall and systematic perspective, providing a theoretical basis for further knowing and application of this formula in the future.


Asunto(s)
Desarrollo de Medicamentos/métodos , Medicamentos Herbarios Chinos/farmacología , Gastritis/tratamiento farmacológico , Regulación de la Expresión Génica/efectos de los fármacos , Simulación del Acoplamiento Molecular/métodos , Mapeo de Interacción de Proteínas/métodos , Biología Computacional/métodos , Bases de Datos Genéticas , Medicamentos Herbarios Chinos/química , Gastritis/genética , Gastritis/patología , Humanos , Transducción de Señal
5.
Pharmaceut Med ; 35(5): 287-295, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34580837

RESUMEN

Pharmaceutical development was at the forefront of efforts to prevent infection with the SARS-CoV-2 virus as well as to treat its often-devastating effects. Drug development, and its multifaceted and multi-disciplined activity toward effective vaccines and drugs, became part of everyday news. I review several key areas of vaccine and drug development that were brought into the public mainstream over the evolution of the pandemic. These include the unprecedented speed of vaccine discovery and development, issues uncovered from early clinical studies, and regulatory concepts that were highlighted throughout the development process. Among these was the importance of pharmacovigilance as each new agent was rapidly deployed to a mostly eager public. Critical challenges around production, packaging, and procurement of product for patient use were often centre stage. Finally, the ever-important need to transition not only from scientific concept to vaccine and drug, but from their authorized and approved use to their implementation in health systems to insure the intended effects both in individuals and populations.


Asunto(s)
Vacunas contra la COVID-19/uso terapéutico , COVID-19/prevención & control , Aprobación de Drogas , Desarrollo de Medicamentos , Descubrimiento de Drogas , Salud Global , Animales , COVID-19/inmunología , COVID-19/virología , Vacunas contra la COVID-19/efectos adversos , Vacunas contra la COVID-19/provisión & distribución , Embalaje de Medicamentos , Conocimientos, Actitudes y Práctica en Salud , Humanos , Seguridad del Paciente , Opinión Pública , Medición de Riesgo , Factores de Riesgo
8.
Lancet Diabetes Endocrinol ; 9(10): 695-707, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34480874

RESUMEN

The first insulin preparation capable of consistently lowering blood glucose was developed in 1921. But 100 years later, blood glucose control with insulin in people with diabetes is nearly universally suboptimal, with essentially the same molecule still delivered by the same inappropriate subcutaneous injection route. Bypassing this route with oral administration appears to have become technologically feasible, accelerating over the past 50 years, either with packaged insulin peptides or by chemical insulin mimetics. Some of the problems of prospective unregulated absorption of insulin into the circulation from subcutaneous depots might be overcome with glucose-responsive insulins. Approaches to these problems could be modification of the peptide by adducts, or the use of nanoparticles or insulin patches, which deliver insulin according to glucose concentration. Some attention has been paid to targeting insulin preferentially to different organs, either by molecular engineering of insulin, or with adducts. But all these approaches still have problems in even beginning to match the responsiveness of physiological insulin delivery to metabolic requirements, both prandially and basally. As would be expected, for all these technically complex approaches, many examples of abandoned development can be found. Meanwhile, it is becoming possible to change the duration of action of subcutaneous injected insulin analogues to act even more rapidly for meals, and towards weekly insulin for basal administration. The state of the art of all these approaches, and the barriers to success, are reviewed here.


Asunto(s)
Desarrollo de Medicamentos , Insulina , Diabetes Mellitus/tratamiento farmacológico , Diabetes Mellitus/epidemiología , Diabetes Mellitus/historia , Vías de Administración de Medicamentos , Composición de Medicamentos/historia , Composición de Medicamentos/tendencias , Desarrollo de Medicamentos/historia , Desarrollo de Medicamentos/tendencias , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Insulina/administración & dosificación , Insulina/historia , Sistemas de Infusión de Insulina/historia
9.
J Agric Food Chem ; 69(37): 10761-10773, 2021 Sep 22.
Artículo en Inglés | MEDLINE | ID: mdl-34516106

