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In the past few decades, chronic hepatitis B caused by hepatitis B virus (HBV) has been one of the most serious diseases to human health. The development of innovative systems is essential for preventing the complex pathogenesis of hepatitis B and reducing side effects caused by drugs. HBV inhibitory drugs have been developed through various compounds, and they are often limited by routine experimental screening and delay drug development. More recently, virtual screening of compounds has gradually been used in drug research with strong computational capability and is further applied in anti-HBV drug screening, thus facilitating a reliable drug screening process. However, the lack of structural information in traditional compound analysis is an important hurdle for unsatisfactory efficiency in drug screening. Here, a natural language processing technique was adopted to analyze compound simplified molecular input line entry system strings. By using the targeted optimized word2vec model for pretraining, we can accurately represent the relationship between the compound and its substructure. The machine learning model based on training results can effectively predict the inhibitory effect of compounds on HBV and liver toxicity. The reliability of the model is verified by the results of wet-lab experiments. In addition, a tool has been published to predict potential compounds. Hence, this article provides a new perspective on the prediction of compound properties for anti-HBV drugs that can help improve hepatitis B diagnosis and further develop human health in the future.
Assuntos
Vírus da Hepatite B , Hepatite B , Antivirais/farmacologia , Antivirais/uso terapêutico , Descoberta de Drogas/métodos , Hepatite B/tratamento farmacológico , Humanos , Reprodutibilidade dos TestesRESUMO
The ubiquitin-proteasome system is a crucial mechanism for regulating protein levels in cells, with substrate-specific E3 ubiquitin ligases serving as an integral component of this system. Among these ligases are SMAD-specific E3 ubiquitin-protein ligase 1 (SMURF1) and SMAD-specific E3 ubiquitin-protein ligase 2 (SMURF2), which belong to the neural precursor cell-expressed developmentally downregulated 4 (NEDD4) subfamily of Homologous to E6-AP COOH terminus (HECT)-type E3 ligases. As E3 ligases, SMURFs have critical functions in regulating the stability of multiple proteins, thereby maintaining physiological processes such as cell migration, proliferation, and apoptosis. The occurrence of many diseases is attributed to abnormal cell physiology and an imbalance in cell homeostasis. It is noteworthy that SMURFs play pivotal roles in disease progression, with the regulatory functions being complex and either facilitative or inhibitory. In this review, we elucidate the mechanisms by which SMURF1 and SMURF2 can regulate disease progression in non-cancerous diseases. These significant findings offer potential novel therapeutic targets for various diseases and new avenues for research on SMURF proteins.
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Apoptose , Ubiquitina-Proteína Ligases , Humanos , Movimento Celular , Progressão da Doença , UbiquitinaRESUMO
BACKGROUND: Endothelial injury caused by Type 2 diabetes mellitus (T2DM) is considered as a mainstay in the pathophysiology of diabetic vascular complications (DVCs). However, the molecular mechanism of T2DM-induced endothelial injury remains largely unknown. Here, we found that endothelial WW domain-containing E3 ubiquitin protein ligase 2 (WWP2) act as a novel regulator for T2DM-induced vascular endothelial injury through modulating ubiquitination and degradation of DEAD-box helicase 3 X-linked (DDX3X). METHODS: Single-cell transcriptome analysis was used to evaluate WWP2 expression in vascular endothelial cells of T2DM patients and healthy controls. Endothelial-specific Wwp2 knockout mice were used to investigate the effect of WWP2 on T2DM-induced vascular endothelial injury. In vitro loss- and gain-of-function studies were performed to assess the function of WWP2 on cell proliferation and apoptosis of human umbilical vein endothelial cells. The substrate protein of WWP2 was verified using mass spectrometry, coimmunoprecipitation assays and immunofluorescence assays. The mechanism of WWP2 regulation on substrate protein was investigated by pulse-chase assay and ubiquitination assay. RESULTS: The expression of WWP2 was significantly down-regulated in vascular endothelial cells during T2DM. Endothelial-specific Wwp2 knockout in mice significantly aggravated T2DM-induced vascular endothelial injury and vascular remodeling after endothelial injury. Our in vitro experiments showed that WWP2 protected against endothelial injury by promoting cell proliferation and inhibiting apoptosis in ECs. Mechanically, we found that WWP2 is down-regulated in high glucose and palmitic acid (HG/PA)-induced ECs due to c-Jun N-terminal kinase (JNK) activation, and uncovered that WWP2 suppresses HG/PA-induced endothelial injury by catalyzing K63-linked polyubiquitination of DDX3X and targeting it for proteasomal degradation. CONCLUSION: Our studies revealed the key role of endothelial WWP2 and the fundamental importance of the JNK-WWP2-DDX3X regulatory axis in T2DM-induced vascular endothelial injury, suggesting that WWP2 may serve as a new therapeutic target for DVCs.
