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【Objective】 To explore the differential expression and functional analysis of circRNA from myocardial mitochondria in diabetes cardiomyopathy (DCM) mice. 【Methods】 The DCM mice model was established in 16-week-old db/db mice, and C57BL/KsJ mice were used as controls. RNA was extracted from the myocardium of two groups of mice, high-throughput sequencing was used to screen mitochondrial circRNA differentially expressed in the two groups, RT-qPCR was used to verify the sequencing results of the first 10 circRNAs with significant differential expression, and functional enrichment analysis was performed on the differentially expressed circRNA target genes, and miRNA target prediction software was used to analyze the circRNA-miRNA co-expression network. 【Results】 There were 147 mitochondrial circRNAs differentially expressed in the myocardium of DCM mice, including 89 highly expressed and 58 low expressed. The expression pattern of differentially expressed circRNAs in tissues was consistent with those of sequencing results. The enrichment analysis of GO and KEGG showed that the differentially expressed circRNA target genes were mainly enriched in cGMP/PKG, glucagon pathways, which were related to mitochondrial energy metabolism and cardiac hypertrophy. circRNA-miRNA co-expression analysis found that the most significantly up-regulated circRNA, chrM:1207-1536+, was associated with miR-491-3p, miR-99a-3p, and miR-99b-3p, and the most significantly down-regulated circRNA, chrM:1453-3205+, was associated with miR-181b-1-3p, miR-181b-2-3p, and miR-672-5p. 【Conclusion】 Compared to the control mice, there is differential expression of circRNAs in myocardial mitochondria of DCM mice. The differentially expressed circRNAs may interact with the corresponding miRNA to affect myocardial fibrosis and hypertrophy through regulation of energy metabolism, apoptosis and other pathways, thus participating in the pathogenesis of DCM.
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Scaffold hopping refers to computer-aided screening for active compounds with different structures against the same receptor to enrich privileged scaffolds, which is a topic of high interest in organic and medicinal chemistry. However, most approaches cannot efficiently predict the potency level of candidates after scaffold hopping. Herein, we identified potent PDE5 inhibitors with a novel scaffold via a free energy perturbation (FEP)-guided scaffold-hopping strategy, and FEP shows great advantages to precisely predict the theoretical binding potencies ΔG FEP between ligands and their target, which were more consistent with the experimental binding potencies ΔG EXP (the mean absolute deviations | Δ G FEP - Δ G EXP | < 2 kcal/mol) than those ΔG MM-PBSA or ΔG MM-GBSA predicted by the MM-PBSA or MM-GBSA method. Lead L12 had an IC50 of 8.7 nmol/L and exhibited a different binding pattern in its crystal structure with PDE5 from the famous starting drug tadalafil. Our work provides the first report via the FEP-guided scaffold hopping strategy for potent inhibitor discovery with a novel scaffold, implying that it will have a variety of future applications in rational molecular design and drug discovery.
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Objective:To explore the action mechanism of medicinal pair Astragali Radix-Angelicae Sinensis Radix against diabetic cardiomyopathy （DCM） based on network pharmacology and<italic> in vivo </italic>animal experiment. Method:The active ingredients and targets of Astragali Radix and Angelicae Sinensis Radix were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform （TCMSP） and Bioinformatics Analysis Tool for Molecular mechANism of Traditional Chinese Medicine （BATMAN-TCM）， and the relevant targets of DCM from the disease database. The common specific targets between the medicinal pair and DCM obtained via comparison were used for constructing the main active ingredients of Astragali Radix-Angelicae Sinensis Radix-DCM-target network， followed by protein-protein interaction （PPI） analysis of compound-DCM common targets and the screening of important modules using Molecular Complex Detection （MCODE） plugin. The gene ontology （GO） and Kyoto encyclopedia of genes and genomes （KEGG） enrichment analysis was carried out based on DAVID for exploring the possible molecular mechanisms， which were then subjected to experimental verification. Result:A total of 126 core targets of Astragali Radix-Angelicae Sinensis Radix for treating DCM were screened out based on network pharmacology. As indicated by KEGG pathway enrichment analysis， the above-mentioned key targets might be related to such pathways as inflammatory response， oxidative stress， insulin resistance， and apoptosis. The findings of <italic>in vivo</italic> animal experiments demonstrated that Astragali Radix-Angelicae Sinensis Radix delayed high glucose-induced cardiomyocyte injury of DCM rats， suggesting that this medicinal pair intervened in the pathological process to a certain extent. Conclusion:Astragali Radix-Angelicae Sinensis Radix alleviates DCM possibly by acting on multiple targets including interleukin-6， vascular endothelial growth factor A， tumor necrosis factor， TP53 gene， and nuclear transcription factor， regulating apoptosis and glucolipid metabolism， and improving oxidative stress and inflammatory response. The research based on network pharmacology and experimental verification has provided new ideas for investigating the pathogenesis of DCM and its clinical treatment.