RESUMEN

Unfavorable bioavailability is an important aspect underlying the failure of drug candidates. Computational approaches for evaluating drug-likeness can minimize these risks. Over the past decades, computational approaches for evaluating drug-likeness have sped up the process of drug development and were also quickly derived to pesticide-likeness. As a result of many critical differences between drugs and pesticides, many kinds of methods for drug-likeness cannot be used for pesticide-likeness. Therefore, it is crucial to comprehensively compare and analyze the differences between drug-likeness and pesticide-likeness, which may provide a basis for solving the problems encountered during the evaluation of pesticide-likeness. Here, we systematically collected the recent advances of drug-likeness and pesticide-likeness and compared their characteristics. We also evaluated the current lack of studies on pesticide-likeness, the molecular descriptors and parameters adopted, the pesticide-likeness model on pesticide target organisms, and comprehensive analysis tools. This work may guide researchers to use appropriate methods for developing pesticide-likeness models. It may also aid non-specialists to understand some important concepts in drug-likeness and pesticide-likeness.


Asunto(s)
Plaguicidas , Preparaciones Farmacéuticas , Disponibilidad Biológica , Simulación por Computador , Desarrollo de Medicamentos
12.
Int J Mol Sci ; 22(15)2021 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-34361055

RESUMEN

Gliomas are solid tumors of the central nervous system (CNS) that originated from different glial cells. The World Health Organization (WHO) classifies these tumors into four groups (I-IV) with increasing malignancy. Glioblastoma (GBM) is the most common and aggressive type of brain tumor classified as grade IV. GBMs are resistant to conventional therapies with poor prognosis after diagnosis even when the Stupp protocol that combines surgery and radiochemotherapy is applied. Nowadays, few novel therapeutic strategies have been used to improve GBM treatment, looking for higher efficiency and lower side effects, but with relatively modest results. The circadian timing system temporally organizes the physiology and behavior of most organisms and daily regulates several cellular processes in organs, tissues, and even in individual cells, including tumor cells. The potentiality of the function of the circadian clock on cancer cells modulation as a new target for novel treatments with a chronobiological basis offers a different challenge that needs to be considered in further detail. The present review will discuss state of the art regarding GBM biology, the role of the circadian clock in tumor progression, and new chrono-chemotherapeutic strategies applied for GBM treatment.


Asunto(s)
Neoplasias Encefálicas/tratamiento farmacológico , Ritmo Circadiano/efectos de los fármacos , Desarrollo de Medicamentos , Glioblastoma/tratamiento farmacológico , Preparaciones Farmacéuticas/administración & dosificación , Animales , Humanos
13.
Life Sci Alliance ; 4(10)2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34353886

RESUMEN

The coronavirus disease 2019 (COVID-19) pandemic caused by the new coronavirus (SARS-CoV-2) is currently responsible for more than 3 million deaths in 219 countries across the world and with more than 140 million cases. The absence of FDA-approved drugs against SARS-CoV-2 has highlighted an urgent need to design new drugs. We developed an integrated model of the human cell and SARS-CoV-2 to provide insight into the virus' pathogenic mechanism and support current therapeutic strategies. We show the biochemical reactions required for the growth and general maintenance of the human cell, first, in its healthy state. We then demonstrate how the entry of SARS-CoV-2 into the human cell causes biochemical and structural changes, leading to a change of cell functions or cell death. A new computational method that predicts 20 unique reactions as drug targets from our models and provides a platform for future studies on viral entry inhibition, immune regulation, and drug optimisation strategies. The model is available in BioModels (https://www.ebi.ac.uk/biomodels/MODEL2007210001) and the software tool, findCPcli, that implements the computational method is available at https://github.com/findCP/findCPcli.


Asunto(s)
COVID-19/tratamiento farmacológico , COVID-19/metabolismo , Desarrollo de Medicamentos/métodos , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/metabolismo , COVID-19/epidemiología , Biología Computacional/métodos , Evaluación Preclínica de Medicamentos/métodos , Humanos , Modelos Biológicos , Pandemias
14.
Molecules ; 26(16)2021 Aug 19.
Artículo en Inglés | MEDLINE | ID: mdl-34443621

