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Objective To explore the therapeutic mechanism of cordycepin for acute kidney injury （AKI） based upon gene chips in gene expression omnibus （GEO） database, network pharmacology, molecular docking and in vitro experiments. Methods Targeted genes of AKI were obtained from two databases, GEO （GSE87025） and GeneCards. Cordycepin-related targets were retrieved from three databases of TargetNet, BATMAN and GeneCards. The common targets of AKI and cordycepin were screened by taking the intersection of two sets. Molecular docking was performed for cordycepin and key targets after gene ontology （GO） annotation and Kyoto Encyclopedia of Genes and Genomes （KEGG） pathway enrichment analysis. Cell experiments were performed for control, hypoxia/reoxygenation and hypoxia/reoxygenation+cordycepin groups for experimental verifications of the relevant targets. Results There were 12 common targets of AKI and cordycepin. GO functional annotation results indicated that these targets participated predominantly in negative regulation of apoptotic signaling pathway and necroptosis process. KEGG enrichment analysis results showed that they played some roles in signaling pathways of Toll-like receptor, necroptosis, nucleotide-binding oligomerization domain （NOD）-like receptor, nuclear factor-κB （NF-kB）, tumor necrosis factor （TNF） and cell apoptosis, etc. Optimal binding energy between cordycepin and receptor interacting protein kinase 1 （RIPK1） in molecular docking was -7.1, denoting potent binding activity. Western blot indicated that cordycepin down-regulated the expressions of RIPK1, bcl-2 associated x protein （Bax） and caspase 3 and up-regulated B cell lymphoma/lewkmia-2（Bcl-2）. Cell immunofluorescence results revealed that cordycepin down-regulated the expression of RIPK1. Conclusion Cordycepin may alleviate hypoxia/reoxygenation-induced renal tubular epithelial cell injury through regulating RIPK1-mediated apoptosis. Thus it achieves the therapeutic efficacy for AKI.

BackgroundHistopathological studies in Wilson's disease (WD) have revealed increased copper and iron concentrations in the deep gray matter nuclei. However, the commonly used mean bulk susceptibility only reflects the regional metal concentration rather than the total metal content, and regional atrophy may affect the assessment of mean bulk susceptibility. Our study aimed to quantitatively assess the changes of metal concentration and total metal content in deep gray matter nuclei by quantitative susceptibility mapping to distinguish patients with neurological and hepatic WD from healthy controls.MethodsQuantitative susceptibility maps were obtained from 20 patients with neurological WD, 10 patients with hepatic WD, and 25 healthy controls on a 3T magnetic resonance imaging system. Mean bulk susceptibility, volumes, and total susceptibility of deep gray matter nuclei in different groups were compared using a linear regression model. The area under the curve (AUC) was calculated by receiver characteristic curve to analyze the diagnostic capability of mean bulk susceptibility and total susceptibility.ResultsMean bulk susceptibility and total susceptibility of multiple deep gray matter nuclei in patients with WD were higher than those in healthy controls. Compared with patients with hepatic WD, patients with neurological WD had higher mean bulk susceptibility but similar total susceptibility in the head of the caudate nuclei, globus pallidus, and putamen. Mean bulk susceptibility of putamen demonstrated the best diagnostic capability for patients with neurological WD, the AUC was 1, and the sensitivity and specificity were all equal to 1. Total susceptibility of pontine tegmentum was most significant for the diagnosis of patients with hepatic WD, the AUC was 0.848, and the sensitivity and specificity were 0.7 and 0.96, respectively.ConclusionBrain atrophy may affect the assessment of mean bulk susceptibility in the deep gray matter nuclei of patients with WD, and total susceptibility should be an additional metric for total metal content assessment. Mean bulk susceptibility and total susceptibility of deep gray matter nuclei may be helpful for the early diagnosis of WD.

BackgroundNeuropathological studies have revealed copper and iron accumulation in the deep gray matter (DGM) nuclei of patients with Wilson’s disease (WD). However, the association between metal accumulation and neurodegeneration in WD has not been well studied in vivo. The study was aimed to investigate whether metal accumulation in the DGM was associated with the structural and functional changes of DGM in neurological WD patients.MethodsSeventeen neurological WD patients and 20 healthy controls were recruited for the study. Mean bulk susceptibility values and volumes of DGM were obtained from quantitative susceptibility mapping (QSM). Regions of interest including the head of the caudate nucleus, globus pallidus, putamen, thalamus, substantia nigra, red nucleus, and dentate nucleus were manually segmented. The susceptibility values and volumes of DGM in different groups were compared using a linear regression model. Correlations between susceptibility values and volumes of DGM and Unified Wilson’s Disease Rating Scale (UWDRS) neurological subscores were investigated.ResultsThe susceptibility values of all examined DGM in WD patients were higher than those in healthy controls (P < 0.05). Volume reductions were observed in the head of the caudate nucleus, globus pallidus, putamen, thalamus, and substantia nigra of WD patients (P < 0.001). Susceptibility values were negatively correlated with the volumes of the head of the caudate nucleus (rp = −0.657, P = 0.037), putamen (rp = −0.667, P = 0.037), and thalamus (rp = −0.613, P = 0.046) in WD patients. UWDRS neurological subscores were positively correlated with the susceptibility values of all examined DGM. The susceptibility values of putamen, head of the caudate nucleus, and dentate nucleus could well predict UWDRS neurological subscores.ConclusionOur study provided in vivo evidence that paramagnetic metal accumulation in the DGM was associated with DGM atrophy and neurological impairment. The susceptibility of DGM could be used as a biomarker to assess the severity of neurodegeneration in WD.

Magnetic resonance spectroscopy (MRS) is useful for rapid and robust liver fat quantification. MR spectra of liver can be acquired in a single breath-hold with the high-speed multi-echo stimulated echo acquisition mode, from which T2-corrected liver proton density fat fraction (PDFF) can be derived. However, the widespread application of this method is hampered by the cumbersome post-processing procedures for the spectroscopy data. In this work, an automated algorithm for liver fat quantification from multi-echo spectroscopy data was developed. The feasibility and accuracy of the algorithm were evaluated with fat-water phantoms experiments and human liver experiments. The results demonstrated excellent correlation and agreement between the PDFF measurements with the proposed algorithm and those obtained with the jMRUI software.

Background: Pulmonary hypertension (PH) is characterized by profound vascular remodeling and alterations in Ca2+ homeostasis in pulmonary arterial smooth muscle cells (PASMCs). Multiple transient receptor potential melastatin-related (TRPM) subtypes have been identified in vascular tissue. However, the changes in the expression and function of TRPM channels in pulmonary hypertension have not been characterized in detail. Methods: We examined the expression of TRPM channels and characterized the functions of the altered TRPM channels in two widely used rat models of chronic hypoxia (CH)- and monocrotaline (MCT)-induced PH. Results: CH-exposed and MCT-treated rats developed severe PH and right ventricular hypertrophy, with a significant decrease in TRPM8 mRNA and protein expression in pulmonary arteries (PAs). The downregulation of TRPM8 was associated with significant reduction in menthol-induced cation-influx. Time-profiles showed that TRPM8 down-regulation occurred prior to the increase of right ventricular systolic pressure (RVSP) and right ventricular mass index (RVMI) in CH-exposed rats, but these changes were delayed in MCT-treated rats. The TRPM8 agonist menthol induced vasorelaxation in phenylephrine-precontracted PAs, and the vasorelaxing effects were significantly attenuated in PAs of both PH rat models, consistent with decreased TRPM8 expression. Conclusion: Downregulation of TRPM8 may contribute to the enhanced vasoreactivity in PH.