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Insulin derivatives such as insulin detemir and insulin degludec are U.S. Food and Drug Administration (FDA)-approved long-acting insulin currently used by millions of people with diabetes. These derivatives are modified in C-terminal B29 lysine to retain insulin bioactivity. New and efficient methods for facile synthesis of insulin derivatives may lead to new discovery of therapeutic insulin. Herein, we report a new method using sortase A (SrtA)-mediated ligation for the synthesis of insulin derivatives with high efficiency and functional group tolerance in the C-terminal B chain. This new insulin molecule (Ins-SA) with an SrtA-recognizing motif can be conjugated to diverse groups with N-terminal oligoglycines to generate new insulin derivatives. We further demonstrated that a new insulin derivative synthesized by this SrtA-mediated ligation shows strong cellular and
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Ferroptosis is a type of cell death accompanied by iron-dependent lipid peroxidation, thus stimulating ferroptosis may be a potential strategy for treating gastric cancer, therapeutic agents against which are urgently required. Jiyuan oridonin A (JDA) is a natural compound isolated from Jiyuan
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Diabetic cardiomyopathy( DCM) is one of the important cardiovascular complications of diabetes mellitus. Metabolic disorders, mitochondrial damage, cardiomyocyte apoptosis and autophagy are involved in the development of DCM. Recent research demonstrates that NLRP3 inflammasome plays a vital role in the pathogenesis of DCM, and has emerged as a potential tar get for the treatment of DCM. In this article, research progress in NLRP3 inflammasome and DCM has been reviewed, aiming to provide novel therapeutic idea for the treatment of DCM.
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Inferior parietal lobule (IPL) and inferior temporal gyrus (ITG) are two important brain regions for the default modenetwork (DMN). IPL has been known to be involved in the control of attention and responding to given information whileITG is involved in the processing and perception awakened by visual stimuli. These two key DMN regions are highlyinterconnected as determined from white matter and fiber tracking studies. However, little is known about their natureof connectivity while the brain is at rest, whether it is linear, bilinear or nonlinear and whether it is of mono- or bidirection.Resting state functional magnetic resonance imaging (rsfMRI) data were obtained from 7 healthy male andfemale participants (average age = 20.7 ± 4.5 years) and were concatenated. Data were analyzed using statisticalparametric mapping (SPM12). Endogenous brain signals were modelled by Fourier series at 0.01 – 0.08 Hz. IPL-ITGconnected linear, bilinear and non-linear causal models in both hemispheres were constructed and estimated by means ofstochastic dynamic causal modelling (sDCM) and were compared using Bayesian Model Selection (BMS) for group studies.Group fixed-effects results indicated that bilateral IPL and ITG exhibited high neural activity at a corrected significantlevel (pFWE 1000) which has the best balance betweenmodel accuracy and difficulty. The minimum free energy (F) = -4.41 × 104 and -4.09 × 104 for left and right hemispherebilinear models respectively. From BMS and DCM results, it was found that IPL and ITG do have a dynamic collaborationbetween each other, a connectivity that belongs to a greater network when the brain is at rest. The intrinsic connectionsbetween them are negative in both directions i.e. IPL and ITG mutually inhibited each other. The effective connectivitywas modulated by the endogenous fluctuation of the brain signal.
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Objective:To study the bone regeneration capacity of the complex of bone marrow mesenchymal stem cells(BMSCs) and platelet rich plasma (PRP) with decellularized cartilage matrix (DCM).Methods:BMSCs were isolated from young rabbit and cultured;PRP were prepared from the fresh blood of rabbit and the DCM were come from the fresh ears of rabbits and processed into a mixture of BMSCs-PRP-DCM.The mixture was injected subcutaneously into nude mice,8 weeks after injection bone regeneration was examine by HE staining and Massons staining decellularization.Results:The BMSCs show good differentiation capacity in vitro and the cartilage fragments were well decellularized.Excellent endochondral ossification ability of the complex was observed by in vivo experiment.Conclusion:The BMSCs-PRP-DCM complex has good capacity of endochondral ossification.
