RESUMEN
The high-throughput genomic and proteomic scanning approaches allow investigators to measure the quantification of genome-wide genes (or gene products) for certain disease conditions, which plays an essential role in promoting the discovery of disease mechanisms. The high-throughput approaches often generate a large gene list of interest (GOIs), such as differentially expressed genes/proteins. However, researchers have to perform manual triage and validation to explore the most promising, biologically plausible linkages between the known disease genes and GOIs (disease signals) for further study. Here, to address this challenge, we proposed a network-based strategy DDK-Linker to facilitate the exploration of disease signals hidden in omics data by linking GOIs to disease knowns genes. Specifically, it reconstructed gene distances in the protein-protein interaction (PPI) network through six network methods (random walk with restart, Deepwalk, Node2Vec, LINE, HOPE, Laplacian) to discover disease signals in omics data that have shorter distances to disease genes. Furthermore, benefiting from the establishment of knowledge base we established, the abundant bioinformatics annotations were provided for each candidate disease signal. To assist in omics data interpretation and facilitate the usage, we have developed this strategy into an application that users can access through a website or download the R package. We believe DDK-Linker will accelerate the exploring of disease genes and drug targets in a variety of omics data, such as genomics, transcriptomics and proteomics data, and provide clues for complex disease mechanism and pharmacological research. DDK-Linker is freely accessible at http://ddklinker.ncpsb.org.cn/.
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Proteómica , Programas Informáticos , Proteómica/métodos , Genómica/métodos , Biología Computacional/métodos , Mapas de Interacción de ProteínasRESUMEN
BACKGROUND: The mitochondrial unfolded protein response (UPRmt) is an evolutionarily conserved mitochondrial response that is critical for maintaining mitochondrial and energetic homeostasis under cellular stress after tissue injury and disease. Here, we ask whether UPRmt may be a potential therapeutic target for ischemic stroke. METHODS: We performed the middle cerebral artery occlusion and oxygen-glucose deprivation models to mimic ischemic stroke in vivo and in vitro, respectively. Oligomycin and meclizine were used to trigger the UPRmt. We used 2,3,5-triphenyltetrazolium chloride staining, behavioral tests, and Nissl staining to evaluate cerebral injury in vivo. The Cell Counting Kit-8 assay and the Calcein AM Assay Kit were conducted to test cerebral injury in vitro. RESULTS: Inducing UPRmt with oligomycin protected neuronal cultures against oxygen-glucose deprivation. UPRmt could also be triggered with meclizine, and this Food and Drug Administration-approved drug also protected neurons against oxygen-glucose deprivation. Blocking UPRmt with siRNA against activating transcription factor 5 eliminated the neuroprotective effects of meclizine. In a mouse model of focal cerebral ischemia, pretreatment with meclizine was able to induce UPRmt in vivo, which reduced infarction and improved neurological outcomes. CONCLUSIONS: These findings suggest that the UPRmt is important in maintaining the survival of neurons facing ischemic/hypoxic stress. The UPRmt mechanism may provide a new therapeutic avenue for ischemic stroke.
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Isquemia Encefálica , Glucosa , Mitocondrias , Neuronas , Respuesta de Proteína Desplegada , Animales , Masculino , Ratones , Isquemia Encefálica/metabolismo , Células Cultivadas , Glucosa/deficiencia , Infarto de la Arteria Cerebral Media/metabolismo , Ratones Endogámicos C57BL , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Oxígeno/metabolismo , Respuesta de Proteína Desplegada/efectos de los fármacosRESUMEN
Heart failure is characterized by high incidence and mortality rates, and the search for effective treatment strategies for heart failure and the improvement of clinical outcomes have always been important research directions. Imbalanced inflammation has been proven to be one of the critical pathological factors in heart failure, positively correlated with adverse events such as impaired cardiac function and myocardial fibrosis. In recent years, studies have confirmed that the activation of the NOD-like receptor thermal protein domain-associated protein 3(NLRP3) inflammasome plays a common regulatory role in the inflammation imbalance induced by various factors in heart failure. Moreover, certain traditional Chinese medicine(TCM) and active components can significantly inhibit the activation of the NLRP3 inflammasome, thereby improving heart failure. This article first overviewed the basic information about the NLRP3 inflammasome, summarized the regulatory mechanisms of the NLRP3 inflammasome in heart failure induced by various factors, introduced recent research progress on TCM and active components that inhibited the NLRP3 inflammasome to improve heart failure, aiming to provide references for innovative drug research in the field of integrated Chinese and western medicine for the prevention and treatment of heart failure.