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Diabetes Mellitus Tipo 2 , Ubiquitina-Proteína Ligases , Humanos , Camundongos , Animais , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/química , Ubiquitina-Proteína Ligases/metabolismo , Regulação para Baixo , Células Endoteliais/metabolismo , Diabetes Mellitus Tipo 2/complicações , Ubiquitinação , Camundongos Knockout , RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/metabolismoRESUMO
Compound-protein interaction (CPI) affinity prediction plays an important role in reducing the cost and time of drug discovery. However, the interpretability of how fragments function in CPI is impacted by the fact that current methods ignore the affinity relationships between fragments of compounds and fragments of proteins in CPI modeling. This article introduces an improved Transformer called FOTF-CPI (a Fusion of Optimal Transport Fragments compound-protein interaction prediction model). We use an optimal transport-based fragmentation approach to improve the model's understanding of compound and protein sequences. Additionally, a fused attention mechanism is employed, which combines the features of fragments to capture full affinity information. This fused attention redistributes higher attention scores to fragments with higher affinity. Experimental results show FOTF-CPI achieves an average 2% higher performance than other models on all three datasets. Furthermore, the visualization confirms the potential of FOTF-CPI for drug discovery applications.
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Soil contamination by arsenic (As) poses potential health risks to humans. As-hyperaccumulator P. vittata has been used in As-contaminated soils for phytoremediation. Clarifying the mechanisms of its As-hyperaccumulation is critical to enhance its efficiency in phytoremediation. Here, based on transcriptome analysis, we determined the concentration-dependent patterns of As-related gene families by comparing As-hyperaccumulator P. vittata and non-hyperaccumulator P. ensiformis after exposing to 20 µM arsenate (AsV). As expected, arsenic induced more stress in P. ensiformis than P. vittata. Based on gene ontology, differences in transporter activity are probably responsible for their differential As accumulation. Though As exposure induced expression of phosphate transporter PvPht1;4 for AsV absorption in both plants, stronger AsV reduction, AsIII transport, and AsIII-GSH complexation were found in P. ensiformis roots. Unlike P. ensiformis, As metabolism processes occurred mainly in P. vittata fronds. Notably, tonoplast-localized ACR3s were only present in P. vittata, making it more effective in sequestrating AsIII into frond vacuoles. Further, vesicle As transformation via PvGAPC1 (glyceraldehyde 3-phosphate dehydrogenase), PvOCT4 (organic cation transporter 4), and PvGSTF1 (glutathione S-transferase) contributed little to As-hyperaccumulation. This study provides information on critical genes responsible for As-hyperaccumulation by P. vittata, which can be applied to construct As-hyperaccumulating plants by genetic engineering to enhance their phytoremediation efficiency in As-contaminated soils.
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Arsênio , Pteris , Poluentes do Solo , Humanos , Arsênio/metabolismo , Pteris/metabolismo , Biodegradação Ambiental , Raízes de Plantas/metabolismo , Perfilação da Expressão Gênica , Solo , Poluentes do Solo/metabolismoRESUMO
As a widely used lipid-lowering drug in clinical practice, atorvastatin is widely recognized for its role in protecting vascular endothelium in the cardiovascular system. However, a clear mechanistic understanding of its action is lacking. Here, we found that atorvastatin counteracted angiotensin II-induced vascular endothelial injury in mice with hypertension. Mechanistically, atorvastatin up-regulated WWP2, a E6AP C-terminus (HECT)-type E3 ubiquitin ligase with an essential role in regulating protein ubiquitination and various biological processes, thereby rescuing vascular endothelial injury. By ubiquitinating ATP5A (ATP synthase mitochondrial F1 complex subunit alpha), WWP2 degraded ATP5A via the proteasome pathway, stabilizing Bcl-2/Bax in the mitochondrial pathway of apoptosis. Moreover, atorvastatin further ameliorated death of vascular endothelial cells and improved vascular endothelial functions under WWP2 overexpression, whereas WWP2 knockout abrogated these beneficial effects of atorvastatin. Furthermore, we generated endothelial cell-specific WWP2 knockout mice, and this WWP2-mediated mechanism was faithfully recapitulated in vivo. Thus, we propose that activation of a WWP2-dependent pathway that is pathologically repressed in damaged vascular endothelium under hypertension is a major mechanism of atorvastatin. Our findings are also pertinent to develop novel therapeutic strategies for vascular endothelial injury-related cardiovascular diseases.