RESUMEN

There are few novel therapeutic options available for companion animals, and medications rely heavily on repurposed drugs developed for other species. Considering the diversity of species and breeds in companion animal medicine, comprehensive PK exposures in the companion animal patient is often lacking. The purpose of this paper was to assess the pharmacokinetics after oral and intravenous dosing in domesticated animal species (dogs, cats, and horses) of a novel soluble epoxide hydrolase inhibitor, EC1728, being developed for the treatment of pain in animals. Results: Intravenous and oral administration revealed that bioavailability was similar for dogs, and horses (42 and 50% F) but lower in mice and cats (34 and 8%, respectively). Additionally, clearance was similar between cats and mice, but >2× faster in cats vs. dogs and horses. Efficacy with EC1728 has been demonstrated in mice, dogs, and horses, and despite the rapid clearance of EC1728 in cats, analgesic efficacy was demonstrated in an acute pain model after intravenous but not oral dosing. Conclusion: These results demonstrate that exposures across species can vary, and investigation of therapeutic exposures in target species is needed to provide adequate care that addresses efficacy and avoids toxicity.


Asunto(s)
Desarrollo de Medicamentos , Inhibidores Enzimáticos/metabolismo , Epóxido Hidrolasas/antagonistas & inhibidores , Animales , Disponibilidad Biológica , Gatos , Perros , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Epóxido Hidrolasas/química , Caballos , Ratones , Solubilidad , Especificidad de la Especie
15.
J Clin Lab Anal ; 35(9): e23937, 2021 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-34396586

RESUMEN

OBJECTIVE: To deal with COVID-19, various countries have made many efforts, including the research and development of vaccines. The purpose of this manuscript was to summarize the development, application, and problems of COVID-19 vaccines. METHODS: This article reviewed the existing literature to see the development of the COVID-19 vaccine. RESULTS: We found that different types of vaccines had their own advantages and disadvantages. At the same time, the side effects of the vaccine, the dose of vaccination, the evaluation of the efficacy, and the application of the vaccine were all things worth studying. CONCLUSION: The successful development of the COVID-19 vaccine concerns almost all countries and people in the world. We must do an excellent job of researching the immunogenicity and immune reactivity of the vaccines. We hope this review can help colleagues at home and abroad.


Asunto(s)
Vacunas contra la COVID-19 , COVID-19/prevención & control , SARS-CoV-2/inmunología , Vacunas contra la COVID-19/administración & dosificación , Vacunas contra la COVID-19/efectos adversos , Vacunas contra la COVID-19/clasificación , Relación Dosis-Respuesta a Droga , Desarrollo de Medicamentos/métodos , Humanos
17.
Molecules ; 26(15)2021 Jul 24.
Artículo en Inglés | MEDLINE | ID: mdl-34361615

RESUMEN

In cell development, the cell cycle is crucial, and the cycle progression's main controllers are endogenous CDK inhibitors, cyclin-dependent kinases (CDKs), and cyclins. In response to the mitogenic signal, cyclin D is produced and retinoblastoma protein (Rb) is phosphorylated due to activated CDK4/CDK6. This causes various proteins required in the cell cycle progression to be generated. In addition, complexes of CDK1-cyclin A/B, CDK2-cyclin E/A, and CDK4/CDK6-cyclin D are required in each phase of this progression. Cell cycle dysregulation has the ability to lead to cancer. Based on its role in the cell cycle, CDK has become a natural target of anticancer therapy. Therefore, understanding the CDK structures and the complex formed with the drug, helps to foster the development of CDK inhibitors. This development starts from non-selective CDK inhibitors to selective CDK4/CDK6 inhibitors, and these have been applied in clinical cancer treatment. However, these inhibitors currently require further development for various hematologic malignancies and solid tumors, based on the results demonstrated. In drug development, the main strategy is primarily to prevent and asphyxiate drug resistance, thus a determination of specific biomarkers is required to increase the therapy's effectiveness as well as patient selection suitability in order to avoid therapy failure. This review is expected to serve as a reference for early and advanced-stage researchers in designing new molecules or repurposing existing molecules as CDK4/CDK6 inhibitors to treat breast cancer.