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Insuficiencia Cardíaca , Inflamasomas , Humanos , Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Medicina Tradicional China , Insuficiencia Cardíaca/tratamiento farmacológico , InflamaciónRESUMEN
Jiming Powder is a traditional ancient prescription with good therapeutic effect in the treatment of heart failure, but its mechanism lacks further exploration. In this study, a mouse model of coronary artery ligation was used to evaluate the effect and mechanism of Jiming Powder on myocardial fibrosis in mice with myocardial infarction. The study constructed a mouse model of heart failure after myocardial infarction using the method of left anterior descending coronary artery ligation. The efficacy of Jiming Powder was evaluated from multiple angles, including ultrasound imaging, hematoxylin-eosin(HE) staining, Masson staining, Sirius Red staining, and serum myocardial enzyme spectrum detection. Western blot analysis was performed to detect key proteins involved in ventricular remodeling, including transforming growth factor-ß1(TGF-ß1), α-smooth muscle actin(α-SMA), wingless-type MMTV integration site family member 3a(Wnt3a), ß-catenin, matrix metallopeptidase 2(MMP2), matrix metallopeptidase 3(MMP3), TIMP metallopeptidase inhibitor 1(TIMP1), and TIMP metallopeptidase inhibitor 2(TIMP2). The results showed that compared with the model group, the high and low-dose Jiming Powder significantly reduced the left ventricular internal diameter in systole(LVID;s) and diastole(LVID;d), increased the left ventricular ejection fraction(LVEF) and left ventricular fractional shortening(LVFS), effectively improved cardiac function in mice after myocardial infarction, and effectively reduced the levels of myocardial injury markers such as creatine kinase(CK), creatine kinase isoenzyme(CK-MB), and lactic dehydrogenase(LDH), thus protecting ischemic myocardium. HE staining showed that Jiming Powder could attenuate myocardial inflammatory cell infiltration after myocardial infarction. Masson and Sirius Red staining demonstrated that Jiming Powder effectively inhibited myocardial fibrosis, reduced the collagen â /â ¢ ratio in myocardial tissues, and improved collagen remodeling after myocardial infarction. Western blot results showed that Jiming Powder reduced the expression of TGF-ß1, α-SMA, Wnt3a, and ß-catenin, decreased the levels of MMP2, MMP3, and TIMP2, and increased the level of TIMP1, suggesting its role in inhibiting cardiac fibroblast transformation, reducing extracellular matrix metabolism in myocardial cells, and lowering collagen â and α-SMA content, thus exerting an anti-myocardial fibrosis effect after myocardial infarction. This study revealed the role of Jiming Powder in improving ventricular remodeling and treating myocardial infarction, laying the foundation for further research on the pharmacological effect of Jiming Powder.
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Insuficiencia Cardíaca , Infarto del Miocardio , Ratones , Animales , Factor de Crecimiento Transformador beta1/metabolismo , Metaloproteinasa 2 de la Matriz/metabolismo , beta Catenina/metabolismo , Metaloproteinasa 3 de la Matriz/metabolismo , Metaloproteinasa 3 de la Matriz/uso terapéutico , Polvos , Remodelación Ventricular , Volumen Sistólico , Función Ventricular Izquierda , Infarto del Miocardio/tratamiento farmacológico , Miocardio/patología , Insuficiencia Cardíaca/metabolismo , Colágeno/metabolismo , Creatina Quinasa , FibrosisRESUMEN
The "Internet Plus" system has made continuous nursing intervention much more feasible to implement, especially in terms of malignant tumors. We aimed to evaluate continuous nursing based on "Internet Plus" for patients diagnosed with bladder cancer with hematuria being treated by drug-eluting bead embolization. This retrospective study included 43 patients, diagnosed with bladder cancer with hemorrhages, who had undergone transcatheter bladder arterial chemoembolization by drug-eluting bead embolization at our hospital between January 2017 and January 2023. They were divided into a control (21 patients) and an observation group (22 patients). The Medical Coping Style Scale, disease knowledge (including regular follow-up and interventional treatment), patient satisfaction, and caregiver burden in both groups were compared on the day of discharge and at the 1-month follow-up for each patient. The confrontation score of the observation group was higher than that of the control group, whereas the resignation and avoidance scores were lower. The disease knowledge was higher in the observation group, and the caregiver burden scores of the observation group were significantly lower. The patient satisfaction scores of the control group (84.7â ±â 2.6) were lower than those of the observation group (90.5â ±â 5.4). Continuous nursing based on "Internet Plus" could improve the quality of life of patients and their satisfaction regarding the meeting of their and their families' psychological and nursing needs.