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Células Endoteliais , Hipertensão , Camundongos , Animais , Atorvastatina/farmacologia , Células Endoteliais/metabolismo , Ubiquitinação , Ubiquitina-Proteína Ligases/metabolismo , Camundongos Knockout , Hipertensão/tratamento farmacológicoRESUMO
Tyrosine phosphorylation by protein tyrosine kinases (PTKs) is a type of post-translational modification. Tec kinases, which are a subfamily of non-receptor PTKs, were originally discovered in the hematopoietic system and include five members: Tec, Btk, Itk/Emt/Tsk, Etk/Bmx, and Txk/Rlk. With the progression of modern research, certain members of the Tec family of kinases have been found to be expressed outside the hematopoietic system and are involved in the development and progression of a variety of diseases. The role of Tec family kinases in cardiovascular disease is receiving increasing attention. Tec kinases are involved in the occurrence and progression of ischemic heart disease, atherosclerosis, cardiac dysfunction associated with sepsis, atrial fibrillation, myocardial hypertrophy, coronary atherosclerotic heart disease, and myocardial infarction and post-myocardial. However, no reviews have comprehensively clarified the role of Tec kinases in the cardiovascular system. Therefore, this review summarizes research on the role of Tec kinases in cardiovascular disease, providing new insights into the prevention and treatment of cardiovascular disease.
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BACKGROUND: The impact of COVID-19 on public health has mandated an 'all hands on deck' scientific response. The current clinical study and basic research on COVID-19 are mainly based on existing publications or our knowledge of coronavirus. However, efficiently retrieval of accurate, relevant knowledge on COVID-19 can pose significant challenges for researchers. METHODS: To improve quality in accessing important literature findings, we developed a novel natural language processing (NLP) method to automatically recognize the associations among potential targeted host organ systems, associated clinical manifestations, and pathways. We further validated these associations through clinician experts' evaluations and prioritize candidate drug targets through bioinformatics network analysis. RESULTS: We found that the angiotensin-converting enzyme 2 (ACE2), a receptor that SARS-CoV-2 required for cell entry, is associated with cardiovascular and endocrine organ system and diseases. Furthermore, we found SARS-CoV-2 is associated with some important pathways such as IL-6, TNF-alpha, and IL-1 beta-induced dyslipidemia, which are related to inflammation, lipogenesis, and oxidative stress mechanisms, suggesting potential drug candidates. CONCLUSION: We prioritized the list of therapeutic targets involved in antiviral and immune modulating drugs for experimental validation, rendering it valuable during public health crises marked by stresses on clinical and research capacity. Our automatic intelligence pipeline also contributes to other novel and emerging disease management and treatments in the future.
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COVID-19 , Humanos , Descoberta do Conhecimento , Processamento de Linguagem Natural , Peptidil Dipeptidase A/metabolismo , SARS-CoV-2RESUMO
OBJECTIVE: To observe the effect of electroacupuncture (EA) of Zusanli(ST36) and Zhongwan (CV12) on intestinal nutritional feeding intolerance in patients with severe acute pancreatitis (SAP). METHODS: A total of 68 SAP patients (hospitalized from January of 2018 to December of 2019 in Cangzhou Hospital of Integrated Medicine) were randomly divided into control and EA groups (n=34 cases in each group). All patients of the two groups received the same early enteral nutrition treatment through nasojejunal tube. EA (5-15 Hz, 1-5 mA) was applied to bilateral ST36 and CV12 for 20 min, twice a day for 7 days. The incidence of feeding intolerance (abdominal distension, vomiting, diarrhea, constipation, gastrointestinal bleeding), time to reach energy target, intraperitoneal pressure and the number of borborygmus in 1 min were recorded. The contents of plasma high sensitivity -C reactive protein (hs-CRP), IL-6 and endotoxin were measured using Latex immunoturbidimetric method, chemiluminescence and Tachypiens Amebocyte Lysate Azo substrate color development method, respectively, and the contents of urinary lactulose and mannitol detected using high-performance liquid chromatography. The total protein and albumin levels in the blood were measured for assessing the patients' nutrition status, and acute physiology and chronic health evaluation scoring system (APACHE-â ¡) score was determined for assessing the severity of disease. RESULTS: Compared with the control group, the incidence of abdominal distension, vomiting and constipation, intolerance rate to feeding, time to reach the energy target, intraperitoneal pressure on day 7, inflammatory indexes, hs-CRP, IL-6, endotoxin, urine L/M on day 4 and 7, and the APACHE â ¡ score on day 7 were significantly lower (P<0.01), and the number of borborygmus in 1 min on day 4 and 7 after the treatment was significantly higher in the EA group (P<0.01). In comparison with pretreatment, the abdominal pressure and plasma endotoxin level on day 4 and 7, hs-CRP, IL-6 and L/M ratio on day 1, 4 and 7, as well as APACHE â ¡ score on day 7 after the treatment were significantly decreased in the two groups (P<0.01), and the number of borborygmus on day 4 and 7, and the total protein and albumin on day 7 significantly increased in both the control and EA groups (P<0.01). CONCLUSION: EA of ST36 and CV12 can shorten the time to reach the energy target, reduce inflammatory response, improve the intestinal mucosal barrier function, and thus reduce the incidence of feeding intolerance in SAP patients.