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Purpose: This fMRI study is about modelling the effective connectivity between Heschl’s gyrus (HG) and the superior temporal gyrus (STG) in human primary auditory cortices. Materials & methods: Ten healthy male participants were required to listen to white noise stimuli during functional magnetic resonance imaging (fMRI) scans. Statistical parametric mapping (SPM) was used to generate individual and group brain activation maps. For input region determination, two intrinsic connectivity models comprising bilateral HG and STG were constructed using dynamic causal modelling (DCM). The models were estimated and inferred using DCM while Bayesian Model Selection (BMS) for group studies was used for model comparison and selection. Based on the winning model, six linear and six non-linear causal models were derived and were again estimated, inferred, and compared to obtain a model that best represents the effective connectivity between HG and the STG, balancing accuracy and complexity. Results: Group results indicated significant asymmetrical activation (puncorr < 0.001) in bilateral HG and STG. Model comparison results showed strong evidence of STG as the input centre. The winning model is preferred by 6 out of 10 participants. The results were supported by BMS results for group studies with the expected posterior probability,r = 0.7830 and exceedance probability, φ = 0.9823. One-sample t-tests performed on connection values obtained from the winning model indicated that the valid connections for the winning model are the unidirectional parallel connections from STG to bilateral HG (p < 0.05). Subsequent model comparison between linear and non-linear models using BMS prefers non-linear connection (r = 0.9160, φ = 1.000) from which the connectivity between STG and the ipsi- and contralateral HG is gated by the activity in STG itself. Conclusion: We are able to demonstrate that the effective connectivity between HG and STG while listening to white noise for the respective participants can be explained by a non-linear dynamic causal model with the activity in STG influencing the STG-HG connectivity non-linearly.
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Objective To analyze the difference of frontal-cingulate functional connection between patients with major depression and healthy controls in recognization of sad facial expression, and discuss the neutral basis of emotional bias in preliminary. Methods 12 female patients with major depression and 12 matched healthy controls were scanned. The intensities of brain activation in the process of sad and neutral facial expression recognition were analyzed, and the strengths of frontal-cingulate functional connection were compared between the two groups based on dynamic causal modeling. Results Comparing the stimulus adjusting connection models with Bayesian model indicated that model Ⅱ matched with the observation data better. In the comparison between model Ⅱ and model I ,the average Bayes factor was more than 7.38. In the comparison between model Ⅱ and model Ⅲ,the average Bayes factor was more than 2.71. Calculating the intrinsic connection parameters and stimulus adjusting connection parameters based on intrinsic connection model and stimulus adjusting connection model( model Ⅱ ), the result showed that connection strength between anterior cingulate and right inferior frontal gyrus in depression was greater than that in healthy controls. Conclusion The frontal-cingulate functional connection of patients with major depression is increased abnormally ,which may be the neural basis of negative emotional bias.
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En el presente trabajo evaluamos la acción biocida sobre larvas del III estadío de Diatraea saccharalis, usando extractos acuoso, diclorometano-metanol (DCM:MeOH, 2:1) y alcohólico (EtOH, 96%) de hojas, tallos y espigas maduras (con frutos y semillas) de Piper tuberculatum, en larvas del III estadío. El método de inoculación del extracto, previamente eluido con agua destilada, fue de aplicación tópica en el mesotorax de las larvas. Solamente los extractos DCM:MeOH y EtOH de espigas maduras y extracto DCM:MeOH de plantas in vitro mostraron niveles significativos de mortalidad larval. El mayor efecto tóxico correspondió a extractos de espigas maduras respecto a plantas in vitro y a extracto EtOH respecto a extracto DCM:MeOH, tal como lo expresan los resultados de las concentraciones letales a 50% (CL50) y 90% (CL90), en 72 h de exposición. Así tenemos que en el caso de espigas maduras fue: CL50 (0,11 mg/mL con EtOH y 0,16 mg/mL con DCM:MeOH) y CL90 (0,35 mg/mL con EtOH y 0,55 mg/mL con DCM:MeOH); en el caso de plantas in vitro, unicamente con DCM:MeOH, fue: CL50 0,39 mg/mL y CL90 2,62 mg/mL. Los resultados de las rectas valores probitos-mortalidad expresaron la misma tendencia.