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Calidad de Vida , Neoplasias de la Vejiga Urinaria , Humanos , Estudios Retrospectivos , Neoplasias de la Vejiga Urinaria/terapia , Internet , Vejiga UrinariaRESUMEN
BACKGROUND: Cardiac arrhythmia, a common cardiovascular disease, is closely related to genetic polymorphisms. However, the associations between polymorphisms in KCNH2 and various arrhythmias remain inadequately explored. METHODS: Guided by the assumption that KCNH2 genetic polymorphisms significantly contribute to the development of arrhythmias, we thoroughly explored the associations between 85 KCNH2 genetic variations and 16 cardiac arrhythmias in a sample obtained from the UK Biobank (UKBB, N = 307,473). The illnesses documented in the electronic medical records of the sample were mapped to a phecode system for a more accurate representation of distinct phenotypes. Survival analysis was used to test the effect of KCNH2 variants on arrhythmia incidence, and a phenotype-wide association study (PheWAS) was performed to investigate the effect of KCNH2 polymorphisms on 102 traits, including physical measurements, biomarkers, and hematological indicators. RESULTS: Novel associations of variants rs2269001 and rs7789585 in KCNH2 with paroxysmal tachycardia (PT) and atrial fibrillation/flutter (AF/AFL), respectively, were identified. Moreover, with an increase in the number of minor alleles of these two variants, the incidence rates of PT and AF/AFL decreased. In addition, the PheWAS results suggested that these two single nucleotide polymorphisms were associated with multiple parameters in physical measurements and neutrophil percentage. CONCLUSION: The multiple novel associations observed in this study illustrate the importance of KCNH2 genetic variations in the pathogenesis of arrhythmia.
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Fibrilación Atrial , Aleteo Atrial , Humanos , Fibrilación Atrial/genética , Aleteo Atrial/genética , Fenotipo , Polimorfismo de Nucleótido Simple , Alelos , Canal de Potasio ERG1/genéticaRESUMEN
Ongoing inflammation in the heart is positively correlated with adverse remodeling, characterized by elevated levels of cytokines that stimulate activation of cardiac fibroblasts. It was found that CaMKIIδ response to Ang II or TAC triggers the accumulation of ROS in cardiomyocytes, which subsequently stimulates NF-κB/NLRP3 and leads to an increase in IL-6, IL-1ß, and IL-18. This is an important causative factor in the occurrence of adverse remodeling in heart failure. Sweroside is a biologically active natural iridoids extracted from Lonicerae Japonicae Flos. It shows potent anti-inflammatory and antioxidant activity in various cardiovascular diseases. In this study, we found that sweroside inhibited ROS-mediated NF-κB/NLRP3 in Ang II-treated cardiomyocytes by directly binding to CaMKIIδ. Knockdown of CaMK⠡δ abrogated the effect of sweroside regulation on NF-κB/NLRP3 in cardiomyocytes. AAV-CaMK⠡δ induced high expression of CaMK⠡δ in the myocardium of TAC/Ang II-mice, and the inhibitory effect of sweroside on TAC/Ang â ¡-induced elevation of NF-κB/NLRP3 was impeded. Sweroside showed significant inhibitory effects on CaMKIIδ/NF-κB/NLRP3 in cardiomyocytes from TAC/Ang â ¡-induced mice. This would be able to mitigate the adverse events of myocardial remodeling and contractile dysfunction at 8 weeks after the onset of the inflammatory response. Taken together, our findings have revealed the direct protein targets and molecular mechanisms by which sweroside improves heart failure, thereby supporting the further development of sweroside as a therapeutic agent for heart failure.