Asunto(s)
Antineoplásicos , Neoplasias de la Mama/tratamiento farmacológico , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Desarrollo de Medicamentos , Reposicionamiento de Medicamentos , Femenino , Humanos , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico
18.
Int J Mol Sci ; 22(16)2021 Aug 18.
Artículo en Inglés | MEDLINE | ID: mdl-34445599

RESUMEN

Not long ago, self-reactive immune activity was considered as pathological trait. A paradigm shift has now led to the recognition of autoimmune processes as part of natural maintenance of molecular homeostasis. The immune system is assigned further roles beneath the defense against pathogenic organisms. Regarding the humoral immune system, the investigation of natural autoantibodies that are frequently found in healthy individuals has led to further hypotheses involving natural autoimmunity in other processes as the clearing of cellular debris or decrease in inflammatory processes. However, their role and origin have not been entirely clarified, but accumulating evidence links their formation to immune reactions against the gut microbiome. Antibodies targeting highly conserved proteins of the commensal microflora are suggested to show self-reactive properties, following the paradigm of the molecular mimicry. Here, we discuss recent findings, which demonstrate potential links of the commensal microflora to the immunological homeostasis and highlight the possible implications for various diseases. Furthermore, specific components of the immune system, especially antibodies, have become a focus of attention for the medical management of various diseases and provide attractive treatment options in the future. Nevertheless, the development and optimization of such macromolecules still represents a very time-consuming task, shifting the need to more medical agents with simple structural properties and low manufacturing costs. Synthesizing only the biologically active sites of antibodies has become of great interest for the pharmaceutical industry and offers a wide range of therapeutic application areas as it will be discussed in the present review article.


Asunto(s)
Autoanticuerpos/inmunología , Enfermedades Autoinmunes/inmunología , Desarrollo de Medicamentos , Microbioma Gastrointestinal , Homeostasis , Sistema Inmunológico/inmunología , Inflamación/inmunología , Animales , Enfermedades Autoinmunes/tratamiento farmacológico , Enfermedades Autoinmunes/patología , Autoinmunidad , Humanos , Sistema Inmunológico/efectos de los fármacos , Inflamación/tratamiento farmacológico , Inflamación/patología
19.
ACS Appl Mater Interfaces ; 13(33): 39100-39111, 2021 Aug 25.
Artículo en Inglés | MEDLINE | ID: mdl-34382406

RESUMEN

In this work, a nanoplatform (FeCORM NPs) loaded with an iron-carbonyl complex was constructed. By exploiting chemodynamic therapy (CDT) and immunogenic cell death (ICD)-induced immunotherapy (IMT), the nanoparticles exhibited excellent efficacy against lung metastasis of melanoma in vivo. The iron-carbonyl compound of the nanomaterials could be initiated by both glutathione (GSH) and hydrogen peroxide (H2O2) to release CO and generate ferrous iron through ligand exchange and oxidative destruction pathways. The released CO caused mitochondria damage, whereas the generated ferrous iron led to oxidative stress via the Fenton reaction. On the other hand, the nanomaterials induced ICD-based IMT, which worked jointly with CDT to exhibit excellent effects against lung metastasis of melanoma through a mouse model. This work demonstrated how a nanoplatform, simple and stable but showing excellent efficacy against tumors, could be built using simple building blocks via a self-assembling approach. Importantly, the system took advantage of relatively high levels of GSH and H2O2 in tumors to initiate the therapeutic effects, which rendered the nanoplatform with a capability to differentiate normal cells from tumor cells. In principle, the system has great potential for future clinical applications, not only in the treatment of lung metastasis of melanoma but also in suppressing other types of tumors.


Asunto(s)
Antineoplásicos/química , Monóxido de Carbono/química , Compuestos de Hierro/química , Neoplasias Pulmonares/tratamiento farmacológico , Melanoma/metabolismo , Nanopartículas del Metal/química , Animales , Antineoplásicos/farmacocinética , Apoptosis/efectos de los fármacos , Monóxido de Carbono/farmacocinética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Desarrollo de Medicamentos , Femenino , Glutatión/química , Humanos , Peróxido de Hidrógeno/química , Inmunoterapia/métodos , Neoplasias Pulmonares/secundario , Ratones , Ratones Endogámicos BALB C , Mitocondrias/efectos de los fármacos , Mitocondrias/ultraestructura , Neoplasias Experimentales , Oxidación-Reducción , Estrés Oxidativo/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacos
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA
...