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Eletroacupuntura , Pancreatite , Pontos de Acupuntura , Doença Aguda , Humanos , Recém-Nascido , Mucosa Intestinal , Pancreatite/terapiaRESUMO
ABSTRACT Introduction The improvement of physical training is a prerequisite to achieving excellent athletic performance in throwing. Following these requirements, it is also necessary to improve the scientificity, effectiveness, and flexibility of the physical training of adolescent athletes. Objective To study the influence of physical training on the physical fitness of young throwing athletes. Methods This article uses mathematical statistics to study the physical fitness of young throwing athletes. We divided the young volunteers included in the experimental study into training and control groups. A comparative analysis of their physical fitness indicators before and after sports practice. Results After physical training, the physical fitness indicators of adolescents showed a more significant impact. The athletics competitions of the young athletes' results also improved significantly (P<0.05). Conclusion The throwing sport can improve the physical fitness of young athletes. In adolescence, the intervention of physical training can be increased to improve indicators of physical fitness in young practitioners. Evidence level II; Therapeutic Studies - Investigating the results.
RESUMO Introdução O aprimoramento do treino físico é um pré-requisito para alcançar o excelente desempenho atlético em arremesso. Acompanhando essas exigências, também é necessário melhorar a cientificidade, eficácia e flexibilidade do treinamento físico dos atletas adolescentes. Objetivo Estudar a influência do treinamento físico na aptidão física de jovens atletas de arremesso. Métodos Este artigo utiliza estatística matemática para estudar a aptidão física de jovens atletas praticantes de arremesso. Dividimos os jovens voluntários incluídos no estudo experimental em grupos de treinamento e controle. Uma análise comparativa de seus indicadores de aptidão física antes e depois da prática esportiva. Resultados Após o treinamento físico, os indicadores de aptidão física dos adolescentes demonstraram maior impacto. Os resultados das competições de atletismo dos jovens atletas também melhoraram significativamente (P<0,05). Conclusão O esporte de arremesso pode melhorar a aptidão física dos jovens atletas. Na fase de adolescência, a intervenção do treinamento físico pode ser aumentada para melhorar os indicadores de aptidão física em seus jovens praticantes. Nível de evidência II; Estudos terapêuticos - Investigação de resultados.
RESUMEN Introducción La mejora de la preparación física es un requisito previo para lograr un excelente rendimiento deportivo en el lanzamiento. Siguiendo estos requisitos, también es necesario mejorar la cientificidad, la eficacia y la flexibilidad del entrenamiento físico de los atletas adolescentes. Objetivo Estudiar la influencia del entrenamiento físico en la condición física de jóvenes atletas de lanzamiento. Métodos Este artículo utiliza estadística matemática para estudiar la condición física de jóvenes atletas de lanzamiento. Dividimos a los jóvenes voluntarios incluidos en el estudio experimental en grupos de entrenamiento y de control. Un análisis comparativo de sus indicadores de aptitud física antes y después de la práctica deportiva. Resultados Después del entrenamiento físico, los indicadores de aptitud física de los adolescentes mostraron un impacto más significativo. Los resultados de las competencias de atletismo de los jóvenes atletas también mejoraron significativamente (P<0.05). Conclusión El deporte del lanzamiento puede mejorar la condición física de los jóvenes atletas. En la adolescencia se puede incrementar la intervención del entrenamiento físico para mejorar los indicadores de condición física en los jóvenes practicantes. Nivel de evidencia II; Estudios terapéuticos - Investigación de resultados.