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Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina , Insuficiencia Cardíaca , Miocitos Cardíacos , FN-kappa B , Proteína con Dominio Pirina 3 de la Familia NLR , Especies Reactivas de Oxígeno , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/efectos de los fármacos , FN-kappa B/metabolismo , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/etiología , Especies Reactivas de Oxígeno/metabolismo , Ratones , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Transducción de Señal/efectos de los fármacos , Masculino , Modelos Animales de EnfermedadRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Shenlingbaizhu (SLBZ) formula, a classical traditional Chinese medicinal (TCM) formula, has been widely used for treating antibiotic-associated diarrhea (AAD). However, the underlying pharmacological mechanisms have not yet been investigated thoroughly. AIM OF THE STUDY: To explore the remission mechanism of SLBZ in the treatment of AAD, we conducted network pharmacological analysis and experimental validation in vitro and in vivo. MATERIALS AND METHODS: In this study, the main compounds of SLBZ were identified by ultra-high-performance liquid chromatography-mass spectroscopy (UHPLC-MS) and online databases. The targets of the active components and AAD-related targets were predicted by network pharmacology, and the potential targets of SLBZ against AAD were obtained. Then the core targets were recognized after Protein-Protein Interaction (PPI) analysis. Based on these, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway analyses were conducted, and the key pathway was screened. Subsequently, molecular docking was performed using Auto Dock Vina to find the key components that played a crucial role in that pathway. Molecular dynamics simulation was performed by Gromacs software to detect the binding mode. Finally, the results were confirmed by in vitro and in vivo experiments. RESULTS: A total of 66 active ingredients of SLBZ were detected by UHPLC-MS, and 128 active ingredients were screened out by network pharmacological analysis. Additionally, 935 drug targets and 1686 AAD-related targets were obtained. Seventy-eight intersected genes were selected as potential therapeutic targets and 19 genes were excavated as core targets. Enrichment analysis revealed PI3K-AKT signaling pathway was the key pathway in SLBZ against AAD. Topological analysis further revealed that JAK2, MTOR, TLR4, and SYK were the key targets affected by SLBZ on the PI3K-AKT pathway, and 52 components of SLBZ were associated with them. Molecular docking and dynamics simulation revealed strong binding affinities between MTOR and diosgenin. Subsequently, after SLBZ treatment, the expression levels of JAK2, MTOR, TLR4, and SYK were found significantly upregulated in the AAD model rats (p < 0.05). The cell experiment further validated the good binding ability between MTOR and diosgenin. CONCLUSION: We demonstrate that the therapeutic effect of SLBZ on AAD was achieved in part by inhibiting the PI3K-AKT pathway.
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Antibacterianos , Diarrea , Medicamentos Herbarios Chinos , Simulación del Acoplamiento Molecular , Farmacología en Red , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Animales , Diarrea/tratamiento farmacológico , Diarrea/inducido químicamente , Antibacterianos/farmacología , Antibacterianos/toxicidad , Masculino , Ratas , Transducción de Señal/efectos de los fármacos , Ratas Sprague-Dawley , Mapas de Interacción de Proteínas , Simulación de Dinámica Molecular , RatonesRESUMEN
BACKGROUND: Alzheimer's disease (AD) is a widespread neurodegenerative disorder characterized by progressive cognitive decline, affecting a significant portion of the aging population. While the cerebral cortex and hippocampus have been the primary focus of AD research, accumulating evidence suggests that white matter lesions in the brain, particularly in the corpus callosum, play an important role in the pathogenesis of the disease. OBJECTIVE: This study aims to investigate the gene expression changes in the corpus callosum of 5xFAD transgenic mice, a widely used AD mouse model. METHODS: We conducted behavioral tests for spatial learning and memory in 5xFAD transgenic mice and performed RNA sequencing analyses on the corpus callosum to examine transcriptomic changes. RESULTS: Our results show cognitive decline and demyelination in the corpus callosum of 5xFAD transgenic mice. Transcriptomic analysis reveals a predominance of upregulated genes in AD mice, particularly those associated with immune cells, including microglia. Conversely, downregulation of genes related to chaperone function and clock genes such as Per1, Per2, and Cry1 is also observed. CONCLUSIONS: This study suggests that activation of neuroinflammation, disruption of chaperone function, and circadian dysfunction are involved in the pathogenesis of white matter lesions in AD. The findings provide insights into potential therapeutic targets and highlight the importance of addressing white matter pathology and circadian dysfunction in AD treatment strategies.