The biocid action of DCM:MeOH (2:1), EtOH and aqueous extracts of leaves, stems and mature spikes (with fruits and seeds) of field plants and DCM:MeOH (2:1) extract of in vitro plants of Piper tuberculatum on III larval stage of Diatraea saccharalis was evaluated. The method was by inoculating the previously eluted extract with distillate water as topic applications on the larval mesothorax. Only DCM:MeOH and EtOH extracts of mature spikes and DCM:MeOH extract of in vitro plants showed significant levels of larval mortality. The corresponding highest toxic effect was (a) for mature spikes respect to in vitro plants and (b) EtOH extract respect to DCM:MeOH extract, according to the results showed for the lethal concentration to 50% (LC50) and 90% (LC90), in 72 hours of exposure. Thus, in the case of mature spikes was: LC50 0,11 mg/mL with EtOH and 0,16 mg/mL with DCM:MeOH) and LC90 (0,35 mg/mL with EtOH and 0,55 mg/mL with DCM:MeOH); and, in the case of in vitro plants, only with DCM:MeOH extract, was: LC50 0,39 mg/mL and LC90 2,62 mg/mL. The results of probit values-mortality lines showed the same tendency.
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Objective To further confirm the role of lipid-peroxidation caused by oxygen free radicals injury played in the pathogenesis of dilsted cardiomypathy. Methods The superoxide dismutase activities and lipids composi tion of erythrocytes in 18 patients with dilated cardiomyopathy and 16 healthy controls were measured. Results ① Su peroxide dismutase(SOD) activites of erythrocytes were lower in dilated cardiomyopathy(DCM) patients than that in healthy controls (P ＜0. 001). ②The lipids composition of erythrocytes has changed in the DCM patients compared with healthy controls: total lipids changed little (P＞0. 05); total phospholipids were lower, but not significantly (P ＞0.05); total cholesterol increased significantly (P ＜0. 05). The cholesterol to phospholipids molecular ratio of erythrocyte membrane has increased remarkably (P＞0. 05). Conclusion It can be supposed that decreased SOD ac tivities play an important role in the damage of membrane system and the pathogensis of DCM.
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Serum cTnT, CK-MB and LDI were measured in 30 patients with AMI, 76 patients with VMC, 12 patients who had undergone operation without cardioplegia, 16 patients who had received open heart operation, 15 patients who had undergone thoracotomy for non-heart surgery and 55 healthy people. Concentration of serum cTnT was 0.057±0.056 μg/L in healthy people,0.069±0.032 μg/L in patients who underwent thoracotomy for non-heart surgery, 0.328±0.472μg/L in patients with VMC, 0.388±0.279 μg/L in patients with DCM, 4.259±4.619 μg/L in patients with AMI, 8.55±6.78 μg/L in patients who had undergone operation without cardioplegia and 16.03±6.01 μg/L in heart operation patients. In patients with VCM and DCM, serum cTnT was more specific and sensitive than CK-MB and LDI for diagnosing myocardial injury. In patients with AMI and heart operation patients, the increasing multiple of serum cTnT was obviously higher than that of CK-MB and LDI. 72 h after heart operation, cTnT was still higher than normal, while CK-MB had returned to normal level. Serum cTnT had higher specificity and sensitivity and longer diagnostic period in diagnosing myocardial injury. Moreover, cTnT assay could indicate the degree of myocardial injury. So, quantitative analysis of cTnT can be used as a routine examination in the diagnosis of myocardial injury.
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Serum cTnT, CK-MB and LDI were measured in 30 patients with AMI, 76 patients with VMC, 12 patients who had undergone operation without cardioplegia, 16 patients who had received open heart operation, 15 patients who had undergone thoracotomy for non-heart surgery and 55 healthy people. Concentration of serum cTnT was 0.057±0.056 μg/L in healthy people,0.069±0.032 μg/L in patients who underwent thoracotomy for non-heart surgery, 0.328±0.472μg/L in patients with VMC, 0.388±0.279 μg/L in patients with DCM, 4.259±4.619 μg/L in patients with AMI, 8.55±6.78 μg/L in patients who had undergone operation without cardioplegia and 16.03±6.01 μg/L in heart operation patients. In patients with VCM and DCM, serum cTnT was more specific and sensitive than CK-MB and LDI for diagnosing myocardial injury. In patients with AMI and heart operation patients, the increasing multiple of serum cTnT was obviously higher than that of CK-MB and LDI. 72 h after heart operation, cTnT was still higher than normal, while CK-MB had returned to normal level. Serum cTnT had higher specificity and sensitivity and longer diagnostic period in diagnosing myocardial injury. Moreover, cTnT assay could indicate the degree of myocardial injury. So, quantitative analysis of cTnT can be used as a routine examination in the diagnosis of myocardial injury.